Bio


C.F. Rehnborg Chair in Disease Prevention at Stanford University, Professor of Medicine, Professor of Health Research and Policy, and Professor (by courtesy) of Biomedical Data Science at the School of Medicine; Professor (by courtesy) of Statistics at the School of Humanities and Sciences; co-Director, Meta-Research Innovation Center at Stanford; Director of the PhD program in Epidemiology and Clinical Research.
Born in New York City in 1965 and raised in Athens, Greece. Valedictorian (1984) at Athens College; National Award of the Greek Mathematical Society (1984); MD (top rank of medical school class) from the National University of Athens in 1990; also received DSc in biopathology from the same institution. Trained at Harvard and Tufts (internal medicine and infectious diseases), then held positions at NIH, Johns Hopkins and Tufts. Chaired the Department of Hygiene and Epidemiology, University of Ioannina Medical School in 1999-2010 (tenured professor since 2003) while also holding adjunct professor positions at Harvard School of Public Health, Tufts, and Imperial College. Senior Advisor on Knowledge Integration at NCI/NIH (2012-6). Served as President, Society for Research Synthesis Methodology, and editorial board member of many leading journals (including PLoS Medicine, Lancet, Annals of Internal Medicine, JNCI, Science Translational Medicine, Clinical Chemistry, Molecular and Cellular Proteomics, AIDS, IJE, JCE, Clinical Trials, and PLoS ONE, among others) and as Editor-in-Chief of the European Journal of Clinical Investigation (2010-now). Delivered ~500 invited and honorary lectures. Recipient of many awards (e.g. European Award for Excellence in Clinical Science [2007], Medal for Distinguished Service, Teachers College, Columbia University [2015], Chanchlani Global Health Award [2017], Epiphany Science Courage Award [2018]). Inducted in the Association of American Physicians (2009), European Academy of Cancer Sciences (2010) American Epidemiological Society (2015), European Academy of Sciences and Arts (2015). Honorary titles from FORTH (2014) and Ioannina (2015) and honorary doctorates from Rotterdam (2015) and Athens (2017). Multiple honorary lectureships/visiting professorships (Caltech, Oxford, LSHTM, Yale, U Utah, U Conn, UC Davis, U Penn among others). The PLoS Medicine paper on “Why most published research findings are false” has been the most-accessed article in the history of Public Library of Science (>2.5 million hits). Author of 7 literary books in Greek, two of which (“Toccata for the Girl with the Burnt Face” (Kedros 2012) and “Variations on the Art of the Fugue and a Desperate Ricercar” (Kedros 2014)) were shortlisted for best book of the year Anagnostis awards. Brave Thinker scientist for 2010 according to Atlantic, “may be one of the most influential scientists alive”. Highly Cited Researcher according to Thomson Reuters in both Clinical Medicine and in Social Sciences. Citation indices: h=173, m=7 per Google Scholar (h=139 per WoS and Scopus). Current citation rates: >3,000 new citations per month per Google Scholar, >1,500 new citations per month per Scopus or Web of Knowledge.
Current citation rates suggest that I am among the 10 scientists worldwide who are currently the most commonly cited, perhaps also the currently most-cited physician. This probably only proves that citation metrics are highly unreliable, since I estimate that I have been rejected over 1,000 times in my life. Regardless, I consider myself privileged to have learned and to continue to learn from interactions with students and young scientists (of all ages) from all over the world and I love to be constantly reminded that I know next to nothing.

Administrative Appointments


  • Co-Director, Meta-Research Innovation Center at Stanford (METRICS) (2013 - Present)
  • Editor-in-chief, European Journal of Clinical Investigation (2010 - Present)
  • Member, Stanford Cardiovascular Institute (2010 - Present)
  • Member, Stanford Cancer Center (2010 - Present)
  • Affiliate, Stanford Center on Longevity (2012 - Present)
  • Affiliated faculty, Woods Institute for the Environment (2011 - Present)
  • Member, Stanford Diabetes Research Center (2018 - Present)
  • Professor of Statistics (by courtesy), Stanford University School of Humanities and Sciences (2011 - Present)
  • Professor of Health Research and Policy, Stanford University School of Medicine (2011 - Present)
  • Professor of Medicine, Stanford University School of Medicine (2010 - Present)
  • Professor of Biomedical Data Science (by courtesy), Stanford University School of Medicine (2016 - Present)
  • Director, Stanford Prevention Research Center (2010 - 2016)

Honors & Awards


  • Epiphany Science Courage Award, Novim (inaugural award) (2018)
  • Elected Councilor, Association of American Physicians (2017-2022)
  • Elected member, Association of American Physicians (2009-)
  • President, Society for Research Synthesis Methodology (2009-2010)
  • Elected fellow, European Academy of Cancer Sciences (2010-)
  • Elected member, American Epidemiological Society (2015-)
  • Elected member, European Academy of Sciences and Arts (2015-)
  • European Award for Excellence in Clinical Science, European Society for Clinical Investigation (2007)
  • Chanchlani Award for Global Health, McMaster University (2017)
  • David-Sackett-Preis, Deutsche Netzwerk Evidenzbasierte Medizin (2017)
  • Lifetime Achievement Award, Hellenic Society for Pharmacological Science (2016)
  • Medal for Distinguished Service, Teachers College, Columbia University (2015)
  • Honorary PhD, Erasmus University Rotterdam (2015)
  • Honorary PhD (health sciences), University of Athens (2017)
  • Litchfield Lectureship, Oxford University (2015)
  • Levine lectureship, Yale (2016)
  • Harris lectureship in science and civilization, Caltech (2016)
  • Snyder Lectureship, University of Utah (2016)
  • Anatomy Lesson lecturer, University of Amsterdam and Academic Medical Center (2016)
  • Annual Distinguished Investigator, University of Connecticut School of Medicine and Health Center (2017)
  • Snively visiting professorship, UC Davis (2017)
  • Gonatas memorial lectureship, University of Pennsylvania (2018)
  • Honorary member, FORTH (2014)
  • Honorary professor (omotimos), University of Ioannina (2014)
  • Executive board member and center director, Human Genome Epidemiology Network (2004-)

Boards, Advisory Committees, Professional Organizations


  • Chair, Scientific Advisory Board, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh (2015 - Present)
  • Faculty Fellow, Stanford Center for Innovation on Global Health (2015 - Present)
  • Member, Scientific Advisory Board, Berkeley Initiative for Transparency in Social Sciences (2014 - Present)
  • Member, Scientific Advisory Board, Center for Open Science (2013 - Present)
  • Member, Scientific Advisory Board, International Epidemiology Institute (2012 - Present)
  • Member, Scientific Advisory Board, Reproducibility Initiative (2012 - Present)
  • Senior Advisor for Knowledge Integration, NCI, NIH (2012 - 2016)
  • Member, Methodology Committee, PCORI (2011 - 2013)
  • Vice President, Board of Directors, Hellenic Center for Infectious Disease Control (2000 - 2001)

Professional Education


  • Fellowship, New England Medical Center, Tufts University School of Medicine, Infectious Diseases (1996)
  • Residency, New England Deaconess Hospital, Harvard Medical School, Internal Medicine (1993)
  • DSc, University of Athens School of Medicine, Athens, Greece, Biopathology (1996)
  • MD, University of Athens School of Medicine, Athens, Greece, Medicine (1990)

Current Research and Scholarly Interests


My work is trying to optimize the chances of getting more reliable, trustworthy, and useful research. I have worked in the fields of evidence-based medicine, clinical investigation, clinical and molecular epidemiology, clinical research methodology, empirical research methods, statistics, and genomics. I have a strong interest in meta-research and in large-scale evidence (in particular randomized trials and meta-analyses) and in appraisal and control of diverse biases in biomedical research and beyond. I am interested in developing and applying new research methods, and in the interdisciplinary enhancement of existing research methods for study design and analysis. Some of my most influential papers in terms of citations are those addressing issues of reproducibility, replication validity, biases in biomedical research and other fields, research synthesis methods, extensions of meta-analysis, genome-wide association studies and agnostic evaluation of associations, and validity of randomized trials and observational research. I have also designed, steered and participated in influential randomized trials (in particular, the major trials that changed decisively the management and outcome of HIV infection, but also trials in nephrology, and in antibiotic use in the community), and large international consortia that have helped transform the efficiency of research in diverse fields of genomic, molecular and clinical epidemiology. I enjoy working with a diverse array of colleagues from very diverse disciplines and to have an opportunity to learn from both senior and junior investigators, and particularly students at all levels.

Clinical Trials


  • Personal Genomics for Preventive Cardiology Not Recruiting

    The purpose of this study is to see if providing information to a person on their inherited (genetic) risk of cardiovascular disease (CVD) helps to motivate that person to change their diet, lifestyle or medication regimen to alter their risk.

    Stanford is currently not accepting patients for this trial. For more information, please contact Josh Knowles, 650-804-2526.

    View full details

2018-19 Courses


Stanford Advisees


All Publications


  • In the Era of Precision Medicine and Big Data, Who Is Normal? JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Manrai, A. K., Patel, C. J., Ioannidis, J. A. 2018; 319 (19): 1981–82

    View details for DOI 10.1001/jama.2018.2009

    View details for Web of Science ID 000432238300012

    View details for PubMedID 29710130

  • All science should inform policy and regulation. PLoS medicine Ioannidis, J. P. 2018; 15 (5): e1002576

    Abstract

    In the context of a recent proposal to exclude research from consideration at the Environmental Protection Agency, John Ioannidis points out that "perceived perfection is not a characteristic of science, but of dogma" and envisions how governments can promote a standard of openness in science.

    View details for DOI 10.1371/journal.pmed.1002576

    View details for PubMedID 29723196

  • The Proposal to Lower P Value Thresholds to .005 JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Loannidis, J. A. 2018; 319 (14): 1429–30

    View details for DOI 10.1001/jama.2018.1536

    View details for Web of Science ID 000429590200008

    View details for PubMedID 29566133

  • Meta-research: Why research on research matters PLOS BIOLOGY Ioannidis, J. A. 2018; 16 (3): e2005468

    Abstract

    Meta-research is the study of research itself: its methods, reporting, reproducibility, evaluation, and incentives. Given that science is the key driver of human progress, improving the efficiency of scientific investigation and yielding more credible and more useful research results can translate to major benefits. The research enterprise grows very fast. Both new opportunities for knowledge and innovation and new threats to validity and scientific integrity emerge. Old biases abound, and new ones continuously appear as novel disciplines emerge with different standards and challenges. Meta-research uses an interdisciplinary approach to study, promote, and defend robust science. Major disruptions are likely to happen in the way we pursue scientific investigation, and it is important to ensure that these disruptions are evidence based.

    View details for DOI 10.1371/journal.pbio.2005468

    View details for Web of Science ID 000428987600023

    View details for PubMedID 29534060

    View details for PubMedCentralID PMC5865753

  • Meta-assessment of bias in science PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Fanelli, D., Costas, R., Ioannidis, J. P. 2017; 114 (14): 3714-3719

    Abstract

    Numerous biases are believed to affect the scientific literature, but their actual prevalence across disciplines is unknown. To gain a comprehensive picture of the potential imprint of bias in science, we probed for the most commonly postulated bias-related patterns and risk factors, in a large random sample of meta-analyses taken from all disciplines. The magnitude of these biases varied widely across fields and was overall relatively small. However, we consistently observed a significant risk of small, early, and highly cited studies to overestimate effects and of studies not published in peer-reviewed journals to underestimate them. We also found at least partial confirmation of previous evidence suggesting that US studies and early studies might report more extreme effects, although these effects were smaller and more heterogeneously distributed across meta-analyses and disciplines. Authors publishing at high rates and receiving many citations were, overall, not at greater risk of bias. However, effect sizes were likely to be overestimated by early-career researchers, those working in small or long-distance collaborations, and those responsible for scientific misconduct, supporting hypotheses that connect bias to situational factors, lack of mutual control, and individual integrity. Some of these patterns and risk factors might have modestly increased in intensity over time, particularly in the social sciences. Our findings suggest that, besides one being routinely cautious that published small, highly-cited, and earlier studies may yield inflated results, the feasibility and costs of interventions to attenuate biases in the literature might need to be discussed on a discipline-specific and topic-specific basis.

    View details for DOI 10.1073/pnas.1618569114

    View details for Web of Science ID 000398159000057

    View details for PubMedID 28320937

  • Empirical assessment of published effect sizes and power in the recent cognitive neuroscience and psychology literature PLOS BIOLOGY Szucs, D., Ioannidis, J. A. 2017; 15 (3): e2000797

    Abstract

    We have empirically assessed the distribution of published effect sizes and estimated power by analyzing 26,841 statistical records from 3,801 cognitive neuroscience and psychology papers published recently. The reported median effect size was D = 0.93 (interquartile range: 0.64-1.46) for nominally statistically significant results and D = 0.24 (0.11-0.42) for nonsignificant results. Median power to detect small, medium, and large effects was 0.12, 0.44, and 0.73, reflecting no improvement through the past half-century. This is so because sample sizes have remained small. Assuming similar true effect sizes in both disciplines, power was lower in cognitive neuroscience than in psychology. Journal impact factors negatively correlated with power. Assuming a realistic range of prior probabilities for null hypotheses, false report probability is likely to exceed 50% for the whole literature. In light of our findings, the recently reported low replication success in psychology is realistic, and worse performance may be expected for cognitive neuroscience.

    View details for DOI 10.1371/journal.pbio.2000797

    View details for Web of Science ID 000397909600008

    View details for PubMedID 28253258

    View details for PubMedCentralID PMC5333800

  • Evaluation of Evidence of Statistical Support and Corroboration of Subgroup Claims in Randomized Clinical Trials. JAMA internal medicine Wallach, J. D., Sullivan, P. G., Trepanowski, J. F., Sainani, K. L., Steyerberg, E. W., Ioannidis, J. P. 2017

    Abstract

    Many published randomized clinical trials (RCTs) make claims for subgroup differences.To evaluate how often subgroup claims reported in the abstracts of RCTs are actually supported by statistical evidence (P < .05 from an interaction test) and corroborated by subsequent RCTs and meta-analyses.This meta-epidemiological survey examines data sets of trials with at least 1 subgroup claim, including Subgroup Analysis of Trials Is Rarely Easy (SATIRE) articles and Discontinuation of Randomized Trials (DISCO) articles. We used Scopus (updated July 2016) to search for English-language articles citing each of the eligible index articles with at least 1 subgroup finding in the abstract.Articles with a subgroup claim in the abstract with or without evidence of statistical heterogeneity (P < .05 from an interaction test) in the text and articles attempting to corroborate the subgroup findings.Study characteristics of trials with at least 1 subgroup claim in the abstract were recorded. Two reviewers extracted the data necessary to calculate subgroup-level effect sizes, standard errors, and the P values for interaction. For individual RCTs and meta-analyses that attempted to corroborate the subgroup findings from the index articles, trial characteristics were extracted. Cochran Q test was used to reevaluate heterogeneity with the data from all available trials.The number of subgroup claims in the abstracts of RCTs, the number of subgroup claims in the abstracts of RCTs with statistical support (subgroup findings), and the number of subgroup findings corroborated by subsequent RCTs and meta-analyses.Sixty-four eligible RCTs made a total of 117 subgroup claims in their abstracts. Of these 117 claims, only 46 (39.3%) in 33 articles had evidence of statistically significant heterogeneity from a test for interaction. In addition, out of these 46 subgroup findings, only 16 (34.8%) ensured balance between randomization groups within the subgroups (eg, through stratified randomization), 13 (28.3%) entailed a prespecified subgroup analysis, and 1 (2.2%) was adjusted for multiple testing. Only 5 (10.9%) of the 46 subgroup findings had at least 1 subsequent pure corroboration attempt by a meta-analysis or an RCT. In all 5 cases, the corroboration attempts found no evidence of a statistically significant subgroup effect. In addition, all effect sizes from meta-analyses were attenuated toward the null.A minority of subgroup claims made in the abstracts of RCTs are supported by their own data (ie, a significant interaction effect). For those that have statistical support (P < .05 from an interaction test), most fail to meet other best practices for subgroup tests, including prespecification, stratified randomization, and adjustment for multiple testing. Attempts to corroborate statistically significant subgroup differences are rare; when done, the initially observed subgroup differences are not reproduced.

    View details for DOI 10.1001/jamainternmed.2016.9125

    View details for PubMedID 28192563

  • A manifesto for reproducible science NATURE HUMAN BEHAVIOUR Munafo, M. R., Nosek, B. A., Bishop, D. M., Button, K. S., Chambers, C. D., du Sert, N., Simonsohn, U., Wagenmakers, E., Ware, J. J., Ioannidis, J. A. 2017; 1 (1)
  • What does research reproducibility mean? SCIENCE TRANSLATIONAL MEDICINE Goodman, S. N., Fanelli, D., Ioannidis, J. P. 2016; 8 (341)

    Abstract

    The language and conceptual framework of "research reproducibility" are nonstandard and unsettled across the sciences. In this Perspective, we review an array of explicit and implicit definitions of reproducibility and related terminology, and discuss how to avoid potential misunderstandings when these terms are used as a surrogate for "truth."

    View details for DOI 10.1126/scitranslmed.aaf5027

    View details for Web of Science ID 000377443000001

    View details for PubMedID 27252173

  • Evidence-based medicine has been hijacked: a report to David Sackett JOURNAL OF CLINICAL EPIDEMIOLOGY Ioannidis, J. P. 2016; 73: 82-86
  • Evolution of Reporting P Values in the Biomedical Literature, 1990-2015 JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Chavalarias, D., Wallach, J. D., Li, A. H., Ioannidis, J. P. 2016; 315 (11): 1141-1148

    Abstract

    The use and misuse of P values has generated extensive debates.To evaluate in large scale the P values reported in the abstracts and full text of biomedical research articles over the past 25 years and determine how frequently statistical information is presented in ways other than P values.Automated text-mining analysis was performed to extract data on P values reported in 12,821,790 MEDLINE abstracts and in 843,884 abstracts and full-text articles in PubMed Central (PMC) from 1990 to 2015. Reporting of P values in 151 English-language core clinical journals and specific article types as classified by PubMed also was evaluated. A random sample of 1000 MEDLINE abstracts was manually assessed for reporting of P values and other types of statistical information; of those abstracts reporting empirical data, 100 articles were also assessed in full text.P values reported.Text mining identified 4,572,043 P values in 1,608,736 MEDLINE abstracts and 3,438,299 P values in 385,393 PMC full-text articles. Reporting of P values in abstracts increased from 7.3% in 1990 to 15.6% in 2014. In 2014, P values were reported in 33.0% of abstracts from the 151 core clinical journals (n = 29,725 abstracts), 35.7% of meta-analyses (n = 5620), 38.9% of clinical trials (n = 4624), 54.8% of randomized controlled trials (n = 13,544), and 2.4% of reviews (n = 71,529). The distribution of reported P values in abstracts and in full text showed strong clustering at P values of .05 and of .001 or smaller. Over time, the "best" (most statistically significant) reported P values were modestly smaller and the "worst" (least statistically significant) reported P values became modestly less significant. Among the MEDLINE abstracts and PMC full-text articles with P values, 96% reported at least 1 P value of .05 or lower, with the proportion remaining steady over time in PMC full-text articles. In 1000 abstracts that were manually reviewed, 796 were from articles reporting empirical data; P values were reported in 15.7% (125/796 [95% CI, 13.2%-18.4%]) of abstracts, confidence intervals in 2.3% (18/796 [95% CI, 1.3%-3.6%]), Bayes factors in 0% (0/796 [95% CI, 0%-0.5%]), effect sizes in 13.9% (111/796 [95% CI, 11.6%-16.5%]), other information that could lead to estimation of P values in 12.4% (99/796 [95% CI, 10.2%-14.9%]), and qualitative statements about significance in 18.1% (181/1000 [95% CI, 15.8%-20.6%]); only 1.8% (14/796 [95% CI, 1.0%-2.9%]) of abstracts reported at least 1 effect size and at least 1 confidence interval. Among 99 manually extracted full-text articles with data, 55 reported P values, 4 presented confidence intervals for all reported effect sizes, none used Bayesian methods, 1 used false-discovery rates, 3 used sample size/power calculations, and 5 specified the primary outcome.In this analysis of P values reported in MEDLINE abstracts and in PMC articles from 1990-2015, more MEDLINE abstracts and articles reported P values over time, almost all abstracts and articles with P values reported statistically significant results, and, in a subgroup analysis, few articles included confidence intervals, Bayes factors, or effect sizes. Rather than reporting isolated P values, articles should include effect sizes and uncertainty metrics.

    View details for DOI 10.1001/jama.2016.1952

    View details for Web of Science ID 000372159800019

  • Reproducible Research Practices and Transparency across the Biomedical Literature. PLoS biology Iqbal, S. A., Wallach, J. D., Khoury, M. J., Schully, S. D., Ioannidis, J. P. 2016; 14 (1)

    Abstract

    There is a growing movement to encourage reproducibility and transparency practices in the scientific community, including public access to raw data and protocols, the conduct of replication studies, systematic integration of evidence in systematic reviews, and the documentation of funding and potential conflicts of interest. In this survey, we assessed the current status of reproducibility and transparency addressing these indicators in a random sample of 441 biomedical journal articles published in 2000-2014. Only one study provided a full protocol and none made all raw data directly available. Replication studies were rare (n = 4), and only 16 studies had their data included in a subsequent systematic review or meta-analysis. The majority of studies did not mention anything about funding or conflicts of interest. The percentage of articles with no statement of conflict decreased substantially between 2000 and 2014 (94.4% in 2000 to 34.6% in 2014); the percentage of articles reporting statements of conflicts (0% in 2000, 15.4% in 2014) or no conflicts (5.6% in 2000, 50.0% in 2014) increased. Articles published in journals in the clinical medicine category versus other fields were almost twice as likely to not include any information on funding and to have private funding. This study provides baseline data to compare future progress in improving these indicators in the scientific literature.

    View details for DOI 10.1371/journal.pbio.1002333

    View details for PubMedID 26726926

    View details for PubMedCentralID PMC4699702

  • Meta-research: Evaluation and Improvement of Research Methods and Practices PLOS BIOLOGY Ioannidis, J. P., Fanelli, D., Dunne, D. D., Goodman, S. N. 2015; 13 (10)

    Abstract

    As the scientific enterprise has grown in size and diversity, we need empirical evidence on the research process to test and apply interventions that make it more efficient and its results more reliable. Meta-research is an evolving scientific discipline that aims to evaluate and improve research practices. It includes thematic areas of methods, reporting, reproducibility, evaluation, and incentives (how to do, report, verify, correct, and reward science). Much work is already done in this growing field, but efforts to-date are fragmented. We provide a map of ongoing efforts and discuss plans for connecting the multiple meta-research efforts across science worldwide.

    View details for DOI 10.1371/journal.pbio.1002264

    View details for Web of Science ID 000364457500001

    View details for PubMedID 26431313

    View details for PubMedCentralID PMC4592065

  • Assessment of vibration of effects due to model specification can demonstrate the instability of observational associations JOURNAL OF CLINICAL EPIDEMIOLOGY Patel, C. J., Burford, B., Ioannidis, J. P. 2015; 68 (9): 1046-1058

    Abstract

    Model specification-what adjusting variables are analytically modeled-may influence results of observational associations. We present a standardized approach to quantify the variability of results obtained with choices of adjustments called the "vibration of effects" (VoE).We estimated the VoE for 417 clinical, environmental, and physiological variables in association with all-cause mortality using National Health and Nutrition Examination Survey data. We selected 13 variables as adjustment covariates and computed 8,192 Cox models for each of 417 variables' associations with all-cause mortality.We present the VoE by assessing the variance of the effect size and in the -log10(P-value) obtained by different combinations of adjustments. We present whether there are multimodality patterns in effect sizes and P-values and the trajectory of results with increasing adjustments. For 31% of the 417 variables, we observed a Janus effect, with the effect being in opposite direction in the 99th versus the 1st percentile of analyses. For example, the vitamin E variant α-tocopherol had a VoE that indicated higher and lower risk for mortality.Estimating VoE offers empirical estimates of associations are under different model specifications. When VoE is large, claims for observational associations should be very cautious.

    View details for DOI 10.1016/j.jclinepi.2015.05.029

    View details for Web of Science ID 000360597300011

    View details for PubMedCentralID PMC4555355

  • Evaluation of Wellness Determinants and Interventions by Citizen Scientists. JAMA Naci, H., Ioannidis, J. P. 2015; 314 (2): 121-122

    View details for DOI 10.1001/jama.2015.6160

    View details for PubMedID 26068643

  • Does screening for disease save lives in asymptomatic adults? Systematic review of meta-analyses and randomized trials INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Saquib, N., Saquib, J., Ioannidis, J. P. 2015; 44 (1): 264-277

    Abstract

    Several popular screening tests, such as mammography and prostate-specific antigen, have met with wide controversy and/or have lost their endorsement recently. We systematically evaluated evidence from randomized controlled trials (RCTs) as to whether screening decreases mortality from diseases where death is a common outcome.We searched three sources: United States Preventive Services Task Force (USPSTF), Cochrane Database of Systematic Reviews, and PubMed. We extracted recommendation status, category of evidence and RCT availability on mortality for screening tests for diseases on asymptomatic adults (excluding pregnant women and children) from USPSTF. We identified meta-analyses and individual RCTs on screening and mortality from Cochrane and PubMed.We selected 19 diseases (39 tests) out of 50 diseases/disorders for which USPSTF provides screening evaluation. Screening is recommended for 6 diseases (12 tests) out of the 19. We assessed 9 non-overlapping meta-analyses and 48 individual trials for these 19 diseases. Among the results of the meta-analyses, reductions where the 95% confidence intervals (CIs) excluded the null occurred for four disease-specific mortality estimates (ultrasound for abdominal aortic aneurysm in men; mammography for breast cancer; fecal occult blood test and flexible sigmoidoscopy for colorectal cancer) and for none of the all-cause mortality estimates. Among individual RCTs, reductions in disease-specific and all-cause mortality where the 95% CIs excluded the null occurred in 30% and 11% of the estimates, respectively.Among currently available screening tests for diseases where death is a common outcome, reductions in disease-specific mortality are uncommon and reductions in all-cause mortality are very rare or non-existent.

    View details for DOI 10.1093/ije/dyu140

    View details for Web of Science ID 000350864200034

    View details for PubMedID 25596211

  • Call to improve transparency of trials of non-regulated interventions. BMJ (Clinical research ed.) Dal-Ré, R., Bracken, M. B., Ioannidis, J. P. 2015; 350: h1323-?

    View details for DOI 10.1136/bmj.h1323

    View details for PubMedID 25820265

  • Lowering the P Value Threshold Reply JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. A. 2018; 320 (9): 937–38

    View details for DOI 10.1001/jama.2018.8743

    View details for Web of Science ID 000443627300027

    View details for PubMedID 30193273

  • Industry-funded versus non-profit-funded critical care research: a meta-epidemiological overview. Intensive care medicine Janiaud, P., Cristea, I., Ioannidis, J. P. 2018

    Abstract

    PURPOSE: To study the landscape of funding in intensive care research and assess whether the reported outcomes of industry-funded randomized controlled trials (RCTs) are more favorable.METHODS: We systematically assembled meta-analyses evaluating any type of intervention in the critical care setting and reporting the source of funding for each included RCT. Furthermore, when the intervention was a drug or biologic, we searched also the original RCT articles, when their funding information was unavailable in the meta-analysis. We then qualitatively summarized the sources of funding. For binary outcomes, separate summary odds ratios were calculated for trials with and without industry funding. We then calculated the ratio of odds ratios (RORs) and the summary ROR (sROR) across topics. ROR<1 implies that the experimental intervention is relatively more favorable in trials with industry funding compared with trials without industry funding. For RCTs included in the ROR analysis, we also examined the conclusions of their abstract.RESULTS: Across 67 topics with 568 RCTs, 88 were funded by industry and another 73 had both industry and non-profit funding. Across 33 topics with binary outcomes, the sROR was 1.10 [95% CI (0.96-1.26), I2=1%]. Conclusions were not significantly more commonly unfavorable for the experimental arm interventions in industry-funded trials (21.3%) compared with trials without industry funding (18.2%).CONCLUSION: Industry-funded RCTs are the minority in intensive care. We found no evidence that industry-funded trials in intensive care yield more favorable results or are less likely to reach unfavorable conclusions.

    View details for DOI 10.1007/s00134-018-5325-3

    View details for PubMedID 30151688

  • Mapping risk factors for depression across the lifespan: An umbrella review of evidence from meta-analyses and Mendelian randomization studies JOURNAL OF PSYCHIATRIC RESEARCH Kohler, C. A., Evangelou, E., Stubbs, B., Solmi, M., Veronese, N., Belbasis, L., Bortolato, B., Melo, M. A., Coelho, C. A., Fernandes, B. S., Olfson, M., Ioannidis, J. A., Carvalho, A. F. 2018; 103: 189–207

    Abstract

    The development of depression may involve a complex interplay of environmental and genetic risk factors. PubMed and PsycInfo databases were searched from inception through August 3, 2017, to identify meta-analyses and Mendelian randomization (MR) studies of environmental risk factors associated with depression. For each eligible meta-analysis, we estimated the summary effect size and its 95% confidence interval (CI) by random-effects modeling, the 95% prediction interval, heterogeneity with I2, and evidence of small-study effects and excess significance bias. Seventy meta-analytic reviews met the eligibility criteria and provided 134 meta-analyses for associations from 1283 primary studies. While 109 associations were nominally significant (P < 0.05), only 8 met the criteria for convincing evidence and, when limited to prospective studies, convincing evidence was found in 6 (widowhood, physical abuse during childhood, obesity, having 4-5 metabolic risk factors, sexual dysfunction, job strain). In studies in which depression was assessed through a structured diagnostic interview, only associations with widowhood, job strain, and being a Gulf War veteran were supported by convincing evidence. Additionally, 8 MR studies were included and provided no consistent evidence for the causal effects of obesity, smoking, and alcohol consumption. The proportion of variance explained by genetic risk factors was extremely small (0.1-0.4%), which limited the evidence provided by the MR studies. Our findings suggest that despite the large number of putative risk factors investigated in the literature, few associations were supported by robust evidence. The current findings may have clinical and research implications for the early identification of individuals at risk for depression.

    View details for DOI 10.1016/j.jpsychires.2018.05.020

    View details for Web of Science ID 000438004900027

    View details for PubMedID 29886003

  • Why Cochrane should prioritise sharing data BMJ-BRITISH MEDICAL JOURNAL Shokraneh, F., Adams, C. E., Clarke, M., Amato, L., Bastian, H., Beller, E., Brassey, J., Buchbinder, R., Davoli, M., Del Mar, C., Glasziou, P., Gluud, C., Heneghan, C., Hoffmann, T., Ioannidis, J. A., Jayaram, M., Kwong, J., Moher, D., Ota, E., Sheriff, R., Vale, L., Ben Goldacre 2018; 362: k3229

    View details for DOI 10.1136/bmj.k3229

    View details for Web of Science ID 000441131800012

    View details for PubMedID 30061322

  • Assessment of Pragmatism in Recently Published Randomized Clinical Trials. JAMA internal medicine Janiaud, P., Dal-Re, R., Ioannidis, J. P. 2018

    View details for DOI 10.1001/jamainternmed.2018.3321

    View details for PubMedID 30039169

  • The association of depression and all-cause and cause-specific mortality: an umbrella review of systematic reviews and meta-analyses BMC MEDICINE Machado, M. O., Veronese, N., Sanches, M., Stubbs, B., Koyanagi, A., Thompson, T., Tzoulaki, I., Solmi, M., Vancampfort, D., Schuch, F. B., Maes, M., Fava, G. A., Ioannidis, J. A., Carvalho, A. F. 2018; 16: 112

    Abstract

    Depression is a prevalent and disabling mental disorder that frequently co-occurs with a wide range of chronic conditions. Evidence has suggested that depression could be associated with excess all-cause mortality across different settings and populations, although the causality of these associations remains unclear.We conducted an umbrella review of systematic reviews and meta-analyses of observational studies. PubMed, PsycINFO, and Embase electronic databases were searched through January 20, 2018. Systematic reviews and meta-analyses that investigated associations of depression and all-cause and cause-specific mortality were selected for the review. The evidence was graded as convincing, highly suggestive, suggestive, or weak based on quantitative criteria that included an assessment of heterogeneity, 95% prediction intervals, small-study effects, and excess significance bias.A total of 26 references providing 2 systematic reviews and data for 17 meta-analytic estimates met inclusion criteria (19 of them on all-cause mortality); data from 246 unique studies (N = 3,825,380) were synthesized. All 17 associations had P < 0.05 per random effects summary effects, but none of them met criteria for convincing evidence. Associations of depression and all-cause mortality in patients after acute myocardial infarction, in individuals with heart failure, in cancer patients as well as in samples from mixed settings met criteria for highly suggestive evidence. However, none of the associations remained supported by highly suggestive evidence in sensitivity analyses that considered studies employing structured diagnostic interviews. In addition, associations of depression and all-cause mortality in cancer and post-acute myocardial infarction samples were supported only by suggestive evidence when studies that tried to adjust for potential confounders were considered.Even though associations between depression and mortality have nominally significant results in all assessed settings and populations, the evidence becomes weaker when focusing on studies that used structured interviews and those that tried to adjust for potential confounders. A causal effect of depression on all-cause and cause-specific mortality remains unproven, and thus interventions targeting depression are not expected to result in lower mortality rates at least based on current evidence from observational studies.

    View details for DOI 10.1186/s12916-018-1101-z

    View details for Web of Science ID 000439499900001

    View details for PubMedID 30025524

    View details for PubMedCentralID PMC6053830

  • Conflict of Interest in Nutrition Research-Reply. JAMA Ioannidis, J. P., Trepanowski, J. F. 2018; 320 (1): 94–95

    View details for DOI 10.1001/jama.2018.5678

    View details for PubMedID 29971394

  • Perspective: Limiting Dependence on Nonrandomized Studies and Improving Randomized Trials in Human Nutrition Research: Why and How. Advances in nutrition (Bethesda, Md.) Trepanowski, J. F., Ioannidis, J. P. 2018; 9 (4): 367–77

    Abstract

    A large majority of human nutrition research uses nonrandomized observational designs, but this has led to little reliable progress. This is mostly due to many epistemologic problems, the most important of which are as follows: difficulty detecting small (or even tiny) effect sizes reliably for nutritional risk factors and nutrition-related interventions; difficulty properly accounting for massive confounding among many nutrients, clinical outcomes, and other variables; difficulty measuring diet accurately; and suboptimal research reporting. Tiny effect sizes and massive confounding are largely unfixable problems that narrowly confine the scenarios in which nonrandomized observational research is useful. Although nonrandomized studies and randomized trials have different priorities (assessment of long-term causality compared with assessment of treatment effects), the odds for obtaining reliable information with the former are limited. Randomized study designs should therefore largely replace nonrandomized studies in human nutrition research going forward. To achieve this, many of the limitations that have traditionally plagued most randomized trials in nutrition, such as small sample size, short length of follow-up, high cost, and selective reporting, among others, must be overcome. Pivotal megatrials with tens of thousands of participants and lifelong follow-up are possible in nutrition science with proper streamlining of operational costs. Fixable problems that have undermined observational research, such as dietary measurement error and selective reporting, need to be addressed in randomized trials. For focused questions in which dietary adherence is important to maximize, trials with direct observation of participants in experimental in-house settings may offer clean answers on short-term metabolic outcomes. Other study designs of randomized trials to consider in nutrition include registry-based designs and "N-of-1" designs. Mendelian randomization designs may also offer some more reliable leads for testing interventions in trials. Collectively, an improved randomized agenda may clarify many things in nutrition science that might never be answered credibly with nonrandomized observational designs.

    View details for DOI 10.1093/advances/nmy014

    View details for PubMedID 30032218

  • Physical activity and cancer: an umbrella review of the literature including 22 major anatomical sites and 770 000 cancer cases BRITISH JOURNAL OF SPORTS MEDICINE Machado de Rezende, L., de Sa, T., Markozannes, G., Rey-Lopez, J., Lee, I., Tsilidis, K. K., Ioannidis, J. A., Eluf-Neto, J. 2018; 52 (13): 826–33

    Abstract

    To provide an overview of the breadth and validity of claimed associations between physical activity and risk of developing or dying from cancer.Umbrella review.We searched Medline, Embase, Cochrane Database and Web of Science.Systematic reviews about physical activity and cancer incidence and cancer mortality in different body sites among general population.We included 19 reviews covering 22 cancer sites, 26 exposure-outcome pairs meta-analyses and 541 original studies. Physical activity was associated with lower risk of seven cancer sites (colon, breast, endometrial, lung, oesophageal, pancreas and meningioma). Only colon (a protective association with recreational physical activity) and breast cancer (a protective association with overall physical activity) were supported by strong evidence and highly suggestive evidence, respectively. Evidence from endometrial, lung, oesophageal, pancreas and meningioma presented hints of uncertainty and bias in the literature (eg, not reaching P values<10-6) showing large between-study heterogeneity and/or not demonstrating a definite direction for the effect when 95% prediction intervals were considered. Four of the 26 meta-analyses showed small study effects and 4 showed excess significance.Physical activity is associated with a lower risk of several cancers, but only colon and breast cancer associations were supported by strong or highly suggestive evidence, respectively. Evidence from other cancer sites was less consistent, presenting hints of uncertainty and/or bias.

    View details for DOI 10.1136/bjsports-2017-098391

    View details for Web of Science ID 000438038900009

    View details for PubMedID 29146752

  • Prevalence and outcomes of incidental imaging findings: umbrella review BMJ-BRITISH MEDICAL JOURNAL O'Sullivan, J. W., Muntinga, T., Grigg, S., Ioannidis, J. A. 2018; 361: k2387

    Abstract

    To provide an overview of the evidence on prevalence and outcomes of incidental imaging findings.Umbrella review of systematic reviews.Searches of MEDLINE, EMBASE up to August 2017; screening of references in included papers.Criteria included systematic reviews and meta-analyses of observational studies that gave a prevalence of incidental abnormalities ("incidentalomas"). An incidental imaging finding was defined as an imaging abnormality in a healthy, asymptomatic patient or an imaging abnormality in a symptomatic patient, where the abnormality was not apparently related to the patient's symptoms. Primary studies that measured the prevalence of incidentalomas in patients with a history of malignancy were also considered in sensitivity analyses.20 systematic reviews (240 primary studies) were identified from 7098 references from the database search. Fifteen systematic reviews provided data to quantify the prevalence of incidentalomas, whereas 18 provided data to quantify the outcomes of incidentalomas (13 provided both). The prevalence of incidentalomas varied substantially between imaging tests; it was less than 5% for chest computed tomography for incidental pulmonary embolism in patients with and without cancer and whole body positron emission tomography (PET) or PET/computed tomography (for patients with and without cancer). Conversely, incidentalomas occurred in more than a third of images in cardiac magnetic resonance imaging (MRI), chest computed tomography (for incidentalomas of thorax, abdomen, spine, or heart), and computed tomography colonoscopy (for extra-colonic incidentalomas). Intermediate rates occurred with MRI of the spine (22%) and brain (22%). The rate of malignancy in incidentalomas varied substantially between organs; the prevalence of malignancy was less than 5% in incidentalomas of the brain, parotid, and adrenal gland. Extra-colonic, prostatic, and colonic incidentalomas were malignant between 10% and 20% of the time, whereas renal, thyroid, and ovarian incidentalomas were malignant around a quarter of the time. Breast incidentalomas had the highest percentage of malignancy (42%, 95% confidence interval 31% to 54%). Many assessments had high between-study heterogeneity (15 of 20 meta-analyses with I2 >50%).There is large variability across different imaging techniques both in the prevalence of incidentalomas and in the prevalence of malignancy for specific organs. This umbrella review will aid clinicians and patients weigh up the pros and cons of requesting imaging scans and will help with management decisions after an incidentaloma diagnosis. Our results can underpin the creation of guidelines to assist these decisions.PROSPERO: CRD42017075679.

    View details for DOI 10.1136/bmj.k2387

    View details for Web of Science ID 000436497400002

    View details for PubMedID 29914908

  • Lack of evidence to favor specific preventive interventions in psychosis: a network meta-analysis WORLD PSYCHIATRY Davies, C., Cipriani, A., Ioannidis, J. A., Radua, J., Stahl, D., Provenzani, U., McGuire, P., Fusar-Poli, P. 2018; 17 (2): 196–209

    Abstract

    Preventing psychosis in patients at clinical high risk may be a promising avenue for pre-emptively ameliorating outcomes of the most severe psychiatric disorder. However, information on how each preventive intervention fares against other currently available treatment options remains unavailable. The aim of the current study was to quantify the consistency and magnitude of effects of specific preventive interventions for psychosis, comparing different treatments in a network meta-analysis. PsycINFO, Web of Science, Cochrane Central Register of Controlled Trials, and unpublished/grey literature were searched up to July 18, 2017, to identify randomized controlled trials conducted in individuals at clinical high risk for psychosis, comparing different types of intervention and reporting transition to psychosis. Two reviewers independently extracted data. Data were synthesized using network meta-analyses. The primary outcome was transition to psychosis at different time points and the secondary outcome was treatment acceptability (dropout due to any cause). Effect sizes were reported as odds ratios and 95% confidence intervals (CIs). Sixteen studies (2,035 patients, 57% male, mean age 20.1 years) reported on risk of transition. The treatments tested were needs-based interventions (NBI); omega-3 + NBI; ziprasidone + NBI; olanzapine + NBI; aripiprazole + NBI; integrated psychological interventions; family therapy + NBI; D-serine + NBI; cognitive behavioural therapy, French & Morrison protocol (CBT-F) + NBI; CBT-F + risperidone + NBI; and cognitive behavioural therapy, van der Gaag protocol (CBT-V) + CBT-F + NBI. The network meta-analysis showed no evidence of significantly superior efficacy of any one intervention over the others at 6 and 12 months (insufficient data were available after 12 months). Similarly, there was no evidence for intervention differences in acceptability at either time point. Tests for inconsistency were non-significant and sensitivity analyses controlling for different clustering of interventions and biases did not materially affect the interpretation of the results. In summary, this study indicates that, to date, there is no evidence that any specific intervention is particularly effective over the others in preventing transition to psychosis. Further experimental research is needed.

    View details for DOI 10.1002/wps.20526

    View details for Web of Science ID 000434185800020

    View details for PubMedID 29856551

    View details for PubMedCentralID PMC5980552

  • Antidepressants might work for people with major depression: where do we go from here? LANCET PSYCHIATRY Cipriani, A., Salanti, G., Furukawa, T. A., Egger, M., Leucht, S., Ruhe, H. G., Turner, E. H., Atkinson, L. Z., Chaimani, A., Higgins, J. T., Ogawa, Y., Takeshima, N., Hayasaka, Y., Imai, H., Shinohara, K., Tajika, A., Ioannidis, J. A., Geddes, J. R. 2018; 5 (6): 461–63
  • Larger effect sizes in nonrandomized studies are associated with higher rates of EMA licensing approval JOURNAL OF CLINICAL EPIDEMIOLOGY Djulbegovic, B., Glasziou, P., Klocksieben, F. A., Reljic, T., VanDenBergh, M., Mhaskar, R., Ioannidis, J. A., Chalmers, L. 2018; 98: 24–32

    Abstract

    The aim of this study was to evaluate how often the European Medicines Agency (EMA) has authorized drugs based on nonrandomized studies and whether there is an association between treatment effects and EMA preference for further testing in randomized clinical trials (RCTs).We reviewed all initial marketing authorizations in the EMA database on human medicines between 1995 and 2015 and included authorizations granted without randomized data. We extracted data on treatment effects and EMA preference for further testing in RCTs.Of 723 drugs, 51 were authorized based on nonrandomized data. These 51 drugs were licensed for 71 indications. In the 51 drug-indication pairs with no preference for further RCT testing, effect estimates were large [odds ratio (OR): 12.0 (95% confidence interval {CI}: 8.1-17.9)] compared to effect estimates in the 20 drug-indication pairs for which future RCTs were preferred [OR: 4.3 (95% CI 2.8-6.6)], with a significant difference between effects (P = 0.0005).Nonrandomized data were used for 7% of EMA drug approvals. Larger effect sizes were associated with greater likelihood of approval based on nonrandomized data alone. We did not find a clear treatment effect threshold for drug approval without RCT evidence.

    View details for DOI 10.1016/j.jclinepi.2018.01.011

    View details for Web of Science ID 000433992800005

    View details for PubMedID 29432860

  • Poor performance of clinical prediction models: the harm of commonly applied methods JOURNAL OF CLINICAL EPIDEMIOLOGY Steyerberg, E. W., Uno, H., Ioannidis, J. A., van Calster, B., Collaborators 2018; 98: 133–43

    Abstract

    To evaluate limitations of common statistical modeling approaches in deriving clinical prediction models and explore alternative strategies.A previously published model predicted the likelihood of having a mutation in germline DNA mismatch repair genes at the time of diagnosis of colorectal cancer. This model was based on a cohort where 38 mutations were found among 870 participants, with validation in an independent cohort with 35 mutations. The modeling strategy included stepwise selection of predictors from a pool of over 37 candidate predictors and dichotomization of continuous predictors. We simulated this strategy in small subsets of a large contemporary cohort (2,051 mutations among 19,866 participants) and made comparisons to other modeling approaches. All models were evaluated according to bias and discriminative ability (concordance index, c) in independent data.We found over 50% bias for five of six originally selected predictors, unstable model specification, and poor performance at validation (median c = 0.74). A small validation sample hampered stable assessment of performance. Model prespecification based on external knowledge and using continuous predictors led to better performance (c = 0.836 and c = 0.852 with 38 and 2,051 events respectively).Prediction models perform poorly if based on small numbers of events and developed with common but suboptimal statistical approaches. Alternative modeling strategies to best exploit available predictive information need wider implementation, with collaborative research to increase sample sizes.

    View details for DOI 10.1016/j.jclinepi.2017.11.013

    View details for Web of Science ID 000433992800017

    View details for PubMedID 29174118

  • Blood Pressure Measurement and Hypertension Diagnosis in the 2017 US Guidelines First Things First HYPERTENSION Stergiou, G., Palatini, P., Asmar, R., de la Sierra, A., Myers, M., Shennan, A., Wang, J., O'Brien, E., Parati, G. 2018; 71 (6): 963–65
  • Probability of major depression diagnostic classification using semi-structured versus fully structured diagnostic interviews BRITISH JOURNAL OF PSYCHIATRY Levis, B., Benedetti, A., Riehm, K. E., Saadat, N., Levis, A. W., Azar, M., Rice, D. B., Chiovitti, M. J., Sanchez, T. A., Cuijpers, P., Gilbody, S., Ioannidis, J. A., Kloda, L. A., McMillan, D., Patten, S. B., Shrier, I., Steele, R. J., Ziegelstein, R. C., Akena, D. H., Arroll, B., Ayalon, L., Baradaran, H. R., Baron, M., Beraldi, A., Bombardier, C. H., Butterworth, P., Carter, G., Chagas, M. H., Chan, J. N., Cholera, R., Chowdhary, N., Clover, K., Conwell, Y., de Man-van Ginkel, J. M., Delgadillo, J., Fann, J. R., Fischer, F. H., Fischler, B., Fung, D., Gelaye, B., Goodyear-Smith, F., Greeno, C. G., Hall, B. J., Hambridge, J., Harrison, P. A., Hegerl, U., Hides, L., Hobfoll, S. E., Hudson, M., Hyphantis, T., Inagaki, M., Ismail, K., Jette, N., Khamseh, M. E., Kiely, K. M., Lamers, F., Liu, S., Lotrakul, M., Loureiro, S. R., Lowe, B., Marsh, L., McGuire, A., Sidik, S., Munhoz, T. N., Muramatsu, K., Osorio, F. L., Patel, V., Pence, B. W., Persoons, P., Picardi, A., Rooney, A. G., Santos, I. S., Shaaban, J., Sidebottom, A., Simning, A., Stafford, L., Sung, S., Tan, P., Turner, A., van der Feltz-Cornelis, C. M., van Weert, H. C., Vohringer, P. A., White, J., Whooley, M. A., Winkley, K., Yamada, M., Zhang, Y., Thombs, B. D. 2018; 212 (6): 377–85

    Abstract

    Different diagnostic interviews are used as reference standards for major depression classification in research. Semi-structured interviews involve clinical judgement, whereas fully structured interviews are completely scripted. The Mini International Neuropsychiatric Interview (MINI), a brief fully structured interview, is also sometimes used. It is not known whether interview method is associated with probability of major depression classification.AimsTo evaluate the association between interview method and odds of major depression classification, controlling for depressive symptom scores and participant characteristics.Data collected for an individual participant data meta-analysis of Patient Health Questionnaire-9 (PHQ-9) diagnostic accuracy were analysed and binomial generalised linear mixed models were fit.A total of 17 158 participants (2287 with major depression) from 57 primary studies were analysed. Among fully structured interviews, odds of major depression were higher for the MINI compared with the Composite International Diagnostic Interview (CIDI) (odds ratio (OR) = 2.10; 95% CI = 1.15-3.87). Compared with semi-structured interviews, fully structured interviews (MINI excluded) were non-significantly more likely to classify participants with low-level depressive symptoms (PHQ-9 scores ≤6) as having major depression (OR = 3.13; 95% CI = 0.98-10.00), similarly likely for moderate-level symptoms (PHQ-9 scores 7-15) (OR = 0.96; 95% CI = 0.56-1.66) and significantly less likely for high-level symptoms (PHQ-9 scores ≥16) (OR = 0.50; 95% CI = 0.26-0.97).The MINI may identify more people as depressed than the CIDI, and semi-structured and fully structured interviews may not be interchangeable methods, but these results should be replicated.Declaration of interestDrs Jetté and Patten declare that they received a grant, outside the submitted work, from the Hotchkiss Brain Institute, which was jointly funded by the Institute and Pfizer. Pfizer was the original sponsor of the development of the PHQ-9, which is now in the public domain. Dr Chan is a steering committee member or consultant of Astra Zeneca, Bayer, Lilly, MSD and Pfizer. She has received sponsorships and honorarium for giving lectures and providing consultancy and her affiliated institution has received research grants from these companies. Dr Hegerl declares that within the past 3 years, he was an advisory board member for Lundbeck, Servier and Otsuka Pharma; a consultant for Bayer Pharma; and a speaker for Medice Arzneimittel, Novartis, and Roche Pharma, all outside the submitted work. Dr Inagaki declares that he has received grants from Novartis Pharma, lecture fees from Pfizer, Mochida, Shionogi, Sumitomo Dainippon Pharma, Daiichi-Sankyo, Meiji Seika and Takeda, and royalties from Nippon Hyoron Sha, Nanzando, Seiwa Shoten, Igaku-shoin and Technomics, all outside of the submitted work. Dr Yamada reports personal fees from Meiji Seika Pharma Co., Ltd., MSD K.K., Asahi Kasei Pharma Corporation, Seishin Shobo, Seiwa Shoten Co., Ltd., Igaku-shoin Ltd., Chugai Igakusha and Sentan Igakusha, all outside the submitted work. All other authors declare no competing interests. No funder had any role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.

    View details for DOI 10.1192/bjp.2018.54

    View details for Web of Science ID 000434294200009

    View details for PubMedID 29717691

  • P values in display items are ubiquitous and almost invariably significant: A survey of top science journals PLOS ONE Cristea, I., Ioannidis, J. A. 2018; 13 (5): e0197440

    Abstract

    P values represent a widely used, but pervasively misunderstood and fiercely contested method of scientific inference. Display items, such as figures and tables, often containing the main results, are an important source of P values. We conducted a survey comparing the overall use of P values and the occurrence of significant P values in display items of a sample of articles in the three top multidisciplinary journals (Nature, Science, PNAS) in 2017 and, respectively, in 1997. We also examined the reporting of multiplicity corrections and its potential influence on the proportion of statistically significant P values. Our findings demonstrated substantial and growing reliance on P values in display items, with increases of 2.5 to 14.5 times in 2017 compared to 1997. The overwhelming majority of P values (94%, 95% confidence interval [CI] 92% to 96%) were statistically significant. Methods to adjust for multiplicity were almost non-existent in 1997, but reported in many articles relying on P values in 2017 (Nature 68%, Science 48%, PNAS 38%). In their absence, almost all reported P values were statistically significant (98%, 95% CI 96% to 99%). Conversely, when any multiplicity corrections were described, 88% (95% CI 82% to 93%) of reported P values were statistically significant. Use of Bayesian methods was scant (2.5%) and rarely (0.7%) articles relied exclusively on Bayesian statistics. Overall, wider appreciation of the need for multiplicity corrections is a welcome evolution, but the rapid growth of reliance on P values and implausibly high rates of reported statistical significance are worrisome.

    View details for DOI 10.1371/journal.pone.0197440

    View details for Web of Science ID 000432118800051

    View details for PubMedID 29763472

    View details for PubMedCentralID PMC5953482

  • An overview of methods for network meta-analysis using individual participant data: when do benefits arise? STATISTICAL METHODS IN MEDICAL RESEARCH Debray, T. A., Schuit, E., Efthimiou, O., Reitsma, J. B., Ioannidis, J. A., Salanti, G., Moons, K. M., GetReal Workpackage 2018; 27 (5): 1351–64

    Abstract

    Network meta-analysis (NMA) is a common approach to summarizing relative treatment effects from randomized trials with different treatment comparisons. Most NMAs are based on published aggregate data (AD) and have limited possibilities for investigating the extent of network consistency and between-study heterogeneity. Given that individual participant data (IPD) are considered the gold standard in evidence synthesis, we explored statistical methods for IPD-NMA and investigated their potential advantages and limitations, compared with AD-NMA. We discuss several one-stage random-effects NMA models that account for within-trial imbalances, treatment effect modifiers, missing response data and longitudinal responses. We illustrate all models in a case study of 18 antidepressant trials with a continuous endpoint (the Hamilton Depression Score). All trials suffered from drop-out; missingness of longitudinal responses ranged from 21 to 41% after 6 weeks follow-up. Our results indicate that NMA based on IPD may lead to increased precision of estimated treatment effects. Furthermore, it can help to improve network consistency and explain between-study heterogeneity by adjusting for participant-level effect modifiers and adopting more advanced models for dealing with missing response data. We conclude that implementation of IPD-NMA should be considered when trials are affected by substantial drop-out rate, and when treatment effects are potentially influenced by participant-level covariates.

    View details for DOI 10.1177/0962280216660741

    View details for Web of Science ID 000429948200004

    View details for PubMedID 27487843

  • Protect us from poor-quality medical research HUMAN REPRODUCTION Ioannidis, J. A., Bhattacharya, S., Evers, J. H., van der Veen, F., Somigliana, E., Barratt, C. R., Bontempi, G., Baird, D. T., Crosignani, P., Devroey, P., Diedrich, K., Farquharson, R. G., Fraser, L. R., Geraedts, J. M., Gianaroli, L., La Vecchia, C., Lundin, K., Magli, C., Negri, E., Sunde, A., Tapanainen, J. S., Tarlatzis, B. C., Van Steirteghem, A., Veiga, A., ESHRE Capri Workshop Grp 2018; 33 (5): 770–76

    Abstract

    Much of the published medical research is apparently flawed, cannot be replicated and/or has limited or no utility. This article presents an overview of the current landscape of biomedical research, identifies problems associated with common study designs and considers potential solutions. Randomized clinical trials, observational studies, systematic reviews and meta-analyses are discussed in terms of their inherent limitations and potential ways of improving their conduct, analysis and reporting. The current emphasis on statistical significance needs to be replaced by sound design, transparency and willingness to share data with a clear commitment towards improving the quality and utility of clinical research.

    View details for DOI 10.1093/humrep/dey056

    View details for Web of Science ID 000432285200002

    View details for PubMedID 29617882

  • Systematic identification of correlates of HIV infection: an X-wide association study AIDS Patel, C. J., Bhattacharya, J., Ioannidis, J. A., Bendavid, E. 2018; 32 (7): 933–43

    Abstract

    Better identification of at-risk groups could benefit HIV-1 care programmes. We systematically identified HIV-1 risk factors in two nationally representative cohorts of women in the Demographic and Health Surveys.We identified and replicated the association of 1415 social, economic, environmental, and behavioral factors with HIV-1 status. We used the 2007 and 2013-2014 surveys conducted among 5715 and 15 433 Zambian women, respectively (688 shared factors). We used false discovery rate criteria to identify factors that are strongly associated with HIV-1 in univariate and multivariate models of the entire population, as well as in subgroups stratified by wealth, residence, age, and past HIV-1 testing.In the univariate analysis, we identified 102 and 182 variables that are associated with HIV-1 in the two surveys, respectively (79 factors were associated in both). Factors that were associated with HIV-1 status in full-sample analyses and in subgroups include being formerly married (adjusted OR 2007, 2.8, P < 10; 2013-2014 2.8, P < 10), widowhood (aOR 3.7, P < 10; and 4.2, P < 10), genital ulcers within 12 months (aOR 2.4, P < 10; and 2.2, P < 10), and having a woman head of the household (aOR 1.7, P < 10; and 2.1, P < 10), while owning a bicycle (aOR 0.6, P < 10; and 0.6, P < 10) and currently breastfeeding (aOR 0.5, P < 10; and 0.4, P < 10) were associated with decreased risk. Area under the curve for HIV-1 positivity was 0.76-0.82.Our X-wide association study identifies under-recognized factors related to HIV-1 infection, including widowhood, breastfeeding, and gender of head of the household. These features could be used to improve HIV-1 identification programs.

    View details for DOI 10.1097/QAD.0000000000001767

    View details for Web of Science ID 000429434300013

    View details for PubMedID 29424772

    View details for PubMedCentralID PMC5869155

  • Randomized controlled trials: Often flawed, mostly useless, clearly indispensable: A commentary on Deaton and Cartwright. Social science & medicine (1982) Ioannidis, J. P. 2018

    View details for DOI 10.1016/j.socscimed.2018.04.029

    View details for PubMedID 29776687

  • Improving Disclosure of Financial Conflicts of Interest for Research on Psychosocial Interventions. JAMA psychiatry Cristea, I., Ioannidis, J. P. 2018

    View details for DOI 10.1001/jamapsychiatry.2018.0382

    View details for PubMedID 29641818

  • Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis LANCET Cipriani, A., Furukawa, T. A., Salanti, G., Chaimani, A., Atkinson, L. Z., Ogawa, Y., Levcht, S., Ruhe, H. G., Turner, E. H., Higgins, J. T., Egger, M., Takeshima, N., Hayasaka, Y., Imai, H., Shinohara, K., Tajika, A., Ioannidis, J. A., Geddes, J. R. 2018; 391 (10128): 1357–66

    Abstract

    Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder.We did a systematic review and network meta-analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD42012002291.We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89-2·41) for amitriptyline and 1·37 (1·16-1·63) for reboxetine. For acceptability, only agomelatine (OR 0·84, 95% CrI 0·72-0·97) and fluoxetine (0·88, 0·80-0·96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1·30, 1·01-1·68). When all trials were considered, differences in ORs between antidepressants ranged from 1·15 to 1·55 for efficacy and from 0·64 to 0·83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19-1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51-0·84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43-0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1·30-2·32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low.All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants.National Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science.

    View details for DOI 10.1016/S0140-6736(17)32802-7

    View details for Web of Science ID 000429342800024

    View details for PubMedID 29477251

    View details for PubMedCentralID PMC5889788

  • Real-world evidence: How pragmatic are randomized controlled trials labeled as pragmatic? BMC MEDICINE Dal-Re, R., Janiaud, P., Ioannidis, J. A. 2018; 16: 49

    Abstract

    Pragmatic randomized controlled trials (RCTs) mimic usual clinical practice and they are critical to inform decision-making by patients, clinicians and policy-makers in real-world settings. Pragmatic RCTs assess effectiveness of available medicines, while explanatory RCTs assess efficacy of investigational medicines. Explanatory and pragmatic are the extremes of a continuum. This debate article seeks to evaluate and provide recommendation on how to characterize pragmatic RCTs in light of the current landscape of RCTs. It is supported by findings from a PubMed search conducted in August 2017, which retrieved 615 RCTs self-labeled in their titles as "pragmatic" or "naturalistic". We focused on 89 of these trials that assessed medicines (drugs or biologics).36% of these 89 trials were placebo-controlled, performed before licensing of the medicine, or done in a single-center. In our opinion, such RCTs overtly deviate from usual care and pragmatism. It follows, that the use of the term 'pragmatic' to describe them, conveys a misleading message to patients and clinicians. Furthermore, many other trials among the 615 coined as 'pragmatic' and assessing other types of intervention are plausibly not very pragmatic; however, this is impossible for a reader to tell without access to the full protocol and insider knowledge of the trial conduct. The degree of pragmatism should be evaluated by the trial investigators themselves using the PRECIS-2 tool, a tool that comprises 9 domains, each scored from 1 (very explanatory) to 5 (very pragmatic).To allow for a more appropriate characterization of the degree of pragmatism in clinical research, submissions of RCTs to funders, research ethics committees and to peer-reviewed journals should include a PRECIS-2 tool assessment done by the trial investigators. Clarity and accuracy on the extent to which a RCT is pragmatic will help understand how much it is relevant to real-world practice.

    View details for DOI 10.1186/s12916-018-1038-2

    View details for Web of Science ID 000429564500001

    View details for PubMedID 29615035

    View details for PubMedCentralID PMC5883397

  • The Obesity Paradox: A Misleading Term That Should Be Abandoned OBESITY Flegal, K. M., Ioannidis, J. A. 2018; 26 (4): 629–30

    Abstract

    The term "obesity paradox" is a figure of speech, not a scientific term. The term has no precise definition and has been used to describe numerous observations that have little in common other than the finding of an association of obesity with a favorable outcome. The terminology has led to misunderstandings among researchers and the public alike. It's time for authors and editors to abandon the use of this term. Simply labeling counterintuitive findings as the "obesity paradox" adds no value. Unexpected findings should not be viewed negatively; such findings can lead to new knowledge, better treatments, and scientific advances.

    View details for DOI 10.1002/oby.22140

    View details for Web of Science ID 000428213200001

    View details for PubMedID 29570246

  • Immunogenicity and safety of the multicomponent meningococcal B vaccine (4CMenB) in children and adolescents: a systematic review and meta-analysis LANCET INFECTIOUS DISEASES Flacco, M., Manzoli, L., Rosso, A., Marzuillo, C., Bergamini, M., Stefanati, A., Cultrera, R., Villari, P., Ricciardi, W., Ioannidis, J. A., Contopoulos-Ioannidis, D. G. 2018; 18 (4): 461–72

    Abstract

    The multicomponent meningococcal serogroup B vaccine (4CMenB) has been licensed in more than 35 countries. However, uncertainties remain about the lowest number of doses required to induce satisfactory, persistent immune responses. We did a systematic review and meta-analysis to provide quantitative estimates for the immunogenicity, persistence of immunogenicity, and safety of 4CMenB vaccine in children and adolescents.For this systematic review and meta-analyses (proportion, head to head, and network), we searched MEDLINE, Scopus, Embase, and ClinicalTrials.gov from database inception to June 30, 2017, for randomised trials that compared the immunogenicity or safety of the 4CMenB vaccine with its originator meningococcal B recombinant vaccine or routine vaccines in children or adolescents. For proportion meta-analyses, we also included single arm trials and follow-up studies of randomised controlled trials. Trials that assessed immunogenicity against at least one of four Neisseria meningitidis serogroup B reference strains (44-76/SL, 5/99, NZ98/254, and M10713) and included participants younger than 18 years who had received two or more doses of the 4CMenB vaccine were eligible for inclusion. We requested individual patient-level data from study authors and extracted data from published reports and online trial registries. We did meta-analyses to assess 4CMenB safety and immunogenicity against the four reference strains 30 days after a primary immunisation course (three doses for children, two doses for adolescents), 30 days after the primary course plus one booster dose (children only), 6 months or more after primary course, and 6 months or more after the booster dose.736 non-duplicate records were screened, and ten randomised trials and eight follow-on extension trials on 4CMenB met the inclusion criteria. In intention-to-treat analyses, the overall proportion of children and adolescents who achieved seroconversion 30 days after the primary course of 4CMenB was 92% (95% CI 89-95 [I2=95%, p<0·0001]) for the 44/76-SL strain, 91% (87-95 [I2=95%, p<0·0001]) for the 5/99 strain, 84% (77-90 [I2=97%, p<0·0001]) for the NZ98-254 strain, and 87% (68-99 [I2=97%, p<0·0001]) for the M10713 strain. 6 months after the primary course, the immunogenicity remained adequate to high against all three tested strains (5/99, 44/76-SL, and NZ98/254) in adolescents (≥77%), and against two of four strains (5/99 and 44/76-SL) in children (≥67%): the proportion of patients who achieved seroconversion substantially declined for M10713 (<50%) and NZ98/254 (<35%). A booster dose re-enhanced the proportion of patients who achieved seroconversion (≥93% for all strains). However, immunogenicity remained high 6 months after the booster dose for strains 5/99 (95%) and M10713 (75%) only, whereas the proportion of patients who achieved seroconversion against strains 44/76-SL and NZ98/254 returned to similar proportions recorded 6 months after the primary course (62% for 44/76-SL, 35% for NZ98/254). The incidence of potentially vaccine-related, acute serious adverse events in individuals receiving 4CMenB was low (5·4 per 1000 individuals), but was significantly higher than routine vaccines (1·2 per 1000 individuals).4CMenB has an acceptable short-term safety profile. The primary course is sufficient to achieve a satisfactory immune response within 30 days of vaccination. A booster dose is required for children to prolong the protection against strain M10713, and the long-term immunogenicity against strain NZ98/254 remains suboptimal.None.

    View details for DOI 10.1016/S1473-3099(18)30048-3

    View details for Web of Science ID 000428231600041

    View details for PubMedID 29371070

  • Are systematic reviews and meta-analyses still useful research? We are not sure INTENSIVE CARE MEDICINE Moller, M., Ioannidis, J. A., Darmon, M. 2018; 44 (4): 518–20

    View details for DOI 10.1007/s00134-017-5039-y

    View details for Web of Science ID 000431171300025

    View details for PubMedID 29663048

  • Two Genetic Variants Associated with Plantar Fascial Disorders INTERNATIONAL JOURNAL OF SPORTS MEDICINE Kim, S. K., Ioannidis, J. A., Ahmed, M. A., Avins, A. L., Kleimeyer, J. P., Fredericson, M., Dragoo, J. L. 2018; 39 (4): 314–21

    Abstract

    Plantar fascial disorder is comprised of plantar fasciitis and plantar fibromatosis. Plantar fasciitis is the most common cause of heel pain, especially for athletes involved in running and jumping sports. Plantar fibromatosis is a rare fibrous hyperproliferation of the deep connective tissue of the foot. To identify genetic loci associated with plantar fascial disorders, a genome-wide association screen was performed using publically available data from the Research Program in Genes, Environment and Health including 21,624 cases of plantar fascial disorders and 80,879 controls. One indel (chr5:118704153:D) and one SNP (rs62051384) showed an association with plantar fascial disorders at genome-wide significance (p<5×10-8) with small effects (odds ratios=0.93 and 1.07 per allele, respectively). The indel chr5:118704153:D is located within TNFAIP8 (encodes a protein induced by TNF alpha) and rs62051384 is located within WWP2 (which is involved in proteasomal degradation). These DNA variants may be informative in explaining why some individuals are at higher risk for plantar fascial disorders than others.

    View details for DOI 10.1055/s-0044-100280

    View details for Web of Science ID 000429040400010

    View details for PubMedID 29534260

  • Improving the integrity of published science: An expanded taxonomy of retractions and corrections EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Fanelli, D., Ioannidis, J. A., Goodman, S. 2018; 48 (4)

    View details for DOI 10.1111/eci.12898

    View details for Web of Science ID 000427247700005

    View details for PubMedID 29369337

  • Meta-analyses in environmental and occupational health. Occupational and environmental medicine Ioannidis, J. P. 2018

    Abstract

    OBJECTIVES: Meta-analyses are considered generally as the highest level of evidence, but concerns have been voiced about their massive, low-quality production. This paper aimed to evaluate the landscape of meta-analyses in the field of occupational and environmental health and medicine.METHODS: Using relevant search terms, all meta-analyses were searched for, but those published in 2015 were assessed for their origin, whether they included randomised trials and individual-level data and whether they had authors from the industry or consultancy firms.RESULTS: PubMed searches (last update February 2017) identified 1251 eligible meta-analyses in this field. There was a rapid increase over time (n=16 published in 1995 vs n=163 published in 2015). Of the 163 eligible meta-analyses published in 2015, 49 were from China, followed at a distance by the USA (n=19). Only 16 considered randomised (intervention) trials and 13 included individual-level data. Only 1 of the 150 meta-analyses had industry authors and none had consultancy firm authors. As an example of conflicting findings, 12 overlapping meta-analyses addressed mobile phones and brain cancer risk and they differed substantially in number of studies included, eligibility criteria and conclusions.CONCLUSIONS: There has been a major increase in the publication of meta-analyses in occupational and environmental health over time, with the majority of these studies focusing on observational data, while a commendable fraction used individual-level data. Authorship is still limited largely to academic and non-profit authors. With massive production of meta-analyses, redundancy needs to be anticipated and efforts should be made to safeguard quality and protect from bias.

    View details for DOI 10.1136/oemed-2016-104128

    View details for PubMedID 29574405

  • A universal standard for the validation of blood pressure measuring devices: Association for the Advancement of Medical Instrumentation/European Society of Hypertension/International Organization for Standardization (AAMI/ESH/ISO) Collaboration Statement JOURNAL OF HYPERTENSION Stergiou, G. S., Alpert, B., Mieke, S., Asmar, R., Atkins, N., Eckert, S., Frick, G., Friedman, B., Grassl, T., Ichikawa, T., Ioannidis, J. P., Lacy, P., McManus, R., Murray, A., Myers, M., Palatini, P., Parati, G., Quinn, D., Sarkis, J., Shennan, A., Usuda, T., Wang, J., Wu, C. O., O'Brien, E. 2018; 36 (3): 472–78

    Abstract

    : In the last 30 years, several organizations, such as the US Association for the Advancement of Medical Instrumentation (AAMI), the British Hypertension Society, the European Society of Hypertension (ESH) Working Group on Blood Pressure (BP) Monitoring and the International Organization for Standardization (ISO) have developed protocols for clinical validation of BP measuring devices. However, it is recognized that science, as well as patients, consumers and manufacturers would be best served if all BP measuring devices were assessed for accuracy according to an agreed single validation protocol that had global acceptance. Therefore, an international initiative was taken by AAMI, ESH and ISO experts who agreed to develop a universal standard for device validation. This statement presents the key aspects of a validation procedure, which were agreed by the AAMI, ESH and ISO representatives as the basis for a single universal validation protocol. As soon as the AAMI/ESH/ISO standard is fully developed, this will be regarded as the single universal standard and will replace all other previous standards/protocols.

    View details for DOI 10.1097/HJH.0000000000001634

    View details for Web of Science ID 000429317500003

    View details for PubMedID 29384983

    View details for PubMedCentralID PMC5796427

  • A Universal Standard for the Validation of Blood Pressure Measuring Devices Association for the Advancement of Medical Instrumentation/European Society of Hypertension/International Organization for Standardization (AAMI/ESH/ISO) Collaboration Statement HYPERTENSION Stergiou, G. S., Alpert, B., Mieke, S., Asmar, R., Atkins, N., Eckert, S., Frick, G., Friedman, B., Grassl, T., Ichikawa, T., Ioannidis, J. P., Lacy, P., McManus, R., Murray, A., Myers, M., Palatini, P., Parati, G., Quinn, D., Sarkis, J., Shennan, A., Usuda, T., Wang, J., Wu, C. O., O'Brien, E. 2018; 71 (3): 368–74

    Abstract

    In the past 30 years, several organizations, such as the US Association for the Advancement of Medical Instrumentation (AAMI), the British Hypertension Society, the European Society of Hypertension (ESH) Working Group on Blood Pressure (BP) Monitoring, and the International Organization for Standardization (ISO), have developed protocols for clinical validation of BP measuring devices. However, it is recognized that science, as well as patients, consumers, and manufacturers, would be best served if all BP measuring devices were assessed for accuracy according to an agreed single validation protocol that had global acceptance. Therefore, an international initiative was taken by the AAMI, ESH, and ISO experts who agreed to develop a universal standard for device validation. This statement presents the key aspects of a validation procedure, which were agreed by the AAMI, ESH, and ISO representatives as the basis for a single universal validation protocol. As soon as the AAMI/ESH/ISO standard is fully developed, this will be regarded as the single universal standard and will replace all other previous standards/protocols.

    View details for DOI 10.1161/HYPERTENSIONAHA.117.10237

    View details for Web of Science ID 000424444600003

    View details for PubMedID 29386350

  • Comparative evidence on harms in pediatric randomized clinical trials from less developed versus more developed countries is limited JOURNAL OF CLINICAL EPIDEMIOLOGY Tedesco, D., Farid-Kapadia, M., Offringa, M., Bhutta, Z. A., Maldonado, Y., Ioannidis, J. A., Contopoulos-Ioannidis, D. G. 2018; 95: 63–72

    Abstract

    Evaluate comparative harm rates from medical interventions in pediatric randomized clinical trials (RCTs) from more developed (MDCs) and less developed countries (LDCs).Meta-epidemiologic empirical evaluation of Cochrane Database of Systematic Reviews (June 2014) meta-analyses reporting clinically important harm-outcomes (severe adverse events [AEs], discontinuations due to AEs, any AE, and mortality) that included at least one pediatric RCT from MDCs and at least one from LDCs. We estimated relative odds ratios (RORs) for each harm, within each meta-analysis, between RCTs from MDCs and LDCs and calculated random-effects-summary-RORs (sRORs) for each harm across multiple meta-analyses.Only 1% (26/2,363) of meta-analyses with clinically important harm-outcomes in the entire Cochrane Database of Systematic Reviews included pediatric RCTs both from MDCs and LDCs. We analyzed 26 meta-analyses with 244 data sets from pediatric RCTs, 116 from MDCs and 128 from LDCs (64 and 66 unique RCTs respectively). The summary ROR was 0.92 (95% confidence intervals: 0.78-1.08) for severe AEs; 1.13 (0.54-2.34) for discontinuations due to AEs; 1.10 (0.77-1.59) for any AE; and 0.99 (0.61-1.61) for mortality and for the all-harms-combined-end point 0.96 (0.83-1.10). Differences of ROR-point-estimates ≥2-fold between MDCs and LDCs were identified in 35% of meta-analyses.We found no major systematic differences in harm rates in pediatric trials between MDCs and LDCs, but data on harms in children were overall very limited.

    View details for DOI 10.1016/j.jclinepi.2017.11.016

    View details for Web of Science ID 000427211500009

    View details for PubMedID 29191447

  • Evidence Based Medicine and Big Genomic Data. Human molecular genetics Ioannidis, J. P., Khoury, M. J. 2018

    Abstract

    Genomic and other related big data (Big Genomic Data, BGD for short) are ushering a new era of precision medicine. This overview discusses whether principles of evidence-based medicine (EBM) hold true for BGD and how they should be operationalized in the current era. Major EBM principles include the systematic identification, description and analysis of the validity and utility of BGD, the combination of individual clinical expertise with individual patient needs and preferences, and the focus on obtaining experimental evidence, whenever possible. BGD emphasize information of single patients with an overemphasis on N-of-1 trials to personalize treatment. However, large-scale comparative population data remain indispensable for meaningful translation of BGD personalized information. The impact of BGD on population health depends on its ability to affect large segments of the population. While several frameworks have been proposed to facilitate and standardize decision-making for use of genomic tests, there are new caveats that arise from BGD that extend beyond the limitations that were applicable for more simple genetic tests. Non-evidence-based use of BGD may be harmful and result in major waste of health care resources. Randomized controlled trials (RCTs) will continue to be the strongest arbitrator for the clinical utility of genomic technologies, including BGD. Research on BGD needs to focus not only on finding robust predictive associations (clinical validity), but more importantly on evaluating the balance of health benefits and potential harms (clinical utility), as well as implementation challenges. Appropriate features of such useful research on BGD are discussed.

    View details for DOI 10.1093/hmg/ddy065

    View details for PubMedID 29474574

  • Effect of Low-Fat vs Low-Carbohydrate Diet on 12-Month Weight Loss in Overweight Adults and the Association With Genotype Pattern or Insulin Secretion The DIETFITS Randomized Clinical Trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Gardner, C. D., Trepanowski, J. F., Del Gobbo, L. C., Hauser, M. E., Rigdon, J., Ioannidis, J. A., Desai, M., King, A. C. 2018; 319 (7): 667–79

    Abstract

    Dietary modification remains key to successful weight loss. Yet, no one dietary strategy is consistently superior to others for the general population. Previous research suggests genotype or insulin-glucose dynamics may modify the effects of diets.To determine the effect of a healthy low-fat (HLF) diet vs a healthy low-carbohydrate (HLC) diet on weight change and if genotype pattern or insulin secretion are related to the dietary effects on weight loss.The Diet Intervention Examining The Factors Interacting with Treatment Success (DIETFITS) randomized clinical trial included 609 adults aged 18 to 50 years without diabetes with a body mass index between 28 and 40. The trial enrollment was from January 29, 2013, through April 14, 2015; the date of final follow-up was May 16, 2016. Participants were randomized to the 12-month HLF or HLC diet. The study also tested whether 3 single-nucleotide polymorphism multilocus genotype responsiveness patterns or insulin secretion (INS-30; blood concentration of insulin 30 minutes after a glucose challenge) were associated with weight loss.Health educators delivered the behavior modification intervention to HLF (n = 305) and HLC (n = 304) participants via 22 diet-specific small group sessions administered over 12 months. The sessions focused on ways to achieve the lowest fat or carbohydrate intake that could be maintained long-term and emphasized diet quality.Primary outcome was 12-month weight change and determination of whether there were significant interactions among diet type and genotype pattern, diet and insulin secretion, and diet and weight loss.Among 609 participants randomized (mean age, 40 [SD, 7] years; 57% women; mean body mass index, 33 [SD, 3]; 244 [40%] had a low-fat genotype; 180 [30%] had a low-carbohydrate genotype; mean baseline INS-30, 93 μIU/mL), 481 (79%) completed the trial. In the HLF vs HLC diets, respectively, the mean 12-month macronutrient distributions were 48% vs 30% for carbohydrates, 29% vs 45% for fat, and 21% vs 23% for protein. Weight change at 12 months was -5.3 kg for the HLF diet vs -6.0 kg for the HLC diet (mean between-group difference, 0.7 kg [95% CI, -0.2 to 1.6 kg]). There was no significant diet-genotype pattern interaction (P = .20) or diet-insulin secretion (INS-30) interaction (P = .47) with 12-month weight loss. There were 18 adverse events or serious adverse events that were evenly distributed across the 2 diet groups.In this 12-month weight loss diet study, there was no significant difference in weight change between a healthy low-fat diet vs a healthy low-carbohydrate diet, and neither genotype pattern nor baseline insulin secretion was associated with the dietary effects on weight loss. In the context of these 2 common weight loss diet approaches, neither of the 2 hypothesized predisposing factors was helpful in identifying which diet was better for whom.clinicaltrials.gov Identifier: NCT01826591.

    View details for DOI 10.1001/jama.2018.0245

    View details for Web of Science ID 000425508400017

    View details for PubMedID 29466592

    View details for PubMedCentralID PMC5839290

  • Disclosures in Nutrition Research Why It Is Different JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. A., Trepanowski, J. F. 2018; 319 (6): 547–48

    View details for DOI 10.1001/jama.2017.18571

    View details for Web of Science ID 000424908400011

    View details for PubMedID 29222543

  • Data sharing and reanalysis of randomized controlled trials in leading biomedical journals with a full data sharing policy: survey of studies published in The BMJ and PLOS Medicine BMJ-BRITISH MEDICAL JOURNAL Naudet, F., Sakarovitch, C., Janiaud, P., Cristea, I., Fanelli, D., Moher, D., Ioannidis, J. A. 2018; 360: 1–11

    Abstract

    To explore the effectiveness of data sharing by randomized controlled trials (RCTs) in journals with a full data sharing policy and to describe potential difficulties encountered in the process of performing reanalyses of the primary outcomes.Survey of published RCTs.PubMed/Medline.RCTs that had been submitted and published by The BMJ and PLOS Medicine subsequent to the adoption of data sharing policies by these journals.The primary outcome was data availability, defined as the eventual receipt of complete data with clear labelling. Primary outcomes were reanalyzed to assess to what extent studies were reproduced. Difficulties encountered were described.37 RCTs (21 from The BMJ and 16 from PLOS Medicine) published between 2013 and 2016 met the eligibility criteria. 17/37 (46%, 95% confidence interval 30% to 62%) satisfied the definition of data availability and 14 of the 17 (82%, 59% to 94%) were fully reproduced on all their primary outcomes. Of the remaining RCTs, errors were identified in two but reached similar conclusions and one paper did not provide enough information in the Methods section to reproduce the analyses. Difficulties identified included problems in contacting corresponding authors and lack of resources on their behalf in preparing the datasets. In addition, there was a range of different data sharing practices across study groups.Data availability was not optimal in two journals with a strong policy for data sharing. When investigators shared data, most reanalyses largely reproduced the original results. Data sharing practices need to become more widespread and streamlined to allow meaningful reanalyses and reuse of data.Open Science Framework osf.io/c4zke.

    View details for DOI 10.1136/bmj.k400

    View details for Web of Science ID 000425582200001

    View details for PubMedID 29440066

    View details for PubMedCentralID PMC5809812

  • Off-label treatments were not consistently better or worse than approved drug treatments in randomized trials JOURNAL OF CLINICAL EPIDEMIOLOGY Ladanie, A., Ioannidis, J. A., Stafford, R. S., Ewald, H., Bucher, H. C., Hemkens, L. G. 2018; 94: 35–45

    Abstract

    Off-label drug use is highly prevalent but controversial and often discouraged assuming generally inferior medical effects associated with off-label use.We searched PubMed, MEDLINE, PubMed Health, and the Cochrane Library up to May 2015 for systematic reviews including meta-analyses of randomized clinical trials (RCTs) comparing off-label and approved drugs head-to-head in any population and on any medical outcome. We combined the comparative effects in meta-analyses providing summary odds ratios (sOR) for each treatment comparison and outcome, and then calculated an overall summary of the sOR across all comparisons (ssOR).We included 25 treatment comparisons with 153 RCTs and 24,592 patients. In six of 25 comparisons (24%), off-label drugs were significantly superior (five of 25) or inferior (one of 25) to approved treatments. There was substantial statistical heterogeneity across comparisons (I2 = 43%). Overall, off-label drugs were more favorable than approved treatments (ssOR 0.72; 95% CI = 0.54-0.95). Analyses of patient-relevant outcomes were similar (statistical significant differences in 24% (six of 25); ssOR 0.74; 95% CI = 0.56-0.98; I2 = 60%). Analyses of primary outcomes of the systematic reviews (n = 22 comparisons) indicated less heterogeneity and no statistically significant difference overall (ssOR 0.85; 95% CI = 0.67-1.06; I2 = 0%).Approval status does not reliably indicate which drugs are more favorable in situations with clinical trial evidence comparing off-label with approved use. Drug effectiveness assessments without considering off-label use may provide incomplete information. To ensure that patients receive the best available care, funding, policy, reimbursement, and treatment decisions should be evidence based considering the entire spectrum of available therapeutic choices.

    View details for DOI 10.1016/j.jclinepi.2017.11.006

    View details for Web of Science ID 000426025000006

    View details for PubMedID 29146289

  • What causes psychosis? An umbrella review of risk and protective factors WORLD PSYCHIATRY Radua, J., Ramella-Cravaro, V., Ioannidis, J. A., Reichenberg, A., Phiphopthatsanee, N., Amir, T., Thoo, H., Oliver, D., Davies, C., Morgan, C., McGuire, P., Murray, R. M., Fusar-Poli, P. 2018; 17 (1): 49–66

    Abstract

    Psychosis is a heterogeneous psychiatric condition for which a multitude of risk and protective factors have been suggested. This umbrella review aimed to classify the strength of evidence for the associations between each factor and psychotic disorders whilst controlling for several biases. The Web of Knowledge database was searched to identify systematic reviews and meta-analyses of observational studies which examined associations between socio-demographic, parental, perinatal, later factors or antecedents and psychotic disorders, and which included a comparison group of healthy controls, published from 1965 to January 31, 2017. The literature search and data extraction followed PRISMA and MOOSE guidelines. The association between each factor and ICD or DSM diagnoses of non-organic psychotic disorders was graded into convincing, highly suggestive, suggestive, weak, or non-significant according to a standardized classification based on: number of psychotic cases, random-effects p value, largest study 95% confidence interval, heterogeneity between studies, 95% prediction interval, small study effect, and excess significance bias. In order to assess evidence for temporality of association, we also conducted sensitivity analyses restricted to data from prospective studies. Fifty-five meta-analyses or systematic reviews were included in the umbrella review, corresponding to 683 individual studies and 170 putative risk or protective factors for psychotic disorders. Only the ultra-high-risk state for psychosis (odds ratio, OR=9.32, 95% CI: 4.91-17.72) and Black-Caribbean ethnicity in England (OR=4.87, 95% CI: 3.96-6.00) showed convincing evidence of association. Six factors were highly suggestive (ethnic minority in low ethnic density area, second generation immigrants, trait anhedonia, premorbid IQ, minor physical anomalies, and olfactory identification ability), and nine were suggestive (urbanicity, ethnic minority in high ethnic density area, first generation immigrants, North-African immigrants in Europe, winter/spring season of birth in Northern hemisphere, childhood social withdrawal, childhood trauma, Toxoplasma gondii IgG, and non-right handedness). When only prospective studies were considered, the evidence was convincing for ultra-high-risk state and suggestive for urbanicity only. In summary, this umbrella review found several factors to be associated with psychotic disorders with different levels of evidence. These risk or protective factors represent a starting point for further etiopathological research and for the improvement of the prediction of psychosis.

    View details for DOI 10.1002/wps.20490

    View details for Web of Science ID 000422959200016

    View details for PubMedID 29352556

    View details for PubMedCentralID PMC5775150

  • Beyond genomics: understanding exposotypes through metabolomics HUMAN GENOMICS Rattray, N. W., Deziel, N. C., Wallach, J. D., Khan, S. A., Vasiliou, V., Ioannidis, J. A., Johnson, C. H. 2018; 12: 4

    Abstract

    Over the past 20 years, advances in genomic technology have enabled unparalleled access to the information contained within the human genome. However, the multiple genetic variants associated with various diseases typically account for only a small fraction of the disease risk. This may be due to the multifactorial nature of disease mechanisms, the strong impact of the environment, and the complexity of gene-environment interactions. Metabolomics is the quantification of small molecules produced by metabolic processes within a biological sample. Metabolomics datasets contain a wealth of information that reflect the disease state and are consequent to both genetic variation and environment. Thus, metabolomics is being widely adopted for epidemiologic research to identify disease risk traits. In this review, we discuss the evolution and challenges of metabolomics in epidemiologic research, particularly for assessing environmental exposures and providing insights into gene-environment interactions, and mechanism of biological impact.Metabolomics can be used to measure the complex global modulating effect that an exposure event has on an individual phenotype. Combining information derived from all levels of protein synthesis and subsequent enzymatic action on metabolite production can reveal the individual exposotype. We discuss some of the methodological and statistical challenges in dealing with this type of high-dimensional data, such as the impact of study design, analytical biases, and biological variance. We show examples of disease risk inference from metabolic traits using metabolome-wide association studies. We also evaluate how these studies may drive precision medicine approaches, and pharmacogenomics, which have up to now been inefficient. Finally, we discuss how to promote transparency and open science to improve reproducibility and credibility in metabolomics.Comparison of exposotypes at the human population level may help understanding how environmental exposures affect biology at the systems level to determine cause, effect, and susceptibilities. Juxtaposition and integration of genomics and metabolomics information may offer additional insights. Clinical utility of this information for single individuals and populations has yet to be routinely demonstrated, but hopefully, recent advances to improve the robustness of large-scale metabolomics will facilitate clinical translation.

    View details for DOI 10.1186/s40246-018-0134-x

    View details for Web of Science ID 000423380700001

    View details for PubMedID 29373992

    View details for PubMedCentralID PMC5787293

  • Altmetric Scores, Citations, and Publication of Studies Posted as Preprints JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Serghiou, S., Ioannidis, J. A. 2018; 319 (4): 402–3

    View details for DOI 10.1001/jama.2017.21168

    View details for Web of Science ID 000423405300027

    View details for PubMedID 29362788

    View details for PubMedCentralID PMC5833561

  • Routinely collected data for randomized trials: promises, barriers, and implications TRIALS Mc Cord, K. A., Salman, R., Treweek, S., Gardner, H., Strech, D., Whiteley, W., Ioannidis, J. A., Hemkens, L. G. 2018; 19: 29

    Abstract

    Routinely collected health data (RCD) are increasingly used for randomized controlled trials (RCTs). This can provide three major benefits: increasing value through better feasibility (reducing costs, time, and resources), expanding the research agenda (performing trials for research questions otherwise not amenable to trials), and offering novel design and data collection options (e.g., point-of-care trials and other designs directly embedded in routine care). However, numerous hurdles and barriers must be considered pertaining to regulatory, ethical, and data aspects, as well as the costs of setting up the RCD infrastructure. Methodological considerations may be different from those in traditional RCTs: RCD are often collected by individuals not involved in the study and who are therefore blinded to the allocation of trial participants. Another consideration is that RCD trials may lead to greater misclassification biases or dilution effects, although these may be offset by randomization and larger sample sizes. Finally, valuable insights into external validity may be provided when using RCD because it allows pragmatic trials to be performed.We provide an overview of the promises, challenges, and potential barriers, methodological implications, and research needs regarding RCD for RCTs.RCD have substantial potential for improving the conduct and reducing the costs of RCTs, but a multidisciplinary approach is essential to address emerging practical barriers and methodological implications.Future research should be directed toward such issues and specifically focus on data quality validation, alternative research designs and how they affect outcome assessment, and aspects of reporting and transparency.

    View details for DOI 10.1186/s13063-017-2394-5

    View details for Web of Science ID 000422699300003

    View details for PubMedID 29325575

    View details for PubMedCentralID PMC5765645

  • Dynamics of co-authorship and productivity across different fields of scientific research PLOS ONE Parish, A. J., Boyack, K. W., Ioannidis, J. A. 2018; 13 (1): e0189742

    Abstract

    We aimed to assess which factors correlate with collaborative behavior and whether such behavior associates with scientific impact (citations and becoming a principal investigator). We used the R index which is defined for each author as log(Np)/log(I1), where I1 is the number of co-authors who appear in at least I1 papers written by that author and Np are his/her total papers. Higher R means lower collaborative behavior, i.e. not working much with others, or not collaborating repeatedly with the same co-authors. Across 249,054 researchers who had published ≥30 papers in 2000-2015 but had not published anything before 2000, R varied across scientific fields. Lower values of R (more collaboration) were seen in physics, medicine, infectious disease and brain sciences and higher values of R were seen for social science, computer science and engineering. Among the 9,314 most productive researchers already reaching Np ≥ 30 and I1 ≥ 4 by the end of 2006, R mostly remained stable for most fields from 2006 to 2015 with small increases seen in physics, chemistry, and medicine. Both US-based authorship and male gender were associated with higher values of R (lower collaboration), although the effect was small. Lower values of R (more collaboration) were associated with higher citation impact (h-index), and the effect was stronger in certain fields (physics, medicine, engineering, health sciences) than in others (brain sciences, computer science, infectious disease, chemistry). Finally, for a subset of 400 U.S. researchers in medicine, infectious disease and brain sciences, higher R (lower collaboration) was associated with a higher chance of being a principal investigator by 2016. Our analysis maps the patterns and evolution of collaborative behavior across scientific disciplines.

    View details for DOI 10.1371/journal.pone.0189742

    View details for Web of Science ID 000419689600014

    View details for PubMedID 29320509

    View details for PubMedCentralID PMC5761855

  • Diagnosis and Treatment of Hypertension in the 2017 ACC/AHA Guidelines and in the Real World JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. A. 2018; 319 (2): 115–16

    View details for DOI 10.1001/jama.2017.19672

    View details for Web of Science ID 000419775500006

    View details for PubMedID 29242891

  • The 10-Item Standardized Cosmesis and Health Nasal Outcomes Survey (SCHNOS) for Functional and Cosmetic Rhinoplasty JAMA FACIAL PLASTIC SURGERY Moubayed, S. P., Ioannidis, J. A., Saltychev, M., Most, S. P. 2018; 20 (1): 37–42

    Abstract

    Rhinoplasty is a common operation in which shape and function are intimately related, whether the procedure is cosmetic, functional, or combined in nature. There is currently no properly developed and validated patient-reported outcome measure (PROM) to evaluate both functional and cosmetic components of rhinoplasty.To develop, validate, and field test the Standardized Cosmesis and Health Nasal Outcomes Survey (SCHNOS) to evaluate both functional and cosmetic outcomes of rhinoplasty.Survey development study between October 2016 and April 2017 in a tertiary referral facial plastic and reconstructive surgery clinic. Preoperative and postoperative adult patients undergoing rhinoplasty, whether cosmetic or reconstructive, were included. A fifth group of adult nonrhinoplasty patients (facial cosmetic or reconstructive) were also included for the field test.Generated and reduced items, psychometric validation measures of the SCHNOS, and differences on scales between groups.For survey development, a total of 18 patients and 5 experts were interviewed. Of these patients, 5 were male, and 13 were female. Their mean (SD) age was 38 (14.8) years (range, 20-64 years). Field testing included 191 patients (67% were women and the mean [SD] age was 41.5 [15.8] years). A total of 10 items were included after generation, cognitive interviews, and item reduction. The 10 items represent 2 domains: nasal obstruction (first 4 items) and nasal cosmesis (last 6 items). For both domains, Cronbach α was excellent: 0.94 (95% CI, 0.92-0.95) for obstruction and 0.94 (95% CI, 0.93-0.95) for cosmesis. Exploratory factor analysis using scree plots for each domain showed that the domains are unidimensional in nature with each domain evaluating what it is intended to assess (nasal obstruction and cosmesis). The factor loading estimates were high for all the items, varying from 0.74 to 0.92. Kruskal-Wallis testing showed a significance level of P < .001 when evaluating the difference between groups (preoperative cosmetic, postoperative cosmetic, preoperative functional, postoperative functional, and nonrhinoplasty) for all individual questions, composite scores, and Nasal Obstruction Symptom Evaluation (NOSE) score. Correlations between the obstruction composite score and the NOSE scores were r = 0.943 (P < .001), which is very strong. The obstruction and cosmesis composite scores were only weakly correlated (r = 0.388; P < .001).We have developed and validated a new PROM to evaluate both functional and cosmetic rhinoplasty patients. The domains of obstruction and cosmesis were found to be internally consistent and unidimensional. The SCHNOS provides a short, validated questionnaire that we recommend for use in all functional or cosmetic rhinoplasty patients.N/A.

    View details for DOI 10.1001/jamafacial.2017.1083

    View details for Web of Science ID 000423037400007

    View details for PubMedID 28880988

    View details for PubMedCentralID PMC5833673

  • Populating the Data Ark: An attempt to retrieve, preserve, and liberate data from the most highly-cited psychology and psychiatry articles. PloS one Hardwicke, T. E., Ioannidis, J. P. 2018; 13 (8): e0201856

    Abstract

    The vast majority of scientific articles published to-date have not been accompanied by concomitant publication of the underlying research data upon which they are based. This state of affairs precludes the routine re-use and re-analysis of research data, undermining the efficiency of the scientific enterprise, and compromising the credibility of claims that cannot be independently verified. It may be especially important to make data available for the most influential studies that have provided a foundation for subsequent research and theory development. Therefore, we launched an initiative-the Data Ark-to examine whether we could retrospectively enhance the preservation and accessibility of important scientific data. Here we report the outcome of our efforts to retrieve, preserve, and liberate data from 111 of the most highly-cited articles published in psychology and psychiatry between 2006-2011 (n = 48) and 2014-2016 (n = 63). Most data sets were not made available (76/111, 68%, 95% CI [60, 77]), some were only made available with restrictions (20/111, 18%, 95% CI [10, 27]), and few were made available in a completely unrestricted form (15/111, 14%, 95% CI [5, 22]). Where extant data sharing systems were in place, they usually (17/22, 77%, 95% CI [54, 91]) did not allow unrestricted access. Authors reported several barriers to data sharing, including issues related to data ownership and ethical concerns. The Data Ark initiative could help preserve and liberate important scientific data, surface barriers to data sharing, and advance community discussions on data stewardship.

    View details for DOI 10.1371/journal.pone.0201856

    View details for PubMedID 30071110

  • Modelling science trustworthiness under publish or perish pressure ROYAL SOCIETY OPEN SCIENCE Grimes, D., Bauch, C. T., Ioannidis, J. A. 2018; 5 (1): 171511

    Abstract

    Scientific publication is immensely important to the scientific endeavour. There is, however, concern that rewarding scientists chiefly on publication creates a perverse incentive, allowing careless and fraudulent conduct to thrive, compounded by the predisposition of top-tier journals towards novel, positive findings rather than investigations confirming null hypothesis. This potentially compounds a reproducibility crisis in several fields, and risks undermining science and public trust in scientific findings. To date, there has been comparatively little modelling on factors that influence science trustworthiness, despite the importance of quantifying the problem. We present a simple phenomenological model with cohorts of diligent, careless and unethical scientists, with funding allocated by published outputs. This analysis suggests that trustworthiness of published science in a given field is influenced by false positive rate, and pressures for positive results. We find decreasing available funding has negative consequences for resulting trustworthiness, and examine strategies to combat propagation of irreproducible science.

    View details for DOI 10.1098/rsos.171511

    View details for Web of Science ID 000423777300068

    View details for PubMedID 29410855

    View details for PubMedCentralID PMC5792932

  • Potential Reporting Bias in Neuroimaging Studies of Sex Differences. Scientific reports David, S. P., Naudet, F., Laude, J., Radua, J., Fusar-Poli, P., Chu, I., Stefanick, M. L., Ioannidis, J. P. 2018; 8 (1): 6082

    Abstract

    Numerous functional magnetic resonance imaging (fMRI) studies have reported sex differences. To empirically evaluate for evidence of excessive significance bias in this literature, we searched for published fMRI studies of human brain to evaluate sex differences, regardless of the topic investigated, in Medline and Scopus over 10 years. We analyzed the prevalence of conclusions in favor of sex differences and the correlation between study sample sizes and number of significant foci identified. In the absence of bias, larger studies (better powered) should identify a larger number of significant foci. Across 179 papers, median sample size was n = 32 (interquartile range 23-47.5). A median of 5 foci related to sex differences were reported (interquartile range, 2-9.5). Few articles (n = 2) had titles focused on no differences or on similarities (n = 3) between sexes. Overall, 158 papers (88%) reached "positive" conclusions in their abstract and presented some foci related to sex differences. There was no statistically significant relationship between sample size and the number of foci (-0.048% increase for every 10 participants, p = 0.63). The extremely high prevalence of "positive" results and the lack of the expected relationship between sample size and the number of discovered foci reflect probable reporting bias and excess significance bias in this literature.

    View details for DOI 10.1038/s41598-018-23976-1

    View details for PubMedID 29666377

  • Redefine statistical significance NATURE HUMAN BEHAVIOUR Benjamin, D. J., Berger, J. O., Johannesson, M., Nosek, B. A., Wagenmakers, E., Berk, R., Bollen, K. A., Brembs, B., Brown, L., Camerer, C., Cesarini, D., Chambers, C. D., Clyde, M., Cook, T. D., De Boeck, P., Dienes, Z., Dreber, A., Easwaran, K., Efferson, C., Fehr, E., Fidler, F., Field, A. P., Forster, M., George, E. I., Gonzalez, R., Goodman, S., Green, E., Green, D. P., Greenwald, A., Hadfield, J. D., Hedges, L. V., Held, L., Ho, T., Hoijtink, H., Hruschka, D. J., Imai, K., Imbens, G., Ioannidis, J. A., Jeon, M., Jones, J., Kirchler, M., Laibson, D., List, J., Little, R., Lupia, A., Machery, E., Maxwell, S. E., McCarthy, M., Moore, D., Morgan, S. L., Munafo, M., Nakagawa, S., Nyhan, B., Parker, T. H., Pericchi, L., Perugini, M., Rouder, J., Rousseau, J., Savalei, V., Schoenbrodt, F. D., Sellke, T., Sinclair, B., Tingley, D., Van Zandt, T., Vazire, S., Watts, D. J., Winship, C., Wolpert, R. L., Xie, Y., Young, C., Zinman, J., Johnson, V. E. 2018; 2 (1): 6–10
  • Genome-wide association study identifies a locus associated with rotator cuff injury PLOS ONE Roos, T. R., Roos, A. K., Avins, A. L., Ahmed, M. A., Kleimeyer, J. P., Fredericson, M., Ioannidis, J. A., Dragoo, J. L., Kim, S. K. 2017; 12 (12): e0189317

    Abstract

    Rotator cuff tears are common, especially in the fifth and sixth decades of life, but can also occur in the competitive athlete. Genetic differences may contribute to overall injury risk. Identifying genetic loci associated with rotator cuff injury could shed light on the etiology of this injury. We performed a genome-wide association screen using publically available data from the Research Program in Genes, Environment and Health including 8,357 cases of rotator cuff injury and 94,622 controls. We found rs71404070 to show a genome-wide significant association with rotator cuff injury with p = 2.31x10-8 and an odds ratio of 1.25 per allele. This SNP is located next to cadherin8, which encodes a protein involved in cell adhesion. We also attempted to validate previous gene association studies that had reported a total of 18 SNPs showing a significant association with rotator cuff injury. However, none of the 18 SNPs were validated in our dataset. rs71404070 may be informative in explaining why some individuals are more susceptible to rotator cuff injury than others.

    View details for DOI 10.1371/journal.pone.0189317

    View details for Web of Science ID 000417648600044

    View details for PubMedID 29228018

    View details for PubMedCentralID PMC5724859

  • Greece: Crisis, smoking and tobacco conflicts in social media EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Ioannidis, J. A. 2017; 47 (12)

    View details for DOI 10.1111/eci.12841

    View details for Web of Science ID 000416334100003

    View details for PubMedID 28981138

  • Ethics and Epistemology in Big Data Research JOURNAL OF BIOETHICAL INQUIRY Lipworth, W., Mason, P. H., Kerridge, I., Ioannidis, J. A. 2017; 14 (4): 489–500
  • Overlapping network meta-analyses on the same topic: survey of published studies INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Naudet, F., Schuit, E., Ioannidis, J. A. 2017; 46 (6): 1999–2008

    Abstract

    To assess how common it is for a published network meta-analysis (NMA) to have other published overlapping NMAs, and to evaluate these overlaps.A total of 88 NMAs of randomized controlled trials evaluating the comparative effectiveness of health interventions were randomly selected. For each of these, we searched for NMAs on the same topic. A random sample of 40 pairs (an index NMA and one of its overlapping NMAs) was selected to assess the overlap in terms of nodes, treatments and references. The topic with the largest number of overlapping NMAs was described in depth.In all, 68 of the 88 index NMAs had at least one overlapping NMA: 77% [95% confidence interval (CI), 69-86%]. We identified 515 pairs of overlapping NMAs. Among the 40 randomly selected pairs, 73% (95% CI, 58-88%) of nodes, 79% (95% CI, 72-86%) of treatments and 48% (95% CI, 37-59%) of references included in the index NMAs were also found in the respective overlapping NMAs. Efficacy of biologics in rheumatoid arthritis had the largest number of overlapping NMAs, with 28 NMAs published between 2003 and 2014. Differences in selection and definition of nodes of treatments resulted in different network geometries. There were also differences in both the direction and the statistical significance of effects.Published NMAs exhibit extensive overlap and potential redundancy. Erratic retrieval of eligible trials, and lack of consensus on the range of interventions to be considered and how they might be merged or split in different nodes, may cause confusion.

    View details for DOI 10.1093/ije/dyx138

    View details for Web of Science ID 000417745100043

    View details for PubMedID 29040566

  • A Genetic Marker Associated with De Quervain's Tenosynovitis INTERNATIONAL JOURNAL OF SPORTS MEDICINE Kim, S. K., Ahmed, M. A., Avins, A. L., Ioannidis, J. A. 2017; 38 (12): 942–48

    Abstract

    De Quervain's tenosynovitis is a repetitive strain injury involving synovial inflammation of the tendons of the first extensor compartment of the wrist. It is relatively common in the general population, and is the most common radial-sided tendinopathy seen in athletes. Identifying a genetic marker associated with de Quervain's tenosynovitis could provide a useful tool to help identify those individuals with an increased risk for injury. A genome-wide association screen was performed using publically available data from the Research Program in Genes, Environment and Health (RPGEH) including 4,129 cases and 98,374 controls. rs35360670 on chromosome 8 showed an association with de Quervain's tenosynovitis at genome-wide significance (p=1.9×10-8; OR=1.46; 95% CI=1.38-1.59). This study is the first genome-wide screen for de Quervain's tenosynovitis and provides insights regarding its genetic etiology as well as a DNA marker with the potential to inform athletes and other high-risk individuals about their relative risk for injury.

    View details for DOI 10.1055/s-0043-116669

    View details for Web of Science ID 000418240600010

    View details for PubMedID 28985641

  • Immunogenicity and safety of the multicomponent meningococcal B vaccine (4CMenB): a meta-analysis Flacco, M. E., Manzoli, L., Rosso, A., Marzuillo, C., Bergamini, M., Stefanati, A., Villari, P., Ricciardi, W., Ioannidis, J. P., Contopoulos-Ioannidis, D. G. OXFORD UNIV PRESS. 2017
  • Exclusion of Elderly People from Randomized Clinical Trials of Drugs for Ischemic Heart Disease JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Bourgeois, F. T., Orenstein, L., Ballakur, S., Mandl, K. D., Ioannidis, J. A. 2017; 65 (11): 2354–61

    Abstract

    To measure exclusion of elderly adults from randomized trials studying drug interventions for ischemic heart disease (IHD) and describe the characteristics of these trials.Cross-sectional analysis.Interventional clinical trials studying a drug intervention for IHD that started in 2006 and after were identified in ClinicalTrials.gov. Data were extracted on study features, including age-based inclusion criteria. Data on participants and their age distribution were collected from trial publications, investigator inquiry, and result data in ClinicalTrials.gov.Individuals aged 65 and older.Proportion of trials excluding individuals based on age, mean age of trial participants, and proportion of enrolled participants aged 65 and older and 75 and older.Of 839 identified trials, 446 (53%) explicitly excluded elderly adults. The most-frequent upper age limits were 80 (n = 164) and 75 (n = 114), with a median upper age limit of 80 (interquartile range 75-80). Trials with upper age limit exclusions tended to be smaller (median number of participants 100 vs 201, P < .001) and were more likely to be funded primarily by nonindustry sources (78.3% vs 70.0%, P = .006). The overall mean age of trial participants was 62.7 (mean maximum age 74). The estimated proportion of participants aged 65 and older was 42.5% and the estimated proportion aged 75 and older was 12.3%.Despite the high burden of IHD in elderly adults, the majority of drug trials do not enroll participants reflective of age-related prevalence of the disease.

    View details for DOI 10.1111/jgs.14833

    View details for Web of Science ID 000417766900004

    View details for PubMedID 28306144

    View details for PubMedCentralID PMC5601009

  • How to survive the medical misinformation mess EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Ioannidis, J. A., Stuart, M. E., Brownlee, S., Strite, S. A. 2017; 47 (11): 795–802

    Abstract

    Most physicians and other healthcare professionals are unaware of the pervasiveness of poor quality clinical evidence that contributes considerably to overuse, underuse, avoidable adverse events, missed opportunities for right care and wasted healthcare resources. The Medical Misinformation Mess comprises four key problems. First, much published medical research is not reliable or is of uncertain reliability, offers no benefit to patients, or is not useful to decision makers. Second, most healthcare professionals are not aware of this problem. Third, they also lack the skills necessary to evaluate the reliability and usefulness of medical evidence. Finally, patients and families frequently lack relevant, accurate medical evidence and skilled guidance at the time of medical decision-making. Increasing the reliability of available, published evidence may not be an imminently reachable goal. Therefore, efforts should focus on making healthcare professionals, more sensitive to the limitations of the evidence, training them to do critical appraisal, and enhancing their communication skills so that they can effectively summarize and discuss medical evidence with patients to improve decision-making. Similar efforts may need to target also patients, journalists, policy makers, the lay public and other healthcare stakeholders.

    View details for DOI 10.1111/eci.12834

    View details for Web of Science ID 000417366100001

    View details for PubMedID 28881000

  • A comparison of bivariate, multivariate random-effects, and Poisson correlated gamma-frailty models to meta-analyze individual patient data of ordinal scale diagnostic tests BIOMETRICAL JOURNAL Simoneau, G., Levis, B., Cuijpers, P., Ioannidis, J. A., Patten, S. B., Shrier, I., Bombardier, C. H., Osorio, F., Fann, J. R., Gjerdingen, D., Lamers, F., Lotrakul, M., Loewe, B., Shaaban, J., Stafford, L., van Weert, H. M., Whooley, M. A., Wittkampf, K. A., Yeung, A. S., Thombs, B. D., Benedetti, A. 2017; 59 (6): 1317–38

    Abstract

    Individual patient data (IPD) meta-analyses are increasingly common in the literature. In the context of estimating the diagnostic accuracy of ordinal or semi-continuous scale tests, sensitivity and specificity are often reported for a given threshold or a small set of thresholds, and a meta-analysis is conducted via a bivariate approach to account for their correlation. When IPD are available, sensitivity and specificity can be pooled for every possible threshold. Our objective was to compare the bivariate approach, which can be applied separately at every threshold, to two multivariate methods: the ordinal multivariate random-effects model and the Poisson correlated gamma-frailty model. Our comparison was empirical, using IPD from 13 studies that evaluated the diagnostic accuracy of the 9-item Patient Health Questionnaire depression screening tool, and included simulations. The empirical comparison showed that the implementation of the two multivariate methods is more laborious in terms of computational time and sensitivity to user-supplied values compared to the bivariate approach. Simulations showed that ignoring the within-study correlation of sensitivity and specificity across thresholds did not worsen inferences with the bivariate approach compared to the Poisson model. The ordinal approach was not suitable for simulations because the model was highly sensitive to user-supplied starting values. We tentatively recommend the bivariate approach rather than more complex multivariate methods for IPD diagnostic accuracy meta-analyses of ordinal scale tests, although the limited type of diagnostic data considered in the simulation study restricts the generalization of our findings.

    View details for DOI 10.1002/bimj.201600184

    View details for Web of Science ID 000418746100014

    View details for PubMedID 28692782

  • Human Genome Sequencing at the Population Scale: A Primer on High-Throughput DNA Sequencing and Analysis AMERICAN JOURNAL OF EPIDEMIOLOGY Goldfeder, R. L., Wall, D. P., Khoury, M. J., Ioannidis, J. A., Ashley, E. A. 2017; 186 (8): 1000–1009

    Abstract

    Most human diseases have underlying genetic causes. To better understand the impact of genes on disease and its implications for medicine and public health, researchers have pursued methods for determining the sequences of individual genes, then all genes, and now complete human genomes. Massively parallel high-throughput sequencing technology, where DNA is sheared into smaller pieces, sequenced, and then computationally reordered and analyzed, enables fast and affordable sequencing of full human genomes. As the price of sequencing continues to decline, more and more individuals are having their genomes sequenced. This may facilitate better population-level disease subtyping and characterization, as well as individual-level diagnosis and personalized treatment and prevention plans. In this review, we describe several massively parallel high-throughput DNA sequencing technologies and their associated strengths, limitations, and error modes, with a focus on applications in epidemiologic research and precision medicine. We detail the methods used to computationally process and interpret sequence data to inform medical or preventative action.

    View details for DOI 10.1093/aje/kww224

    View details for Web of Science ID 000412798300013

    View details for PubMedID 29040395

  • THE POWER OF BIAS IN ECONOMICS RESEARCH ECONOMIC JOURNAL Ioannidis, J. A., Stanley, T. D., Doucouliagos, H. 2017; 127 (605): F236–F265

    View details for DOI 10.1111/ecoj.12461

    View details for Web of Science ID 000418017100011

  • Next-generation systematic reviews: prospective meta-analysis, individual-level data, networks and umbrella reviews BRITISH JOURNAL OF SPORTS MEDICINE Ioannidis, J. 2017; 51 (20): 1456–58

    View details for DOI 10.1136/bjsports-2017-097621

    View details for Web of Science ID 000412656200007

    View details for PubMedID 28223307

  • Two genetic loci associated with ankle injury PLOS ONE Kim, S. K., Kleimeyer, J. P., Ahmed, M. A., Avins, A. L., Fredericson, M., Dragoo, J. L., Ioannidis, J. A. 2017; 12 (9): e0185355

    Abstract

    Ankle injuries, including sprains, strains and other joint derangements and instability, are common, especially for athletes involved in indoor court or jumping sports. Identifying genetic loci associated with these ankle injuries could shed light on their etiologies. A genome-wide association screen was performed using publicly available data from the Research Program in Genes, Environment and Health (RPGEH) including 1,694 cases of ankle injury and 97,646 controls. An indel (chr21:47156779:D) that lies close to a collagen gene, COL18A1, showed an association with ankle injury at genome-wide significance (p = 3.8x10-8; OR = 1.99; 95% CI = 1.75-2.23). A second DNA variant (rs13286037 on chromosome 9) that lies within an intron of the transcription factor gene NFIB showed an association that was nearly genome-wide significant (p = 5.1x10-8; OR = 1.63; 95% CI = 1.46-1.80). The ACTN3 R577X mutation was previously reported to show an association with acute ankle sprains, but did not show an association in this cohort. This study is the first genome-wide screen for ankle injury that yields insights regarding the genetic etiology of ankle injuries and provides DNA markers with the potential to inform athletes about their genetic risk for ankle injury.

    View details for DOI 10.1371/journal.pone.0185355

    View details for Web of Science ID 000411985200050

    View details for PubMedID 28957384

    View details for PubMedCentralID PMC5619760

  • Systematic reviews: guidance relevant for studies of older people AGE AND AGEING Shenkin, S. D., Harrison, J. K., Wilkinson, T., Dodds, R. M., Ioannidis, J. A. 2017; 46 (5): 722–28

    Abstract

    Systematic reviews and meta-analyses are increasingly common. This article aims to provide guidance for people conducting systematic reviews relevant to the healthcare of older people. An awareness of these issues will also help people reading systematic reviews to determine whether the results will influence their clinical practice. It is essential that systematic reviews are performed by a team which includes the required technical and clinical expertise. Those performing reviews for the first time should ensure they have appropriate training and support. They must be planned and performed in a transparent and methodologically robust way: guidelines are available. The protocol should be written-and if possible published-before starting the review. Geriatricians will be interested in a table of baseline characteristics, which will help to determine if the studied samples or populations are similar to their patients. Reviews of studies of older people should consider how they will manage issues such as different age cut-offs; non-specific presentations; multiple predictors and outcomes; potential biases and confounders. Systematic reviews and meta-analyses may provide evidence to improve older people's care, or determine where new evidence is required. Newer methodologies, such as meta-analyses of individual level data, network meta-analyses and umbrella reviews, and realist synthesis, may improve the reliability and clinical utility of systematic reviews.

    View details for DOI 10.1093/ageing/afx105

    View details for Web of Science ID 000408341000007

    View details for PubMedID 28655142

    View details for PubMedCentralID PMC5860219

  • When Null Hypothesis Significance Testing Is Unsuitable for Research: A Reassessment FRONTIERS IN HUMAN NEUROSCIENCE Szucs, D., Ioannidis, J. A. 2017; 11: 390

    Abstract

    Null hypothesis significance testing (NHST) has several shortcomings that are likely contributing factors behind the widely debated replication crisis of (cognitive) neuroscience, psychology, and biomedical science in general. We review these shortcomings and suggest that, after sustained negative experience, NHST should no longer be the default, dominant statistical practice of all biomedical and psychological research. If theoretical predictions are weak we should not rely on all or nothing hypothesis tests. Different inferential methods may be most suitable for different types of research questions. Whenever researchers use NHST they should justify its use, and publish pre-study power calculations and effect sizes, including negative findings. Hypothesis-testing studies should be pre-registered and optimally raw data published. The current statistics lite educational approach for students that has sustained the widespread, spurious use of NHST should be phased out.

    View details for DOI 10.3389/fnhum.2017.00390

    View details for Web of Science ID 000407070000001

    View details for PubMedID 28824397

    View details for PubMedCentralID PMC5540883

  • Inconsistent Guideline Recommendations for Cardiovascular Prevention and the Debate About Zeroing in on and Zeroing LDL-C Levels With PCSK9 Inhibitors JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. A. 2017; 318 (5): 419–20

    View details for DOI 10.1001/jama.2017.6765

    View details for Web of Science ID 000406659800008

    View details for PubMedID 28738115

  • A meta-analysis of individual participant data constructed to align with prior expert views: comments on Bhupathiraju et al JOURNAL OF CLINICAL EPIDEMIOLOGY Flegal, K. M., Ioannidis, J. A. 2017; 88: 33–36
  • A meta-analysis but not a systematic review: an evaluation of the Global BMI Mortality Collaboration JOURNAL OF CLINICAL EPIDEMIOLOGY Flegal, K. M., Ioannidis, J. A. 2017; 88: 21–29

    Abstract

    Meta-analyses of individual participant data (MIPDs) offer many advantages and are considered the highest level of evidence. However, MIPDs can be seriously compromised when they are not solidly founded upon a systematic review. These data-intensive collaborative projects may be led by experts who already have deep knowledge of the literature in the field and of the results of published studies and how these results vary based on different analytical approaches. If investigators tailor the searches, eligibility criteria, and analysis plan of the MIPD, they run the risk of reaching foregone conclusions. We exemplify this potential bias in a MIPD on the association of body mass index with mortality conducted by a collaboration of outstanding and extremely knowledgeable investigators. Contrary to a previous meta-analysis of group data that used a systematic review approach, the MIPD did not seem to use a formal search: it considered 239 studies, of which the senior author was previously aware of at least 238, and it violated its own listed eligibility criteria to include those studies and exclude other studies. It also preferred an analysis plan that was also known to give a specific direction of effects in already published results of most of the included evidence. MIPDs where results of constituent studies are already largely known need safeguards to their validity. These may include careful systematic searches, adherence to the Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data guidelines, and exploration of the robustness of results with different analyses. They should also avoid selective emphasis on foregone conclusions based on previously known results with specific analytical choices.

    View details for DOI 10.1016/j.jclinepi.2017.04.007

    View details for Web of Science ID 000411916500005

    View details for PubMedID 28435099

  • Enhancing the usability of systematic reviews by improving the consideration and description of interventions BMJ-BRITISH MEDICAL JOURNAL Hoffmann, T. C., Oxman, A. D., Ioannidis, J. A., Moher, D., Lasserson, T. J., Tovey, D. I., Stein, K., Sutcliffe, K., Ravaud, P., Altman, D. G., Perera, R., Glasziou, P. 2017; 358: j2998

    View details for DOI 10.1136/bmj.j2998

    View details for Web of Science ID 000406318500001

    View details for PubMedID 28729459

  • Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness NATURE COMMUNICATIONS Willems, S. M., Wright, D. J., Day, F. R., Trajanoska, K., Joshi, P. K., Morris, J. A., Matteini, A. M., Garton, F. C., Grarup, N., Oskolkov, N., Thalamuthu, A., Mangino, M., Liu, J., Demirkan, A., Lek, M., Xu, L., Wang, G., Oldmeadow, C., Gaulton, K. J., Lotta, L. A., Miyamoto-Mikami, E., Rivas, M. A., White, T., Loh, P., Aadahl, M., Amin, N., Attia, J. R., Austin, K., Benyamin, B., Brage, S., Cheng, Y., Cieszczyk, P., Derave, W., Eriksson, K., Eynon, N., Linneberg, A., Lucia, A., Massidda, M., Mitchell, B. D., Miyachi, M., Murakami, H., Padmanabhan, S., Pandey, A., Papadimitriou, L., Rajpal, D. K., Sale, C., Schnurr, T. M., Sessa, F., Shrine, N., Tobin, M. D., Varley, I., Wain, L. V., Wray, N. R., Lindgren, C. M., MacArthur, D. G., Waterworth, D. M., McCarthy, M. I., Pedersen, O., Khaw, K., Kie, D. P., Pitsiladis, Y., Fuku, N., Franks, P. W., North, K. N., van Duijn, C. M., Mather, K. A., Hansen, T., Hansson, O., Spector, T., Murabito, J. M., Richards, J., Rivadeneira, F., Langenberg, C., Perry, J. B., Wareham, N. J., Scott, R. A., GEFOS Anytype Fracture Consortium 2017; 8: 16015

    Abstract

    Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10-8) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.

    View details for DOI 10.1038/ncomms16015

    View details for Web of Science ID 000405270700002

    View details for PubMedID 29313844

    View details for PubMedCentralID PMC5510175

  • Drivers of poor medical care LANCET Saini, V., Garcia-Armesto, S., Klemperer, D., Paris, V., Elshaug, A. G., Brownlee, S., Ioannidis, J. A., Fisher, E. S. 2017; 390 (10090): 178–90

    Abstract

    The global ubiquity of overuse and underuse of health-care resources and the gravity of resulting harms necessitate an investigation of drivers to inform potential solutions. We describe the network of influences that contribute to poor care and suggest that it is driven by factors that fall into three domains: money and finance; knowledge, bias, and uncertainty; and power and human relationships. In each domain the drivers operate at the global, national, regional, and individual level, and are modulated by the specific contexts within which they act. We discuss in detail drivers of poor care in each domain.

    View details for DOI 10.1016/S0140-6736(16)30947-3

    View details for Web of Science ID 000404976600035

    View details for PubMedID 28077235

  • Perspective: Improving Nutritional Guidelines for Sustainable Health Policies: Current Status and Perspectives ADVANCES IN NUTRITION Magni, P., Bier, D. M., Pecorelli, S., Agostoni, C., Astrup, A., Brighenti, F., Cook, R., Folco, E., Fontana, L., Gibson, R. A., Guerra, R., Guyatt, G. H., Ioannidis, J. A., Jackson, A. S., Klurfeld, D. M., Makrides, M., Mathioudakis, B., Monaco, A., Patel, C. J., Racagni, G., Schunemann, H. J., Shamir, R., Zmora, N., Peracino, A. 2017; 8 (4): 532–45

    Abstract

    A large body of evidence supports the notion that incorrect or insufficient nutrition contributes to disease development. A pivotal goal is thus to understand what exactly is appropriate and what is inappropriate in food ingestion and the consequent nutritional status and health. The effective application of these concepts requires the translation of scientific information into practical approaches that have a tangible and measurable impact at both individual and population levels. The agenda for the future is expected to support available methodology in nutrition research to personalize guideline recommendations, properly grading the quality of the available evidence, promoting adherence to the well-established evidence hierarchy in nutrition, and enhancing strategies for appropriate vetting and transparent reporting that will solidify the recommendations for health promotion. The final goal is to build a constructive coalition among scientists, policy makers, and communication professionals for sustainable health and nutritional policies. Currently, a strong rationale and available data support a personalized dietary approach according to personal variables, including sex and age, circulating metabolic biomarkers, food quality and intake frequency, lifestyle variables such as physical activity, and environmental variables including one's microbiome profile. There is a strong and urgent need to develop a successful commitment among all the stakeholders to define novel and sustainable approaches toward the management of the health value of nutrition at individual and population levels. Moving forward requires adherence to well-established principles of evidence evaluation as well as identification of effective tools to obtain better quality evidence. Much remains to be done in the near future.

    View details for DOI 10.3945/an.116.014738

    View details for Web of Science ID 000406567000002

    View details for PubMedID 28710141

    View details for PubMedCentralID PMC5502870

  • Defending Biomedical Science in an Era of Threatened Funding JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. A. 2017; 317 (24): 2483–84

    View details for DOI 10.1001/jama.2017.5811

    View details for Web of Science ID 000404106600014

    View details for PubMedID 28459974

  • Nonreproducibility of Preclinical Research Reply JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. A. 2017; 317 (23): 2453

    View details for DOI 10.1001/jama.2017.5987

    View details for Web of Science ID 000403654600023

    View details for PubMedID 28632861

  • Serum uric acid levels and multiple health outcomes: umbrella review of evidence from observational studies, randomised controlled trials, and Mendelian randomisation studies BMJ-BRITISH MEDICAL JOURNAL Li, X., Meng, X., Timofeeva, M., Tzoulaki, I., Tsilidis, K. K., Ioannidis, P. A., Campbell, H., Theodoratou, E. 2017; 357: j2376

    Abstract

    Objective To map the diverse health outcomes associated with serum uric acid (SUA) levels.Design Umbrella review.Data sources Medline, Embase, Cochrane Database of Systematic Reviews, and screening of citations and references.Eligibility criteria Systematic reviews and meta-analyses of observational studies that examined associations between SUA level and health outcomes, meta-analyses of randomised controlled trials that investigated health outcomes related to SUA lowering treatment, and Mendelian randomisation studies that explored the causal associations of SUA level with health outcomes.Results 57 articles reporting 15 systematic reviews and144 meta-analyses of observational studies (76 unique outcomes), 8 articles reporting 31 meta-analyses of randomised controlled trials (20 unique outcomes), and 36 articles reporting 107 Mendelian randomisation studies (56 unique outcomes) met the eligibility criteria. Across all three study types, 136 unique health outcomes were reported. 16 unique outcomes in meta-analyses of observational studies had P<10-6, 8 unique outcomes in meta-analyses of randomised controlled trials had P<0.001, and 4 unique outcomes in Mendelian randomisation studies had P<0.01. Large between study heterogeneity was common (80% and 45% in meta-analyses of observational studies and of randomised controlled trials, respectively). 42 (55%) meta-analyses of observational studies and 7 (35%) meta-analyses of randomised controlled trials showed evidence of small study effects or excess significance bias. No associations from meta-analyses of observational studies were classified as convincing; five associations were classified as highly suggestive (increased risk of heart failure, hypertension, impaired fasting glucose or diabetes, chronic kidney disease, coronary heart disease mortality with high SUA levels). Only one outcome from randomised controlled trials (decreased risk of nephrolithiasis recurrence with SUA lowering treatment) had P<0.001, a 95% prediction interval excluding the null, and no large heterogeneity or bias. Only one outcome from Mendelian randomisation studies (increased risk of gout with high SUA levels) presented convincing evidence. Hypertension and chronic kidney disease showed concordant evidence in meta-analyses of observational studies, and in some (but not all) meta-analyses of randomised controlled trials with respective intermediate or surrogate outcomes, but they were not statistically significant in Mendelian randomisation studies.Conclusion Despite a few hundred systematic reviews, meta-analyses, and Mendelian randomisation studies exploring 136 unique health outcomes, convincing evidence of a clear role of SUA level only exists for gout and nephrolithiasis.

    View details for DOI 10.1136/bmj.j2376

    View details for Web of Science ID 000403221400001

    View details for PubMedID 28592419

    View details for PubMedCentralID PMC5461476

  • Timing and Characteristics of Cumulative Evidence Available on Novel Therapeutic Agents Receiving Food and Drug Administration Accelerated Approval MILBANK QUARTERLY Naci, H., Wouters, O. J., Gupta, R., Ioannidis, J. A. 2017; 95 (2): 261–90

    Abstract

    Policy Points: Randomized trials-the gold standard of evaluating effectiveness-constitute a small minority of existing evidence on agents given accelerated approval. One-third of randomized trials are in therapeutic areas outside of FDA approval and less than half evaluate the therapeutic benefits of these agents but use them instead as common backbone treatments. Agents receiving accelerated approval are often tested concurrently in several therapeutic areas. For most agents, no substantial time lag is apparent between the average start dates of randomized trials evaluating their effectiveness and those using them as part of background therapies. There appears to be a tendency for therapeutic agents receiving accelerated approval to quickly become an integral component of standard treatment, despite potential shortcomings in their evidence base.Therapeutic agents treating serious conditions are eligible for Food and Drug Administration (FDA) accelerated approval. The clinical evidence accrued on agents receiving accelerated approval has not been systematically evaluated. Our objective was to assess the timing and characteristics of available studies.We first identified clinical studies of novel therapeutic agents receiving accelerated approval. We then (1) categorized those studies as randomized or nonrandomized, (2) explored whether they evaluated the FDA-approved indications, and (3) documented the available treatment comparisons. We also meta-analyzed the difference in start times between randomized studies that (1) did or did not evaluate approved indications and (2) were or were not designed to evaluate the agent's effectiveness.In total, 37 novel therapeutic agents received accelerated approval between 2000 and 2013. Our search of ClinicalTrials.gov identified 7,757 studies, which included 1,258,315 participants. Only one-third of identified studies were randomized controlled trials. Of 1,631 randomized trials with advanced recruitment status, 906 were conducted in therapeutic areas for which agents received initial accelerated approval, 202 were in supplemental indications, and 523 were outside approved indications. Only 411 out of 906 (45.4%) trials were designed to test the effectiveness of agents that received accelerated approval ("evaluation" trials); others used these agents as common background treatment in both arms ("background" trials). There was no detectable lag between average start times of trials conducted within and outside initially approved indications. Evaluation trials started on average 1.52 years (95% CI: 0.87 to 2.17) earlier than background trials.Cumulative evidence on agents with accelerated approvals has major limitations. Most clinical studies including these agents are small and nonrandomized, and about a third are conducted in unapproved areas, typically concurrently with those conducted in approved areas. Most randomized trials including these therapeutic agents are not designed to directly evaluate their clinical benefits but to incorporate them as standard treatment.

    View details for DOI 10.1111/1468-0009.12261

    View details for Web of Science ID 000402994600011

    View details for PubMedID 28589600

    View details for PubMedCentralID PMC5461381

  • International journal of sports medicine Kim, S., Kleimeyer, J. P., Ahmed, M. A., Avins, A. L., Fredericson, M., Dragoo, J. L., Ioannidis, J. P. 2017

    Abstract

    Shoulder dislocations are common shoulder injuries associated with athletic activity in contact sports, such as football, rugby, wrestling, and hockey. Identifying genetic loci associated with shoulder dislocation could shed light on underlying mechanisms for injury and identify predictive genetic markers. To identify DNA polymorphisms associated with shoulder dislocation, a genome-wide association screen was performed using publically available data from the Research Program in Genes, Environment and Health including 662 cases of shoulder dislocation and 82 602 controls from the European ancestry group. rs12913965 showed an association with shoulder dislocation at genome-wide significance (p=9.7×10(-9); odds ratio=1.6) from the European ancestry group. Individuals carrying one copy of the risk allele (T) at rs12913965 showed a 69% increased risk for shoulder dislocation in our cohort. rs12913965 is located within an intron of the TICRR gene, which encodes TOPBP1 interacting checkpoint and replication regulator involved in the cell cycle. rs12913965 is also associated with changes in expression of the ISG20 gene, which encodes an antiviral nuclease induced by interferons. This genetic marker may one day be used to identify athletes with a higher genetic risk for shoulder dislocation. It will be important to replicate this finding in future studies.

    View details for DOI 10.1055/s-0043-106190

    View details for PubMedID 28521375

  • Selective Cutoff Reporting in Studies of Diagnostic Test Accuracy: A Comparison of Conventional and Individual-Patient-Data Meta-Analyses of the Patient Health Questionnaire-9 Depression Screening Tool AMERICAN JOURNAL OF EPIDEMIOLOGY Levis, B., Benedetti, A., Levis, A. W., Ioannidis, J. A., Shrier, I., Cuijpers, P., Gilbody, S., Kloda, L. A., McMillan, D., Patten, S. B., Steele, R. J., Ziegelstein, R. C., Bombardier, C. H., Osorio, F., Fann, J. R., Gjerdingen, D., Lamers, F., Lotrakul, M., Loureiro, S. R., Lowe, B., Shaaban, J., Stafford, L., van Weert, H. M., Whooley, M. A., Williams, L. S., Wittkampf, K. A., Yeung, A. S., Thombs, B. D. 2017; 185 (10): 954–64

    Abstract

    In studies of diagnostic test accuracy, authors sometimes report results only for a range of cutoff points around data-driven "optimal" cutoffs. We assessed selective cutoff reporting in studies of the diagnostic accuracy of the Patient Health Questionnaire-9 (PHQ-9) depression screening tool. We compared conventional meta-analysis of published results only with individual-patient-data meta-analysis of results derived from all cutoff points, using data from 13 of 16 studies published during 2004-2009 that were included in a published conventional meta-analysis. For the "standard" PHQ-9 cutoff of 10, accuracy results had been published by 11 of the studies. For all other relevant cutoffs, 3-6 studies published accuracy results. For all cutoffs examined, specificity estimates in conventional and individual-patient-data meta-analyses were within 1% of each other. Sensitivity estimates were similar for the cutoff of 10 but differed by 5%-15% for other cutoffs. In samples where the PHQ-9 was poorly sensitive at the standard cutoff, authors tended to report results for lower cutoffs that yielded optimal results. When the PHQ-9 was highly sensitive, authors more often reported results for higher cutoffs. Consequently, in the conventional meta-analysis, sensitivity increased as cutoff severity increased across part of the cutoff range-an impossibility if all data are analyzed. In sum, selective reporting by primary study authors of only results from cutoffs that perform well in their study can bias accuracy estimates in meta-analyses of published results.

    View details for DOI 10.1093/aje/kww191

    View details for Web of Science ID 000401938300013

    View details for PubMedID 28419203

    View details for PubMedCentralID PMC5430941

  • Finding the power to reduce publication bias STATISTICS IN MEDICINE STANLEY, T. D., Doucouliagos, H., Ioannidis, J. P. 2017; 36 (10): 1580-1598

    Abstract

    The central purpose of this study is to document how a sharper focus upon statistical power may reduce the impact of selective reporting bias in meta-analyses. We introduce the weighted average of the adequately powered (WAAP) as an alternative to the conventional random-effects (RE) estimator. When the results of some of the studies have been selected to be positive and statistically significant (i.e. selective reporting), our simulations show that WAAP will have smaller bias than RE at no loss to its other statistical properties. When there is no selective reporting, the difference between RE's and WAAP's statistical properties is practically negligible. Nonetheless, when selective reporting is especially severe or heterogeneity is very large, notable bias can remain in all weighted averages. The main limitation of this approach is that the majority of meta-analyses of medical research do not contain any studies with adequate power (i.e. >80%). For such areas of medical research, it remains important to document their low power, and, as we demonstrate, an alternative unrestricted weighted least squares weighted average can be used instead of WAAP. Copyright © 2017 John Wiley & Sons, Ltd.

    View details for DOI 10.1002/sim.7228

    View details for Web of Science ID 000398518600005

    View details for PubMedID 28127782

  • Two Genetic Loci associated with Medial Collateral Ligament Injury. International journal of sports medicine Roos, A. K., Avins, A. L., Ahmed, M. A., Kleimeyer, J. P., Roos, T. R., Fredericson, M., Ioannidis, J. P., Dragoo, J. L., Kim, S. 2017

    Abstract

    Medial collateral ligament (MCL) injuries are a common knee injury, especially in competitive athletes. Identifying genetic loci associated with MCL injury could shed light on its etiology. A genome-wide association screen was performed using data from the Research Program in Genes, Environment and Health (RPGEH) including 1 572 cases of MCL injury and 100 931 controls. 2 SNPs (rs80351309 and rs6083471) showed an association with MCL injury at genome-wide significance (p<5×10(-8)) with moderate effects (odds ratios=2.12 and 1.57, respectively). For rs80351309, the genotypes were imputed with only moderate accuracy, so this SNP should be viewed with caution until its association with MCL injury can be validated. The SNPs rs80351309 and rs6083471 show a statistically significant association with MCL injury. It will be important to replicate this finding in future studies.

    View details for DOI 10.1055/s-0043-104853

    View details for PubMedID 28482362

  • The Reproducibility Wars: Successful, Unsuccessful, Uninterpretable, Exact, Conceptual, Triangulated, Contested Replication CLINICAL CHEMISTRY Ioannidis, J. A. 2017; 63 (5): 943–45

    View details for DOI 10.1373/clinchem.2017.271965

    View details for Web of Science ID 000401951900003

    View details for PubMedID 28298413

  • Waste, Leaks, and Failures in the Biomarker Pipeline CLINICAL CHEMISTRY Ioannidis, J. A., Bossuyt, P. M. 2017; 63 (5): 963–72

    Abstract

    The large, expanding literature on biomarkers is characterized by almost ubiquitous significant results, with claims about the potential importance, but few of these discovered biomarkers are used in routine clinical care.The pipeline of biomarker development includes several specific stages: discovery, validation, clinical translation, evaluation, implementation (and, in the case of nonutility, deimplementation). Each of these stages can be plagued by problems that cause failures of the overall pipeline. Some problems are nonspecific challenges for all biomedical investigation, while others are specific to the peculiarities of biomarker research. Discovery suffers from poor methods and incomplete and selective reporting. External independent validation is limited. Selection for clinical translation is often shaped by nonrational choices. Evaluation is sparse and the clinical utility of many biomarkers remains unknown. The regulatory environment for biomarkers remains weak and guidelines can reach biased or divergent recommendations. Removing inefficient or even harmful biomarkers that have been entrenched in clinical care can meet with major resistance.The current biomarker pipeline is too prone to failures. Consideration of clinical needs should become a starting point for the development of biomarkers. Improvements can include the use of more stringent methodology, better reporting, larger collaborative studies, careful external independent validation, preregistration, rigorous systematic reviews and umbrella reviews, pivotal randomized trials, and implementation and deimplementation studies. Incentives should be aligned toward delivering useful biomarkers.

    View details for DOI 10.1373/clinchem.2016.254649

    View details for Web of Science ID 000401951900009

    View details for PubMedID 28270433

  • Systematic evaluation of the associations between environmental risk factors and dementia: An umbrella review of systematic reviews and meta-analyses ALZHEIMERS & DEMENTIA Bellou, V., Belbasis, L., Tzoulaki, I., Middleton, L. T., Ioannidis, J. P., Evangelou, E. 2017; 13 (4): 406-418

    Abstract

    Dementia is a heterogeneous neurodegenerative disease, whose etiology results from a complex interplay between environmental and genetic factors.We searched PubMed to identify meta-analyses of observational studies that examined associations between nongenetic factors and dementia. We estimated the summary effect size using random-effects and fixed-effects model, the 95% CI, and the 95% prediction interval. We assessed the between-study heterogeneity (I-square), evidence of small-study effects, and excess significance.A total of 76 unique associations were examined. By applying standardized criteria, seven associations presented convincing evidence. These associations pertained to benzodiazepines use, depression at any age, late-life depression, and frequency of social contacts for all types of dementia; late-life depression for Alzheimer's disease; and type 2 diabetes mellitus for vascular dementia and Alzheimer's disease.Several risk factors present substantial evidence for association with dementia and should be assessed as potential targets for interventions, but these associations may not necessarily be causal.

    View details for DOI 10.1016/j.jalz.2016.07.152

    View details for Web of Science ID 000398565000005

  • Meta-analyses Can Be Credible and Useful A New Standard JAMA PSYCHIATRY Ioannidis, J. A. 2017; 74 (4): 311–12
  • The credibility crisis in research: Can economics tools help? PLOS BIOLOGY Gall, T., Ioannidis, J. A., Maniadis, Z. 2017; 15 (4): e2001846

    Abstract

    The issue of nonreplicable evidence has attracted considerable attention across biomedical and other sciences. This concern is accompanied by an increasing interest in reforming research incentives and practices. How to optimally perform these reforms is a scientific problem in itself, and economics has several scientific methods that can help evaluate research reforms. Here, we review these methods and show their potential. Prominent among them are mathematical modeling and laboratory experiments that constitute affordable ways to approximate the effects of policies with wide-ranging implications.

    View details for DOI 10.1371/journal.pbio.2001846

    View details for Web of Science ID 000400423600020

    View details for PubMedID 28445470

    View details for PubMedCentralID PMC5405914

  • Hijacked evidence-based medicine: stay the course and throw the pirates overboard JOURNAL OF CLINICAL EPIDEMIOLOGY Ioannidis, J. A. 2017; 84: 11–13

    Abstract

    The article discusses a number of criticisms that have been raised against evidence-based medicine, such as focusing on benefits and ignoring adverse events; being interested in averages and ignoring the wide variability in individual risks and responsiveness; ignoring clinician-patient interaction and clinical judgement; leading to some sort of reductionism; and falling prey to corruption from conflicts of interest. I argue that none of these deficiencies are necessarily inherent to evidence-based medicine. In fact, work in evidence-based medicine has contributed a lot towards minimizing these deficiencies in medical research and medical care. However, evidence-based medicine is paying the price of its success: having become more widely recognized, it is manipulated and misused to support subverted or perverted agendas that are hijacking its reputation value. Sometimes the conflicts behind these agendas are so strong that one worries about whether the hijacking of evidence-based medicine is reversible. Nevertheless, evidence-based medicine is a valuable conceptual toolkit and it is worth to try to remove the biases of the pirates who have hijacked its ship.

    View details for DOI 10.1016/j.jclinepi.2017.02.001

    View details for Web of Science ID 000402849500004

    View details for PubMedID 28532611

  • Genome-wide association screens for Achilles tendon and ACL tears and tendinopathy PLOS ONE Kim, S. K., Roos, T. R., Roos, A. K., Kleimeyer, J. P., Ahmed, M. A., Goodlin, G. T., Fredericson, M., Ioannidis, J. P., Avins, A. L., Dragoo, J. L. 2017; 12 (3)

    Abstract

    Achilles tendinopathy or rupture and anterior cruciate ligament (ACL) rupture are substantial injuries affecting athletes, associated with delayed recovery or inability to return to competition. To identify genetic markers that might be used to predict risk for these injuries, we performed genome-wide association screens for these injuries using data from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort consisting of 102,979 individuals. We did not find any single nucleotide polymorphisms (SNPs) associated with either of these injuries with a p-value that was genome-wide significant (p<5x10-8). We found, however, four and three polymorphisms with p-values that were borderline significant (p<10-6) for Achilles tendon injury and ACL rupture, respectively. We then tested SNPs previously reported to be associated with either Achilles tendon injury or ACL rupture. None showed an association in our cohort with a false discovery rate of less than 5%. We obtained, however, moderate to weak evidence for replication in one case; specifically, rs4919510 in MIR608 had a p-value of 5.1x10-3 for association with Achilles tendon injury, corresponding to a 7% chance of false replication. Finally, we tested 2855 SNPs in 90 candidate genes for musculoskeletal injury, but did not find any that showed a significant association below a false discovery rate of 5%. We provide data containing summary statistics for the entire genome, which will be useful for future genetic studies on these injuries.

    View details for DOI 10.1371/journal.pone.0170422

    View details for Web of Science ID 000399174800001

    View details for PubMedID 28358823

  • Genome-wide association screens for Achilles tendon and ACL tears and tendinopathy PLOS ONE Kim, S. K., Roos, T. R., Roos, A. K., Kleimeyer, J. P., Ahmed, M. A., Goodlin, G. T., Fredericson, M., Ioannidis, J. P., Avins, A. L., Dragoo, J. L. 2017; 12 (3)

    Abstract

    Achilles tendinopathy or rupture and anterior cruciate ligament (ACL) rupture are substantial injuries affecting athletes, associated with delayed recovery or inability to return to competition. To identify genetic markers that might be used to predict risk for these injuries, we performed genome-wide association screens for these injuries using data from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort consisting of 102,979 individuals. We did not find any single nucleotide polymorphisms (SNPs) associated with either of these injuries with a p-value that was genome-wide significant (p<5x10-8). We found, however, four and three polymorphisms with p-values that were borderline significant (p<10-6) for Achilles tendon injury and ACL rupture, respectively. We then tested SNPs previously reported to be associated with either Achilles tendon injury or ACL rupture. None showed an association in our cohort with a false discovery rate of less than 5%. We obtained, however, moderate to weak evidence for replication in one case; specifically, rs4919510 in MIR608 had a p-value of 5.1x10-3 for association with Achilles tendon injury, corresponding to a 7% chance of false replication. Finally, we tested 2855 SNPs in 90 candidate genes for musculoskeletal injury, but did not find any that showed a significant association below a false discovery rate of 5%. We provide data containing summary statistics for the entire genome, which will be useful for future genetic studies on these injuries.

    View details for DOI 10.1371/journal.pone.0170422

    View details for Web of Science ID 000399174800001

    View details for PubMedID 28358823

  • Acknowledging and Overcoming Nonreproducibility in Basic and Preclinical Research JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. A. 2017; 317 (10): 1019–20

    View details for DOI 10.1001/jama.2017.0549

    View details for Web of Science ID 000396713400011

    View details for PubMedID 28192565

  • A simulation study of the strength of evidence in the recommendation of medications based on two trials with statistically significant results PLOS ONE van Ravenzwaaij, D., Ioannidis, J. A. 2017; 12 (3): e0173184

    Abstract

    A typical rule that has been used for the endorsement of new medications by the Food and Drug Administration is to have two trials, each convincing on its own, demonstrating effectiveness. "Convincing" may be subjectively interpreted, but the use of p-values and the focus on statistical significance (in particular with p < .05 being coined significant) is pervasive in clinical research. Therefore, in this paper, we calculate with simulations what it means to have exactly two trials, each with p < .05, in terms of the actual strength of evidence quantified by Bayes factors. Our results show that different cases where two trials have a p-value below .05 have wildly differing Bayes factors. Bayes factors of at least 20 in favor of the alternative hypothesis are not necessarily achieved and they fail to be reached in a large proportion of cases, in particular when the true effect size is small (0.2 standard deviations) or zero. In a non-trivial number of cases, evidence actually points to the null hypothesis, in particular when the true effect size is zero, when the number of trials is large, and when the number of participants in both groups is low. We recommend use of Bayes factors as a routine tool to assess endorsement of new medications, because Bayes factors consistently quantify strength of evidence. Use of p-values may lead to paradoxical and spurious decision-making regarding the use of new medications.

    View details for DOI 10.1371/journal.pone.0173184

    View details for Web of Science ID 000396073700043

    View details for PubMedID 28273140

    View details for PubMedCentralID PMC5342224

  • Increasing efficiency of preclinical research by group sequential designs PLOS BIOLOGY Neumann, K., Grittner, U., Piper, S. K., Rex, A., Florez-Vargas, O., Karystianis, G., Schneider, A., Wellwood, I., Siegerink, B., Ioannidis, J. P., Kimmelman, J., Dirnagl, U. 2017; 15 (3)

    Abstract

    Despite the potential benefits of sequential designs, studies evaluating treatments or experimental manipulations in preclinical experimental biomedicine almost exclusively use classical block designs. Our aim with this article is to bring the existing methodology of group sequential designs to the attention of researchers in the preclinical field and to clearly illustrate its potential utility. Group sequential designs can offer higher efficiency than traditional methods and are increasingly used in clinical trials. Using simulation of data, we demonstrate that group sequential designs have the potential to improve the efficiency of experimental studies, even when sample sizes are very small, as is currently prevalent in preclinical experimental biomedicine. When simulating data with a large effect size of d = 1 and a sample size of n = 18 per group, sequential frequentist analysis consumes in the long run only around 80% of the planned number of experimental units. In larger trials (n = 36 per group), additional stopping rules for futility lead to the saving of resources of up to 30% compared to block designs. We argue that these savings should be invested to increase sample sizes and hence power, since the currently underpowered experiments in preclinical biomedicine are a major threat to the value and predictiveness in this research domain.

    View details for DOI 10.1371/journal.pbio.2001307

    View details for Web of Science ID 000397909600012

    View details for PubMedID 28282371

  • Does evidence-based hearsay determine the use of medical treatments? SOCIAL SCIENCE & MEDICINE Ioannidis, J. A. 2017; 177: 256–58
  • Outcome reporting bias in clinical trials: why monitoring matters. BMJ (Clinical research ed.) Ioannidis, J. P., Caplan, A. L., Dal-Ré, R. 2017; 356: j408-?

    View details for DOI 10.1136/bmj.j408

    View details for PubMedID 28196819

  • DIETFITS study (diet intervention examining the factors interacting with treatment success) - Study design and methods. Contemporary clinical trials Stanton, M. V., Robinson, J. L., Kirkpatrick, S. M., Farzinkhou, S., Avery, E. C., Rigdon, J., Offringa, L. C., Trepanowski, J. F., Hauser, M. E., Hartle, J. C., Cherin, R. J., King, A. C., Ioannidis, J. P., Desai, M., Gardner, C. D. 2017; 53: 151-161

    Abstract

    Numerous studies have attempted to identify successful dietary strategies for weight loss, and many have focused on Low-Fat vs. Low-Carbohydrate comparisons. Despite relatively small between-group differences in weight loss found in most previous studies, researchers have consistently observed relatively large between-subject differences in weight loss within any given diet group (e.g., ~25kg weight loss to ~5kg weight gain). The primary objective of this study was to identify predisposing individual factors at baseline that help explain differential weight loss achieved by individuals assigned to the same diet, particularly a pre-determined multi-locus genotype pattern and insulin resistance status. Secondary objectives included discovery strategies for further identifying potential genetic risk scores. Exploratory objectives included investigation of an extensive set of physiological, psychosocial, dietary, and behavioral variables as moderating and/or mediating variables and/or secondary outcomes. The target population was generally healthy, free-living adults with BMI 28-40kg/m(2) (n=600). The intervention consisted of a 12-month protocol of 22 one-hour evening instructional sessions led by registered dietitians, with ~15-20 participants/class. Key objectives of dietary instruction included focusing on maximizing the dietary quality of both Low-Fat and Low-Carbohydrate diets (i.e., Healthy Low-Fat vs. Healthy Low-Carbohydrate), and maximally differentiating the two diets from one another. Rather than seeking to determine if one dietary approach was better than the other for the general population, this study sought to examine whether greater overall weight loss success could be achieved by matching different people to different diets. Here we present the design and methods of the study.

    View details for DOI 10.1016/j.cct.2016.12.021

    View details for PubMedID 28027950

  • Biomedical Journals and Preprint Services: Friends or Foes? CLINICAL CHEMISTRY Annesley, T., Scott, M., Bastian, H., Fonseca, V., Ioannidis, J. A., Keller, M. A., Polka, J. 2017; 63 (2): 453–58

    View details for DOI 10.1373/clinchem.2016.268227

    View details for Web of Science ID 000393360000004

    View details for PubMedID 27998906

  • Underperforming Big Ideas in Biomedical Research In Reply JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Joyner, M. J., Paneth, N., Ioannidis, J. A. 2017; 317 (3): 322

    View details for DOI 10.1001/jama.2016.20003

    View details for Web of Science ID 000392089200030

    View details for PubMedID 28114549

  • Methods to increase reproducibility in differential gene expression via meta-analysis. Nucleic acids research Sweeney, T. E., Haynes, W. A., Vallania, F., Ioannidis, J. P., Khatri, P. 2017; 45 (1)

    Abstract

    Findings from clinical and biological studies are often not reproducible when tested in independent cohorts. Due to the testing of a large number of hypotheses and relatively small sample sizes, results from whole-genome expression studies in particular are often not reproducible. Compared to single-study analysis, gene expression meta-analysis can improve reproducibility by integrating data from multiple studies. However, there are multiple choices in designing and carrying out a meta-analysis. Yet, clear guidelines on best practices are scarce. Here, we hypothesized that studying subsets of very large meta-analyses would allow for systematic identification of best practices to improve reproducibility. We therefore constructed three very large gene expression meta-analyses from clinical samples, and then examined meta-analyses of subsets of the datasets (all combinations of datasets with up to N/2 samples and K/2 datasets) compared to a 'silver standard' of differentially expressed genes found in the entire cohort. We tested three random-effects meta-analysis models using this procedure. We showed relatively greater reproducibility with more-stringent effect size thresholds with relaxed significance thresholds; relatively lower reproducibility when imposing extraneous constraints on residual heterogeneity; and an underestimation of actual false positive rate by Benjamini-Hochberg correction. In addition, multivariate regression showed that the accuracy of a meta-analysis increased significantly with more included datasets even when controlling for sample size.

    View details for DOI 10.1093/nar/gkw797

    View details for PubMedID 27634930

    View details for PubMedCentralID PMC5224496

  • Impact of vaccine herd-protection effects in cost-effectiveness analyses of childhood vaccinations. A quantitative comparative analysis. PloS one Holubar, M., Stavroulakis, M. C., Maldonado, Y., Ioannidis, J. P., Contopoulos-Ioannidis, D. 2017; 12 (3)

    Abstract

    Inclusion of vaccine herd-protection effects in cost-effectiveness analyses (CEAs) can impact the CEAs-conclusions. However, empirical epidemiologic data on the size of herd-protection effects from original studies are limited.We performed a quantitative comparative analysis of the impact of herd-protection effects in CEAs for four childhood vaccinations (pneumococcal, meningococcal, rotavirus and influenza). We considered CEAs reporting incremental-cost-effectiveness-ratios (ICERs) (per quality-adjusted-life-years [QALY] gained; per life-years [LY] gained or per disability-adjusted-life-years [DALY] avoided), both with and without herd protection, while keeping all other model parameters stable. We calculated the size of the ICER-differences without vs with-herd-protection and estimated how often inclusion of herd-protection led to crossing of the cost-effectiveness threshold (of an assumed societal-willingness-to-pay) of $50,000 for more-developed countries or X3GDP/capita (WHO-threshold) for less-developed countries.We identified 35 CEA studies (20 pneumococcal, 4 meningococcal, 8 rotavirus and 3 influenza vaccines) with 99 ICER-analyses (55 per-QALY, 27 per-LY and 17 per-DALY). The median ICER-absolute differences per QALY, LY and DALY (without minus with herd-protection) were $15,620 (IQR: $877 to $48,376); $54,871 (IQR: $787 to $115,026) and $49 (IQR: $15 to $1,636) respectively. When the target-vaccination strategy was not cost-saving without herd-protection, inclusion of herd-protection always resulted in more favorable results. In CEAs that had ICERs above the cost-effectiveness threshold without herd-protection, inclusion of herd-protection led to crossing of that threshold in 45% of the cases. This impacted only CEAs for more developed countries, as all but one CEAs for less developed countries had ICERs below the WHO-cost-effectiveness threshold even without herd-protection. In several analyses, recommendation for the adoption of the target vaccination strategy depended on the inclusion of the herd protection effect.Inclusion of herd-protection effects in CEAs had a substantial impact in the estimated ICERs and made target-vaccination strategies more attractive options in almost half of the cases where ICERs were above the societal-willingness to pay threshold without herd-protection. More empirical epidemiologic data are needed to determine the size of herd-protection effects across diverse settings and also the size of negative vaccine effects, e.g. from serotype substitution.

    View details for DOI 10.1371/journal.pone.0172414

    View details for PubMedID 28249046

    View details for PubMedCentralID PMC5332092

  • METHODS TO ENSURE THE REPRODUCIBILITY OF BIOMEDICAL RESEARCH Karczewski, K. J., Tatonetti, N. P., Manrai, A. K., Patel, C. J., Brown, C., Ioannidis, J. A., Altman, R. B., Dunker, A. K., Hunter, L., Ritchie, M. D., Murray, T., Klein, T. E. WORLD SCIENTIFIC PUBL CO PTE LTD. 2017: 117–19

    Abstract

    Science is not done in a vacuum - across fields of biomedicine, scientists have built on previous research and used data published in previous papers. A mainstay of scientific inquiry is the publication of one's research and recognition for this work is given in the form of citations and notoriety - ideally given in proportion to the quality of the work. Academic incentives, however, may encourage individual researchers to prioritize career ambitions over scientific truth. Recently, the New England Journal of Medicine published a commentary calling scientists who repurpose data "research parasites" who misuse data generated by others to demonstrate alternative hypotheses. In our opinion, the concept of data hoarding not only runs contrary to the spirit of, but also hinders scientific progress. Scientific research is meant to seek objective truth, rather than promote a personal agenda, and the only way to do so is through maximum transparency and reproducibility, no matter who is using the data….

    View details for Web of Science ID 000391254200012

    View details for PubMedID 27896967

  • Nature, Nurture, and Cancer Risks: Genetic and Nutritional Contributions to Cancer ANNUAL REVIEW OF NUTRITION, VOL 37 Theodoratou, E., Timofeeva, M., Li, X., Meng, X., Ioannidis, J. A., Stover, P. J., Balling, R. 2017; 37: 293–320

    Abstract

    It is speculated that genetic variants are associated with differential responses to nutrients (known as gene-diet interactions) and that these variations may be linked to different cancer risks. In this review, we critically evaluate the evidence across 314 meta-analyses of observational studies and randomized controlled trials of dietary risk factors and the five most common cancers (breast, lung, prostate, colorectal, and stomach). We also critically evaluate the evidence across 13 meta-analyses of observational studies of gene-diet interactions for the same cancers. Convincing evidence for association was found only for the intake of alcohol and whole grains in relation to colorectal cancer risk. Three nutrient associations had highly suggestive evidence and another 15 associations had suggestive evidence. Among the examined gene-diet interactions, only one had moderately strong evidence.

    View details for DOI 10.1146/annurev-nutr-071715-051004

    View details for Web of Science ID 000410544800013

    View details for PubMedID 28826375

  • Interpretation of epidemiologic studies very often lacked adequate consideration of confounding. Journal of clinical epidemiology Hemkens, L. G., Ewald, H., Naudet, F., Ladanie, A., Shaw, J. G., Sajeev, G., Ioannidis, J. P. 2017

    Abstract

    Confounding bias is a most pervasive threat to validity of observational epidemiologic research. We assessed whether authors of observational epidemiologic studies consider confounding bias when interpreting the findings.We randomly selected 120 cohort or case-control studies published in 2011 and 2012 by the general medical, epidemiologic, and specialty journals with the highest impact factors. We used Web of Science to assess citation metrics through January 2017.Sixty-eight studies (56.7%, 95% confidence interval: 47.8-65.5%) mentioned "confounding" in the Abstract or Discussion sections, another 20 (16.7%; 10.0-23.3%) alluded to it, and there was no mention or allusion at all in 32 studies (26.7%; 18.8-34.6%). Authors often acknowledged that for specific confounders, there was no adjustment (34 studies; 28.3%) or deem it possible or likely that confounding affected their main findings (29 studies; 24.2%). However, only two studies (1.7%; 0-4.0%) specifically used the words "caution" or "cautious" for the interpretation because of confounding-related reasons and eventually only four studies (3.3%; 0.1-6.5%) had limitations related to confounding or any other bias in their Conclusions. Studies mentioning that the findings were possibly or likely affected by confounding were more frequently cited than studies with a statement that findings were unlikely affected (median 6.3 vs. 4.0 citations per year, P = 0.04).Many observational studies lack satisfactory discussion of confounding bias. Even when confounding bias is mentioned, authors are typically confident that it is rather irrelevant to their findings and they rarely call for cautious interpretation. More careful acknowledgment of possible impact of confounding is not associated with lower citation impact.

    View details for DOI 10.1016/j.jclinepi.2017.09.013

    View details for PubMedID 28943377

  • Neurosurgical Randomized Controlled Trials-Distance Travelled. Neurosurgery Azad, T. D., Veeravagu, A., Mittal, V., Esparza, R., Johnson, E., Ioannidis, J. P., Grant, G. A. 2017

    Abstract

    The evidence base for many neurosurgical procedures has been limited. We performed a comprehensive and systematic analysis of study design, quality of reporting, and trial results of neurosurgical randomized controlled trials (RCTs).To systematically assess the design and quality characteristics of neurosurgical RCTs.From January 1961 to June 2016, RCTs with >5 patients assessing any 1 neurosurgical procedure against another procedure, nonsurgical treatment, or no treatment were retrieved from MEDLINE, Scopus, and Cochrane Library.The median sample size in the 401 eligible RCTs was 73 patients with a mean patient age of 49.6. Only 111 trials (27.1%) described allocation concealment, 140 (34.6%) provided power calculations, and 117 (28.9%) were adequately powered. Significant efficacy or trend for efficacy was claimed in 226 reports (56.4%), no difference between the procedures was found in 166 trials (41.4%), and significant harm was reported in 9 trials (2.2%). Trials with a larger sample size were more likely to report randomization mode, specify allocation concealment, and power calculations (all P < .001). Government funding was associated with better specification of power calculations ( P = .008) and of allocation concealment ( P = .026), while industry funding was associated with reporting significant efficacy ( P = .02). Reporting of funding, specification of randomization mode and primary outcomes, and mention of power calculations improved significantly (all, P < .05) over time.Several aspects of the design and reporting of RCTs on neurosurgical procedures have improved over time. Better powered and accurately reported trials are needed in neurosurgery to deliver evidence-based care and achieve optimal outcomes.

    View details for DOI 10.1093/neuros/nyx319

    View details for PubMedID 28645203

  • Opportunities and challenges in developing risk prediction models with electronic health records data: a systematic review JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION Goldstein, B. A., Navar, A. M., Pencina, M. J., Ioannidis, J. P. 2017; 24 (1): 198-208

    Abstract

    Electronic health records (EHRs) are an increasingly common data source for clinical risk prediction, presenting both unique analytic opportunities and challenges. We sought to evaluate the current state of EHR based risk prediction modeling through a systematic review of clinical prediction studies using EHR data.We searched PubMed for articles that reported on the use of an EHR to develop a risk prediction model from 2009 to 2014. Articles were extracted by two reviewers, and we abstracted information on study design, use of EHR data, model building, and performance from each publication and supplementary documentation.We identified 107 articles from 15 different countries. Studies were generally very large (median sample size = 26 100) and utilized a diverse array of predictors. Most used validation techniques (n = 94 of 107) and reported model coefficients for reproducibility (n = 83). However, studies did not fully leverage the breadth of EHR data, as they uncommonly used longitudinal information (n = 37) and employed relatively few predictor variables (median = 27 variables). Less than half of the studies were multicenter (n = 50) and only 26 performed validation across sites. Many studies did not fully address biases of EHR data such as missing data or loss to follow-up. Average c-statistics for different outcomes were: mortality (0.84), clinical prediction (0.83), hospitalization (0.71), and service utilization (0.71).EHR data present both opportunities and challenges for clinical risk prediction. There is room for improvement in designing such studies.

    View details for DOI 10.1093/jamia/ocw042

    View details for Web of Science ID 000397028000028

    View details for PubMedID 27189013

  • Impact of a Genetic Risk Score for Coronary Artery Disease on Reducing Cardiovascular Risk: A Pilot Randomized Controlled Study. Frontiers in cardiovascular medicine Knowles, J. W., Zarafshar, S., Pavlovic, A., Goldstein, B. A., Tsai, S., Li, J., McConnell, M. V., Absher, D., Ashley, E. A., Kiernan, M., Ioannidis, J. P., Assimes, T. L. 2017; 4: 53

    Abstract

    We tested whether providing a genetic risk score (GRS) for coronary artery disease (CAD) would serve as a motivator to improve adherence to risk-reducing strategies.We randomized 94 participants with at least moderate risk of CAD to receive standard-of-care with (N = 49) or without (N = 45) their GRS at a subsequent 3-month follow-up visit. Our primary outcome was change in low density lipoprotein cholesterol (LDL-C) between the 3- and 6-month follow-up visits (ΔLDL-C). Secondary outcomes included other CAD risk factors, weight loss, diet, physical activity, risk perceptions, and psychological outcomes. In pre-specified analyses, we examined whether there was a greater motivational effect in participants with a higher GRS.Sixty-five participants completed the protocol including 30 participants in the GRS arm. We found no change in the primary outcome between participants receiving their GRS and standard-of-care participants (ΔLDL-C: -13 vs. -9 mg/dl). Among participants with a higher GRS, we observed modest effects on weight loss and physical activity. All other secondary outcomes were not significantly different, including anxiety and worry.Adding GRS to standard-of-care did not change lipids, adherence, or psychological outcomes. Potential modest benefits in weight loss and physical activity for participants with high GRS need to be validated in larger trials.

    View details for DOI 10.3389/fcvm.2017.00053

    View details for PubMedID 28856136

    View details for PubMedCentralID PMC5558259

  • Insomnia From Drug Treatments: Evidence From Meta-analyses of Randomized Trials and Concordance With Prescribing Information. Mayo Clinic proceedings Doufas, A. G., Panagiotou, O. A., Panousis, P., Wong, S. S., Ioannidis, J. P. 2017; 92 (1): 72-87

    Abstract

    To determine whether drugs used to treat diverse conditions cause insomnia symptoms and whether their prescription information is concordant with this evidence.We conducted a survey of meta-analyses (Cochrane Database of Systematic Reviews) and comparisons with package inserts compiled in the Physicians' Desk Reference (PDR). We identified randomized controlled trials (RCTs) in which any drug had been evaluated vs placebo and sleep had been assessed. We collectively referred to insomnia-related outcomes as sleep disturbance. We also searched the PDR to identify any insomnia symptoms listed for drugs with RCT evidence available.Seventy-four Cochrane systematic reviews corresponding to 274 RCTs assessed 88 drugs in 27 different conditions, providing evidence on 109 drug-condition pairs. Of these 88 drugs, 5 decreased sleep problems and 19 increased sleep problems; 64 drugs had no nominally statistically significant effect on sleep. Acetylcholinesterase inhibitors, dopamine agonists, and selective serotonin reuptake inhibitors were the drug classes most importantly associated with sleep disturbance. Of 35 drugs that included disturbed sleep as an adverse effect in the PDR, only 14 had RCT evidence supporting such effect, and 2 had evidence of increasing and decreasing sleep problems in RCTs, although this was not shown in the PDR. We identified weak concordance between the PDR and RCTs (weighted κ=0.31; P<.001).The RCTs offer substantial evidence about the common effects of drugs on the risk of sleep disturbance; currently, prescription information only partially agrees with the available randomized evidence.

    View details for DOI 10.1016/j.mayocp.2016.09.005

    View details for PubMedID 27842706

  • Bias in medical literature on health outcomes: bias in commentary? Reply BMJ-BRITISH MEDICAL JOURNAL Stavropoulou, C., Parmar, D., Ioannidis, J. A. 2016; 355: i6639

    View details for DOI 10.1136/bmj.i6639

    View details for Web of Science ID 000390151900003

    View details for PubMedID 27986758

  • Routinely collected data may usefully supplement randomised controlled data on treatment effects for mortality Reply BMJ-BRITISH MEDICAL JOURNAL Hemkens, L. G., Contopoulos-Ioannidis, D. G., Ioannidis, J. A. 2016; 355: i6747

    View details for DOI 10.1136/bmj.i6747

    View details for Web of Science ID 000390151900007

    View details for PubMedID 27986652

  • Enhancing reproducibility for computational methods SCIENCE Stodden, V., McNutt, M., Bailey, D. H., Deelman, E., Gil, Y., Hanson, B., Heroux, M. A., Ioannidis, J. A., Taufer, M. 2016; 354 (6317): 1240–41

    View details for DOI 10.1126/science.aah6168

    View details for Web of Science ID 000389598800044

    View details for PubMedID 27940837

  • Sex based subgroup differences in randomized controlled trials: empirical evidence from Cochrane meta-analyses BMJ-BRITISH MEDICAL JOURNAL Wallach, J. D., Sullivan, P. G., Trepanowski, J. F., Steyerberg, E. W., Ioannidis, J. P. 2016; 355

    Abstract

     To evaluate the frequency, validity, and relevance of statistically significant (P<0.05) sex-treatment interactions in randomized controlled trials in Cochrane meta-analyses. Meta-epidemiological study. Cochrane Database of Systematic Reviews (CDSR) and PubMed. Reviews published in the CDSR with sex-treatment subgroup analyses in the forest plots, using data from randomized controlled trials. Information on the study design and sex subgroup data were extracted from reviews and forest plots that met inclusion criteria. For each statistically significant sex-treatment interaction, the potential for biological plausibility and clinical significance was considered. Among the 41 reviews with relevant data, there were 109 separate treatment-outcome analyses ("topics"). Among the 109 topics, eight (7%) had a statistically significant sex-treatment interaction. The 109 topics included 311 randomized controlled trials (162 with both sexes, 46 with males only, 103 with females only). Of the 162 individual randomized controlled trials that included both sexes, 15 (9%) had a statistically significant sex-treatment interaction. Of four topics where the first published randomized controlled trial had a statistically significant sex-treatment interaction, no meta-analyses that included other randomized controlled trials retained the statistical significance and no meta-analyses showed statistical significance when data from the first published randomized controlled trial were excluded. Of the eight statistically significant sex-treatment interactions from the overall analyses, only three were discussed by the CDSR reviewers for a potential impact on different clinical management for males compared with females. None of these topics had a sex-treatment interaction that influenced treatment recommendations in recent guidelines. UpToDate, an online physician-authored clinical decision support resource, suggested differential management of men and women for one of these sex-treatment interactions. Statistically significant sex-treatment interactions are only slightly more frequent than what would be expected by chance and there is little evidence of subsequent corroboration or clinical relevance of sex-treatment interactions.

    View details for DOI 10.1136/bmj.i5826

    View details for Web of Science ID 000388917400001

    View details for PubMedID 27884869

    View details for PubMedCentralID PMC5122320

  • Meta-Analysis Comparing Established Risk Prediction Models (EuroSCORE II, STS Score, and ACEF Score) for Perioperative Mortality During Cardiac Surgery. American journal of cardiology Sullivan, P. G., Wallach, J. D., Ioannidis, J. P. 2016; 118 (10): 1574-1582

    Abstract

    A wide variety of multivariable risk models have been developed to predict mortality in the setting of cardiac surgery; however, the relative utility of these models is unknown. This study investigated the literature related to comparisons made between established risk prediction models for perioperative mortality used in the setting of cardiac surgery. A systematic review was conducted to capture studies in cardiac surgery comparing the relative performance of at least 2 prediction models cited in recent guidelines (European System for Cardiac Operative Risk Evaluation [EuroSCORE II], Society for Thoracic Surgeons 2008 Cardiac Surgery Risk Models [STS] score, and Age, Creatinine, Ejection Fraction [ACEF] score) for the outcomes of 1-month or inhospital mortality. For articles that met inclusion criteria, we extracted information on study design, predictive performance of risk models, and potential for bias. Meta-analyses were conducted to calculate a summary estimate of the difference in AUCs between models. We identified 22 eligible studies that contained 33 comparisons among the above models. Meta-analysis of differences in AUCs revealed that the EuroSCORE II and STS score performed similarly (with a summary difference in AUC = 0.00), while outperforming the ACEF score (with summary differences in AUC of 0.10 and 0.08, respectively, p <0.05). Other metrics of discrimination and calibration were presented less consistently, and no study presented any metric of reclassification. Small sample size and absent descriptions of missing data were common in these studies. In conclusion, the EuroSCORE II and STS score outperform the ACEF score on discrimination.

    View details for DOI 10.1016/j.amjcard.2016.08.024

    View details for PubMedID 27687052

  • Diet, body size, physical activity and risk of prostate cancer: An umbrella review of the evidence. European journal of cancer Markozannes, G., Tzoulaki, I., Karli, D., Evangelou, E., Ntzani, E., Gunter, M. J., Norat, T., Ioannidis, J. P., Tsilidis, K. K. 2016; 69: 61-69

    Abstract

    The existing literature on the relationship between diet, body size, physical activity and prostate cancer risk was summarised by the World Cancer Research Fund Continuous Update Project (CUP). An evaluation of the robustness of this evidence is required to help inform public health policy. The robustness of this evidence was evaluated using several criteria addressing evidence strength and validity, including the statistical significance of the random effects summary estimate and of the largest study in a meta-analysis, number of prostate cancer cases, between-study heterogeneity, 95% prediction intervals, small-study effects bias, excess significance bias and sensitivity analyses with credibility ceilings. A total of 248 meta-analyses were extracted from the CUP, which studied associations of 23 foods, 31 nutrients, eight indices of body size and three indices of physical activity with risk of total prostate cancer development, mortality or cancer development by stage and grade. Of the 176 meta-analyses using a continuous scale to measure the exposures, no association presented strong evidence by satisfying all the aforementioned criteria. Only the association of height with total prostate cancer incidence and mortality presented highly suggestive evidence with a 4% higher risk per 5 cm greater height (95% confidence interval, 1.03, 1.05). Associations for body mass index, weight, height, dietary calcium and spirits intake were supported by suggestive evidence. Overall, the association of diet, body size, physical activity and prostate cancer has been extensively studied, but no association was graded with strong evidence.

    View details for DOI 10.1016/j.ejca.2016.09.026

    View details for PubMedID 27816833

  • Randomized trials are frequently fragmented in multiple secondary publications JOURNAL OF CLINICAL EPIDEMIOLOGY Ebrahim, S., Montoya, L., el Din, M. K., Sohani, Z. N., Agarwal, A., Bance, S., Saquib, J., Saquib, N., Ioannidis, J. P. 2016; 79: 130-139

    Abstract

    To assess the frequency and features of secondary publications of randomized controlled trials (RCTs).For 191 RCTs published in high-impact journals in 2009, we searched for secondary publications coauthored by at least one same author of the primary trial publication. We evaluated the probability of having secondary publications, characteristics of the primary trial publication that predict having secondary publications, types of secondary analyses conducted, and statistical significance of those analyses.Of 191 primary trials, 88 (46%) had a total of 475 secondary publications by 2/2014. Eight trials had >10 (up to 51) secondary publications each. In multivariable modeling, the risk of having subsequent secondary publications increased 1.32-fold (95% CI 1.05-1.68) per 10-fold increase in sample size, and 1.71-fold (95% CI 1.19-2.45) in the presence of a design article. In a sample of 197 secondary publications examined in depth, 193 tested different hypotheses than the primary publication. Of the 193, 43 tested differences between subgroups, 85 assessed predictive factors associated with an outcome of interest, 118 evaluated different outcomes than the original article, 71 had differences in eligibility criteria, and 21 assessed different durations of follow-up; 176 (91%) presented at least one analysis with statistically significant results.Approximately half of randomized trials in high-impact journals have secondary publications published with a few trials followed by numerous secondary publications. Almost all of these publications report some statistically significant results.

    View details for DOI 10.1016/j.jclinepi.2016.05.016

    View details for Web of Science ID 000389967700020

    View details for PubMedID 27387965

  • Very large treatment effects in randomised trials as an empirical marker to indicate whether subsequent trials are necessary: meta-epidemiological assessment. BMJ (Clinical research ed.) Nagendran, M., Pereira, T. V., Kiew, G., Altman, D. G., Maruthappu, M., Ioannidis, J. P., McCulloch, P. 2016; 355: i5432-?

    Abstract

     To examine whether a very large effect (VLE; defined as a relative risk of ≤0.2 or ≥5) in a randomised trial could be an empirical marker that subsequent trials are unnecessary. Meta-epidemiological assessment of existing published data on randomised trials. Cochrane Database of Systematic Reviews (2010, issue 7) with data on subsequent large trials updated to 2015, issue 12. All binary outcome forest plots were selected, which contained an index randomised trial with a VLE that was nominally statistically significant (P<0.05), included a subsequent large randomised trial (≥200 events and ≥200 non-events) for validation of the effect, assessed a primary outcome of the review, and was not a subgroup or sensitivity analysis. Of 3082 reviews yielding 85 002 forest plots, only 44 (0.05%) satisfied the inclusion criteria. Index trials were generally small, with a median sample of 99 (median 14 events). Few index trials were rated at low risk of bias (9 of 44; 20%). The relative risk was closer to the null in the subsequent large trials in 43 of 44 cases. Subsequent large trial data failed to find a statistically significant (P<0.05) effect in the same direction in 19 cases (43%, 95% confidence interval 29% to 58%). Even when the subsequent large trials did find a significant effect in the same direction, the additional primary outcomes in most of these trials would have to be considered before deciding in favour of using the intervention. Subsequent large trial data found a statistically significant effect in the same direction in 19 of 21 cases when the index trial also had a value of P<0.001. The frequency of VLEs followed by a large trial is vanishingly small, and where they occur they do not appear to be a reliable marker for a benefit that is reproducible and directly actionable. An empirical rule using a VLE in a randomised controlled trial as a marker that further trials are unnecessary would be neither practical nor useful. Caution should be taken when interpreting small studies with very large treatment effects.

    View details for DOI 10.1136/bmj.i5432

    View details for PubMedID 27789483

    View details for PubMedCentralID PMC5081692

  • What Happens When Underperforming Big Ideas in Research Become Entrenched? JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Joyner, M. J., Paneth, N., Ioannidis, J. A. 2016; 316 (13): 1355–56

    View details for DOI 10.1001/jama.2016.11076

    View details for Web of Science ID 000384591300011

    View details for PubMedID 27467098

  • Comparative rates of harms in randomized trials from more developed versus less developed countries may be different JOURNAL OF CLINICAL EPIDEMIOLOGY Contopoulos-Ioannidis, D., Tseretopoulou, X., Ancker, M., Walterspiel, J. N., Panagiotou, O. A., Maldonado, Y., Ioannidis, J. P. 2016; 78: 10-21

    Abstract

    We set up to evaluate the relative risk of harms in trials performed in less developed vs. more developed countries.Meta-epidemiologic evaluation using the Cochrane Database of Systematic Reviews. We considered meta-analyses with at least one randomized clinical trial (RCT) in a less developed country and one RCT in a more developed country. We targeted severe adverse events (AEs), discontinuations due to AEs, any AE, organ system-specific AEs, individual AEs, and all discontinuations due to any reason. We estimated the relative odds ratio (ROR) of harms between more and less developed countries for each topic and the summary ROR (sROR) across topics under each category of harms.We identified 42 systematic reviews (128 meta-analyses, 521 independent RCTs). Summary sRORs did not differ significantly from 1.00 for any harm category. Nominally significant RORs were found in only 6/128 meta-analyses. However, in 27% (35/128) of meta-analyses the ROR point estimates indicated relative differences between country settings >2-fold. Considering also ROR 95% confidence intervals, in 92% (118/128) of meta-analyses one could not exclude a 2-fold difference in both directions.We identified limited comparative evidence on harms in trials from these two country settings. Substantial differences in the risk point estimates were common; the potential for modest differences could rarely be excluded with confidence.

    View details for DOI 10.1016/j.jclinepi.2016.02.032

    View details for Web of Science ID 000389615400004

    View details for PubMedID 27063207

  • Short-term economic impact of the Zika virus outbreak NEW MICROBIOLOGICA Macciocchi, D., Lanini, S., Vairo, F., Zumla, A., Moraes Figueiredo, L., Lauria, F., Strada, G., Brouqui, P., Puro, V., Krishna, S., Kremsner, P., Scognamiglio, P., Kohler, C., Nicastri, E., Di Caro, A., Cieri, R., Ioannidis, J. A., Kobinger, G., Burattini, M., Ippolito, G. 2016; 39 (4): 287–89

    Abstract

    Zika virus (ZIKV) is mainly transmitted by mosquitoes bites. However, transmission by sexual contacts has been reported in 11 non endemic countries. The rapid spread of ZIKV in Latin American and Caribbean Countries (LCR), person-to-person transmission and perceived risk on people's well being can affect the emerging economies of LCR which historically dependent on truism. Here we present an analysis on economic outputs for assessing the current impact of ZIKV on markets. Our analysis show an unexpected resilience of LCR markets to international alerts. This positive response represents an opportunity to scale-up interventions for preventing the further spreading of the ZIKV epidemic.

    View details for Web of Science ID 000392469400007

    View details for PubMedID 28004846

  • High quality of the evidence for medical and other health-related interventions was uncommon in Cochrane systematic reviews JOURNAL OF CLINICAL EPIDEMIOLOGY Fleming, P. S., Koletsi, D., Ioannidis, J. A., Pandis, N. 2016; 78: 34–42

    Abstract

    To appraise the quality of evidence in systematic reviews (SRs) within the Cochrane Database of Systematic Reviews (CDSRs) across diverse topics and to explore the relationship between the strength of evidence using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) and the probability that authors would interpret that an intervention may be of value.We evaluated the SRs published on the CDSR from January 1, 2013, to June 30, 2014. Two authors identified relevant SRs by independent searching of the Cochrane register. We further focused on SRs that incorporated tables with GRADE [summary of findings (SoF)]. Data were extracted independently by two authors. The quality of the evidence for the first listed primary outcome in SoF tables in each review and reasons for upgrade or downgrade were recorded.Overall, 1,394 SRs were identified. Of these, 608 (43.6%) incorporated GRADE. Within these reviews, only 13.5% (n = 82) reported a high quality and 30.8% (n = 187) a moderate quality of evidence for the first listed primary outcome, whereas 31.7% (n = 193) had low level and 24% (n = 146) had very low level of evidence. High quality of evidence was more common in updated compared to new reviews and in pharmacologic than other types of interventions. Even when all outcomes listed in the SoFs were considered, only 116/608 (19.1%) of SRs had at least one outcome with high quality of evidence. Overall, only 4.1% (25/608) of SRs incorporating GRADE in SoF tables had high quality of evidence, allied both to significant results and a favorable interpretation of the intervention by the reviewers.Evidence of high quality is uncommon for medical and health-related interventions assessed with GRADE within the CDSR, and favorable evidence of high quality is even more uncommon.

    View details for DOI 10.1016/j.jclinepi.2016.03.012

    View details for Web of Science ID 000389615400006

    View details for PubMedID 27032875

  • Effect of diastolic dysfunction on postoperative outcomes after cardiovascular surgery: A systematic review and meta-analysis JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Kaw, R., Hernandez, A. V., Pasupuleti, V., Deshpande, A., Nagarajan, V., Bueno, H., Coleman, C. I., Ioannidis, J. P., Bhatt, D. L., Blackstone, E. H. 2016; 152 (4): 1142-1153

    Abstract

    The objective of this study was to investigate the effect of preoperative diastolic dysfunction on postoperative mortality and morbidity after cardiovascular surgery.We systematically searched for articles that assessed the prognostic role of diastolic dysfunction on cardiovascular surgery in PubMed, Cochrane Library, Web of Science, Embase, and Scopus until February 2016. Twelve studies (n = 8224) met our inclusion criteria. Because of the scarcity of outcome events, fixed-effects meta-analysis was performed via the Mantel-Haenszel method.Preoperative diagnosis of diastolic dysfunction was associated with greater postoperative mortality (odds ratio [OR], 2.41; 95% confidence interval [CI], 1.54-3.71; P < .0001), major adverse cardiac events (OR, 2.07; 95% CI, 1.55-2.78; P ≤ .0001), and prolonged mechanical ventilation (OR, 2.08; 95% CI, 1.04-4.16; P = .04) compared with patients without diastolic dysfunction among patients who underwent cardiovascular surgery. The odds of postoperative myocardial infarction (OR, 1.29; 95% CI, 0.82-2.05; P = .28) and atrial fibrillation (OR, 2.67; 95% CI, 0.49-14.43; P = .25) did not significantly differ between the 2 groups. Severity of preoperative diastolic dysfunction was associated with increased postoperative mortality (OR, 21.22; 95% CI, 3.74-120.33; P = .0006) for Grade 3 diastolic dysfunction compared with patients with normal diastolic function. Inclusion of left ventricular ejection fraction (LVEF) <40% accompanying diastolic dysfunction did not further impact postoperative mortality (P = .27; I(2) = 18%) compared with patients with normal LVEF and diastolic dysfunction.Presence of preoperative diastolic dysfunction was associated with greater postoperative mortality and major adverse cardiac events, regardless of LVEF. Mortality was significantly greater in grade III diastolic dysfunction.

    View details for DOI 10.1016/j.jtcvs.2016.05.057

    View details for Web of Science ID 000386748700055

    View details for PubMedID 27364601

  • The Cancer Epidemiology Descriptive Cohort Database: A Tool to Support Population-Based Interdisciplinary Research CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Kennedy, A. E., Khoury, M. J., Ioannidis, J. P., Brotzman, M., Miller, A., Lane, C., Lai, G. Y., Rogers, S. D., Harvey, C., Elena, J. W., Seminara, D. 2016; 25 (10): 1392-1401

    Abstract

    We report on the establishment of a web-based Cancer Epidemiology Descriptive Cohort Database (CEDCD). The CEDCD's goals are to enhance awareness of resources, facilitate interdisciplinary research collaborations, and support existing cohorts for the study of cancer-related outcomes.Comprehensive descriptive data were collected from large cohorts established to study cancer as primary outcome using a newly developed questionnaire. These included an inventory of baseline and follow-up data, biospecimens, genomics, policies, and protocols. Additional descriptive data extracted from publicly available sources were also collected. This information was entered in a searchable and publicly accessible database. We summarized the descriptive data across cohorts and reported the characteristics of this resource.As of December 2015, the CEDCD includes data from 46 cohorts representing more than 6.5 million individuals (29% ethnic/racial minorities). Overall, 78% of the cohorts have collected blood at least once, 57% at multiple time points, and 46% collected tissue samples. Genotyping has been performed by 67% of the cohorts, while 46% have performed whole-genome or exome sequencing in subsets of enrolled individuals. Information on medical conditions other than cancer has been collected in more than 50% of the cohorts. More than 600,000 incident cancer cases and more than 40,000 prevalent cases are reported, with 24 cancer sites represented.The CEDCD assembles detailed descriptive information on a large number of cancer cohorts in a searchable database.Information from the CEDCD may assist the interdisciplinary research community by facilitating identification of well-established population resources and large-scale collaborative and integrative research. Cancer Epidemiol Biomarkers Prev; 25(10); 1392-401. ©2016 AACR.

    View details for DOI 10.1158/1055-9965.EPI-16-0412

    View details for Web of Science ID 000385642800004

    View details for PubMedID 27439404

  • Health outcomes during the 2008 financial crisis in Europe: systematic literature review BMJ-BRITISH MEDICAL JOURNAL Parmar, D., Stavropoulou, C., Ioannidis, J. A. 2016; 354: i4588

    Abstract

     To systematically identify, critically appraise, and synthesise empirical studies about the impact of the 2008 financial crisis in Europe on health outcomes. Systematic literature review. Structural searches of key databases, healthcare journals, and organisation based websites. Empirical studies reporting on the impact of the financial crisis on health outcomes in Europe, published from January 2008 to December 2015, were included. All selected studies were assessed for risk of bias. Owing to the heterogeneity of studies in terms of study design and analysis and the use of overlapping datasets across studies, studies were analysed thematically per outcome, and the evidence was synthesised on different health outcomes without formal meta-analysis. 41 studies met the inclusion criteria, and focused on suicide, mental health, self rated health, mortality, and other health outcomes. Of those studies, 30 (73%) were deemed to be at high risk of bias, nine (22%) at moderate risk of bias, and only two (5%) at low risk of bias, limiting the conclusions that can be drawn. Although there were differences across countries and groups, there was some indication that suicides increased and mental health deteriorated during the crisis. The crisis did not seem to reverse the trend of decreasing overall mortality. Evidence on self rated health and other indicators was mixed. Most published studies on the impact of financial crisis on health in Europe had a substantial risk of bias; therefore, results need to be cautiously interpreted. Overall, the financial crisis in Europe seemed to have had heterogeneous effects on health outcomes, with the evidence being most consistent for suicides and mental health. There is a need for better empirical studies, especially those focused on identifying mechanisms that can mitigate the adverse effects of the crisis.

    View details for DOI 10.1136/bmj.i4588

    View details for Web of Science ID 000383100600003

    View details for PubMedID 27601477

    View details for PubMedCentralID PMC5013230

  • Systematic evaluation of the associations between environmental risk factors and dementia: An umbrella review of systematic reviews and meta-analyses. Alzheimer's & dementia : the journal of the Alzheimer's Association Bellou, V., Belbasis, L., Tzoulaki, I., Middleton, L. T., Ioannidis, J. P., Evangelou, E. 2016

    Abstract

    Dementia is a heterogeneous neurodegenerative disease, whose etiology results from a complex interplay between environmental and genetic factors.We searched PubMed to identify meta-analyses of observational studies that examined associations between nongenetic factors and dementia. We estimated the summary effect size using random-effects and fixed-effects model, the 95% CI, and the 95% prediction interval. We assessed the between-study heterogeneity (I-square), evidence of small-study effects, and excess significance.A total of 76 unique associations were examined. By applying standardized criteria, seven associations presented convincing evidence. These associations pertained to benzodiazepines use, depression at any age, late-life depression, and frequency of social contacts for all types of dementia; late-life depression for Alzheimer's disease; and type 2 diabetes mellitus for vascular dementia and Alzheimer's disease.Several risk factors present substantial evidence for association with dementia and should be assessed as potential targets for interventions, but these associations may not necessarily be causal.

    View details for DOI 10.1016/j.jalz.2016.07.152

    View details for PubMedID 27599208

  • The Mass Production of Redundant, Misleading, and Conflicted Systematic Reviews and Meta-analyses MILBANK QUARTERLY Ioannidis, J. P. 2016; 94 (5): 485-514

    Abstract

    Currently, there is massive production of unnecessary, misleading, and conflicted systematic reviews and meta-analyses. Instead of promoting evidence-based medicine and health care, these instruments often serve mostly as easily produced publishable units or marketing tools. Suboptimal systematic reviews and meta-analyses can be harmful given the major prestige and influence these types of studies have acquired. The publication of systematic reviews and meta-analyses should be realigned to remove biases and vested interests and to integrate them better with the primary production of evidence.Currently, most systematic reviews and meta-analyses are done retrospectively with fragmented published information. This article aims to explore the growth of published systematic reviews and meta-analyses and to estimate how often they are redundant, misleading, or serving conflicted interests.Data included information from PubMed surveys and from empirical evaluations of meta-analyses.Publication of systematic reviews and meta-analyses has increased rapidly. In the period January 1, 1986, to December 4, 2015, PubMed tags 266,782 items as "systematic reviews" and 58,611 as "meta-analyses." Annual publications between 1991 and 2014 increased 2,728% for systematic reviews and 2,635% for meta-analyses versus only 153% for all PubMed-indexed items. Currently, probably more systematic reviews of trials than new randomized trials are published annually. Most topics addressed by meta-analyses of randomized trials have overlapping, redundant meta-analyses; same-topic meta-analyses may exceed 20 sometimes. Some fields produce massive numbers of meta-analyses; for example, 185 meta-analyses of antidepressants for depression were published between 2007 and 2014. These meta-analyses are often produced either by industry employees or by authors with industry ties and results are aligned with sponsor interests. China has rapidly become the most prolific producer of English-language, PubMed-indexed meta-analyses. The most massive presence of Chinese meta-analyses is on genetic associations (63% of global production in 2014), where almost all results are misleading since they combine fragmented information from mostly abandoned era of candidate genes. Furthermore, many contracting companies working on evidence synthesis receive industry contracts to produce meta-analyses, many of which probably remain unpublished. Many other meta-analyses have serious flaws. Of the remaining, most have weak or insufficient evidence to inform decision making. Few systematic reviews and meta-analyses are both non-misleading and useful.The production of systematic reviews and meta-analyses has reached epidemic proportions. Possibly, the large majority of produced systematic reviews and meta-analyses are unnecessary, misleading, and/or conflicted.

    View details for DOI 10.1111/1468-0009.12210

    View details for Web of Science ID 000384419900010

    View details for PubMedCentralID PMC5020151

  • Citation Metrics: A Primer on How (Not) to Normalize. PLoS biology Ioannidis, J. P., Boyack, K., Wouters, P. F. 2016; 14 (9)

    Abstract

    Citation metrics are increasingly used to appraise published research. One challenge is whether and how to normalize these metrics to account for differences across scientific fields, age (year of publication), type of document, database coverage, and other factors. We discuss the pros and cons for normalizations using different approaches. Additional challenges emerge when citation metrics need to be combined across multiple papers to appraise the corpus of scientists, institutions, journals, or countries, as well as when trying to attribute credit in multiauthored papers. Different citation metrics may offer complementary insights, but one should carefully consider the assumptions that underlie their calculation.

    View details for DOI 10.1371/journal.pbio.1002542

    View details for PubMedID 27599158

    View details for PubMedCentralID PMC5012555

  • Registered Randomized Trials Comparing Generic and Brand-Name Drugs: A Survey. Mayo Clinic proceedings Flacco, M. E., Manzoli, L., Boccia, S., Puggina, A., Rosso, A., Marzuillo, C., Scaioli, G., Gualano, M. R., Ricciardi, W., Villari, P., Ioannidis, J. P. 2016; 91 (8): 1021-1034

    Abstract

    To evaluate the research agenda of registered randomized trials comparing generic and brand-name drugs in terms of who sponsors them, whether they are published promptly, and whether they find favorable results.We included randomized trials comparing the safety or efficacy of brand-name vs generic medications that were registered in ClinicalTrials.gov or other registries from January 1, 2000, through July 31, 2015. To identify published articles or results generated from such trials, we searched PubMed, Scopus, Google, and registry databases. Data were compared across sponsorship categories ("inbred" if the compared drugs were owned by the same company or its partners/subsidiaries, "competitive" if the compared drugs were owned by competing companies, and "apparently nonprofit"), and time to publication was evaluated with Cox analysis.We found 207 registered protocols reporting on 186 completed trials. Among those trials, 37 had published their results and another 56 had posted results in registries, for a total of 93 trials with available results. Four years after trial completion, results were available for 64 of 138 trials (46.4%), with substantial differences by sponsor: 70.8% (34 of 48), 28.1% (18 of 64), and 46.2% (12 of 26) of the inbred, competitive, and nonprofit trials, respectively. In multivariate modeling, inbred trials had a 1.73-fold risk of having results available compared with competitive trials (P=.04). Almost all trials reported favorable results, with the exception of 4 (4.3% of the 93 trials with results).Despite the importance of generic drugs, relatively few registered randomized trials have compared the health effects of generic vs brand-name medicines, and there is an associated unsatisfactory publication rate and almost ubiquitous favorable results. The overall literature on the topic is at high risk of bias, possibly in favor of generic drugs. Higher nonprofit funding and stronger pressure to register trials and publish results are needed.

    View details for DOI 10.1016/j.mayocp.2016.04.032

    View details for PubMedID 27402583

  • Stealth Research and Theranos Reflections and Update 1 Year Later JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. A. 2016; 316 (4): 389–90

    View details for DOI 10.1001/jama.2016.6986

    View details for Web of Science ID 000380221700012

    View details for PubMedID 27191700

  • Multiple Citation Indicators and Their Composite across Scientific Disciplines. PLoS biology Ioannidis, J. P., Klavans, R., Boyack, K. W. 2016; 14 (7)

    Abstract

    Many fields face an increasing prevalence of multi-authorship, and this poses challenges in assessing citation metrics. Here, we explore multiple citation indicators that address total impact (number of citations, Hirsch H index [H]), co-authorship adjustment (Schreiber Hm index [Hm]), and author order (total citations to papers as single; single or first; or single, first, or last author). We demonstrate the correlation patterns between these indicators across 84,116 scientists (those among the top 30,000 for impact in a single year [2013] in at least one of these indicators) and separately across 12 scientific fields. Correlation patterns vary across these 12 fields. In physics, total citations are highly negatively correlated with indicators of co-authorship adjustment and of author order, while in other sciences the negative correlation is seen only for total citation impact and citations to papers as single author. We propose a composite score that sums standardized values of these six log-transformed indicators. Of the 1,000 top-ranked scientists with the composite score, only 322 are in the top 1,000 based on total citations. Many Nobel laureates and other extremely influential scientists rank among the top-1,000 with the composite indicator, but would rank much lower based on total citations. Conversely, many of the top 1,000 authors on total citations have had no single/first/last-authored cited paper. More Nobel laureates of 2011-2015 are among the top authors when authors are ranked by the composite score than by total citations, H index, or Hm index; 40/47 of these laureates are among the top 30,000 by at least one of the six indicators. We also explore the sensitivity of indicators to self-citation and alphabetic ordering of authors in papers across different scientific fields. Multiple indicators and their composite may give a more comprehensive picture of impact, although no citation indicator, single or composite, can be expected to select all the best scientists.

    View details for DOI 10.1371/journal.pbio.1002501

    View details for PubMedID 27367269

    View details for PubMedCentralID PMC4930269

  • Inadequacies of 'Inadequacies of Physical Examination' Reply AMERICAN JOURNAL OF MEDICINE Verghese, A., Charlton, B., Kassirer, J. P., Ramsey, M., Ioannidis, J. A. 2016; 129 (7): E85

    View details for DOI 10.1016/j.amjmed.2016.02.034

    View details for Web of Science ID 000378065800016

    View details for PubMedID 27320713

  • Long noncoding RNAs as novel predictors of survival in human cancer: a systematic review and meta-analysis MOLECULAR CANCER Serghiou, S., Kyriakopoulou, A., Ioannidis, J. P. 2016; 15

    Abstract

    Expression of various long noncoding RNAs (lncRNAs) may affect cancer prognosis. Here, we aim to gather and examine all evidence on the potential role of lncRNAs as novel predictors of survival in human cancer.We systematically searched through PubMed, to identify all published studies reporting on the association between any individual lncRNA or group of lncRNAs with prognosis in human cancer (death or other clinical outcomes). Where appropriate, we then performed quantitative synthesis of those results using meta-analytic methods to identify the true effect size of lncRNAs on cancer prognosis. The reliability of those results was then examined using measures of heterogeneity and testing for selective reporting biases.Three hundred ninety-two studies were screened to eventually identify 111 eligible studies on 127 datasets. In total, these represented 16,754 independent participants pertaining to 53 individual and 6 grouped lncRNAs within a total of 19 cancer sites. Overall, 83 % of the studies we identified addressed overall survival and 32 % of the studies addressed recurrence-free survival. For overall survival, 96 % (88/92) of studies identified a statistically significant association of lncRNA expression to prognosis. Meta-analysis of 6 out of 7 lncRNAs for which three or more studies were available, identified statistically significant associations with overall survival. The lncRNA HOTAIR was by far the most broadly studied lncRNA (n = 29; of 111 studies) and featured a summary hazard ratio (HR) of 2.22 (95 % confidence interval (CI), 1.86-2.65) with modest heterogeneity (I(2) = 49 %; 95 % CI, 14-79 %). Prominent excess significance was demonstrated across all meta-analyses (p-value = 0.0003), raising the possibility of substantial selective reporting biases.Multiple lncRNAs have been shown to be strongly associated with prognosis in diverse cancers, but substantial bias cannot be excluded in this field and larger studies are needed to understand whether these prognostic information may eventually be useful.

    View details for DOI 10.1186/s12943-016-0535-1

    View details for Web of Science ID 000379401400001

    View details for PubMedID 27352941

    View details for PubMedCentralID PMC4924330

  • Response to Therapy in Antiretroviral Therapy-Naive Patients With Isolated Nonnucleoside Reverse Transcriptase Inhibitor-Associated Transmitted Drug Resistance JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Clutter, D. S., Fessel, W. J., Rhee, S., Hurley, L. B., Klein, D. B., Ioannidis, J. P., Silverberg, M. J., Shafer, R. W. 2016; 72 (2): 171-176

    Abstract

    Nonnucleoside reverse-transcriptase inhibitor (NNRTI)-associated transmitted drug resistance (TDR) is the most common type of TDR. Few data guide the selection of antiretroviral therapy (ART) for patients with such resistance.We reviewed treatment outcomes in a cohort of HIV-1-infected patients with isolated NNRTI TDR who initiated ART between April 2002 and May 2014. In an as-treated analysis, virological failure (VF) was defined as not reaching undetectable virus levels within 24 weeks, virological rebound, or switching regimens during viremia. In an intention-to-treat (ITT) analysis, failure was defined more broadly as VF, loss to follow-up (LTFU), and switching during virological suppression.Of 3,245 patients, 131 (4.0%) had isolated NNRTI TDR. 122 received a standard regimen comprising two NRTIs plus a boosted protease inhibitor (bPI; n=54), an integrase strand transfer inhibitor (INSTI; n=52), or an NNRTI (n=16). The median follow-up was 100 weeks. In the as-treated analysis, VF occurred in 15% (n=8), 2% (n=1) and 25% (n=4) of patients in the bPI, INSTI and NNRTI groups, respectively. In multivariate regression, there was a trend toward a lower risk of VF with INSTIs than with bPIs (HR 0.14; 95% CI, 0.02,1.1; p = 0.07). In ITT multivariate regression, INSTIs had a lower risk of failure than bPIs (HR 0.38; 95% CI, 0.18,0.82; p = 0.01).Patients with isolated NNRTI TDR experienced low VF rates with INSTIs and bPIs. INSTIs were non-inferior to bPIs in an analysis of VF but superior to bPIs when frequency of switching and LTFU were also considered.

    View details for Web of Science ID 000378059300017

    View details for PubMedID 26855248

  • We need more randomized trials in nutrition-preferably large, long-term, and with negative results AMERICAN JOURNAL OF CLINICAL NUTRITION Ioannidis, J. A. 2016; 103 (6): 1385–86

    View details for DOI 10.3945/ajcn.116.136085

    View details for Web of Science ID 000377054000003

    View details for PubMedID 27146649

  • Why Most Clinical Research Is Not Useful PLOS MEDICINE Ioannidis, J. P. 2016; 13 (6)

    Abstract

    John Ioannidis argues that problem base, context placement, information gain, pragmatism, patient centeredness, value for money, feasibility, and transparency define useful clinical research. He suggests most clinical research is not useful and reform is overdue.

    View details for DOI 10.1371/journal.pmed.1002049

    View details for Web of Science ID 000379128200003

    View details for PubMedID 27328301

  • Exposure-wide epidemiology: revisiting Bradford Hill STATISTICS IN MEDICINE Ioannidis, J. P. 2016; 35 (11): 1749-1762

    Abstract

    Fifty years after Bradford Hill published his extremely influential criteria to offer some guides for separating causation from association, we have accumulated millions of papers and extensive data on observational research that depends on epidemiologic methods and principles. This allows us to re-examine the accumulated empirical evidence for the nine criteria, and to re-approach epidemiology through the lens of exposure-wide approaches. The lecture discusses the evolution of these exposure-wide approaches and tries to use the evidence from meta-epidemiologic assessments to reassess each of the nine criteria and whether they work well as guides for causation. I argue that of the nine criteria, experiment remains important and consistency (replication) is also very essential. Temporality also makes sense, but it is often difficult to document. Of the other six criteria, strength mostly does not work and may even have to be inversed: small and even tiny effects are more plausible than large effects; when large effects are seen, they are mostly transient and almost always represent biases and errors. There is little evidence for specificity in causation in nature. Biological gradient is often unclear how it should it modeled and thus difficult to prove. Coherence remains usually unclear how to operationalize. Finally, plausibility as well as analogy do not work well in most fields of investigation, and their invocation has been mostly detrimental, although exceptions may exist. Copyright © 2015 John Wiley & Sons, Ltd.

    View details for DOI 10.1002/sim.6825

    View details for Web of Science ID 000373935700001

    View details for PubMedID 26646432

  • Prevalence and Characteristics of Interventional Trials Conducted Exclusively in Elderly Persons: A Cross-Sectional Analysis of Registered Clinical Trials PLOS ONE Bourgeois, F. T., Olson, K. L., Tse, T., Ioannidis, J. P., Mandl, K. D. 2016; 11 (5)

    Abstract

    Elderly patients represent the greatest consumers of healthcare per capita but have historically been underrepresented in clinical trials. It is unknown how many trials are designed to focus exclusively on elderly patients.To define the prevalence of interventional trials that study exclusively elderly persons and describe the characteristics of these trials, including their distribution across conditions most prevalent in the elderly.All interventional clinical trials enrolling exclusively elderly patients (≥65 years), conducted primarily in high-income countries, and initiated between 2006 and 2014, identified through ClincialTrials.gov.Trials were identified and characterized according to design features and disease categories studied. Across disease categories we examined the burden of disease in the elderly in high-income countries (measured in disability-adjusted life years [DALYs]) and compared to the number of trials conducted exclusively in the elderly.Among 80,965 interventional trials, 1,112 (1.4%) focused on elderly patients. Diverse types of interventions were studied in these trials (medications 33%, behavioral interventions 18%, and dietary supplements 10%) and the majority was funded by non-profit organizations (81%). Studies tended to be small (median sample size 122 participants [IQR 58, 305]), single-center studies (67%). Only 43% of 126 disease categories affecting elderly persons were studied in trials focused on the elderly. Among these disease categories, there was a 5162-fold range in the ratio of DALYs per trial. Across 5 conditions where over 80% of DALYs are in the elderly, there were a total of only 117 trials done exclusively in the elderly.Very few and mostly small studies are conducted exclusively in elderly persons, even for conditions that affect almost exclusively the elderly.

    View details for DOI 10.1371/journal.pone.0155948

    View details for Web of Science ID 000376291100140

    View details for PubMedID 27196289

    View details for PubMedCentralID PMC4873036

  • Routinely collected data and comparative effectiveness evidence: promises and limitations CANADIAN MEDICAL ASSOCIATION JOURNAL Hemkens, L. G., Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2016; 188 (8): E158-E164

    View details for DOI 10.1503/cmaj.150653

    View details for Web of Science ID 000379981400009

    View details for PubMedID 26883316

  • The departure/flight of Greek scientists. A meta-analysis ARCHIVES OF HELLENIC MEDICINE Ioannidis, J. A. 2016; 33 (3): 297–306
  • Obtaining evidence by a single well-powered trial or several modestly powered trials STATISTICAL METHODS IN MEDICAL RESEARCH IntHout, J., Ioannidis, J. P., Borm, G. F. 2016; 25 (2): 538-552

    Abstract

    There is debate whether clinical trials with suboptimal power are justified and whether results from large studies are more reliable than the (combined) results of smaller trials. We quantified the error rates for evaluations based on single conventionally powered trials (80% or 90% power) versus evaluations based on the random-effects meta-analysis of a series of smaller trials. When a treatment was assumed to have no effect but heterogeneity was present, the error rates for a single trial were increased more than 10-fold above the nominal rate, even for low heterogeneity. Conversely, for meta-analyses on a series of trials, the error rates were correct. When selective publication was present, the error rates were always increased, but they still tended to be lower for a series of trials than single trials. We conclude that evidence of efficacy based on a series of (smaller) trials, may lower the error rates compared with using a single well-powered trial. Only when both heterogeneity and selective publication can be excluded, a single trial is able to provide conclusive evidence.

    View details for DOI 10.1177/0962280212461098

    View details for Web of Science ID 000374792800003

    View details for PubMedID 23070590

  • Biases in obesity research: Identify, correct, endorse, or abandon effort? OBESITY Ioannidis, J. A. 2016; 24 (4): 767

    View details for DOI 10.1002/oby.21457

    View details for Web of Science ID 000373613200001

    View details for PubMedID 27028277

  • Non-randomised Ebola trials-lessons for optimal outbreak research LANCET INFECTIOUS DISEASES Ippolito, G., Lanini, S., Brouqui, P., Di Caro, A., Vairo, F., Fusco, F., Krishna, S., Capobianchi, M., Kyobe-Bosa, H., Puro, V., Woelfel, R., Avsic-Zupanc, T., Ioannidis, J. A., Portella, G., Kremsner, P., Dar, O., Bates, M., Zumla, A. 2016; 16 (4): 407–8
  • Current use of routinely collected health data to complement randomized controlled trials: a meta-epidemiological survey. CMAJ open Hemkens, L. G., Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2016; 4 (2): E132-40

    Abstract

    Studies that use routinely collected health data (RCD studies) are advocated to complement evidence from randomized controlled trials (RCTs) for comparative effectiveness research and to inform health care decisions when RCTs would be unfeasible. We aimed to evaluate the current use of routinely collected health data to complement RCT evidence.We searched PubMed for RCD studies published to 2010 that evaluated the comparative effectiveness of medical treatments on mortality using propensity scores. We identified RCTs of the same treatment comparisons and evaluated how frequently the RCD studies analyzed treatments that had not been compared previously in randomized trials. When RCTs did exist, we noted the claimed motivations for each RCD study. We also analyzed the citation impact of the RCD studies.Of 337 eligible RCD studies identified, 231 (68.5%) analyzed treatments that had already been compared in RCTs. The study investigators rarely claimed that it would be unethical (6/337) or difficult (18/337) to perform RCTs on the same question. Evidence from RCTs was mentioned or cited by authors of 213 RCD studies. The most common motivations for conducting the RCD studies were alleged limited generalizability of trial results to the "real world" (37.6%), evaluation of specific outcomes (31.9%) or specific populations (23.5%), and inconclusive or inconsistent evidence from randomized trials (25.8%). Studies evaluating "real world" effects had the lowest citation impact.Most of the RCD studies we identified explored comparative treatment effects that had already been investigated in RCTs. The objective of such studies needs to shift more toward answering pivotal questions that are not supported by trial evidence or for which RCTs would be unfeasible.

    View details for DOI 10.9778/cmajo.20150036

    View details for PubMedID 27398355

    View details for PubMedCentralID PMC4933635

  • Generic versus brand-name drugs used in cardiovascular diseases EUROPEAN JOURNAL OF EPIDEMIOLOGY Manzoli, L., Flacco, M. E., Boccia, S., D'Andrea, E., Panic, N., Marzuillo, C., Siliquini, R., Ricciardi, W., Villari, P., Ioannidis, J. P. 2016; 31 (4): 351-368

    Abstract

    This meta-analysis aimed to compare the efficacy and adverse events, either serious or mild/moderate, of all generic versus brand-name cardiovascular medicines. We searched randomized trials in MEDLINE, Scopus, EMBASE, Cochrane Controlled Clinical Trial Register, and ClinicalTrials.gov (last update December 1, 2014). Attempts were made to contact the investigators of all potentially eligible trials. Two investigators independently extracted and analyzed soft (including systolic blood pressure, LDL cholesterol, and others) and hard efficacy outcomes (including major cardiovascular adverse events and death), minor/moderate and serious adverse events. We included 74 randomized trials; 53 reported ≥1 efficacy outcome (overall sample 3051), 32 measured mild/moderate adverse events (n = 2407), and 51 evaluated serious adverse events (n = 2892). We included trials assessing ACE inhibitors (n = 12), anticoagulants (n = 5), antiplatelet agents (n = 17), beta-blockers (n = 11), calcium channel blockers (n = 7); diuretics (n = 13); statins (n = 6); and others (n = 3). For both soft and hard efficacy outcomes, 100 % of the trials showed non-significant differences between generic and brand-name drugs. The aggregate effect size was 0.01 (95 % CI -0.05; 0.08) for soft outcomes; -0.06 (-0.71; 0.59) for hard outcomes. All but two trials showed non-significant differences in mild/moderate adverse events, and aggregate effect size was 0.07 (-0.06; 0.20). Comparable results were observed for each drug class and in each stratified meta-analysis. Overall, 8 serious possibly drug-related adverse events were reported: 5/2074 subjects on generics; 3/2076 subjects on brand-name drugs (OR 1.69; 95 % CI 0.40-7.20). This meta-analysis strengthens the evidence for clinical equivalence between brand-name and generic cardiovascular drugs. Physicians could be reassured about prescribing generic cardiovascular drugs, and health care organization about endorsing their wider use.

    View details for DOI 10.1007/s10654-015-0104-8

    View details for Web of Science ID 000376675000003

    View details for PubMedID 26620809

  • Clinical Genomics: From Pathogenicity Claims to Quantitative Risk Estimates. JAMA Manrai, A. K., Ioannidis, J. P., Kohane, I. S. 2016; 315 (12): 1233-1234

    View details for DOI 10.1001/jama.2016.1519

    View details for PubMedID 26925924

  • Field-wide meta-analyses of observational associations can map selective availability of risk factors and the impact of model specifications JOURNAL OF CLINICAL EPIDEMIOLOGY Serghiou, S., Patel, C. J., Tan, Y. Y., Koay, P., Ioannidis, J. P. 2016; 71: 58-67

    Abstract

    Instead of evaluating one risk factor at a time, we illustrate the utility of "field-wide meta-analyses" in considering all available data on all putative risk factors of a disease simultaneously.We identified studies on putative risk factors of pterygium (surfer's eye) in PubMed, EMBASE, and Web of Science. We mapped which factors were considered, reported, and adjusted for in each study. For each putative risk factor, four meta-analyses were done using univariate only, multivariate only, preferentially univariate, or preferentially multivariate estimates.A total of 2052 records were screened to identify 60 eligible studies reporting on 65 putative risk factors. Only 4 of 60 studies reported both multivariate and univariate regression analyses. None of the 32 studies using multivariate analysis adjusted for the same set of risk factors. Effect sizes from different types of regression analyses led to significantly different summary effect sizes (P-value < 0.001). Observed heterogeneity was very high for both multivariate (median I(2), 76.1%) and univariate (median I(2), 85.8%) estimates. No single study investigated all 11 risk factors that were statistically significant in at least one of our meta-analyses.Field-wide meta-analyses can map availability of risk factors and trends in modeling, adjustments and reporting, as well as the impact of differences in model specification.

    View details for DOI 10.1016/j.jclinepi.2015.09.004

    View details for Web of Science ID 000370908900009

    View details for PubMedID 26415577

    View details for PubMedCentralID PMC5108175

  • Prediction of Melanoma Risk in a Southern European Population Based on a Weighted Genetic Risk Score JOURNAL OF INVESTIGATIVE DERMATOLOGY Kypreou, K. P., Stefanaki, I., Antonopoulou, K., Karagianni, F., Ntritsos, G., Zaras, A., Nikolaou, V., Kalfa, I., Chasapi, V., Polydorou, D., Gogas, H., Spyrou, G. M., Bertram, L., Lill, C. M., Ioannidis, J. P., Antoniou, C., Evangelou, E., Stratigos, A. I. 2016; 136 (3): 690-695

    Abstract

    Many single nucleotide polymorphisms (SNPs) have been described as putative risk factors for melanoma. The aim of our study was to validate the most prominent genetic risk loci in an independent Greek melanoma case-control dataset and to assess their cumulative effect solely or combined with established phenotypic risk factors on individualized risk prediction. We genotyped 59 SNPs in 800 patients and 800 controls and tested their association with melanoma using logistic regression analyses. We constructed a weighted genetic risk score (GRSGWS) based on SNPs that showed genome-wide significant (GWS) association with melanoma in previous studies and assessed their impact on risk prediction. Fifteen independent SNPs from 12 loci were significantly associated with melanoma (P < 0.05). Risk score analysis yielded an odds ratio of 1.36 per standard deviation increase of the GRSGWS (P = 1.1 × 10(-7)). Individuals in the highest 20% of the GRSGWS had a 1.88-fold increase in melanoma risk compared with those in the middle quintile. By adding the GRSGWS to a phenotypic risk model, the C-statistic increased from 0.764 to 0.775 (P = 0.007). In summary, the GRSGWS is associated with melanoma risk and achieves a modest improvement in risk prediction when added to a phenotypic risk model.

    View details for DOI 10.1016/j.jid.2015.12.007

    View details for Web of Science ID 000370623100024

  • p-Curve and p-Hacking in Observational Research PLOS ONE Bruns, S. B., Ioannidis, J. P. 2016; 11 (2)

    Abstract

    The p-curve, the distribution of statistically significant p-values of published studies, has been used to make inferences on the proportion of true effects and on the presence of p-hacking in the published literature. We analyze the p-curve for observational research in the presence of p-hacking. We show by means of simulations that even with minimal omitted-variable bias (e.g., unaccounted confounding) p-curves based on true effects and p-curves based on null-effects with p-hacking cannot be reliably distinguished. We also demonstrate this problem using as practical example the evaluation of the effect of malaria prevalence on economic growth between 1960 and 1996. These findings call recent studies into question that use the p-curve to infer that most published research findings are based on true effects in the medical literature and in a wide range of disciplines. p-values in observational research may need to be empirically calibrated to be interpretable with respect to the commonly used significance threshold of 0.05. Violations of randomization in experimental studies may also result in situations where the use of p-curves is similarly unreliable.

    View details for DOI 10.1371/journal.pone.0149144

    View details for Web of Science ID 000371218400062

    View details for PubMedID 26886098

    View details for PubMedCentralID PMC4757561

  • Agreement of treatment effects for mortality from routinely collected data and subsequent randomized trials: meta-epidemiological survey BMJ-BRITISH MEDICAL JOURNAL Hemkens, L. G., Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2016; 352

    Abstract

     To assess differences in estimated treatment effects for mortality between observational studies with routinely collected health data (RCD; that are published before trials are available) and subsequent evidence from randomized controlled trials on the same clinical question. Meta-epidemiological survey. PubMed searched up to November 2014. Eligible RCD studies were published up to 2010 that used propensity scores to address confounding bias and reported comparative effects of interventions for mortality. The analysis included only RCD studies conducted before any trial was published on the same topic. The direction of treatment effects, confidence intervals, and effect sizes (odds ratios) were compared between RCD studies and randomized controlled trials. The relative odds ratio (that is, the summary odds ratio of trial(s) divided by the RCD study estimate) and the summary relative odds ratio were calculated across all pairs of RCD studies and trials. A summary relative odds ratio greater than one indicates that RCD studies gave more favorable mortality results. The evaluation included 16 eligible RCD studies, and 36 subsequent published randomized controlled trials investigating the same clinical questions (with 17 275 patients and 835 deaths). Trials were published a median of three years after the corresponding RCD study. For five (31%) of the 16 clinical questions, the direction of treatment effects differed between RCD studies and trials. Confidence intervals in nine (56%) RCD studies did not include the RCT effect estimate. Overall, RCD studies showed significantly more favorable mortality estimates by 31% than subsequent trials (summary relative odds ratio 1.31 (95% confidence interval 1.03 to 1.65; I(2)=0%)). Studies of routinely collected health data could give different answers from subsequent randomized controlled trials on the same clinical questions, and may substantially overestimate treatment effects. Caution is needed to prevent misguided clinical decision making.

    View details for DOI 10.1136/bmj.i493

    View details for Web of Science ID 000370380000002

    View details for PubMedID 26858277

    View details for PubMedCentralID PMC4772787

  • Registration practices for observational studies on ClinicalTrials.gov indicated low adherence. Journal of clinical epidemiology Boccia, S., Rothman, K. J., Panic, N., Flacco, M. E., Rosso, A., Pastorino, R., Manzoli, L., La Vecchia, C., Villari, P., Boffetta, P., Ricciardi, W., Ioannidis, J. P. 2016; 70: 176-182

    Abstract

    The study aims to assess the status of registration of observational studies.We identified studies on cancer research with prospective recruitment of participants that were registered from February 2000 to December 2011 in ClinicalTrials.gov. We recorded the dates of registration and start of recruitment, outcomes, and description of statistical method. We searched for publications corresponding to the registered studies through May 31, 2014.One thousand one hundred nine registered studies were eligible. Primary and secondary outcomes were reported in 809 (73.0%) and 464 (41.8%) of them. The date of registration preceded the month of the study start in 145 (13.8%) and coincided in 205 (19.5%). A total of 151 publications from 120 (10.8%) registered studies were identified. In 2 (33.3%) of the 6 publications where ClinicalTrials.gov reported that the study started recruitment after registration, and in 9 (50.0%) of 18 publications where ClinicalTrials.gov reported the same date for registration and start of recruitment, the articles showed that the study had actually started recruiting before registration.During the period reviewed, few observational studies have been registered. Registration usually occurred after the study started, and prespecification of outcomes and statistical analysis rarely occurred.

    View details for DOI 10.1016/j.jclinepi.2015.09.009

    View details for PubMedID 26386325

  • Meta-analyses with industry involvement are massively published and report no caveats for antidepressants. Journal of clinical epidemiology Ebrahim, S., Bance, S., Athale, A., Malachowski, C., Ioannidis, J. P. 2016; 70: 155-163

    Abstract

    To identify the impact of industry involvement in the publication and interpretation of meta-analyses of antidepressant trials in depression.Using MEDLINE, we identified all meta-analyses evaluating antidepressants for depression published in January 2007-March 2014. We extracted data pertaining to author affiliations, conflicts of interest, and whether the conclusion of the abstract included negative statements on whether the antidepressant(s) were effective or safe.We identified 185 eligible meta-analyses. Fifty-four meta-analyses (29%) had authors who were employees of the assessed drug manufacturer, and 147 (79%) had some industry link (sponsorship or authors who were industry employees and/or had conflicts of interest). Only 58 meta-analyses (31%) had negative statements in the concluding statement of the abstract. Meta-analyses including an author who were employees of the manufacturer of the assessed drug were 22-fold less likely to have negative statements about the drug than other meta-analyses [1/54 (2%) vs. 57/131 (44%); P < 0.001].There is a massive production of meta-analyses of antidepressants for depression authored by or linked to the industry, and they almost never report any caveats about antidepressants in their abstracts. Our findings add a note of caution for meta-analyses with ties to the manufacturers of the assessed products.

    View details for DOI 10.1016/j.jclinepi.2015.08.021

    View details for PubMedID 26399904

  • Environmental risk factors and Parkinson's disease: An umbrella review of meta-analyses. Parkinsonism & related disorders Bellou, V., Belbasis, L., Tzoulaki, I., Evangelou, E., Ioannidis, J. P. 2016; 23: 1-9

    Abstract

    Parkinson's disease is a neurological disorder with complex pathogenesis implicating both environmental and genetic factors. We aimed to summarise the environmental risk factors that have been studied for potential association with Parkinson's disease, assess the presence of diverse biases, and identify the risk factors with the strongest support.We searched PubMed from inception to September 18, 2015, to identify systematic reviews and meta-analyses of observational studies that examined associations between environmental factors and Parkinson's disease. For each meta-analysis we estimated the summary effect size by random-effects and fixed-effects models, the 95% confidence interval and the 95% prediction interval. We estimated the between-study heterogeneity expressed by I(2), evidence of small-study effects and evidence of excess significance bias.Overall, 75 unique meta-analyses on different risk factors for Parkinson's disease were examined, covering diverse biomarkers, dietary factors, drugs, medical history or comorbid diseases, exposure to toxic environmental agents and habits. 21 of 75 meta-analyses had results that were significant at p < 0.001 by random-effects. Evidence for an association was convincing (more than 1000 cases, p < 10(-6) by random-effects, not large heterogeneity, 95% prediction interval excluding the null value and absence of hints for small-study effects and excess significance bias) for constipation, and physical activity.Many environmental factors have substantial evidence of association with Parkinson's disease, but several, perhaps most, of them may reflect reverse causation, residual confounding, information bias, sponsor conflicts or other caveats.

    View details for DOI 10.1016/j.parkreldis.2015.12.008

    View details for PubMedID 26739246

  • PRISMA harms checklist: improving harms reporting in systematic reviews BMJ-BRITISH MEDICAL JOURNAL Zorzela, L., Loke, Y. K., Ioannidis, J. P., Golder, S., Santaguida, P., Altman, D. G., Moher, D., Vohra, S. 2016; 352

    Abstract

     For any health intervention, accurate knowledge of both benefits and harms is needed. Systematic reviews often compound poor reporting of harms in primary studies by failing to report harms or doing so inadequately. While the PRISMA statement (Preferred Reporting Items for Systematic reviews and Meta-Analyses) helps systematic review authors ensure complete and transparent reporting, it is focused mainly on efficacy. Thus, a PRISMA harms checklist has been developed to improve harms reporting in systematic reviews, promoting a more balanced assessment of benefits and harms. A development strategy, endorsed by the EQUATOR Network and existing reporting guidelines (including the PRISMA statement, PRISMA for abstracts, and PRISMA for protocols), was used. After the development of a draft checklist of items, a modified Delphi process was initiated. The Delphi consisted of three rounds of electronic feedback followed by an in-person meeting. The PRISMA harms checklist contains four essential reporting elements to be added to the original PRISMA statement to improve harms reporting in reviews. These are reported in the title ("Specifically mention 'harms' or other related terms, or the harm of interest in the review"), synthesis of results ("Specify how zero events were handled, if relevant"), study characteristics ("Define each harm addressed, how it was ascertained (eg, patient report, active search), and over what time period"), and synthesis of results ("Describe any assessment of possible causality"). Additional guidance regarding existing PRISMA items was developed to demonstrate relevance when synthesising information about harms. The PRISMA harms checklist identifies a minimal set of items to be reported when reviewing adverse events. This guideline extension is intended to improve harms reporting in systematic reviews, whether harms are a primary or secondary outcome.

    View details for DOI 10.1136/bmj.i157

    View details for Web of Science ID 000369766400002

    View details for PubMedID 26830668

  • Anticipating consequences of sharing raw data and code and of awarding badges for sharing. Journal of clinical epidemiology Ioannidis, J. P. 2016; 70: 258-260

    View details for DOI 10.1016/j.jclinepi.2015.04.015

    View details for PubMedID 26163123

  • Reply to letter by Ferrante di Ruffano et al.: Patient outcomes in randomized comparisons of diagnostic tests are still the ultimate judge JOURNAL OF CLINICAL EPIDEMIOLOGY Siontis, K. C., Siontis, G. C., Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2016; 69: 267-268
  • Response to letter by Forike et al.: more rigorous, not less, external validation is needed JOURNAL OF CLINICAL EPIDEMIOLOGY Siontis, G. M., Ioannidis, J. A. 2016; 69: 250–51
  • METHODS TO ENHANCE THE REPRODUCIBILITY OF PRECISION MEDICINE. Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing Manrai, A. K., Patel, C. J., Gehlenborg, N., Tatonetti, N. P., Ioannidis, J. P., Kohane, I. S. 2016; 21: 180-182

    View details for PubMedID 28004011

    View details for PubMedCentralID PMC5167531

  • Transparent Communication of Radiology Research: Reporting Guidelines and Beyond. Academic radiology Lu, Y., Ioannidis, J. P. 2016; 23 (5): 529–30

    View details for DOI 10.1016/j.acra.2016.02.009

    View details for PubMedID 27017133

  • Plea for routinely presenting prediction intervals in meta-analysis BMJ OPEN IntHout, J., Ioannidis, J. P., Rovers, M. M., Goeman, J. J. 2016; 6 (7)

    Abstract

    Evaluating the variation in the strength of the effect across studies is a key feature of meta-analyses. This variability is reflected by measures like τ(2) or I(2), but their clinical interpretation is not straightforward. A prediction interval is less complicated: it presents the expected range of true effects in similar studies. We aimed to show the advantages of having the prediction interval routinely reported in meta-analyses.We show how the prediction interval can help understand the uncertainty about whether an intervention works or not. To evaluate the implications of using this interval to interpret the results, we selected the first meta-analysis per intervention review of the Cochrane Database of Systematic Reviews Issues 2009-2013 with a dichotomous (n=2009) or continuous (n=1254) outcome, and generated 95% prediction intervals for them.In 72.4% of 479 statistically significant (random-effects p<0.05) meta-analyses in the Cochrane Database 2009-2013 with heterogeneity (I(2)>0), the 95% prediction interval suggested that the intervention effect could be null or even be in the opposite direction. In 20.3% of those 479 meta-analyses, the prediction interval showed that the effect could be completely opposite to the point estimate of the meta-analysis. We demonstrate also how the prediction interval can be used to calculate the probability that a new trial will show a negative effect and to improve the calculations of the power of a new trial.The prediction interval reflects the variation in treatment effects over different settings, including what effect is to be expected in future patients, such as the patients that a clinician is interested to treat. Prediction intervals should be routinely reported to allow more informative inferences in meta-analyses.

    View details for DOI 10.1136/bmjopen-2015-010247

    View details for Web of Science ID 000382252100059

    View details for PubMedID 27406637

    View details for PubMedCentralID PMC4947751

  • Systematic assessment of pharmaceutical prescriptions in association with cancer risk: a method to conduct a population-wide medication-wide longitudinal study. Scientific reports Patel, C. J., Ji, J., Sundquist, J., Ioannidis, J. P., Sundquist, K. 2016; 6: 31308-?

    Abstract

    It is a public health priority to identify the adverse and non-adverse associations between pharmaceutical medications and cancer. We search for and evaluate associations between all prescribed medications and longitudinal cancer risk in participants of the Swedish Cancer Register (N = 9,014,975). We associated 552 different medications with incident cancer risk (any, breast, colon, and prostate) during 5.5 years of follow-up (7/1/2005-12/31/2010) in two types of statistical models, time-to-event and case-crossover. After multiple hypotheses correction and replication, 141 (26%) drugs were associated with any cancer in a time-to-event analysis constraining drug exposure to 1 year before first cancer diagnosis and adjusting for history of medication use. In a case-crossover analysis, 36 drugs (7%) were associated with decreased cancer risk. 12 drugs were found in common in both analyses with concordant direction of association. We found 14, 10, 7% of all drugs associated with colon, prostate, and breast cancers in time-to-event models. We only found 1, 2%, and 0% for these cancers, respectively, in case-crossover analyses. Pharmacoepidemiologic analyses of cancer risk are sensitive to modeling choices and false-positive findings are a threat. Medication-wide analyses using different analytical models may help suggest consistent signals of increased cancer risk.

    View details for DOI 10.1038/srep31308

    View details for PubMedID 27507038

    View details for PubMedCentralID PMC4979093

  • METHODS TO ENHANCE THE REPRODUCIBILITY OF PRECISION MEDICINE. Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing Manrai, A. K., Patel, C. J., Gehlenborg, N., Tatonetti, N. P., Ioannidis, J. P., Kohane, I. S. 2016; 21: 180-182

    Abstract

    During January 2015, President Obama announced the Precision Medicine Initiative [1], strengthening communal efforts to integrate patient-centric molecular, environmental, and clinical "big" data. Such efforts have already improved aspects of clinical management for diseases such as non-small cell lung carcinoma [2], breast cancer [3], and hypertrophic cardiomyopathy [4]. To maintain this track record, it is necessary to cultivate practices that ensure reproducibility as large-scale heterogeneous datasets and databases proliferate. For example, the NIH has outlined initiatives to enhance reproducibility in preclinical research [5], both Science [6] and Nature [7] have featured recent editorials on reproducibility, and several authors have noted the issues of utilizing big data for public health [8], but few methods exist to ensure that big data resources motivated by precision medicine are being used reproducibly. Relevant challenges include: (1) integrative analyses of heterogeneous measurement platforms (e.g. genomic, clinical, quantified self, and exposure data), (2) the tradeoff in making personalized decisions using more targeted (e.g. individual-level) but potentially much noisier subsets of data, and (3) the unprecedented scale of asynchronous observational and population level inquiry (i.e. many investigators separately mining shared/publicly-available data)….

    View details for PubMedID 26776184

  • Commentary: Salt and the assault of opinion on evidence. International journal of epidemiology Ioannidis, J. P. 2016

    View details for DOI 10.1093/ije/dyw015

    View details for PubMedID 26888871

  • Academic criteria for appointment, promotion and rewards in medical research: where's the evidence? European journal of clinical investigation Moher, D., Goodman, S. N., Ioannidis, J. P. 2016

    Abstract

    It has been argued that incentive systems should be multi-dimensional, including productivity, quality, reproducibility, sharing, and translation potential ("PQRST"),(1) but many current systems weight productivity particularly heavily. These systems directly affect the volume, and indirectly the quality of the scientific publication record. This was recognized at least as far back as the 1980s, with a proposal that promotion committees consider only a handful of a scientist's publications, in the hopes of improving the quality of our "large and largely trivial" literature. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/eci.12612

    View details for PubMedID 26924551

  • Korean National Health Insurance Database Reply JAMA INTERNAL MEDICINE Hsing, A., Ioannidis, J. P. 2016; 176 (1): 138-139

    View details for Web of Science ID 000367549100042

    View details for PubMedID 26747668

  • Noninferiority is almost certain with lenient noninferiority margins. Journal of clinical epidemiology Flacco, M. E., Manzoli, L., Ioannidis, J. P. 2016; 71: 118

    View details for DOI 10.1016/j.jclinepi.2015.11.010

    View details for PubMedID 26607237

  • Network meta-analyses performed by contracting companies and commissioned by industry. Systematic reviews Schuit, E., Ioannidis, J. P. 2016; 5 (1): 198

    Abstract

    BACKGROUND: Industry commissions contracting companies to perform network meta-analysis for health technology assessment (HTA) and reimbursement submissions. Our objective was to estimate the number of network meta-analyses performed by consulting companies contracted by industry, to assess whether they were published, and to explore reasons for non-publication.METHODS: We searched MEDLINE for network meta-analyses of randomized trials. Papers were included if they had authors affiliated with any contracting company. All identified contracting companies as well as additional ones from the list of the exhibitors at the International Society for Pharmacoeconomics and Outcomes Research, an annual meeting that representatives from many contracting companies attend and exhibit at, were surveyed regarding conduct and publication of network meta-analyses.RESULTS: In 162 of 822 (20%) network meta-analysis papers, authors were affiliated to 66 contracting companies. Another 36 contracting companies were identified by the exhibitors list. Three companies had no contact information and six merged with others, therefore 93 companies were contacted. Thirty seven out of ninety three (40%) companies responded, and 19 indicated that they had performed a total of 476 network meta-analyses, but only 102 (21%) papers were published. Thirteen companies that disclosed to have conducted 174 network meta-analyses (45 published) provided reasons for non-publication. Of the 129 still unpublished meta-analyses, for 40 there were plans for future publication, for 37 the sponsor did not allow publication, for 16 the contracting companies did not plan to publish the meta-analysis, for another 23 plans were unclear, and the remaining 13 were used as HTA submission. The protocol of the network meta-analysis was publically available from 11/162 (6.8%) network meta-analyses published by authors affiliated with contracting companies.CONCLUSIONS: There is a prolific sector of professional contracting companies that perform network meta-analyses. Industry commissions many network meta-analyses, but most are not registered before or published after analyses in the scientific literature. Mechanisms to improve publication rates of network meta-analysis commissioned by industry are warranted.

    View details for PubMedID 27884175

  • Diagnostic accuracy of the Depression subscale of the Hospital Anxiety and Depression Scale (HADS-D) for detecting major depression: protocol for a systematic review and individual patient data meta-analyses BMJ OPEN Thombs, B. D., Benedetti, A., Kloda, L. A., Levis, B., Azar, M., Riehm, K. E., Saadat, N., Cuijpers, P., Gilbody, S., Ioannidis, J. P., McMillan, D., Patten, S. B., Shrier, I., Steele, R. J., Ziegelstein, R. C., Loiselle, C. G., Henry, M., Ismail, Z., Mitchell, N., Tonelli, M. 2016; 6 (4)

    Abstract

    The Depression subscale of the Hospital Anxiety and Depression Scale (HADS-D) has been recommended for depression screening in medically ill patients. Many existing HADS-D studies have used exploratory methods to select optimal cut-offs. Often, these studies report results from a small range of cut-off thresholds; cut-offs with more favourable accuracy results are more likely to be reported than others with worse accuracy estimates. When published data are combined in meta-analyses, selective reporting may generate biased summary estimates. Individual patient data (IPD) meta-analyses can address this problem by estimating accuracy with data from all studies for all relevant cut-off scores. In addition, a predictive algorithm can be generated to estimate the probability that a patient has depression based on a HADS-D score and clinical characteristics rather than dichotomous screening classification alone. The primary objectives of our IPD meta-analyses are to determine the diagnostic accuracy of the HADS-D to detect major depression among adults across all potentially relevant cut-off scores and to generate a predictive algorithm for individual patients. We are already aware of over 100 eligible studies, and more may be identified with our comprehensive search.Data sources will include MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, PsycINFO and Web of Science. Eligible studies will have datasets where patients are assessed for major depression based on a validated structured or semistructured clinical interview and complete the HADS-D within 2 weeks (before or after). Risk of bias will be assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Bivariate random-effects meta-analysis will be conducted for the full range of plausible cut-off values, and a predictive algorithm for individual patients will be generated.The findings of this study will be of interest to stakeholders involved in research, clinical practice and policy.

    View details for DOI 10.1136/bmjopen-2016-011913

    View details for Web of Science ID 000376391400152

    View details for PubMedID 27075844

    View details for PubMedCentralID PMC4838677

  • Most psychotherapies do not really work, but those that might work should be assessed in biased studies. Epidemiology and psychiatric sciences Ioannidis, J. P. 2016: 1–3

    View details for DOI 10.1017/S2045796015000888

    View details for PubMedID 26952766

  • Inadequacies of Physical Examination as a Cause of Medical Errors and Adverse Events: A Collection of Vignettes. American journal of medicine Verghese, A., Charlton, B., Kassirer, J. P., Ramsey, M., Ioannidis, J. P. 2015; 128 (12): 1322-1324 e3

    Abstract

    Oversights in the physical examination are a type of medical error not easily studied by chart review. They may be a major contributor to missed or delayed diagnosis, unnecessary exposure to contrast and radiation, incorrect treatment, and other adverse consequences. Our purpose was to collect vignettes of physical examination oversights and to capture the diversity of their characteristics and consequences.A cross-sectional study using an 11-question qualitative survey for physicians was distributed electronically, with data collected from February to June of 2011. The participants were all physicians responding to e-mail or social media invitations to complete the survey. There were no limitations on geography, specialty, or practice setting.Of the 208 reported vignettes that met inclusion criteria, the oversight was caused by a failure to perform the physical examination in 63%; 14% reported that the correct physical examination sign was elicited but misinterpreted, whereas 11% reported that the relevant sign was missed or not sought. Consequence of the physical examination inadequacy included missed or delayed diagnosis in 76% of cases, incorrect diagnosis in 27%, unnecessary treatment in 18%, no or delayed treatment in 42%, unnecessary diagnostic cost in 25%, unnecessary exposure to radiation or contrast in 17%, and complications caused by treatments in 4%. The mode of the number of physicians missing the finding was 2, but many oversights were missed by many physicians. Most oversights took up to 5 days to identify, but 66 took longer. Special attention and skill in examining the skin and its appendages, as well as the abdomen, groin, and genitourinary area could reduce the reported oversights by half.Physical examination inadequacies are a preventable source of medical error, and adverse events are caused mostly by failure to perform the relevant examination.

    View details for DOI 10.1016/j.amjmed.2015.06.004

    View details for PubMedID 26144103

  • Comparative effectiveness of exercise and drug interventions on mortality outcomes: metaepidemiological study BRITISH JOURNAL OF SPORTS MEDICINE Naci, H., Ioannidis, J. P. 2015; 49 (21): 1414-1422

    Abstract

    To determine the comparative effectiveness of exercise versus drug interventions on mortality outcomes.Metaepidemiological study.Meta-analyses of randomised controlled trials with mortality outcomes comparing the effectiveness of exercise and drug interventions with each other or with control (placebo or usual care).Medline and Cochrane Database of Systematic Reviews, May 2013.Mortality.We combined study level death outcomes from exercise and drug trials using random effects network meta-analysis.We included 16 (four exercise and 12 drug) meta-analyses. Incorporating an additional three recent exercise trials, our review collectively included 305 randomised controlled trials with 339,274 participants. Across all four conditions with evidence on the effectiveness of exercise on mortality outcomes (secondary prevention of coronary heart disease, rehabilitation of stroke, treatment of heart failure, prevention of diabetes), 14,716 participants were randomised to physical activity interventions in 57 trials. No statistically detectable differences were evident between exercise and drug interventions in the secondary prevention of coronary heart disease and prediabetes. Physical activity interventions were more effective than drug treatment among patients with stroke (odds ratios, exercise vanticoagulants 0.09, 95% credible intervals 0.01 to 0.70 and exercise v antiplatelets 0.10, 0.01 to 0.62). Diuretics were more effective than exercise in heart failure (exercise v diuretics 4.11,1.17 to 24.76). Inconsistency between direct and indirect comparisons was not significant.Although limited in quantity, existing randomised trial evidence on exercise interventions suggests that exercise and many drug interventions are often potentially similar in terms of their mortality benefits in the secondary prevention of coronary heart disease, rehabilitation after stroke, treatment of heart failure, and prevention of diabetes.

    View details for DOI 10.1136/bjsports-2015-f5577rep

    View details for Web of Science ID 000363144200013

    View details for PubMedID 26476429

    View details for PubMedCentralID PMC4680125

  • Unhealthy stealth NEW SCIENTIST Ioannidis, J. 2015; 228 (3045): 26-+
  • Diagnosis of Parkinson's disease on the basis of clinical and genetic classification: a population-based modelling study. The Lancet. Neurology Nalls, M. A., McLean, C. Y., Rick, J., Eberly, S., Hutten, S. J., Gwinn, K., Sutherland, M., Martinez, M., Heutink, P., Williams, N. M., Hardy, J., Gasser, T., Brice, A., Price, T. R., Nicolas, A., Keller, M. F., Molony, C., Gibbs, J. R., Chen-Plotkin, A., Suh, E., Letson, C., Fiandaca, M. S., Mapstone, M., Federoff, H. J., Noyce, A. J., Morris, H., Van Deerlin, V. M., Weintraub, D., Zabetian, C., Hernandez, D. G., Lesage, S., Mullins, M., Conley, E. D., Northover, C. A., Frasier, M., Marek, K., Day-Williams, A. G., Stone, D. J., Ioannidis, J. P., Singleton, A. B. 2015; 14 (10): 1002-1009

    Abstract

    Accurate diagnosis and early detection of complex diseases, such as Parkinson's disease, has the potential to be of great benefit for researchers and clinical practice. We aimed to create a non-invasive, accurate classification model for the diagnosis of Parkinson's disease, which could serve as a basis for future disease prediction studies in longitudinal cohorts.We developed a model for disease classification using data from the Parkinson's Progression Marker Initiative (PPMI) study for 367 patients with Parkinson's disease and phenotypically typical imaging data and 165 controls without neurological disease. Olfactory function, genetic risk, family history of Parkinson's disease, age, and gender were algorithmically selected by stepwise logistic regression as significant contributors to our classifying model. We then tested the model with data from 825 patients with Parkinson's disease and 261 controls from five independent cohorts with varying recruitment strategies and designs: the Parkinson's Disease Biomarkers Program (PDBP), the Parkinson's Associated Risk Study (PARS), 23andMe, the Longitudinal and Biomarker Study in PD (LABS-PD), and the Morris K Udall Parkinson's Disease Research Center of Excellence cohort (Penn-Udall). Additionally, we used our model to investigate patients who had imaging scans without evidence of dopaminergic deficit (SWEDD).In the population from PPMI, our initial model correctly distinguished patients with Parkinson's disease from controls at an area under the curve (AUC) of 0·923 (95% CI 0·900-0·946) with high sensitivity (0·834, 95% CI 0·711-0·883) and specificity (0·903, 95% CI 0·824-0·946) at its optimum AUC threshold (0·655). All Hosmer-Lemeshow simulations suggested that when parsed into random subgroups, the subgroup data matched that of the overall cohort. External validation showed good classification of Parkinson's disease, with AUCs of 0·894 (95% CI 0·867-0·921) in the PDBP cohort, 0·998 (0·992-1·000) in PARS, 0·955 (no 95% CI available) in 23andMe, 0·929 (0·896-0·962) in LABS-PD, and 0·939 (0·891-0·986) in the Penn-Udall cohort. Four of 17 SWEDD participants who our model classified as having Parkinson's disease converted to Parkinson's disease within 1 year, whereas only one of 38 SWEDD participants who were not classified as having Parkinson's disease underwent conversion (test of proportions, p=0·003).Our model provides a potential new approach to distinguish participants with Parkinson's disease from controls. If the model can also identify individuals with prodromal or preclinical Parkinson's disease in prospective cohorts, it could facilitate identification of biomarkers and interventions.National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Michael J Fox Foundation.

    View details for DOI 10.1016/S1474-4422(15)00178-7

    View details for PubMedID 26271532

    View details for PubMedCentralID PMC4575273

  • John Ioannidis: Uncompromising gentle maniac BMJ-BRITISH MEDICAL JOURNAL Ioannidis, J. 2015; 351: h4992

    View details for DOI 10.1136/bmj.h4992

    View details for Web of Science ID 000361959200003

    View details for PubMedID 26404555

  • Is It Possible to Recognize a Major Scientific Discovery? JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P. 2015; 314 (11): 1135-1137

    View details for Web of Science ID 000361284500022

    View details for PubMedID 26372580

  • Nationwide Population Science: Lessons From the Taiwan National Health Insurance Research Database. JAMA internal medicine Hsing, A. W., Ioannidis, J. P. 2015; 175 (9): 1527-1529

    View details for DOI 10.1001/jamainternmed.2015.3540

    View details for PubMedID 26192815

  • Small studies are more heterogeneous than large ones: a meta-meta-analysis JOURNAL OF CLINICAL EPIDEMIOLOGY IntHout, J., Ioannidis, J. P., Borm, G. F., Goeman, J. J. 2015; 68 (8): 860-869

    Abstract

    Between-study heterogeneity plays an important role in random-effects models for meta-analysis. Most clinical trials are small, and small trials are often associated with larger effect sizes. We empirically evaluated whether there is also a relationship between trial size and heterogeneity (τ).We selected the first meta-analysis per intervention review of the Cochrane Database of Systematic Reviews Issues 2009-2013 with a dichotomous (n = 2,009) or continuous (n = 1,254) outcome. The association between estimated τ and trial size was evaluated across meta-analyses using regression and within meta-analyses using a Bayesian approach. Small trials were predefined as those having standard errors (SEs) over 0.2 standardized effects.Most meta-analyses were based on few (median 4) trials. Within the same meta-analysis, the small study τS(2) was larger than the large-study τL(2) [average ratio 2.11; 95% credible interval (1.05, 3.87) for dichotomous and 3.11 (2.00, 4.78) for continuous meta-analyses]. The imprecision of τS was larger than of τL: median SE 0.39 vs. 0.20 for dichotomous and 0.22 vs. 0.13 for continuous small-study and large-study meta-analyses.Heterogeneity between small studies is larger than between larger studies. The large imprecision with which τ is estimated in a typical small-studies' meta-analysis is another reason for concern, and sensitivity analyses are recommended.

    View details for DOI 10.1016/j.jclinepi.2015.03.017

    View details for Web of Science ID 000357623700004

    View details for PubMedID 25959635

  • Research and Theories on the Etiology of Mental Diseases: Doomed to Failure? PSYCHOLOGICAL INQUIRY Ioannidis, J. A. 2015; 26 (3): 239–43
  • Head-to-head randomized trials are mostly industry sponsored and almost always favor the industry sponsor JOURNAL OF CLINICAL EPIDEMIOLOGY Flacco, M. E., Manzoli, L., Boccia, S., Capasso, L., Aleksovska, K., Rosso, A., Scaioli, G., De Vito, C., Siliquini, R., Villari, P., Ioannidis, J. P. 2015; 68 (7): 811-820

    Abstract

    To map the current status of head-to-head comparative randomized evidence and to assess whether funding may impact on trial design and results.From a 50% random sample of the randomized controlled trials (RCTs) published in journals indexed in PubMed during 2011, we selected the trials with ≥ 100 participants, evaluating the efficacy and safety of drugs, biologics, and medical devices through a head-to-head comparison.We analyzed 319 trials. Overall, 238,386 of the 289,718 randomized subjects (82.3%) were included in the 182 trials funded by companies. Of the 182 industry-sponsored trials, only 23 had two industry sponsors and only three involved truly antagonistic comparisons. Industry-sponsored trials were larger, more commonly registered, used more frequently noninferiority/equivalence designs, had higher citation impact, and were more likely to have "favorable" results (superiority or noninferiority/equivalence for the experimental treatment) than nonindustry-sponsored trials. Industry funding [odds ratio (OR) 2.8; 95% confidence interval (CI): 1.6, 4.7] and noninferiority/equivalence designs (OR 3.2; 95% CI: 1.5, 6.6), but not sample size, were strongly associated with "favorable" findings. Fifty-five of the 57 (96.5%) industry-funded noninferiority/equivalence trials got desirable "favorable" results.The literature of head-to-head RCTs is dominated by the industry. Industry-sponsored comparative assessments systematically yield favorable results for the sponsors, even more so when noninferiority designs are involved.

    View details for DOI 10.1016/j.jclinepi.2014.12.016

    View details for Web of Science ID 000356634100013

  • The PRISMA Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses of Health Care Interventions: Checklist and Explanations ANNALS OF INTERNAL MEDICINE Hutton, B., Salanti, G., Caldwell, D. M., Chaimani, A., Schmid, C. H., Cameron, C., Ioannidis, J. P., Straus, S., Thorlund, K., Jansen, J. P., Mulrow, C., Catala-Lopez, F., Gotzsche, P. C., Dickersin, K., Boutron, I., Altman, D. G., Moher, D. 2015; 162 (11): 777-784

    Abstract

    The PRISMA statement is a reporting guideline designed to improve the completeness of reporting of systematic reviews and meta-analyses. Authors have used this guideline worldwide to prepare their reviews for publication. In the past, these reports typically compared 2 treatment alternatives. With the evolution of systematic reviews that compare multiple treatments, some of them only indirectly, authors face novel challenges for conducting and reporting their reviews. This extension of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement was developed specifically to improve the reporting of systematic reviews incorporating network meta-analyses. A group of experts participated in a systematic review, Delphi survey, and face-to-face discussion and consensus meeting to establish new checklist items for this extension statement. Current PRISMA items were also clarified. A modified, 32-item PRISMA extension checklist was developed to address what the group considered to be immediately relevant to the reporting of network meta-analyses. This document presents the extension and provides examples of good reporting, as well as elaborations regarding the rationale for new checklist items and the modification of previously existing items from the PRISMA statement. It also highlights educational information related to key considerations in the practice of network meta-analysis. The target audience includes authors and readers of network meta-analyses, as well as journal editors and peer reviewers.

    View details for DOI 10.7326/M14-2385

    View details for Web of Science ID 000355572300005

    View details for PubMedID 26030634

  • Clinical trials: A transparent future for clinical trial reporting. Nature reviews. Rheumatology Karassa, F. B., Ioannidis, J. P. 2015; 11 (6): 324-326

    View details for DOI 10.1038/nrrheum.2015.65

    View details for PubMedID 25939418

  • Are adaptive randomised trials or non-randomised studies the best way to address the Ebola outbreak in west Africa? LANCET INFECTIOUS DISEASES Lanini, S., Zumla, A., Ioannidis, J. A., Di Caro, A., Krishna, S., Gostin, L., Girardi, E., Pletschette, M., Strada, G., Baritussio, A., Portella, G., Apolone, G., Cavuto, S., Satolli, R., Kremsner, P., Vairo, F., Ippolito, G. 2015; 15 (6): 738–45

    Abstract

    The Ebola outbreak that has devastated parts of west Africa represents an unprecedented challenge for research and ethics. Estimates from the past three decades emphasise that the present effort to contain the epidemic in the three most affected countries (Guinea, Liberia, and Sierra Leone) has been insufficient, with more than 24,900 cases and about 10,300 deaths, as of March 25, 2015. Faced with such an exceptional event and the urgent response it demands, the use of randomised controlled trials (RCT) for Ebola-related research might be both unethical and infeasible and that potential interventions should be assessed in non-randomised studies on the basis of compassionate use. However, non-randomised studies might not yield valid conclusions, leading to large residual uncertainty about how to interpret the results, and can also waste scarce intervention-related resources, making them profoundly unethical. Scientifically sound and rigorous study designs, such as adaptive RCTs, could provide the best way to reduce the time needed to develop new interventions and to obtain valid results on their efficacy and safety while preserving the application of ethical precepts. We present an overview of clinical studies registered at present at the four main international trial registries and provide a simulation on how adaptive RCTs can behave in this context, when mortality varies simultaneously in either the control or the experimental group.

    View details for DOI 10.1016/S1473-3099(15)70106-4

    View details for Web of Science ID 000354638000039

    View details for PubMedID 25881871

  • An overview of recommendations and translational milestones for genomic tests in cancer GENETICS IN MEDICINE Chang, C. Q., Tingle, S. R., Filipski, K. K., Khoury, M. J., Lam, T. K., Schully, S. D., Ioannidis, J. P. 2015; 17 (6): 431-440

    Abstract

    To understand the translational trajectory of genomic tests in cancer screening, diagnosis, prognosis, and treatment, we reviewed tests that have been assessed by recommendation and guideline developers.For each test, we marked translational milestones by determining when the genomic association with cancer was first discovered and studied in patients, and when a health application for a specified clinical use was successfully demonstrated and approved or cleared by the US Food and Drug Administration. To identify recommendations and guidelines, we reviewed the websites of cancer, genomic, and general guideline developers and professional organizations. We searched the in vitro diagnostics database of the US Food and Drug Administration for information, and we searched PubMed for translational milestones. Milestones were examined against type of recommendation, Food and Drug Administration approval or clearance, disease rarity, and test purpose.Of the 45 tests we identified, 9 received strong recommendations for their usage in clinical settings, 14 received positive but moderate recommendations, and 22 were not currently recommended. For 18 tests, two or more different sources had issued recommendations, with 67% concordance. Only five tests had Food and Drug Administration approval, and an additional five had clearance. The median time from discovery to recommendation statement was 14.7 years.In general, there were no associations found between translational trajectory and recommendation category.Genet Med 17 6, 431-440.

    View details for DOI 10.1038/gim.2014.133

    View details for Web of Science ID 000355564200001

    View details for PubMedID 25341115

  • Epidemiologic Design and Analysis for Proteomic Studies: A Primer on -Omic Technologies AMERICAN JOURNAL OF EPIDEMIOLOGY Mischak, H., Critselis, E., Hanash, S., Gallagher, W. M., Vlahou, A., Ioannidis, J. P. 2015; 181 (9): 635-647

    Abstract

    Proteome analysis is increasingly being used in investigations elucidating the molecular basis of disease, identifying diagnostic and prognostic markers, and ultimately improving patient care. We appraised the current status of proteomic investigations using human samples, including the state of the art in proteomic technologies, from sample preparation to data evaluation approaches, as well as key epidemiologic, statistical, and translational issues. We systematically reviewed the most highly cited clinical proteomic studies published between January 2009 and March 2014 that included a minimum of 100 samples, as well as strategies that have been successfully implemented to enhance the translational relevance of proteomic investigations. Limited comparability between studies and lack of specification of biomarker context of use are frequently observed. Nevertheless, there are initial examples of successful biomarker discovery in cross-sectional studies followed by validation in high-risk longitudinal cohorts. Translational potential is currently hindered, as limitations in proteomic investigations are not accounted for. Interdisciplinary communication between proteomics experts, basic researchers, epidemiologists, and clinicians, an orchestrated assimilation of required resources, and a more systematic translational outlook for accumulation of evidence may augment the public health impact of proteomic investigations.

    View details for DOI 10.1093/aje/kwu462

    View details for Web of Science ID 000353817100001

    View details for PubMedID 25792606

  • Modern health care as a game theory problem: reply. European journal of clinical investigation Djulbegovic, B., Hozo, I., Ioannidis, J. 2015; 45 (4): 443-?

    View details for DOI 10.1111/eci.12414

    View details for PubMedID 25630659

  • Updated Field Synopsis and Systematic Meta-Analyses of Genetic Association Studies in Cutaneous Melanoma: The MelGene Database JOURNAL OF INVESTIGATIVE DERMATOLOGY Antonopoulou, K., Stefanaki, I., Lill, C. M., Chatzinasiou, F., Kypreou, K. P., Karagianni, F., Athanasiadis, E., Spyrou, G. M., Ioannidis, J. P., Bertram, L., Evangelou, E., Stratigos, A. J. 2015; 135 (4): 1074-1079

    Abstract

    We updated a field synopsis of genetic associations of cutaneous melanoma (CM) by systematically retrieving and combining data from all studies in the field published as of August 31, 2013. Data were available from 197 studies, which included 83,343 CM cases and 187,809 controls and reported on 1,126 polymorphisms in 289 different genes. Random-effects meta-analyses of 81 eligible polymorphisms evaluated in >4 data sets confirmed 20 single-nucleotide polymorphisms across 10 loci (TYR, AFG3L1P, CDK10, MYH7B, SLC45A2, MTAP, ATM, CLPTM1L, FTO, and CASP8) that have previously been published with genome-wide significant evidence for association (P<5 × 10(-8)) with CM risk, with certain variants possibly functioning as proxies of already tagged genes. Four other loci (MITF, CCND1, MX2, and PLA2G6) were also significantly associated with 5 × 10(-8)

    View details for DOI 10.1038/jid.2014.491

    View details for Web of Science ID 000351188600023

    View details for PubMedID 25407435

  • Geographic and Temporal Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted HIV-1 Drug Resistance: An Individual-Patient- and Sequence-Level Meta-Analysis. PLoS medicine Rhee, S., Blanco, J. L., Jordan, M. R., Taylor, J., Lemey, P., Varghese, V., Hamers, R. L., Bertagnolio, S., de Wit, T. F., Aghokeng, A. F., Albert, J., Avi, R., Avila-Rios, S., Bessong, P. O., Brooks, J. I., Boucher, C. A., Brumme, Z. L., Busch, M. P., Bussmann, H., Chaix, M., Chin, B. S., D'Aquin, T. T., De Gascun, C. F., Derache, A., Descamps, D., Deshpande, A. K., Djoko, C. F., Eshleman, S. H., Fleury, H., Frange, P., Fujisaki, S., Harrigan, P. R., Hattori, J., Holguin, A., Hunt, G. M., Ichimura, H., Kaleebu, P., Katzenstein, D., Kiertiburanakul, S., Kim, J. H., Kim, S. S., Li, Y., Lutsar, I., Morris, L., Ndembi, N., Ng, K. P., Paranjape, R. S., Peeters, M., Poljak, M., Price, M. A., Ragonnet-Cronin, M. L., Reyes-Terán, G., Rolland, M., Sirivichayakul, S., Smith, D. M., Soares, M. A., Soriano, V. V., Ssemwanga, D., Stanojevic, M., Stefani, M. A., Sugiura, W., Sungkanuparph, S., Tanuri, A., Tee, K. K., Truong, H. M., Van De Vijver, D. A., Vidal, N., Yang, C., Yang, R., Yebra, G., Ioannidis, J. P., Vandamme, A., Shafer, R. W. 2015; 12 (4)

    View details for DOI 10.1371/journal.pmed.1001810

    View details for PubMedID 25849352

  • Environmental risk factors and multiple sclerosis: an umbrella review of systematic reviews and meta-analyses LANCET NEUROLOGY Belbasis, L., Bellou, V., Evangelou, E., Ioannidis, J. P., Tzoulaki, I. 2015; 14 (3): 263-273

    Abstract

    The cause of multiple sclerosis is believed to involve environmental exposure and genetic susceptibility. We aimed to summarise the environmental risk factors that have been studied in relation to onset of multiple sclerosis, assess whether there is evidence for diverse biases in this literature, and identify risk factors without evidence of biases.We searched PubMed from inception to Nov 22, 2014, to identify systematic reviews and meta-analyses of observational studies that examined associations between environmental factors and multiple sclerosis. For each meta-analysis we estimated the summary effect size by use of random-effects and fixed-effects models, the 95% CI, and the 95% prediction interval. We estimated the between-study heterogeneity expressed by I(2) (defined as large for I(2)≥50%), evidence of small-study effects (ie, large studies had significantly more conservative results than smaller studies), and evidence of excess significance bias (ie, more studies than expected with significant results).Overall, 44 unique meta-analyses including 416 primary studies of different risk factors and multiple sclerosis were examined, covering a wide range of risk factors: vaccinations, comorbid diseases, surgeries, traumatic events and accidents, exposure to environmental agents, and biochemical, infectious, and musculoskeletal biomarkers. 23 of 44 meta-analyses had results that were significant at p values less than 0·05 and 11 at p values less than 0·001 under the random-effects model. Only three of the 11 significant meta-analyses (p<0·001) included more than 1000 cases, had 95% prediction intervals excluding the null value, and were not suggestive of large heterogeneity (I(2)<50%), small-study effects (p for Egger's test >0·10), or excess significance (p>0·05). These were IgG seropositivity to Epstein-Barr virus nuclear antigen (EBNA) (random effects odds ratio [OR] 4·46, 95% CI 3·26-6·09; p for effect size=1·5 × 10(-19); I(2)=43%), infectious mononucleosis (2·17, 1·97-2·39; p=3·1 × 10(-50); I(2)=0%), and smoking (1·52, 1·39-1·66; p=1·7 × 10(-18;)I(2)=0%).Many studies on environmental factors associated with multiple sclerosis have caveats casting doubts on their validity. Data from more and better-designed studies are needed to establish robust evidence. A biomarker of Epstein-Barr virus (anti-EBNA IgG seropositivity), infectious mononucleosis, and smoking showed the strongest consistent evidence of an association.None.

    View details for DOI 10.1016/S1474-4422(14)70267-4

    View details for Web of Science ID 000349594000009

    View details for PubMedID 25662901

  • Preventing tooth loss with biannual dental visits and genetic testing Does it work? JOURNAL OF THE AMERICAN DENTAL ASSOCIATION Ioannidis, J. A. 2015; 146 (3): 141–43

    View details for DOI 10.1016/j.adaj.2015.01.015

    View details for Web of Science ID 000352152600001

    View details for PubMedID 25726336

  • Recent Randomized Controlled Trials in Otolaryngology OTOLARYNGOLOGY-HEAD AND NECK SURGERY Banglawala, S. M., Lawrence, L. A., Franko-Tobin, E., Soler, Z. M., Schlosser, R. J., Ioannidis, J. 2015; 152 (3): 418–23

    Abstract

    To assess recent trends in the prevalence and quality of reporting of randomized controlled trials (RCTs) in 4 otolaryngology journals.Methodology and reporting analysis.Randomized controlled trials in 4 otolaryngology journals.All RCTs published from 2011 to 2013 in 4 major otolaryngology journals were examined for characteristics of study design, quality of design and reporting, and funding.Of 5279 articles published in 4 leading otolaryngology journals from 2011 to 2013, 189 (3.3%) were RCTs. The majority of RCTs were clinical studies (86%), with the largest proportion consisting of sinonasal topics (31%). Most interventions were medical (46%), followed by surgical (38%) and mixed (16%). In terms of quality, randomization method was reported in 54% of RCTs, blinding in 33%, and adverse events in 65%. Intention-to-treat analysis was used in 32%; P values were reported in 87% and confidence intervals in 10%. Research funding was most often absent or not reported (55%), followed by not-for-profit (25%).Based on review of 4 otolaryngology journals, RCTs are still a small proportion of all published studies in the field of otolaryngology. There seem to be trends toward improvement in quality of design and reporting of RCTs, although many quality features remain suboptimal. Practitioners both designing and interpreting RCTs should critically evaluate RCTs for quality.

    View details for DOI 10.1177/0194599814563518

    View details for Web of Science ID 000350477100006

    View details for PubMedID 25550226

  • SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease GASTROINTESTINAL ENDOSCOPY Laine, L., Kaltenbach, T., Barkun, A., Mcquaid, K. R., Subramanian, V., Soetikno, R. 2015; 81 (3): 489-U417

    View details for DOI 10.1016/j.gie.2014.12.009

    View details for Web of Science ID 000351666800001

    View details for PubMedID 25708752

  • SCENIC International Consensus Statement on Surveillance and Management of Dysplasia in Inflammatory Bowel Disease GASTROENTEROLOGY Laine, L., Kaltenbach, T., Barkun, A., Mcquaid, K. R., Subramanian, V., Soetikno, R. 2015; 148 (3): 639-?

    View details for DOI 10.1053/j.gastro.2015.01.031

    View details for Web of Science ID 000349968200034

    View details for PubMedID 25702852

  • Stealth Research Is Biomedical Innovation Happening Outside the Peer-Reviewed Literature? JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. A. 2015; 313 (7): 663–64

    View details for DOI 10.1001/jama.2014.17662

    View details for Web of Science ID 000349476100006

    View details for PubMedID 25688775

  • New genetic loci link adipose and insulin biology to body fat distribution. Nature Shungin, D., Winkler, T. W., Croteau-Chonka, D. C., Ferreira, T., Locke, A. E., Mägi, R., Strawbridge, R. J., Pers, T. H., Fischer, K., Justice, A. E., Workalemahu, T., Wu, J. M., Buchkovich, M. L., Heard-Costa, N. L., Roman, T. S., Drong, A. W., Song, C., Gustafsson, S., Day, F. R., Esko, T., Fall, T., Kutalik, Z., Luan, J., Randall, J. C., Scherag, A., Vedantam, S., Wood, A. R., Chen, J., Fehrmann, R., Karjalainen, J., Kahali, B., Liu, C., Schmidt, E. M., Absher, D., Amin, N., Anderson, D., Beekman, M., Bragg-Gresham, J. L., Buyske, S., Demirkan, A., Ehret, G. B., Feitosa, M. F., Goel, A., Jackson, A. U., Johnson, T., Kleber, M. E., Kristiansson, K., Mangino, M., Mateo Leach, I., Medina-Gomez, C., Palmer, C. D., Pasko, D., Pechlivanis, S., Peters, M. J., Prokopenko, I., Stancáková, A., Ju Sung, Y., Tanaka, T., Teumer, A., van Vliet-Ostaptchouk, J. V., Yengo, L., Zhang, W., Albrecht, E., Ärnlöv, J., Arscott, G. M., Bandinelli, S., Barrett, A., Bellis, C., Bennett, A. J., Berne, C., Blüher, M., Böhringer, S., Bonnet, F., Böttcher, Y., Bruinenberg, M., Carba, D. B., Caspersen, I. H., Clarke, R., Daw, E. W., Deelen, J., Deelman, E., Delgado, G., Doney, A. S., Eklund, N., Erdos, M. R., Estrada, K., Eury, E., Friedrich, N., Garcia, M. E., Giedraitis, V., Gigante, B., Go, A. S., Golay, A., Grallert, H., Grammer, T. B., Gräßler, J., Grewal, J., Groves, C. J., Haller, T., Hallmans, G., Hartman, C. A., Hassinen, M., Hayward, C., Heikkilä, K., Herzig, K., Helmer, Q., Hillege, H. L., Holmen, O., Hunt, S. C., Isaacs, A., Ittermann, T., James, A. L., Johansson, I., Juliusdottir, T., Kalafati, I., Kinnunen, L., Koenig, W., Kooner, I. K., Kratzer, W., Lamina, C., Leander, K., Lee, N. R., Lichtner, P., Lind, L., Lindström, J., Lobbens, S., Lorentzon, M., Mach, F., Magnusson, P. K., Mahajan, A., McArdle, W. L., Menni, C., Merger, S., Mihailov, E., Milani, L., Mills, R., Moayyeri, A., Monda, K. L., Mooijaart, S. P., Mühleisen, T. W., Mulas, A., Müller, G., Müller-Nurasyid, M., Nagaraja, R., Nalls, M. A., Narisu, N., Glorioso, N., Nolte, I. M., Olden, M., Rayner, N. W., Renstrom, F., Ried, J. S., Robertson, N. R., Rose, L. M., Sanna, S., Scharnagl, H., Scholtens, S., Sennblad, B., Seufferlein, T., Sitlani, C. M., Vernon Smith, A., Stirrups, K., Stringham, H. M., Sundström, J., Swertz, M. A., Swift, A. J., Syvänen, A., Tayo, B. O., Thorand, B., Thorleifsson, G., Tomaschitz, A., Troffa, C., van Oort, F. V., Verweij, N., Vonk, J. M., Waite, L. L., Wennauer, R., Wilsgaard, T., Wojczynski, M. K., Wong, A., Zhang, Q., Hua Zhao, J., Brennan, E. P., Choi, M., Eriksson, P., Folkersen, L., Franco-Cereceda, A., Gharavi, A. G., Hedman, Å. K., Hivert, M., Huang, J., Kanoni, S., Karpe, F., Keildson, S., Kiryluk, K., Liang, L., Lifton, R. P., Ma, B., McKnight, A. J., McPherson, R., Metspalu, A., Min, J. L., Moffatt, M. F., Montgomery, G. W., Murabito, J. M., Nicholson, G., Nyholt, D. R., Olsson, C., Perry, J. R., Reinmaa, E., Salem, R. M., Sandholm, N., Schadt, E. E., Scott, R. A., Stolk, L., Vallejo, E. E., Westra, H., Zondervan, K. T., Amouyel, P., Arveiler, D., Bakker, S. J., Beilby, J., Bergman, R. N., Blangero, J., Brown, M. J., Burnier, M., Campbell, H., Chakravarti, A., Chines, P. S., Claudi-Boehm, S., Collins, F. S., Crawford, D. C., Danesh, J., de Faire, U., de Geus, E. J., Dörr, M., Erbel, R., Eriksson, J. G., Farrall, M., Ferrannini, E., Ferrières, J., Forouhi, N. G., Forrester, T., Franco, O. H., Gansevoort, R. T., Gieger, C., Gudnason, V., Haiman, C. A., Harris, T. B., Hattersley, A. T., Heliövaara, M., Hicks, A. A., Hingorani, A. D., Hoffmann, W., Hofman, A., Homuth, G., Humphries, S. E., Hyppönen, E., Illig, T., Jarvelin, M., Johansen, B., Jousilahti, P., Jula, A. M., Kaprio, J., Kee, F., Keinanen-Kiukaanniemi, S. M., Kooner, J. S., Kooperberg, C., Kovacs, P., Kraja, A. T., Kumari, M., Kuulasmaa, K., Kuusisto, J., Lakka, T. A., Langenberg, C., Le Marchand, L., Lehtimäki, T., Lyssenko, V., Männistö, S., Marette, A., Matise, T. C., McKenzie, C. A., McKnight, B., Musk, A. W., Möhlenkamp, S., Morris, A. D., Nelis, M., Ohlsson, C., Oldehinkel, A. J., Ong, K. K., Palmer, L. J., Penninx, B. W., Peters, A., Pramstaller, P. P., Raitakari, O. T., Rankinen, T., Rao, D. C., Rice, T. K., Ridker, P. M., Ritchie, M. D., Rudan, I., Salomaa, V., Samani, N. J., Saramies, J., Sarzynski, M. A., Schwarz, P. E., Shuldiner, A. R., Staessen, J. A., Steinthorsdottir, V., Stolk, R. P., Strauch, K., Tönjes, A., Tremblay, A., Tremoli, E., Vohl, M., Völker, U., Vollenweider, P., Wilson, J. F., Witteman, J. C., Adair, L. S., Bochud, M., Boehm, B. O., Bornstein, S. R., Bouchard, C., Cauchi, S., Caulfield, M. J., Chambers, J. C., Chasman, D. I., Cooper, R. S., Dedoussis, G., Ferrucci, L., Froguel, P., Grabe, H., Hamsten, A., Hui, J., Hveem, K., Jöckel, K., Kivimaki, M., Kuh, D., Laakso, M., Liu, Y., März, W., Munroe, P. B., Njølstad, I., Oostra, B. A., Palmer, C. N., Pedersen, N. L., Perola, M., Pérusse, L., Peters, U., Power, C., Quertermous, T., Rauramaa, R., Rivadeneira, F., Saaristo, T. E., Saleheen, D., Sinisalo, J., Slagboom, P. E., Snieder, H., Spector, T. D., Thorsteinsdottir, U., Stumvoll, M., Tuomilehto, J., Uitterlinden, A. G., Uusitupa, M., van der Harst, P., Veronesi, G., Walker, M., Wareham, N. J., Watkins, H., Wichmann, H., Abecasis, G. R., Assimes, T. L., Berndt, S. I., Boehnke, M., Borecki, I. B., Deloukas, P., Franke, L., Frayling, T. M., Groop, L. C., Hunter, D. J., Kaplan, R. C., O'Connell, J. R., Qi, L., Schlessinger, D., Strachan, D. P., Stefansson, K., van Duijn, C. M., Willer, C. J., Visscher, P. M., Yang, J., Hirschhorn, J. N., Zillikens, M. C., McCarthy, M. I., Speliotes, E. K., North, K. E., Fox, C. S., Barroso, I., Franks, P. W., Ingelsson, E., Heid, I. M., Loos, R. J., Cupples, L. A., Morris, A. P., Lindgren, C. M., Mohlke, K. L. 2015; 518 (7538): 187-196

    Abstract

    Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

    View details for DOI 10.1038/nature14132

    View details for PubMedID 25673412

    View details for PubMedCentralID PMC4338562

  • Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature Do, R., Stitziel, N. O., Won, H., Jørgensen, A. B., Duga, S., Angelica Merlini, P., Kiezun, A., Farrall, M., Goel, A., Zuk, O., Guella, I., Asselta, R., Lange, L. A., Peloso, G. M., Auer, P. L., Girelli, D., Martinelli, N., Farlow, D. N., DePristo, M. A., Roberts, R., Stewart, A. F., Saleheen, D., Danesh, J., Epstein, S. E., Sivapalaratnam, S., Hovingh, G. K., Kastelein, J. J., Samani, N. J., Schunkert, H., Erdmann, J., Shah, S. H., Kraus, W. E., Davies, R., Nikpay, M., Johansen, C. T., Wang, J., Hegele, R. A., Hechter, E., Marz, W., Kleber, M. E., Huang, J., Johnson, A. D., Li, M., Burke, G. L., Gross, M., Liu, Y., Assimes, T. L., Heiss, G., Lange, E. M., Folsom, A. R., Taylor, H. A., Olivieri, O., Hamsten, A., Clarke, R., Reilly, D. F., Yin, W., Rivas, M. A., Donnelly, P., Rossouw, J. E., Psaty, B. M., Herrington, D. M., Wilson, J. G., Rich, S. S., Bamshad, M. J., Tracy, R. P., Cupples, L. A., Rader, D. J., Reilly, M. P., Spertus, J. A., Cresci, S., Hartiala, J., Tang, W. H., Hazen, S. L., Allayee, H., Reiner, A. P., Carlson, C. S., Kooperberg, C., Jackson, R. D., Boerwinkle, E., Lander, E. S., Schwartz, S. M., Siscovick, D. S., McPherson, R., Tybjaerg-Hansen, A., Abecasis, G. R., Watkins, H., Nickerson, D. A., Ardissino, D., Sunyaev, S. R., O'Donnell, C. J., Altshuler, D., Gabriel, S., Kathiresan, S. 2015; 518 (7537): 102-106

    Abstract

    Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.

    View details for DOI 10.1038/nature13917

    View details for PubMedID 25487149

  • Systematic assessment of the correlations of household income with infectious, biochemical, physiological, and environmental factors in the United States, 1999-2006. American journal of epidemiology Patel, C. J., Ioannidis, J. P., Cullen, M. R., Rehkopf, D. H. 2015; 181 (3): 171-179

    Abstract

    A fuller understanding of the social epidemiology of disease requires an extended description of the relationships between social factors and health indicators in a systematic manner. In the present study, we investigated the correlations between income and 330 indicators of physiological, biochemical, and environmental health in participants in the US National Health and Nutrition Examination Survey (NHANES) (1999-2006). We combined data from 3 survey waves (n = 249-23,649 for various indicators) to search for linear and nonlinear (quadratic) correlates of income, and we validated significant (P < 0.00015) correlations in an independent testing data set (n = 255-7,855). We validated 66 out of 330 factors, including infectious (e.g., hepatitis A), biochemical (e.g., carotenoids, high-density lipoprotein cholesterol), physiological (e.g., upper leg length), and environmental (e.g., lead, cotinine) measures. We found only a modest amount of association modification by age, race/ethnicity, and gender, and there was no association modification for blacks. The present study is descriptive, not causal. We have shown in our systematic investigation the crucial place income has in relation to health risk factors. Future research can use these correlations to better inform theory and studies of pathways to disease, as well as utilize these findings to understand when confounding by income is most likely to introduce bias.

    View details for DOI 10.1093/aje/kwu277

    View details for PubMedID 25589242

    View details for PubMedCentralID PMC4312426

  • Application of credibility ceilings probes the robustness of meta-analyses of biomarkers and cancer risk JOURNAL OF CLINICAL EPIDEMIOLOGY Papatheodorou, S. I., Tsilidis, K. K., Evangelou, E., Ioannidis, J. P. 2015; 68 (2): 163-174

    Abstract

    Meta-analyses of biomarkers often present spurious significant results and large effects. We applied sensitivity analyses with the use of credibility ceilings to assess whether and how the results of meta-analyses of biomarkers and cancer risk would change.We evaluated 98 meta-analyses, 43 (44%) of which had nominally statistically significant results. We assumed that any single study cannot give more than a maximum certainty 100 - c% (c, credibility ceiling) that the effect estimate [odds ratio (OR)] exceeds 1 (null) or 1.2.Nominal statistical significance was maintained for 21 (21%) meta-analyses, for c = 10% and OR >1, and these proportions changed to 7%, 3%, and 6% with ceilings of 20%, 30%, and 40%, respectively. For ceilings for OR >1.2, the respective proportions were 37%, 21%, 7%, and 3%. Seven meta-analyses on infectious agents retained statistical significance even with a high ceiling of c = 20% for OR >1.00. Meta-analyses without other hints of bias (large between-study heterogeneity, small-study effects, excess significance) were more likely to retain statistical significance than those that had such hints of bias.Credibility ceilings may be helpful in meta-analyses of biomarkers to understand the robustness of the results to different levels of uncertainty.

    View details for DOI 10.1016/j.jclinepi.2014.09.004

    View details for Web of Science ID 000348974400007

    View details for PubMedID 25433443

  • Completeness of main outcomes across randomized trials in entire discipline: survey of chronic lung disease outcomes in preterm infants BMJ-BRITISH MEDICAL JOURNAL Ioannidis, J. P., Horbar, J. D., Ovelman, C. M., Brosseau, Y., Thorlund, K., Buus-Frank, M. E., Mills, E. J., Soll, R. F. 2015; 350

    Abstract

    To map the availability of information on a major clinical outcome--chronic lung disease--across the randomized controlled trials in systematic reviews of an entire specialty, specifically interventions in preterm infants.Survey of systematic reviews.Cochrane Database of Systematic Reviews.All Cochrane systematic reviews (as of November 2013) that had evaluated interventions in preterm infants. We identified how many of those systematic reviews had looked for information on chronic lung disease, how many reported on chronic lung disease, and how many of the randomized controlled trials included in the systematic reviews reported on chronic lung disease. We also randomly selected 10 systematic reviews that did not report on chronic lung disease and 10 that reported on any such outcomes and identified whether any information on chronic lung disease appeared in the primary reports of the randomized controlled trials but not in the systematic reviews.Whether availability of chronic lung disease outcomes differed by type of population and intervention and whether additional non-extracted data might have been available in trial reports.174 systematic reviews with 1041 trials exclusively concerned preterm infants. Of those, 105 reviews looked for chronic lung disease outcomes, and 79 reported on these outcomes. Of the 1041 included trials, 202 reported on chronic lung disease at 28 days and 200 at 36 weeks postmenstrual; 320 reported on chronic lung disease with any definition. The proportion of systematic reviews that looked for or reported on chronic lung disease and the proportion of trials that reported on chronic lung disease was larger in preterm infants with respiratory distress or support than others (P<0.001) and differed across interventions (P<0.001). Even for trials on children with ventilation interventions, only 56% (48/86) reported on chronic lung disease. In the random sample, 45 of 84 trials (54%) had no outcomes on chronic lung disease in the systematic reviews, and only 9/45 (20%) had such information in the primary trial reports.Most trials included in systematic reviews of interventions on preterm infants are missing information on one of the most common serious outcomes in this population. Use of standardized clinical outcomes that would have to be collected and reported by default in all trials in a given specialty should be considered.

    View details for DOI 10.1136/bmj.h72

    View details for Web of Science ID 000348775100017

    View details for PubMedID 25623087

  • Reanalyses of trial results--reply. JAMA Ebrahim, S., Ioannidis, J. P. 2015; 313 (1): 93-?

    View details for DOI 10.1001/jama.2014.15644

    View details for PubMedID 25562278

  • Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD): Explanation and Elaboration ANNALS OF INTERNAL MEDICINE Moons, K. G., Altman, D. G., Reitsma, J. B., Ioannidis, J. P., Macaskill, P., Steyerberg, E. W., Vickers, A. J., Ransohoff, D. F., Collins, G. S. 2015; 162 (1): W1-W73

    Abstract

    The TRIPOD (Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis) Statement includes a 22-item checklist, which aims to improve the reporting of studies developing, validating, or updating a prediction model, whether for diagnostic or prognostic purposes. The TRIPOD Statement aims to improve the transparency of the reporting of a prediction model study regardless of the study methods used. This explanation and elaboration document describes the rationale; clarifies the meaning of each item; and discusses why transparent reporting is important, with a view to assessing risk of bias and clinical usefulness of the prediction model. Each checklist item of the TRIPOD Statement is explained in detail and accompanied by published examples of good reporting. The document also provides a valuable reference of issues to consider when designing, conducting, and analyzing prediction model studies. To aid the editorial process and help peer reviewers and, ultimately, readers and systematic reviewers of prediction model studies, it is recommended that authors include a completed checklist in their submission. The TRIPOD checklist can also be downloaded from www.tripod-statement.org.

    View details for DOI 10.7326/M14-0698

    View details for Web of Science ID 000360564000001

  • Reproducibility in Science Improving the Standard for Basic and Preclinical Research CIRCULATION RESEARCH Begley, C. G., Ioannidis, J. P. 2015; 116 (1): 116-126

    Abstract

    Medical and scientific advances are predicated on new knowledge that is robust and reliable and that serves as a solid foundation on which further advances can be built. In biomedical research, we are in the midst of a revolution with the generation of new data and scientific publications at a previously unprecedented rate. However, unfortunately, there is compelling evidence that the majority of these discoveries will not stand the test of time. To a large extent, this reproducibility crisis in basic and preclinical research may be as a result of failure to adhere to good scientific practice and the desperation to publish or perish. This is a multifaceted, multistakeholder problem. No single party is solely responsible, and no single solution will suffice. Here we review the reproducibility problems in basic and preclinical biomedical research, highlight some of the complexities, and discuss potential solutions that may help improve research quality and reproducibility.

    View details for DOI 10.1161/CIRCRESAHA.114.303819

    View details for Web of Science ID 000347052800019

    View details for PubMedID 25552691

  • Modern health care as a game theory problem EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Djulbegovic, B., Hozo, I., Ioannidis, J. P. 2015; 45 (1): 1-12

    View details for DOI 10.1111/eci.12380

    View details for Web of Science ID 000347056700001

  • A generalized view of self-citation: Direct, co-author, collaborative, and coercive induced self-citation JOURNAL OF PSYCHOSOMATIC RESEARCH Ioannidis, J. A. 2015; 78 (1): 7–11

    Abstract

    The phenomenon of self-citation can present in many different forms, including direct, co-author, collaborative, and coercive induced self-citation. It can also pertain to the citation of single scientists, groups of scientists, journals, and institutions. This article presents some case studies of extreme self-citation practices. It also discusses the implications of different types of self-citation. Self-citation is not necessarily inappropriate by default. In fact, usually it is fully appropriate but often it is even necessary. Conversely, inappropriate self-citation practices may be highly misleading and may distort the scientific literature. Coercive induced self-citation is the most difficult to discover. Coercive Induced self-citation may happen directly from reviewers of articles, but also indirectly from reviewers of grants, scientific advisors who steer a research agenda, and leaders of funding agencies who may espouse spending disproportionately large funds in research domains that perpetuate their own self-legacy. Inappropriate self-citation can be only a surrogate marker of what might be much greater distortions of the scientific corpus towards conformity to specific opinions and biases. Inappropriate self-citations eventually affect also impact metrics. Different impact metrics vary in the extent to which they can be gamed through self-citation practices. Citation indices that are more gaming-proof are available and should be more widely used. We need more empirical studies to dissect the impact of different types of inappropriate self-citation and to examine the effectiveness of interventions to limit them.

    View details for DOI 10.1016/j.jpsychores.2014.11.008

    View details for Web of Science ID 000348247400002

    View details for PubMedID 25466321

  • Inferior vena cava filters and postoperative outcomes in patients undergoing bariatric surgery: a meta-analysis (vol 10, pg 725, 2014) SURGERY FOR OBESITY AND RELATED DISEASES Kaw, R., Pasupuleti, V., Overby, D., Deshpande, A., Coleman, C. I., Ioannidis, J. A., Hernandez, A. V., Cardiovasc Meta-analyses Res Grp 2015; 11 (1): 268–69
  • Making Optimal Use of and Extending beyond Polygenic Additive Liability Models HUMAN HEREDITY Ioannidis, J. A. 2015; 80 (4): 158–61

    View details for DOI 10.1159/000448200

    View details for Web of Science ID 000382711600002

    View details for PubMedID 27576754

  • HANDLING THE FRAGILE VASE OF SCIENTIFIC PRACTICES ADDICTION Ioannidis, J. A. 2015; 110 (1): 9–10

    View details for DOI 10.1111/add.12720

    View details for Web of Science ID 000346699700003

    View details for PubMedID 25515825

  • Corrigendum: Simple, standardized incorporation of genetic risk into non-genetic risk prediction tools for complex traits: coronary heart disease as an example. Frontiers in genetics Goldstein, B. A., Knowles, J. W., Salfati, E., Ioannidis, J. P., Assimes, T. L. 2015; 6: 231-?

    Abstract

    [This corrects the article on p. 254 in vol. 5, PMID: 25136350.].

    View details for DOI 10.3389/fgene.2015.00231

    View details for PubMedID 26217377

    View details for PubMedCentralID PMC4493401

  • Is widespread screening for hepatitis C justified? BMJ (Clinical research ed.) Koretz, R. L., Lin, K. W., Ioannidis, J. P., Lenzer, J. 2015; 350: g7809-?

    View details for DOI 10.1136/bmj.g7809

    View details for PubMedID 25587052

  • Authors' reply to Foster and colleagues. BMJ (Clinical research ed.) Koretz, R. L., Lin, K. W., Ioannidis, J. P., Lenzer, J. 2015; 350: h1000-?

    View details for DOI 10.1136/bmj.h1000

    View details for PubMedID 25711887

  • Type 2 diabetes and cancer: umbrella review of meta-analyses of observational studies. BMJ (Clinical research ed.) Tsilidis, K. K., Kasimis, J. C., Lopez, D. S., Ntzani, E. E., Ioannidis, J. P. 2015; 350: g7607-?

    Abstract

    To summarise the evidence and evaluate the validity of the associations between type 2 diabetes and the risk of developing or dying from cancer.An umbrella review of the evidence across meta-analyses of observational studies of type 2 diabetes with risk of developing or dying from any cancer.PubMed, Embase, Cochrane database of systematic reviews, and manual screening of references.Meta-analyses or systematic reviews of observational studies in humans that examined the association between type 2 diabetes and risk of developing or dying from cancer.Eligible meta-analyses assessed associations between type 2 diabetes and risk of developing cancer in 20 sites and mortality for seven cancer sites. The summary random effects estimates were significant at P=0.05 in 20 meta-analyses (74%); and all reported increased risks of developing cancer for participants with versus without diabetes. Of the 27 meta-analyses, eventually only seven (26%) compiled evidence on more than 1000 cases, had significant summary associations at P ≤ 0.001 for both random and fixed effects calculations, and had neither evidence of small study effects nor evidence for excess significance. Of those, only six (22%) did not have substantial heterogeneity (I(2)>75%), pertaining to associations between type 2 diabetes and risk of developing breast, cholangiocarcinoma (both intrahepatic and extrahepatic), colorectal, endometrial, and gallbladder cancer. The 95% prediction intervals excluded the null value for four of these associations (breast, intrahepatic cholangiocarcinoma, colorectal, and endometrial cancer).Though type 2 diabetes has been extensively studied in relation to risk of developing cancer and cancer mortality and strong claims of significance exist for most of the studied associations, only a minority of these associations have robust supporting evidence without hints of bias.

    View details for DOI 10.1136/bmj.g7607

    View details for PubMedID 25555821

  • How Good Is "Evidence" from Clinical Studies of Drug Effects and Why Might Such Evidence Fail in the Prediction of the Clinical Utility of Drugs? ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 55 Naci, H., Ioannidis, J. P. 2015; 55: 169-189

    Abstract

    Promising evidence from clinical studies of drug effects does not always translate to improvements in patient outcomes. In this review, we discuss why early evidence is often ill suited to the task of predicting the clinical utility of drugs. The current gap between initially described drug effects and their subsequent clinical utility results from deficits in the design, conduct, analysis, reporting, and synthesis of clinical studies-often creating conditions that generate favorable, but ultimately incorrect, conclusions regarding drug effects. There are potential solutions that could improve the relevance of clinical evidence in predicting the real-world effectiveness of drugs. What is needed is a new emphasis on clinical utility, with nonconflicted entities playing a greater role in the generation, synthesis, and interpretation of clinical evidence. Clinical studies should adopt strong design features, reflect clinical practice, and evaluate outcomes and comparisons that are meaningful to patients. Transformative changes to the research agenda may generate more meaningful and accurate evidence on drug effects to guide clinical decision making.

    View details for DOI 10.1146/annurev-pharmtox-010814-124614

    View details for Web of Science ID 000348560500011

    View details for PubMedID 25149917

  • External validation of new risk prediction models is infrequent and reveals worse prognostic discrimination JOURNAL OF CLINICAL EPIDEMIOLOGY Siontis, G. C., Tzoulaki, J., Castaldi, P. J., Ioannidis, J. P. 2015; 68 (1): 25-34

    Abstract

    To evaluate how often newly developed risk prediction models undergo external validation and how well they perform in such validations.We reviewed derivation studies of newly proposed risk models and their subsequent external validations. Study characteristics, outcome(s), and models' discriminatory performance [area under the curve, (AUC)] in derivation and validation studies were extracted. We estimated the probability of having a validation, change in discriminatory performance with more stringent external validation by overlapping or different authors compared to the derivation estimates.We evaluated 127 new prediction models. Of those, for 32 models (25%), at least an external validation study was identified; in 22 models (17%), the validation had been done by entirely different authors. The probability of having an external validation by different authors within 5 years was 16%. AUC estimates significantly decreased during external validation vs. the derivation study [median AUC change: -0.05 (P < 0.001) overall; -0.04 (P = 0.009) for validation by overlapping authors; -0.05 (P < 0.001) for validation by different authors]. On external validation, AUC decreased by at least 0.03 in 19 models and never increased by at least 0.03 (P < 0.001).External independent validation of predictive models in different studies is uncommon. Predictive performance may worsen substantially on external validation.

    View details for DOI 10.1016/j.jclinepi.2014.09.007

    View details for Web of Science ID 000346690800004

    View details for PubMedID 25441703

  • Diagnostic accuracy of the Edinburgh Postnatal Depression Scale (EPDS) for detecting major depression in pregnant and postnatal women: protocol for a systematic review and individual patient data meta-analyses BMJ OPEN Thombs, B. D., Benedetti, A., Kloda, L. A., Levis, B., Riehm, K. E., Azar, M., Cuijpers, P., Gilbody, S., Ioannidis, J. P., McMillan, D., Patten, S. B., Shrier, I., Steele, R. J., Ziegelstein, R. C., Tonelli, M., Mitchell, N., Comeau, L., Schinazi, J., Vigod, S. 2015; 5 (10)

    Abstract

    Studies of the diagnostic accuracy of depression screening tools often used data-driven methods to select optimal cut-offs. Typically, these studies report results from a small range of cut-off points around whatever cut-off score is identified as most accurate. When published data are combined in meta-analyses, estimates of accuracy for different cut-off points may be based on data from different studies, rather than data from all studies for each cut-off point. Thus, traditional meta-analyses may exaggerate accuracy estimates. Individual patient data (IPD) meta-analyses synthesise data from all studies for each cut-off score to obtain accuracy estimates. The 10-item Edinburgh Postnatal Depression Scale (EPDS) is commonly recommended for depression screening in the perinatal period. The primary objective of this IPD meta-analysis is to determine the diagnostic accuracy of the EPDS to detect major depression among women during pregnancy and in the postpartum period across all potentially relevant cut-off scores, accounting for patient factors that may influence accuracy (age, pregnancy vs postpartum).Data sources will include Medline, Medline In-Process & Other Non-Indexed Citations, PsycINFO, and Web of Science. Studies that include a diagnosis of major depression based on a validated structured or semistructured clinical interview administered within 2 weeks of (before or after) the administration of the EPDS will be included. Risk of bias will be assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Bivariate random-effects meta-analysis will be conducted for the full range of plausible cut-off values. Analyses will evaluate data from pregnancy and the postpartum period separately, as well as combining data from all women in a single model.This study does not require ethics approval. Dissemination will include journal articles and presentations to policymakers, healthcare providers and researchers.PROSPERO 2015:CRD42015024785.

    View details for DOI 10.1136/bmjopen-2015-009742

    View details for Web of Science ID 000365467600117

    View details for PubMedID 26486977

    View details for PubMedCentralID PMC4620163

  • Modern health care as a game theory problem. European journal of clinical investigation Djulbegovic, B., Hozo, I., Ioannidis, J. P. 2015; 45 (1): 1-12

    View details for DOI 10.1111/eci.12380

    View details for PubMedID 25413314

  • Authors' reply to editorial linked to their umbrella review of meta-analyses of observational studies on type 2 diabetes and cancer. BMJ (Clinical research ed.) Tsilidis, K. K., Ioannidis, J. P. 2015; 350: h711-?

    View details for DOI 10.1136/bmj.h711

    View details for PubMedID 25673332

  • Authors' reply to Selvapatt and colleagues, Matthews and colleagues, Badrinath, and Ward and Lee. BMJ (Clinical research ed.) Koretz, R. L., Lin, K. W., Ioannidis, J. P., Lenzer, J. 2015; 350: h674-?

    View details for DOI 10.1136/bmj.h674

    View details for PubMedID 25711896

  • Clinical trials: what a waste BMJ-BRITISH MEDICAL JOURNAL Ioannidis, J. A. 2014; 349: g7089

    View details for DOI 10.1136/bmj.g7089

    View details for Web of Science ID 000346165000002

    View details for PubMedID 25499097

  • A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip ANNALS OF THE RHEUMATIC DISEASES Evangelou, E., Kerkhof, H. J., Styrkarsdottir, U., Ntzani, E. E., Bos, S. D., Esko, T., Evans, D. S., Metrustry, S., Panoutsopoulou, K., Ramos, Y. F., Thorleifsson, G., Tsilidis, K. K., Arden, N., Aslam, N., Bellamy, N., Birrell, F., Blanco, F. J., Carr, A., Chapman, K., Day-Williams, A. G., Deloukas, P., Doherty, M., Engstrom, G., Helgadottir, H. T., Hofman, A., Ingvarsson, T., Jonsson, H., Keis, A., Keurentjes, J. C., Kloppenburg, M., Lind, P. A., McCaskie, A., Martin, N. G., Milani, L., Montgomery, G. W., Nelissen, R. G., Nevitt, M. C., Nilsson, P. M., Ollier, W. E., Parimi, N., Rai, A., Ralston, S. H., Reed, M. R., Riancho, J. A., Rivadeneira, F., Rodriguez-Fontenla, C., Southam, L., Thorsteinsdottir, U., Tsezou, A., AWallis, G., Wilkinson, J. M., Gonzalez, A., Lane, N. E., Lohmander, L. S., Loughlin, J., Metspalu, A., Uitterlinden, A. G., Jonsdottir, I., Stefansson, K., Slagboom, P. E., Zeggini, E., Meulenbelt, I., Ioannidis, J. P., Spector, T. D., van Meurs, J. B., Valdes, A. M. 2014; 73 (12): 2130-2136

    Abstract

    Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects.We performed a two-stage meta-analysis on more than 78 000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used.We accumulated 11 277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9×10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p=5.6×10(-8)) and follow-up studies (p=7.3×10(-4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9×10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2×10(-6), OR=1.27 in male specific analysis).Novel genetic loci for hip OA were found in this meta-analysis of GWAS.

    View details for DOI 10.1136/annrheumdis-2012-203114

    View details for Web of Science ID 000344783900016

    View details for PubMedID 23989986

  • Big data meets public health SCIENCE Khoury, M. J., Ioannidis, J. A. 2014; 346 (6213): 1054–55

    View details for DOI 10.1126/science.aaa2709

    View details for Web of Science ID 000345763400019

    View details for PubMedID 25430753

    View details for PubMedCentralID PMC4684636

  • A Web-based database of genetic association studies in cutaneous melanoma enhanced with network-driven data exploration tools DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION Athanasiadis, E. I., Antonopoulou, K., Chatzinasiou, F., Lill, C. M., Bourdakou, M. M., Sakellariou, A., Kypreou, K., Stefanaki, I., Evangelou, E., Ioannidis, J. P., Bertram, L., Stratigos, A. J., Spyrou, G. M. 2014

    Abstract

    The publicly available online database MelGene provides a comprehensive, regularly updated, collection of data from genetic association studies in cutaneous melanoma (CM), including random-effects meta-analysis results of all eligible polymorphisms. The updated database version includes data from 192 publications with information on 1114 significantly associated polymorphisms across 280 genes, along with new front-end and back-end capabilities. Various types of relationships between data are calculated and visualized as networks. We constructed 13 different networks containing the polymorphisms and the genes included in MelGene. We explored the derived network representations under the following questions: (i) are there nodes that deserve consideration regarding their network connectivity characteristics? (ii) What is the relation of either the genome-wide or nominally significant CM polymorphisms/genes with the ones highlighted by the network representation? We show that our network approach using the MelGene data reveals connections between statistically significant genes/ polymorphisms and other genes/polymorphisms acting as 'hubs' in the reconstructed networks. To the best of our knowledge, this is the first database containing data from a comprehensive field synopsis and systematic meta-analyses of genetic polymorphisms in CM that provides user-friendly tools for in-depth molecular network visualization and exploration. The proposed network connections highlight potentially new loci requiring further investigation of their relation to melanoma risk. Database URL: http://www.melgene.org.

    View details for DOI 10.1093/database/bau101

    View details for Web of Science ID 000344943700001

    View details for PubMedID 25380778

    View details for PubMedCentralID PMC4224266

  • HELOW: A program for testing extreme homogeneity in meta-analysis COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE Zintzaras, E., Ioannidis, J. P. 2014; 117 (2): 383-386

    Abstract

    Meta-analysis aims to synthesize results from different studies. Although, in a meta-analysis the presence of large between-study heterogeneity is routinely evaluated, in some instances is also important to probe whether there is extreme between-study homogeneity (i.e. extreme low between-study heterogeneity). HELOW (HEterogeneity LOW) is a program for testing extreme homogeneity in a meta-analysis of risk ratios when binary outcome and Mantel-Haenszel fixed effects summary risk ratio estimate are employed. The significance of extreme homogeneity is assessed using a Monte Carlo test. Extreme homogeneity may yield insights for the statistical and clinical interpretation of the data.

    View details for DOI 10.1016/j.cmpb.2014.06.009

    View details for Web of Science ID 000343091400031

    View details for PubMedID 25023534

  • Placing epidemiological results in the context of multiplicity and typical correlations of exposures JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH Patel, C. J., Ioannidis, J. P. 2014; 68 (11): 1096-1100

    Abstract

    Epidemiological studies evaluate multiple exposures, but the extent of multiplicity often remains non-transparent when results are reported. There is extensive debate in the literature on whether multiplicity should be adjusted for in the design, analysis, and reporting of most epidemiological studies, and, if so, how this should be done. The challenges become more acute in an era where the number of exposures that can be studied (the exposome) can be very large. Here, we argue that it can be very insightful to visualize and describe the extent of multiplicity by reporting the number of effective exposures for each category of exposures being assessed, and to describe the distribution of correlation between exposures and/or between exposures and outcomes in epidemiological datasets. The results of new proposed associations can be placed in the context of this background information. An association can be assigned to a percentile of magnitude of effect based on the distribution of effects seen in the field. We offer an example of how such information can be routinely presented in an epidemiological study/dataset using data on 530 exposure and demographic variables classified in 32 categories in the National Health and Nutrition Examination Survey (NHANES). Effects that survive multiplicity considerations and that are large may be prioritized for further scrutiny.

    View details for DOI 10.1136/jech-2014-204195

    View details for Web of Science ID 000343225800014

    View details for PubMedID 24923805

  • Bibliometrics: Is your most cited work your best? Nature Ioannidis, J. P., Boyack, K. W., Small, H., Sorensen, A. A., Klavans, R. 2014; 514 (7524): 561-562

    View details for DOI 10.1038/514561a

    View details for PubMedID 25355346

  • How to Make More Published Research True PLOS MEDICINE Ioannidis, J. A. 2014; 11 (10): e1001747

    Abstract

    In a 2005 paper that has been accessed more than a million times, John Ioannidis explained why most published research findings were false. Here he revisits the topic, this time to address how to improve matters. Please see later in the article for the Editors' Summary.

    View details for DOI 10.1371/journal.pmed.1001747

    View details for Web of Science ID 000344460900009

    View details for PubMedID 25334033

    View details for PubMedCentralID PMC4204808

  • Metformin and cancer risk: A cohort study in the UK Clinical Practice Research Datalink analyzed like a randomized trial Tsilidis, K. K., Capothanassi, D., Allen, N., Rizos, E., Lopez, D., van Veldhoven, K., Sacerdote, C., Ashby, D., Vineis, P., Tzoulaki, I., Ioannidis, J. AMER ASSOC CANCER RESEARCH. 2014
  • A test for reporting bias in trial networks: simulation and case studies BMC MEDICAL RESEARCH METHODOLOGY Trinquart, L., Ioannidis, J. A., Chatellier, G., Ravaud, P. 2014; 14: 112

    Abstract

    Networks of trials assessing several treatment options available for the same condition are increasingly considered. Randomized trial evidence may be missing because of reporting bias. We propose a test for reporting bias in trial networks.We test whether there is an excess of trials with statistically significant results across a network of trials. The observed number of trials with nominally statistically significant p-values across the network is compared with the expected number. The performance of the test (type I error rate and power) was assessed using simulation studies under different scenarios of selective reporting bias. Examples are provided for networks of antidepressant and antipsychotic trials, where reporting biases have been previously demonstrated by comparing published to Food and Drug Administration (FDA) data.In simulations, the test maintained the type I error rate and was moderately powerful after adjustment for type I error rate, except when the between-trial variance was substantial. In all, a positive test result increased moderately or markedly the probability of reporting bias being present, while a negative test result was not very informative. In the two examples, the test gave a signal for an excess of statistically significant results in the network of published data but not in the network of FDA data.The test could be useful to document an excess of significant findings in trial networks, providing a signal for potential publication bias or other selective analysis and outcome reporting biases.

    View details for DOI 10.1186/1471-2288-14-112

    View details for Web of Science ID 000346746600001

    View details for PubMedID 25262204

    View details for PubMedCentralID PMC4193287

  • Editorial: Updated Guidance on Human Genome Epidemiology (HuGE) Reviews and Meta-Analyses of Genetic Associations AMERICAN JOURNAL OF EPIDEMIOLOGY Gwinn, M., Ioannidis, J. P., Little, J., Khoury, M. J. 2014; 180 (6): 559–61

    View details for DOI 10.1093/aje/kwu196

    View details for Web of Science ID 000343033400001

    View details for PubMedID 25164421

  • Reanalyses of randomized clinical trial data. JAMA Ebrahim, S., Sohani, Z. N., Montoya, L., Agarwal, A., Thorlund, K., Mills, E. J., Ioannidis, J. P. 2014; 312 (10): 1024-1032

    Abstract

    Reanalyses of randomized clinical trial (RCT) data may help the scientific community assess the validity of reported trial results.To identify published reanalyses of RCT data, to characterize methodological and other differences between the original trial and reanalysis, to evaluate the independence of authors performing the reanalyses, and to assess whether the reanalysis changed interpretations from the original article about the types or numbers of patients who should be treated.We completed an electronic search of MEDLINE from inception to March 9, 2014, to identify all published studies that completed a reanalysis of individual patient data from previously published RCTs addressing the same hypothesis as the original RCT. Four data extractors independently screened articles and extracted data.Changes in direction and magnitude of treatment effect, statistical significance, and interpretation about the types or numbers of patients who should be treated.We identified 37 eligible reanalyses in 36 published articles, 5 of which were performed by entirely independent authors (2 based on publicly available data and 2 on data that were provided on request; data availability was unclear for 1). Reanalyses differed most commonly in statistical or analytical approaches (n = 18) and in definitions or measurements of the outcome of interest (n = 12). Four reanalyses changed the direction and 2 changed the magnitude of treatment effect, whereas 4 led to changes in statistical significance of findings. Thirteen reanalyses (35%) led to interpretations different from that of the original article, 3 (8%) showing that different patients should be treated; 1 (3%), that fewer patients should be treated; and 9 (24%), that more patients should be treated.A small number of reanalyses of RCTs have been published to date. Only a few were conducted by entirely independent authors. Thirty-five percent of published reanalyses led to changes in findings that implied conclusions different from those of the original article about the types and number of patients who should be treated.

    View details for DOI 10.1001/jama.2014.9646

    View details for PubMedID 25203082

  • Metformin Does Not Affect Cancer Risk: A Cohort Study in the UK Clinical Practice Research Datalink Analyzed Like an Intention-to-Treat Trial DIABETES CARE Tsilidis, K. K., Capothanassi, D., Allen, N. E., Rizos, E. C., Lopez, D. S., van Veldhoven, K., Sacerdote, C., Ashby, D., Vineis, P., Tzoulaki, I., Ioannidis, J. P. 2014; 37 (9): 2522-2532

    Abstract

    Meta-analyses of epidemiologic studies have suggested that metformin may reduce cancer incidence, but randomized controlled trials did not support this hypothesis.RESEARCH DESIGN AND METHODS: A retrospective cohort study, Clinical Practice Research Datalink, was designed to investigate the association between use of metformin compared with other antidiabetes medications and cancer risk by emulating an intention-to-treat analysis as in a trial. A total of 95,820 participants with type 2 diabetes who started taking metformin and other oral antidiabetes medications within 12 months of their diagnosis (initiators) were followed up for first-incident cancer diagnosis without regard to any subsequent changes in pharmacotherapy. Cox proportional hazards models were used to estimate multivariable-adjusted hazard ratios (HR) and 95% CI.RESULTS: A total of 51,484 individuals (54%) were metformin initiators and 18,264 (19%) were sulfonylurea initiators, and 3,805 first-incident cancers were diagnosed during a median follow-up time of 5.1 years. Compared with initiators of sulfonylurea, initiators of metformin had a similar incidence of total cancer (HR 0.96; 95% CI 0.89-1.04) and colorectal (HR 0.92; 95% CI 0.76-1.13), prostate (HR 1.02; 95% CI 0.83-1.25), lung (HR 0.85; 95% CI 0.68-1.07), or postmenopausal breast (HR 1.03; 95% CI 0.82-1.31) cancer, or any other cancer.CONCLUSIONS: In this large study, individuals with diabetes who used metformin had a similar risk of developing cancer compared with those who used sulfonylureas.

    View details for DOI 10.2337/dc14-0584

    View details for Web of Science ID 000340846300026

    View details for PubMedID 24898303

  • Citation Classic: Modeling and Research on Research CLINICAL CHEMISTRY Ioannidis, J. A. 2014; 60 (9): 1238–39

    View details for DOI 10.1373/clinchem.2013.218453

    View details for Web of Science ID 000344779400019

    View details for PubMedID 25037936

  • Unscientific Beliefs about Scientific Topics in Nutrition ADVANCES IN NUTRITION Brown, A. W., Ioannidis, J. P., Cope, M. B., Bier, D. M., Allison, D. B. 2014; 5 (5): 563-565

    Abstract

    Humans interact with food daily. Such repeated exposure creates a widespread, superficial familiarity with nutrition. Personal familiarity with nutrition from individual and cultural perspectives may give rise to beliefs about food not grounded in scientific evidence. In this summary of the session entitled “Unscientific Beliefs about Scientific Topics in Nutrition,” we discuss accumulated work illustrating and quantifying potentially misleading practices in the conduct and, more so, reporting of nutrition science along with proposed approaches to amelioration. We begin by defining “unscientific beliefs” and from where such beliefs may come, followed by discussing how large bodies of nutritional epidemiologic observations not only create highly improbable patterns of association but implausible magnitudes of implied effect. Poor reporting practices, biases, and methodologic issues that have distorted scientific understandings of nutrition are presented, followed by potential influences of conflicts of interest that extend beyond financial considerations. We conclude with recommendations for improving the conduct, reporting, and communication of nutrition-related research to ground discussions in evidence rather than solely on beliefs.

    View details for DOI 10.3945/an.114006577

    View details for Web of Science ID 000342972200016

    View details for PubMedID 25469397

    View details for PubMedCentralID PMC4188234

  • Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease NATURE GENETICS Nalls, M. A., Pankratz, N., Lill, C. M., Do, C. B., Hernandez, D. G., Saad, M., DeStefano, A. L., Kara, E., Bras, J., Sharma, M., Schulte, C., Keller, M. F., Arepalli, S., Letson, C., Edsall, C., Stefansson, H., Liu, X., Pliner, H., Lee, J. H., Cheng, R., Ikram, M. A., Ioannidis, J. P., Hadjigeorgiou, G. M., Bis, J. C., Martinez, M., Perlmutter, J. S., Goate, A., Marder, K., Fiske, B., Sutherland, M., Xiromerisiou, G., Myers, R. H., Clark, L. N., Stefansson, K., Hardy, J. A., Heutink, P., Chen, H., Wood, N. W., Houlden, H., Payami, H., Brice, A., Scott, W. K., Gasser, T., Bertram, L., Eriksson, N., Foroud, T., Singleton, A. B. 2014; 46 (9): 989-?

    Abstract

    We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55-4.30; P = 2 × 10(-16)). We also show six risk loci associated with proximal gene expression or DNA methylation.

    View details for DOI 10.1038/ng.3043

    View details for Web of Science ID 000341579400013

    View details for PubMedID 25064009

  • Meta-analysis identifies loci affecting levels of the potential osteoarthritis biomarkers sCOMP and uCTX-II with genome wide significance JOURNAL OF MEDICAL GENETICS Ramos, Y. F., Metrustry, S., Arden, N., Bay-Jensen, A. C., Beekman, M., de Craen, A. J., Cupples, L. A., Esko, T., Evangelou, E., Felson, D. T., Hart, D. J., Ioannidis, J. P., Karsdal, M., Kloppenburg, M., Lafeber, F., Metspalu, A., Panoutsopoulou, K., Slagboom, P. E., Spector, T. D., van Spil, E. W., Uitterlinden, A. G., Zhu, Y., Valdes, A. M., van Meurs, J. B., Meulenbelt, I. 2014; 51 (9): 596-604

    Abstract

    Research for the use of biomarkers in osteoarthritis (OA) is promising, however, adequate discrimination between patients and controls may be hampered due to innate differences. We set out to identify loci influencing levels of serum cartilage oligomeric protein (sCOMP) and urinary C-telopeptide of type II collagen (uCTX-II).Meta-analysis of genome-wide association studies was applied to standardised residuals of sCOMP (N=3316) and uCTX-II (N=4654) levels available in 6 and 7 studies, respectively, from TreatOA. Effects were estimated using a fixed-effects model. Six promising signals were followed up by de novo genotyping in the Cohort Hip and Cohort Knee study (N = 964). Subsequently, their role in OA susceptibility was investigated in large-scale genome-wide association studies meta-analyses for OA. Differential expression of annotated genes was assessed in cartilage.Genome-wide significant association with sCOMP levels was found for a SNP within MRC1 (rs691461, p = 1.7 × 10(-12)) and a SNP within CSMD1 associated with variation in uCTX-II levels with borderline genome-wide significance (rs1983474, p = 8.5 × 10(-8)). Indication for association with sCOMP levels was also found for a locus close to the COMP gene itself (rs10038, p = 7.1 × 10(-6)). The latter SNP was subsequently found to be associated with hip OA whereas COMP expression appeared responsive to the OA pathophysiology in cartilage.We have identified genetic loci affecting either uCTX-II or sCOMP levels. The genome wide significant association of MRC1 with sCOMP levels was found likely to act independent of OA subtypes. Increased sensitivity of biomarkers with OA may be accomplished by taking genetic variation into account.

    View details for DOI 10.1136/jmedgenet-2014-102478

    View details for Web of Science ID 000340242400006

    View details for PubMedID 25057126

  • Changes of serum adhesion molecules and cytokines in post-ERCP pancreatitis Adhesion molecules and cytokines in acute pancreatitis CLINICAL BIOCHEMISTRY Sigounas, D. E., Christodoulou, D. K., Karamoutsios, A., Tatsioni, A., Dova, L., Vartholomatos, G., Kolaitis, N., Katsanos, K. H., Zervou, E., Ioannidis, J. P., Tsianos, E. V. 2014; 47 (13-14): 1245-1249

    Abstract

    To assess the early changes of soluble IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, TNF-α, TNF-β, IL-17A, IL-22, soluble (s) P-Selectin, sE-Selectin and sICAM-1 in post-ERCP pancreatitis (PEP).Single center, prospective study of 318 ERCP procedures. Serum samples were acquired from all patients prior to ERCP, 6hours and 24hours after the procedure. For every PEP case, another patient was chosen as a control, matched for gender, age and time period in which ERCP took place.Totally, 28 cases and 28 controls were studied. Except for significantly higher IL-1b levels in cases at baseline, no significant differences were observed between cases and controls after Bonferroni corrections. An increase in IL-6 was noted between baseline and 6h in cases alone (p=0.016). There was a significant fall in sP-selectin levels at 6 and 24hours compared to baseline in all patients (corrected p=0.008 and 0.016 for cases and 0.016 and 0.048 for controls respectively). An increase of sE-selectin in cases was observed between 6 and 24hours post-ERCP (corrected p=0.03).Soluble forms of cytokines and adhesion molecules studied seem not to play a major role in PEP.

    View details for DOI 10.1016/j.clinbiochem.2014.05.007

    View details for Web of Science ID 000341329000014

    View details for PubMedID 24845714

  • Assessing Value in Biomedical Research The PQRST of Appraisal and Reward JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. A., Khoury, M. J. 2014; 312 (5): 483–84

    View details for DOI 10.1001/jama.2014.6932

    View details for Web of Science ID 000339808600013

    View details for PubMedID 24911291

    View details for PubMedCentralID PMC4687964

  • Simple, standardized incorporation of genetic risk into non-genetic risk prediction tools for complex traits: coronary heart disease as an example FRONTIERS IN GENETICS Goldstein, B. A., Knowles, J. W., Salfati, E., Ioannidis, J. P., Assimes, T. L. 2014; 5

    Abstract

    Genetic risk assessment is becoming an important component of clinical decision-making. Genetic Risk Scores (GRSs) allow the composite assessment of genetic risk in complex traits. A technically and clinically pertinent question is how to most easily and effectively combine a GRS with an assessment of clinical risk derived from established non-genetic risk factors as well as to clearly present this information to patient and health care providers.We illustrate a means to combine a GRS with an independent assessment of clinical risk using a log-link function. We apply the method to the prediction of coronary heart disease (CHD) in the Atherosclerosis Risk in Communities (ARIC) cohort. We evaluate different constructions based on metrics of effect change, discrimination, and calibration.The addition of a GRS to a clinical risk score (CRS) improves both discrimination and calibration for CHD in ARIC. RESULTS are similar regardless of whether external vs. internal coefficients are used for the CRS, risk factor single nucleotide polymorphisms (SNPs) are included in the GRS, or subjects with diabetes at baseline are excluded. We outline how to report the construction and the performance of a GRS using our method and illustrate a means to present genetic risk information to subjects and/or their health care provider.The proposed method facilitates the standardized incorporation of a GRS in risk assessment.

    View details for DOI 10.3389/fgene.2014.00254

    View details for Web of Science ID 000347445200001

  • Design and Analysis of Metabolomics Studies in Epidemiologic Research: A Primer on -Omic Technologies AMERICAN JOURNAL OF EPIDEMIOLOGY Tzoulaki, I., Ebbels, T. M., Valdes, A., Elliott, P., Ioannidis, J. P. 2014; 180 (2): 129-139

    Abstract

    Metabolomics is the field of "-omics" research concerned with the comprehensive characterization of the small low-molecular-weight metabolites in biological samples. In epidemiology, it represents an emerging technology and an unprecedented opportunity to measure environmental and other exposures with improved precision and far less measurement error than with standard epidemiologic methods. Advances in the application of metabolomics in large-scale epidemiologic research are now being realized through a combination of improved sample preparation and handling, automated laboratory and processing methods, and reduction in costs. The number of epidemiologic studies that use metabolic profiling is still limited, but it is fast gaining popularity in this area. In the present article, we present a roadmap for metabolomic analyses in epidemiologic studies and discuss the various challenges these data pose to large-scale studies. We discuss the steps of data preprocessing, univariate and multivariate data analysis, correction for multiplicity of comparisons with correlated data, and finally the steps of cross-validation and external validation. As data from metabolomic studies accumulate in epidemiology, there is a need for large-scale replication and synthesis of findings, increased availability of raw data, and a focus on good study design, all of which will highlight the potential clinical impact of metabolomics in this field.

    View details for DOI 10.1093/aje/kwu143

    View details for Web of Science ID 000339808700002

    View details for PubMedID 24966222

  • Design and Analysis for Studying microRNAs in Human Disease: A Primer on -Omic Technologies AMERICAN JOURNAL OF EPIDEMIOLOGY Nair, V. S., Pritchard, C. C., Tewari, M., Ioannidis, J. P. 2014; 180 (2): 140-152

    Abstract

    microRNAs (miRNAs) are fundamental to cellular biology. Although only approximately 22 bases long, miRNAs regulate complex processes in health and disease, including human cancer. Because miRNAs are highly stable in circulation when compared with several other classes of nucleic acids, they have generated intense interest as clinical biomarkers in diverse epidemiologic studies. As with other molecular biomarker fields, however, miRNA research has become beleaguered by pitfalls related to terminology and classification; procedural, assay, and study cohort heterogeneity; and methodological inconsistencies. Together, these issues have led to both false-positive and potentially false-negative miRNA associations. In this review, we summarize the biological rationale for studying miRNAs in human disease with a specific focus on circulating miRNAs, which highlight some of the most challenging topics in the field to date. Examples from lung cancer are used to illustrate the potential utility and some of the pitfalls in contemporary miRNA research. Although the field is in its infancy, several important lessons have been learned relating to cohort development, sample preparation, and statistical analysis that should be considered for future studies. The goal of this primer is to equip epidemiologists and clinical researchers with sound principles of study design and analysis when using miRNAs.

    View details for DOI 10.1093/aje/kwu135

    View details for Web of Science ID 000339808700003

    View details for PubMedID 24966218

    View details for PubMedCentralID PMC4082346

  • Engaging Patients and Stakeholders in Research Proposal Review: The Patient-Centered Outcomes Research Institute ANNALS OF INTERNAL MEDICINE Fleurence, R. L., Forsythe, L. P., Lauer, M., Rotter, J., Ioannidis, J. P., Beal, A., Frank, L., Selby, J. V. 2014; 161 (2): 122-?

    Abstract

    The inaugural round of merit review for the Patient-Centered Outcomes Research Institute (PCORI) in November 2012 included patients and other stakeholders, as well as scientists. This article examines relationships among scores of the 3 reviewer types, changes in scoring after in-person discussion, and the effect of inclusion of patient and stakeholder reviewers on the review process. In the first phase, 363 scientists scored 480 applications. In the second phase, 59 scientists, 21 patients, and 31 stakeholders provided a "prediscussion" score and a final "postdiscussion" score after an in-person meeting for applications. Bland-Altman plots were used to characterize levels of agreement among and within reviewer types before and after discussion. Before discussion, there was little agreement among average scores given by the 4 lead scientific reviewers and patient and stakeholder reviewers. After discussion, the 4 primary reviewers showed mild convergence in their scores, and the 21-member panel came to a much stronger agreement. Of the 25 awards with the best (and lowest) scores after phase 2, only 13 had ranked in the top 25 after the phase 1 review by scientists. Five percent of the 480 proposals submitted were funded. The authors conclude that patient and stakeholder reviewers brought different perspectives to the review process but that in-person discussion led to closer agreement among reviewer types. It is not yet known whether these conclusions are generalizable to future rounds of peer review. Future work would benefit from additional data collection for evaluation purposes and from long-term evaluation of the effect on the funded research.

    View details for DOI 10.7326/M13-2412

    View details for Web of Science ID 000339764600021

    View details for PubMedID 25023251

  • How to Read a Systematic Review and Meta-analysis and Apply the Results to Patient Care Users' Guides to the Medical Literature JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Murad, M. H., Montori, V. M., Ioannidis, J. P., Jaeschke, R., Devereaux, P. J., Prasad, K., Neumann, I., Carrasco-Labra, A., Agoritsas, T., Hatala, R., Meade, M. O., Wyer, P., Cook, D. J., Guyatt, G. 2014; 312 (2): 171-179

    Abstract

    Clinical decisions should be based on the totality of the best evidence and not the results of individual studies. When clinicians apply the results of a systematic review or meta-analysis to patient care, they should start by evaluating the credibility of the methods of the systematic review, ie, the extent to which these methods have likely protected against misleading results. Credibility depends on whether the review addressed a sensible clinical question; included an exhaustive literature search; demonstrated reproducibility of the selection and assessment of studies; and presented results in a useful manner. For reviews that are sufficiently credible, clinicians must decide on the degree of confidence in the estimates that the evidence warrants (quality of evidence). Confidence depends on the risk of bias in the body of evidence; the precision and consistency of the results; whether the results directly apply to the patient of interest; and the likelihood of reporting bias. Shared decision making requires understanding of the estimates of magnitude of beneficial and harmful effects, and confidence in those estimates.

    View details for DOI 10.1001/jama.2014.5559

    View details for Web of Science ID 000338511200023

    View details for PubMedID 25005654

  • Evidence of reporting biases in voxel-based morphometry (VBM) studies of psychiatric and neurological disorders. Human brain mapping Fusar-Poli, P., Radua, J., Frascarelli, M., Mechelli, A., Borgwardt, S., Di Fabio, F., Biondi, M., Ioannidis, J. P., David, S. P. 2014; 35 (7): 3052-3065

    Abstract

    To evaluate whether biases may influence the findings of whole-brain structural imaging literature.Forty-seven whole-brain voxel-based meta-analyses including voxel-based morphometry (VBM) studies in neuropsychiatric conditions were included, for a total of 324 individual VBM studies. The total sample size, the overall number of foci, and different moderators were extracted both at the level of the individual studies and at the level of the meta-analyses.Sample size ranged from 12 to 545 (median n = 47) per VBM study. The median number of reported foci per study was six. VBM studies with larger sample sizes reported only slightly more abnormalities than smaller studies (2% increase in the number of foci per 10-patients increase in sample size). A similar pattern was seen in several analyses according to different moderator variables with some possible modulating evidence for the statistical threshold employed, publication year and number of coauthors. Whole-brain meta-analyses (median sample size n = 534) found fewer foci (median = 3) than single studies and overall they showed no significant increase in the number of foci with increasing sample size. Meta-analyses with ≥10 VBM studies reported a median of three foci and showed a significant increase with increasing sample size, while there was no relationship between sample size and number of foci (median = 5) in meta-analyses with <10 VBM studies.The number of foci reported in small VBM studies and even in meta-analyses with few studies may often be inflated. This picture is consistent with reporting biases affecting small studies. Hum Brain Mapp, 2013. © 2013 Wiley Periodicals, Inc.

    View details for DOI 10.1002/hbm.22384

    View details for PubMedID 24123491

  • Inferior vena cava filters and postoperative outcomes in patients undergoing bariatric surgery: a meta-analysis SURGERY FOR OBESITY AND RELATED DISEASES Kaw, R., Pasupuleti, V., Overby, D. W., Deshpande, A., Coleman, C. I., Ioannidis, J. P., Hernandez, A. V. 2014; 10 (4): 725-733

    View details for DOI 10.1016/j.soard.2014.04.008

    View details for Web of Science ID 000342329800036

    View details for PubMedID 25224168

  • Diagnostic tests often fail to lead to changes in patient outcomes. Journal of clinical epidemiology Siontis, K. C., Siontis, G. C., Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2014; 67 (6): 612-621

    Abstract

    To evaluate the effects of diagnostic testing on patient outcomes in a large sample of diagnostic randomized controlled trials (D-RCTs) and to examine whether the effects for patient outcomes correlate with the effects on management and with diagnostic accuracy.We considered D-RCTs that evaluated diagnostic interventions for any condition and reported effectiveness data on one or more patient outcomes. We calculated odds ratios for patient outcomes and outcomes pertaining to the use of further diagnostic and therapeutic interventions and the diagnostic odds ratio (DOR) for the accuracy of experimental tests.One hundred forty trials (153 comparisons) were eligible. Patient outcomes were significantly improved in 28 comparisons (18%). There was no concordance in significance and direction of effects between the patient outcome and outcomes for use of further diagnostic or therapeutic interventions (weighted κ 0.02 and 0.09, respectively). The effect size for the patient outcome did not correlate with the effect sizes for use of further diagnostic (r = 0.05; P = 0.78) or therapeutic interventions (r = 0.18; P = 0.08) or the experimental intervention DOR in the same trial (r = -0.24; P = 0.51).Few tests have well-documented benefits on patient outcomes. Diagnostic performance or the effects on management decisions are not necessarily indicative of patient benefits.

    View details for DOI 10.1016/j.jclinepi.2013.12.008

    View details for PubMedID 24679598

  • Diagnostic tests often fail to lead to changes in patient outcomes JOURNAL OF CLINICAL EPIDEMIOLOGY Siontis, K. C., Siontis, G. C., Contopoutos-Ioannidis, D. G., Ioannidis, J. P. 2014; 67 (6): 612-621

    Abstract

    To evaluate the effects of diagnostic testing on patient outcomes in a large sample of diagnostic randomized controlled trials (D-RCTs) and to examine whether the effects for patient outcomes correlate with the effects on management and with diagnostic accuracy.We considered D-RCTs that evaluated diagnostic interventions for any condition and reported effectiveness data on one or more patient outcomes. We calculated odds ratios for patient outcomes and outcomes pertaining to the use of further diagnostic and therapeutic interventions and the diagnostic odds ratio (DOR) for the accuracy of experimental tests.One hundred forty trials (153 comparisons) were eligible. Patient outcomes were significantly improved in 28 comparisons (18%). There was no concordance in significance and direction of effects between the patient outcome and outcomes for use of further diagnostic or therapeutic interventions (weighted κ 0.02 and 0.09, respectively). The effect size for the patient outcome did not correlate with the effect sizes for use of further diagnostic (r = 0.05; P = 0.78) or therapeutic interventions (r = 0.18; P = 0.08) or the experimental intervention DOR in the same trial (r = -0.24; P = 0.51).Few tests have well-documented benefits on patient outcomes. Diagnostic performance or the effects on management decisions are not necessarily indicative of patient benefits.

    View details for DOI 10.1016/j.jclinepi.2013.12.008

    View details for Web of Science ID 000335610000003

  • Effects of interventions on survival in acute respiratory distress syndrome: an umbrella review of 159 published randomized trials and 29 meta-analyses INTENSIVE CARE MEDICINE Tonelli, A. R., Zein, J., Adams, J., Ioannidis, J. P. 2014; 40 (6): 769-787

    Abstract

    Multiple interventions have been tested in acute respiratory distress syndrome (ARDS). We examined the entire agenda of published randomized controlled trials (RCTs) in ARDS that reported on mortality and of respective meta-analyses.We searched PubMed, the Cochrane Library, and Web of Knowledge until July 2013. We included RCTs in ARDS published in English. We excluded trials of newborns and children; and those on short-term interventions, ARDS prevention, or post-traumatic lung injury. We also reviewed all meta-analyses of RCTs in this field that addressed mortality. Treatment modalities were grouped in five categories: mechanical ventilation strategies and respiratory care, enteral or parenteral therapies, inhaled/intratracheal medications, nutritional support, and hemodynamic monitoring.We identified 159 published RCTs of which 93 had overall mortality reported (n = 20,671 patients)-44 trials (14,426 patients) reported mortality as a primary outcome. A statistically significant survival benefit was observed in eight trials (seven interventions) and two trials reported an adverse effect on survival. Among RCTs with more than 50 deaths in at least one treatment arm (n = 21), two showed a statistically significant mortality benefit of the intervention (lower tidal volumes and prone positioning), one showed a statistically significant mortality benefit only in adjusted analyses (cisatracurium), and one (high-frequency oscillatory ventilation) showed a significant detrimental effect. Across 29 meta-analyses, the most consistent evidence was seen for low tidal volumes and prone positioning in severe ARDS.There is limited supportive evidence that specific interventions can decrease mortality in ARDS. While low tidal volumes and prone positioning in severe ARDS seem effective, most sporadic findings of interventions suggesting reduced mortality are not corroborated consistently in large-scale evidence including meta-analyses.

    View details for DOI 10.1007/s00134-014-3272-1

    View details for Web of Science ID 000336281100001

    View details for PubMedID 24667919

    View details for PubMedCentralID PMC4031289

  • Study design and the drug development process--reply. JAMA Ioannidis, J. P., Hozo, I., Djulbegovic, B. 2014; 311 (19): 2023-2024

    View details for DOI 10.1001/jama.2014.3829

    View details for PubMedID 24846045

  • Prevention and control of neglected tropical diseases: overview of randomized trials, systematic reviews and meta-analyses. Bulletin of the World Health Organization Kappagoda, S., Ioannidis, J. P. 2014; 92 (5): 356-366C

    Abstract

    To analyse evidence from randomized controlled trials (RCTs) on the prevention and control of neglected tropical diseases (NTDs) and to identify areas where evidence is lacking.The Cochrane Central Register of Controlled Trials and PubMed were searched for RCTs and the Cochrane Database of Systematic Reviews and PubMed were searched for meta-analyses and systematic reviews, both from inception to 31 December 2012.Overall, 258 RCTs were found on American trypanosomiasis, Buruli ulcer, dengue, geohelminth infection, leishmaniasis, leprosy, lymphatic filariasis, onchocerciasis, rabies, schistosomiasis or trachoma. No RCTs were found on cysticercosis, dracunculiasis, echinococcosis, foodborne trematodes, or human African trypanosomiasis. The most studied diseases were geohelminth infection (51 RCTs) and leishmaniasis (46 RCTs). Vaccines, chemoprophylaxis and interventions targeting insect vectors were evaluated in 113, 99 and 39 RCTs, respectively. Few addressed how best to deliver preventive chemotherapy, such as the choice of dosing interval (10) or target population (4), the population coverage needed to reduce transmission (2) or the method of drug distribution (1). Thirty-one publications containing 32 systematic reviews (16 with and 16 without meta-analyses) were found on American trypanosomiasis, dengue, geohelminths, leishmaniasis, leprosy, lymphatic filariasis, onchocerciasis, schistosomiasis or trachoma. Together, they included only 79 of the 258 published RCTs (30.6%). Of 36 interventions assessed, 8 were judged effective in more than one review.Few RCTs on the prevention or control of the principal NTDs were found. Trials on how best to deliver preventive chemotherapy were particularly rare.

    View details for DOI 10.2471/BLT.13.129601

    View details for PubMedID 24839325

  • Prevention and control of neglected tropical diseases; overview of randomized trials, systematic reviews and meta-analyses BULLETIN OF THE WORLD HEALTH ORGANIZATION Kappagoda, S., Ioannidis, J. P. 2014; 92 (5): 356-366

    Abstract

    To analyse evidence from randomized controlled trials (RCTs) on the prevention and control of neglected tropical diseases (NTDs) and to identify areas where evidence is lacking.The Cochrane Central Register of Controlled Trials and PubMed were searched for RCTs and the Cochrane Database of Systematic Reviews and PubMed were searched for meta-analyses and systematic reviews, both from inception to 31 December 2012.Overall, 258 RCTs were found on American trypanosomiasis, Buruli ulcer, dengue, geohelminth infection, leishmaniasis, leprosy, lymphatic filariasis, onchocerciasis, rabies, schistosomiasis or trachoma. No RCTs were found on cysticercosis, dracunculiasis, echinococcosis, foodborne trematodes, or human African trypanosomiasis. The most studied diseases were geohelminth infection (51 RCTs) and leishmaniasis (46 RCTs). Vaccines, chemoprophylaxis and interventions targeting insect vectors were evaluated in 113, 99 and 39 RCTs, respectively. Few addressed how best to deliver preventive chemotherapy, such as the choice of dosing interval (10) or target population (4), the population coverage needed to reduce transmission (2) or the method of drug distribution (1). Thirty-one publications containing 32 systematic reviews (16 with and 16 without meta-analyses) were found on American trypanosomiasis, dengue, geohelminths, leishmaniasis, leprosy, lymphatic filariasis, onchocerciasis, schistosomiasis or trachoma. Together, they included only 79 of the 258 published RCTs (30.6%). Of 36 interventions assessed, 8 were judged effective in more than one review.Few RCTs on the prevention or control of the principal NTDs were found. Trials on how best to deliver preventive chemotherapy were particularly rare.

    View details for DOI 10.2471/BLT.13.129601

    View details for Web of Science ID 000336478400015

    View details for PubMedCentralID PMC4007126

  • Mapping the expanded often inappropriate use of the Framingham Risk Score in the medical literature. Journal of clinical epidemiology Tzoulaki, I., Seretis, A., Ntzani, E. E., Ioannidis, J. P. 2014; 67 (5): 571-577

    Abstract

    To systematically evaluate the use of Framingham Risk Score (FRS) in the medical literature and specifically examine the use of FRS in different populations and settings and for different outcomes than the ones originally developed for.We identified all the citations to the article by Wilson et al. (1998), in which FRS was originally described through ISI Web of Science until April 2011. We selected studies that stated in their abstract that they calculated or used the FRS for any reason and extracted information on publication date, population studied, outcome, or disease risk factor with which FRS was associated and study design.We identified 375 eligible articles corresponding to 471 analyses using the FRS in cohort (n = 141), case-control (n = 16), or cross-sectional (n = 314) settings. Only a minority of the cohort studies had as a primary aim to externally validate the FRS (n = 45). The studied population was different (from general or healthy) in 35 (25%) and 133 (42%) of the cohort and cross-sectional analyses, respectively. All case-control studies examined healthy controls. The studied outcome was different (from coronary heart disease) in 79 (56%) of the cohort analyses and 10 (63%) of the case-control studies. Overall, only 46 (33%) of the 141 cohort analyses examined the same outcome and population as FRS was originally developed for.A large number of studies use FRS in populations and for outcomes other than the ones it has been developed for and therefore for which its performance is unknown and nonvalidated.

    View details for DOI 10.1016/j.jclinepi.2013.10.021

    View details for PubMedID 24513280

  • Publication and other reporting biases in cognitive sciences: detection, prevalence, and prevention TRENDS IN COGNITIVE SCIENCES Ioannidis, J. P., Munafo, M. R., Fusar-Poli, P., Nosek, B. A., David, S. P. 2014; 18 (5): 235-241

    Abstract

    Recent systematic reviews and empirical evaluations of the cognitive sciences literature suggest that publication and other reporting biases are prevalent across diverse domains of cognitive science. In this review, we summarize the various forms of publication and reporting biases and other questionable research practices, and overview the available methods for probing into their existence. We discuss the available empirical evidence for the presence of such biases across the neuroimaging, animal, other preclinical, psychological, clinical trials, and genetics literature in the cognitive sciences. We also highlight emerging solutions (from study design to data analyses and reporting) to prevent bias and improve the fidelity in the field of cognitive science research.

    View details for DOI 10.1016/j.tics.2014.02.010

    View details for Web of Science ID 000336113400007

    View details for PubMedID 24656991

  • Scientific reporting is suboptimal for aspects that characterize genetic risk prediction studies: a review of published articles based on the Genetic RIsk Prediction Studies statement JOURNAL OF CLINICAL EPIDEMIOLOGY Iglesias, A. I., Mihaescu, R., Ioannidis, J. P., Khoury, M. J., Little, J., van Duijn, C. M., Janssens, A. C. 2014; 67 (5): 487-499

    Abstract

    Our main objective was to raise awareness of the areas that need improvements in the reporting of genetic risk prediction articles for future publications, based on the Genetic RIsk Prediction Studies (GRIPS) statement.We evaluated studies that developed or validated a prediction model based on multiple DNA variants, using empirical data, and were published in 2010. A data extraction form based on the 25 items of the GRIPS statement was created and piloted.Forty-two studies met our inclusion criteria. Overall, more than half of the evaluated items (34 of 62) were reported in at least 85% of included articles. Seventy-seven percentage of the articles were identified as genetic risk prediction studies through title assessment, but only 31% used the keywords recommended by GRIPS in the title or abstract. Seventy-four percentage mentioned which allele was the risk variant. Overall, only 10% of the articles reported all essential items needed to perform external validation of the risk model.Completeness of reporting in genetic risk prediction studies is adequate for general elements of study design but is suboptimal for several aspects that characterize genetic risk prediction studies such as description of the model construction. Improvements in the transparency of reporting of these aspects would facilitate the identification, replication, and application of genetic risk prediction models.

    View details for DOI 10.1016/j.jclinepi.2013.10.006

    View details for Web of Science ID 000334974900002

    View details for PubMedID 24411311

  • Quantifying rare, deleterious variation in 12 human cytochrome P450 drug-metabolism genes in a large-scale exome dataset. Human molecular genetics Gordon, A. S., Tabor, H. K., Johnson, A. D., Snively, B. M., Assimes, T. L., Auer, P. L., Ioannidis, J. P., Peters, U., Robinson, J. G., Sucheston, L. E., Wang, D., Sotoodehnia, N., Rotter, J. I., Psaty, B. M., Jackson, R. D., Herrington, D. M., O'Donnell, C. J., Reiner, A. P., Rich, S. S., Rieder, M. J., Bamshad, M. J., Nickerson, D. A. 2014; 23 (8): 1957-1963

    Abstract

    The study of genetic influences on drug response and efficacy ('pharmacogenetics') has existed for over 50 years. Yet, we still lack a complete picture of how genetic variation, both common and rare, affects each individual's responses to medications. Exome sequencing is a promising alternative method for pharmacogenetic discovery as it provides information on both common and rare variation in large numbers of individuals. Using exome data from 2203 AA and 4300 Caucasian individuals through the NHLBI Exome Sequencing Project, we conducted a survey of coding variation within 12 Cytochrome P450 (CYP) genes that are collectively responsible for catalyzing nearly 75% of all known Phase I drug oxidation reactions. In addition to identifying many polymorphisms with known pharmacogenetic effects, we discovered over 730 novel nonsynonymous alleles across the 12 CYP genes of interest. These alleles include many with diverse functional effects such as premature stop codons, aberrant splicesites and mutations at conserved active site residues. Our analysis considering both novel, predicted functional alleles as well as known, actionable CYP alleles reveals that rare, deleterious variation contributes markedly to the overall burden of pharmacogenetic alleles within the populations considered, and that the contribution of rare variation to this burden is over three times greater in AA individuals as compared with Caucasians. While most of these impactful alleles are individually rare, 7.6-11.7% of individuals interrogated in the study carry at least one newly described potentially deleterious alleles in a major drug-metabolizing CYP.

    View details for DOI 10.1093/hmg/ddt588

    View details for PubMedID 24282029

  • Quantifying rare, deleterious variation in 12 human cytochrome P450 drug-metabolism genes in a large-scale exome dataset HUMAN MOLECULAR GENETICS Gordon, A. S., Tabor, H. K., Johnson, A. D., Snively, B. M., Assimes, T. L., Auer, P. L., Ioannidis, J. P., Peters, U., Robinson, J. G., Sucheston, L. E., Wang, D., Sotoodehnia, N., Rotter, J. I., Psaty, B. M., Jackson, R. D., Herrington, D. M., ODonnell, C. J., Reiner, A. P., Rich, S. S., Rieder, M. J., Bamshad, M. J., Nickerson, D. A. 2014; 23 (8): 1957-1963

    Abstract

    The study of genetic influences on drug response and efficacy ('pharmacogenetics') has existed for over 50 years. Yet, we still lack a complete picture of how genetic variation, both common and rare, affects each individual's responses to medications. Exome sequencing is a promising alternative method for pharmacogenetic discovery as it provides information on both common and rare variation in large numbers of individuals. Using exome data from 2203 AA and 4300 Caucasian individuals through the NHLBI Exome Sequencing Project, we conducted a survey of coding variation within 12 Cytochrome P450 (CYP) genes that are collectively responsible for catalyzing nearly 75% of all known Phase I drug oxidation reactions. In addition to identifying many polymorphisms with known pharmacogenetic effects, we discovered over 730 novel nonsynonymous alleles across the 12 CYP genes of interest. These alleles include many with diverse functional effects such as premature stop codons, aberrant splicesites and mutations at conserved active site residues. Our analysis considering both novel, predicted functional alleles as well as known, actionable CYP alleles reveals that rare, deleterious variation contributes markedly to the overall burden of pharmacogenetic alleles within the populations considered, and that the contribution of rare variation to this burden is over three times greater in AA individuals as compared with Caucasians. While most of these impactful alleles are individually rare, 7.6-11.7% of individuals interrogated in the study carry at least one newly described potentially deleterious alleles in a major drug-metabolizing CYP.

    View details for DOI 10.1093/hmg/ddt588

    View details for Web of Science ID 000333269400001

  • Network geometry shows evidence sequestration for medical vs. surgical practices: treatments for basal cell carcinoma. Journal of clinical epidemiology Kim, D. D., Tang, J. Y., Ioannidis, J. P. 2014; 67 (4): 391-400

    Abstract

    Basal cell carcinoma (BCC) is the most common cancer with 2 million treatments per year with little evidence-based guidelines for treatment. There are three classes of interventions (surgical, destructive, and topical) for BCC, and this study aimed to determine whether there are preferences or avoidances in comparisons of different types of treatments for BCC in randomized controlled trials (RCTs).PubMed, Cochrane Central Registry of Clinical Trials, and ClinicalTrials.Gov were used to identify eligible published and registered ongoing RCTs.Fifty-five trials (42 published and 13 registered trials) were identified. Only one unpublished registered trial compared a topical vs. a surgical intervention, and only one trial compared a topical vs. a destructive intervention. Conversely, 44 of the 55 trials compared interventions within the same treatment class and 9 of 55 trials compared surgical vs. destructive interventions. In most trials, selection of same-class comparators was not necessitated by the type of BCC lesions (nonaggressive superficial or nodular vs. aggressive, infiltrative, morpheic BCCs, P = 0.155) or their location (face vs. nonfacial, P = 0.137).This is the first time that an evaluation of network geometry is applied to address issues of comparisons between different families of interventions that belong to different specialties and practices (medical vs. surgical). Previous evaluations of homophily have addressed different families of interventions, in which all interventions are medical (drugs) and performed in the same health-care settings. The noncommunicating bodies of evidence between medical and surgical interventions that we document highlight a problem of unnecessary sequestration of the evidence and the corresponding health-care practices.

    View details for DOI 10.1016/j.jclinepi.2013.10.015

    View details for PubMedID 24491794

  • Assessment of osteoarthritis candidate genes in a meta-analysis of nine genome-wide association studies. Arthritis & rheumatology (Hoboken, N.J.) Rodriguez-Fontenla, C., Calaza, M., Evangelou, E., Valdes, A. M., Arden, N., Blanco, F. J., Carr, A., Chapman, K., Deloukas, P., Doherty, M., Esko, T., Garcés Aletá, C. M., Gomez-Reino Carnota, J. J., Helgadottir, H., Hofman, A., Jonsdottir, I., Kerkhof, H. J., Kloppenburg, M., McCaskie, A., Ntzani, E. E., Ollier, W. E., Oreiro, N., Panoutsopoulou, K., Ralston, S. H., Ramos, Y. F., Riancho, J. A., Rivadeneira, F., Slagboom, P. E., Styrkarsdottir, U., Thorsteinsdottir, U., Thorleifsson, G., Tsezou, A., Uitterlinden, A. G., Wallis, G. A., Wilkinson, J. M., Zhai, G., Zhu, Y., Felson, D. T., Ioannidis, J. P., Loughlin, J., Metspalu, A., Meulenbelt, I., Stefansson, K., van Meurs, J. B., Zeggini, E., Spector, T. D., Gonzalez, A. 2014; 66 (4): 940-949

    View details for DOI 10.1002/art.38300

    View details for PubMedID 24757145

  • Assessment of osteoarthritis candidate genes in a meta-analysis of nine genome-wide association studies. Arthritis & rheumatology Rodriguez-Fontenla, C., Calaza, M., Evangelou, E., Valdes, A. M., Arden, N., Blanco, F. J., Carr, A., Chapman, K., Deloukas, P., Doherty, M., Esko, T., Garcés Aletá, C. M., Gomez-Reino Carnota, J. J., Helgadottir, H., Hofman, A., Jonsdottir, I., Kerkhof, H. J., Kloppenburg, M., McCaskie, A., Ntzani, E. E., Ollier, W. E., Oreiro, N., Panoutsopoulou, K., Ralston, S. H., Ramos, Y. F., Riancho, J. A., Rivadeneira, F., Slagboom, P. E., Styrkarsdottir, U., Thorsteinsdottir, U., Thorleifsson, G., Tsezou, A., Uitterlinden, A. G., Wallis, G. A., Wilkinson, J. M., Zhai, G., Zhu, Y., Felson, D. T., Ioannidis, J. P., Loughlin, J., Metspalu, A., Meulenbelt, I., Stefansson, K., van Meurs, J. B., Zeggini, E., Spector, T. D., Gonzalez, A. 2014; 66 (4): 940-949

    Abstract

    To assess candidate genes for association with osteoarthritis (OA) and identify promising genetic factors and, secondarily, to assess the candidate gene approach in OA.A total of 199 candidate genes for association with OA were identified using Human Genome Epidemiology (HuGE) Navigator. All of their single-nucleotide polymorphisms (SNPs) with an allele frequency of >5% were assessed by fixed-effects meta-analysis of 9 genome-wide association studies (GWAS) that included 5,636 patients with knee OA and 16,972 control subjects and 4,349 patients with hip OA and 17,836 control subjects of European ancestry. An additional 5,921 individuals were genotyped for significantly associated SNPs in the meta-analysis. After correction for the number of independent tests, P values less than 1.58 × 10(-5) were considered significant.SNPs at only 2 of the 199 candidate genes (COL11A1 and VEGF) were associated with OA in the meta-analysis. Two SNPs in COL11A1 showed association with hip OA in the combined analysis: rs4907986 (P = 1.29 × 10(-5) , odds ratio [OR] 1.12, 95% confidence interval [95% CI] 1.06-1.17) and rs1241164 (P = 1.47 × 10(-5) , OR 0.82, 95% CI 0.74-0.89). The sex-stratified analysis also showed association of COL11A1 SNP rs4908291 in women (P = 1.29 × 10(-5) , OR 0.87, 95% CI 0.82-0.92); this SNP showed linkage disequilibrium with rs4907986. A single SNP of VEGF, rs833058, showed association with hip OA in men (P = 1.35 × 10(-5) , OR 0.85, 95% CI 0.79-0.91). After additional samples were genotyped, association at one of the COL11A1 signals was reinforced, whereas association at VEGF was slightly weakened.Two candidate genes, COL11A1 and VEGF, were significantly associated with OA in this focused meta-analysis. The remaining candidate genes were not associated.

    View details for DOI 10.1002/art.38300

    View details for PubMedID 24757145

  • Research: increasing value, reducing waste - Authors' reply. Lancet Glasziou, P., Macleod, M., Chalmers, I., Ioannidis, J. P., Al-Shahi Salman, R., Chan, A. 2014; 383 (9923): 1126-1127

    View details for DOI 10.1016/S0140-6736(14)60563-8

    View details for PubMedID 24679627

  • Clinical interpretation and implications of whole-genome sequencing. JAMA Dewey, F. E., Grove, M. E., Pan, C., Goldstein, B. A., Bernstein, J. A., Chaib, H., Merker, J. D., Goldfeder, R. L., Enns, G. M., David, S. P., Pakdaman, N., Ormond, K. E., Caleshu, C., Kingham, K., Klein, T. E., Whirl-Carrillo, M., Sakamoto, K., Wheeler, M. T., Butte, A. J., Ford, J. M., Boxer, L., Ioannidis, J. P., Yeung, A. C., Altman, R. B., Assimes, T. L., Snyder, M., Ashley, E. A., Quertermous, T. 2014; 311 (10): 1035-1045

    Abstract

    Whole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication.To examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings.An exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings.Genome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up.Depending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross κ, 0.52; 95% CI, 0.40-0.64), and reclassified 69% of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss κ, 0.24; P < 001).In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings. In certain cases, WGS will identify clinically actionable genetic variants warranting early medical intervention. These issues should be considered when determining the role of WGS in clinical medicine.

    View details for DOI 10.1001/jama.2014.1717

    View details for PubMedID 24618965

    View details for PubMedCentralID PMC4119063

  • Clinical interpretation and implications of whole-genome sequencing. JAMA : the journal of the American Medical Association Dewey, F. E., Grove, M. E., Pan, C., Goldstein, B. A., Bernstein, J. A., Chaib, H., Merker, J. D., Goldfeder, R. L., Enns, G. M., David, S. P., Pakdaman, N., Ormond, K. E., Caleshu, C., Kingham, K., Klein, T. E., Whirl-Carrillo, M., Sakamoto, K., Wheeler, M. T., Butte, A. J., Ford, J. M., Boxer, L., Ioannidis, J. P., Yeung, A. C., Altman, R. B., Assimes, T. L., Snyder, M., Ashley, E. A., Quertermous, T. 2014; 311 (10): 1035-1045

    Abstract

    Whole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication.To examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings.An exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings.Genome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up.Depending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross κ, 0.52; 95% CI, 0.40-0.64), and reclassified 69% of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss κ, 0.24; P < 001).In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings. In certain cases, WGS will identify clinically actionable genetic variants warranting early medical intervention. These issues should be considered when determining the role of WGS in clinical medicine.

    View details for DOI 10.1001/jama.2014.1717

    View details for PubMedID 24618965

    View details for PubMedCentralID PMC4119063

  • Safety of medical interventions in children versus adults. Pediatrics Lathyris, D., Panagiotou, O. A., Baltogianni, M., Ioannidis, J. P., Contopoulos-Ioannidis, D. G. 2014; 133 (3): e666-73

    Abstract

    Compare the risk of harm from pharmacologic interventions in pediatric versus adult randomized controlled trials (RCTs).We used systematic reviews from the Cochrane Database of Systematic Reviews. We considered separately 7 categories of harms/harm-related end points: severe harms, withdrawals due to harms, any harm, organ system-level harms, specific harms, withdrawals for any reason, and mortality. Systematic reviews with quantitative synthesis from at least 1 adult and 1 pediatric RCT for any of those end points were eligible. We calculated the summary odds ratio (experimental versus control intervention) in adult and pediatric trials/meta-analysis; the relative odds ratio (ROR) in adults versus children per meta-analysis; and the summary ROR (sROR) across all meta-analyses for each end point. ROR <1 means that the experimental intervention fared worse in children than adults.We identified 176 meta-analyses for 52 types of harms/harm-related end points with 669 adult and 184 pediatric RCTs. Of those, 165 had sufficient data for ROR estimation. sRORs showed statistically significant discrepancy between adults and children only for headache (sROR 0.82; 95% confidence interval 0.70-0.96). Nominally significant discrepancies for specific harms were identified in 12 of 165 meta-analyses (RORs <1 in 7, ROR >1 in 5). In 36% of meta-analyses, the ROR estimates suggested twofold or greater differences between children and adults, and the 95% confidence intervals could exclude twofold differences only in 18% of meta-analyses.Available evidence on harms/harm-related end points from pharmacologic interventions has large uncertainty. Extrapolation of evidence from adults to children may be tenuous. Some clinically important discrepancies were identified.

    View details for DOI 10.1542/peds.2013-3128

    View details for PubMedID 24567023

  • Safety of medical interventions in children versus adults. Pediatrics Lathyris, D., Panagiotou, O. A., Baltogianni, M., Ioannidis, J. P., Contopoulos-Ioannidis, D. G. 2014; 133 (3): e666-73

    View details for DOI 10.1542/peds.2013-3128

    View details for PubMedID 24567023

  • Making Prospective Registration of Observational Research a Reality SCIENCE TRANSLATIONAL MEDICINE Dal-Re, R., Ioannidis, J. P., Bracken, M. B., Buffler, P. A., Chan, A., Franco, E. L., La Vecchia, C., Weiderpass, E. 2014; 6 (224)

    Abstract

    The vast majority of health-related observational studies are not prospectively registered and the advantages of registration have not been fully appreciated. Nonetheless, international standards require approval of study protocols by an independent ethics committee before the study can begin. We suggest that there is an ethical and scientific imperative to publicly preregister key information from newly approved protocols, which should be required by funders. Ultimately, more complete information may be publicly available by disclosing protocols, analysis plans, data sets, and raw data.

    View details for DOI 10.1126/scitranslmed.3007513

    View details for Web of Science ID 000331476700002

    View details for PubMedID 24553383

  • Reply to Nuijten et al.: Reanalyses actually confirm that US studies overestimate effects in softer research PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Fanelli, D., Ioannidis, J. P. 2014; 111 (7): E714-E715

    View details for DOI 10.1073/pnas.1322565111

    View details for Web of Science ID 000331396500002

    View details for PubMedID 24693543

    View details for PubMedCentralID PMC3932901

  • Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol. American journal of human genetics Lange, L. A., Hu, Y., Zhang, H., Xue, C., Schmidt, E. M., Tang, Z., Bizon, C., Lange, E. M., Smith, J. D., Turner, E. H., Jun, G., Kang, H. M., Peloso, G., Auer, P., Li, K., Flannick, J., Zhang, J., Fuchsberger, C., Gaulton, K., Lindgren, C., Locke, A., Manning, A., Sim, X., Rivas, M. A., Holmen, O. L., Gottesman, O., Lu, Y., Ruderfer, D., Stahl, E. A., Duan, Q., Li, Y., Durda, P., Jiao, S., Isaacs, A., Hofman, A., Bis, J. C., Correa, A., Griswold, M. E., Jakobsdottir, J., Smith, A. V., Schreiner, P. J., Feitosa, M. F., Zhang, Q., Huffman, J. E., Crosby, J., Wassel, C. L., Do, R., Franceschini, N., Martin, L. W., Robinson, J. G., Assimes, T. L., Crosslin, D. R., Rosenthal, E. A., Tsai, M., Rieder, M. J., Farlow, D. N., Folsom, A. R., Lumley, T., Fox, E. R., Carlson, C. S., Peters, U., Jackson, R. D., van Duijn, C. M., Uitterlinden, A. G., Levy, D., Rotter, J. I., Taylor, H. A., Gudnason, V., Siscovick, D. S., Fornage, M., Borecki, I. B., Hayward, C., Rudan, I., Chen, Y. E., Bottinger, E. P., Loos, R. J., Sætrom, P., Hveem, K., Boehnke, M., Groop, L., McCarthy, M., Meitinger, T., Ballantyne, C. M., Gabriel, S. B., O'Donnell, C. J., Post, W. S., North, K. E., Reiner, A. P., Boerwinkle, E., Psaty, B. M., Altshuler, D., Kathiresan, S., Lin, D., Jarvik, G. P., Cupples, L. A., Kooperberg, C., Wilson, J. G., Nickerson, D. A., Abecasis, G. R., Rich, S. S., Tracy, R. P., Willer, C. J. 2014; 94 (2): 233-245

    Abstract

    Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.

    View details for DOI 10.1016/j.ajhg.2014.01.010

    View details for PubMedID 24507775

  • Genome-wide association study for radiographic vertebral fractures: a potential role for the 16q24 BMD locus. Bone Oei, L., Estrada, K., Duncan, E. L., Christiansen, C., Liu, C., Langdahl, B. L., Obermayer-Pietsch, B., Riancho, J. A., Prince, R. L., van Schoor, N. M., McCloskey, E., Hsu, Y., Evangelou, E., Ntzani, E., Evans, D. M., Alonso, N., Husted, L. B., Valero, C., Hernandez, J. L., Lewis, J. R., Kaptoge, S. K., Zhu, K., Cupples, L. A., Medina-Gómez, C., Vandenput, L., Kim, G. S., Hun Lee, S., Castaño-Betancourt, M. C., Oei, E. H., Martinez, J., Daroszewska, A., van der Klift, M., Mellström, D., Herrera, L., Karlsson, M. K., Hofman, A., Ljunggren, Ö., Pols, H. A., Stolk, L., van Meurs, J. B., Ioannidis, J. P., Zillikens, M. C., Lips, P., Karasik, D., Uitterlinden, A. G., Styrkarsdottir, U., Brown, M. A., Koh, J., Richards, J. B., Reeve, J., Ohlsson, C., Ralston, S. H., Kiel, D. P., Rivadeneira, F. 2014; 59: 20-27

    Abstract

    Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fractures applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged > 55 years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey–Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey–Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han–Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p < 5 × 10− 8. In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p = 4.6 × 10− 8. However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% CI: 0.98–1.14; p = 0.17), displaying high degree of heterogeneity (I2 = 57%; Qhet p = 0.0006). Under Han–Eskin alternative random effects model the summary effect was significant (p = 0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size > 1.25) may still be consistent with an effect size < 1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures.

    View details for PubMedID 24516880

    View details for PubMedCentralID PMC4102322

  • Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus BONE Oei, L., Estrada, K., Duncan, E. L., Christiansen, C., Liu, C., Langdahl, B. L., Obermayer-Pietsch, B., Riancho, J. A., Prince, R. L., van Schoor, N. M., McCloskey, E., Hsu, Y., Evangelou, E., Ntzani, E., Evans, D. M., Alonso, N., Husted, L. B., Valero, C., Hernandez, J. L., Lewis, J. R., Kaptoge, S. K., Zhu, K., Cupples, L. A., Medina-Gomez, C., Vandenput, L., Kim, G. S., Lee, S. H., Castano-Betancourt, M. C., Oei, E. H., Martinez, J., Daroszewska, A., van der Klift, M., Mellstrom, D., Herrera, L., Karlsson, M. K., Hofman, A., Ljunggren, O., Pols, H. A., Stolk, L., van Meurs, J. B., Ioannidis, J. P., Zillikens, M. C., Lips, P., Karasik, D., Uitterlinden, A. G., Styrkarsdottir, U., Brown, M. A., Koh, J., Richards, J. B., Reeve, J., Ohlsson, C., Ralston, S. H., Kiel, D. P., Rivadeneira, F. 2014; 59: 20-27

    Abstract

    Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fractures applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged > 55 years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey–Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey–Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han–Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p < 5 × 10− 8. In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p = 4.6 × 10− 8. However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% CI: 0.98–1.14; p = 0.17), displaying high degree of heterogeneity (I2 = 57%; Qhet p = 0.0006). Under Han–Eskin alternative random effects model the summary effect was significant (p = 0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size > 1.25) may still be consistent with an effect size < 1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures.

    View details for DOI 10.1016/j.bone.2013.10.015

    View details for Web of Science ID 000329558600004

    View details for PubMedID 24516880

    View details for PubMedCentralID PMC4102322

  • Antiretroviral therapy for initial human immunodeficiency virus/AIDS treatment: critical appraisal of the evidence from over 100 randomized trials and 400 systematic reviews and meta-analyses. Clinical microbiology and infection Kanters, S., Mills, E. J., Thorlund, K., Bucher, H. C., Ioannidis, J. P. 2014; 20 (2): 114-122

    Abstract

    There have been over 100 randomized clinical trials (RCTs) of diverse regimens of antiretroviral therapy for treatment-naïve human immunodeficiency virus-positive patients. A further 400 systematic reviews and meta-analyses are informed by these trials. There are, however, difficulties in using systematic reviews and meta-analyses of this clinical evidence to inform guidelines and clinical practice. Several issues can make the interpretation of comparative effectiveness challenging. In this article, we review the key challenges in interpreting multiple trials in this population. We specifically examine the network geometry of the clinical trial comparisons, the predominance of non-inferiority trial designs, issues related to potential class effects, heterogeneous documentation of adverse events, and a relative lack of RCTs that reflect specific current clinical guideline recommendations. We conclude with recommendations for future clinical trials and meta-analyses.

    View details for DOI 10.1111/1469-0691.12475

    View details for PubMedID 24274661

  • A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus. Journal of medical genetics Oei, L., Hsu, Y., Styrkarsdottir, U., Eussen, B. H., de Klein, A., Peters, M. J., Halldorsson, B., Liu, C., Alonso, N., Kaptoge, S. K., Thorleifsson, G., Hallmans, G., Hocking, L. J., Husted, L. B., Jameson, K. A., Kruk, M., Lewis, J. R., Patel, M. S., Scollen, S., Svensson, O., Trompet, S., van Schoor, N. M., Zhu, K., Buckley, B. M., Cooper, C., Ford, I., Goltzman, D., González-Macías, J., Langdahl, B. L., Leslie, W. D., Lips, P., Lorenc, R. S., Olmos, J. M., Pettersson-Kymmer, U., Reid, D. M., Riancho, J. A., Slagboom, P. E., Garcia-Ibarbia, C., Ingvarsson, T., Johannsdottir, H., Luben, R., Medina-Gómez, C., Arp, P., Nandakumar, K., Palsson, S. T., Sigurdsson, G., van Meurs, J. B., Zhou, Y., Hofman, A., Jukema, J. W., Pols, H. A., Prince, R. L., Cupples, L. A., Marshall, C. R., Pinto, D., Sato, D., Scherer, S. W., Reeve, J., Thorsteinsdottir, U., Karasik, D., Richards, J. B., Stefansson, K., Uitterlinden, A. G., Ralston, S. H., Ioannidis, J. P., Kiel, D. P., Rivadeneira, F., Estrada, K. 2014; 51 (2): 122-131

    Abstract

    Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk.To identify CNVs associated with osteoporotic bone fracture risk.We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies.A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p = 8.69 × 10(-5)). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p = 0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk.These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.

    View details for DOI 10.1136/jmedgenet-2013-102064

    View details for PubMedID 24343915

  • Improving the drug development process: more not less randomized trials. JAMA Djulbegovic, B., Hozo, I., Ioannidis, J. P. 2014; 311 (4): 355-356

    View details for DOI 10.1001/jama.2013.283742

    View details for PubMedID 24449311

  • How to Use a Subgroup Analysis JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Sun, X., Ioannidis, J. P., Agoritsas, T., Alba, A. C., Guyatt, G. 2014; 311 (4): 405-411

    Abstract

    Clinicians, when trying to apply trial results to patient care, need to individualize patient care and, potentially, manage patients based on results of subgroup analyses. Apparently compelling subgroup effects often prove spurious, and guidance is needed to differentiate credible from less credible subgroup claims. We therefore provide 5 criteria to use when assessing the validity of subgroup analyses: (1) Can chance explain the apparent subgroup effect; (2) Is the effect consistent across studies; (3) Was the subgroup hypothesis one of a small number of hypotheses developed a priori with direction specified; (4) Is there strong preexisting biological support; and (5) Is the evidence supporting the effect based on within- or between-study comparisons. The first 4 criteria are applicable to individual studies or systematic reviews, the last only to systematic reviews of multiple studies. These criteria will help clinicians deciding whether to use subgroup analyses to guide their patient care.

    View details for DOI 10.1001/jama.2013.285063

    View details for Web of Science ID 000329939300026

  • How to use a subgroup analysis: users' guide to the medical literature. JAMA Sun, X., Ioannidis, J. P., Agoritsas, T., Alba, A. C., Guyatt, G. 2014; 311 (4): 405-411

    Abstract

    Clinicians, when trying to apply trial results to patient care, need to individualize patient care and, potentially, manage patients based on results of subgroup analyses. Apparently compelling subgroup effects often prove spurious, and guidance is needed to differentiate credible from less credible subgroup claims. We therefore provide 5 criteria to use when assessing the validity of subgroup analyses: (1) Can chance explain the apparent subgroup effect; (2) Is the effect consistent across studies; (3) Was the subgroup hypothesis one of a small number of hypotheses developed a priori with direction specified; (4) Is there strong preexisting biological support; and (5) Is the evidence supporting the effect based on within- or between-study comparisons. The first 4 criteria are applicable to individual studies or systematic reviews, the last only to systematic reviews of multiple studies. These criteria will help clinicians deciding whether to use subgroup analyses to guide their patient care.

    View details for DOI 10.1001/jama.2013.285063

    View details for PubMedID 24449319

  • Increasing value and reducing waste in research design, conduct, and analysis. Lancet Ioannidis, J. P., Greenland, S., Hlatky, M. A., Khoury, M. J., Macleod, M. R., Moher, D., Schulz, K. F., Tibshirani, R. 2014; 383 (9912): 166-175

    Abstract

    Correctable weaknesses in the design, conduct, and analysis of biomedical and public health research studies can produce misleading results and waste valuable resources. Small effects can be difficult to distinguish from bias introduced by study design and analyses. An absence of detailed written protocols and poor documentation of research is common. Information obtained might not be useful or important, and statistical precision or power is often too low or used in a misleading way. Insufficient consideration might be given to both previous and continuing studies. Arbitrary choice of analyses and an overemphasis on random extremes might affect the reported findings. Several problems relate to the research workforce, including failure to involve experienced statisticians and methodologists, failure to train clinical researchers and laboratory scientists in research methods and design, and the involvement of stakeholders with conflicts of interest. Inadequate emphasis is placed on recording of research decisions and on reproducibility of research. Finally, reward systems incentivise quantity more than quality, and novelty more than reliability. We propose potential solutions for these problems, including improvements in protocols and documentation, consideration of evidence from studies in progress, standardisation of research efforts, optimisation and training of an experienced and non-conflicted scientific workforce, and reconsideration of scientific reward systems.

    View details for DOI 10.1016/S0140-6736(13)62227-8

    View details for PubMedID 24411645

  • How to increase value and reduce waste when research priorities are set. Lancet Chalmers, I., Bracken, M. B., Djulbegovic, B., Garattini, S., Grant, J., Gülmezoglu, A. M., Howells, D. W., Ioannidis, J. P., Oliver, S. 2014; 383 (9912): 156-165

    Abstract

    The increase in annual global investment in biomedical research--reaching US$240 billion in 2010--has resulted in important health dividends for patients and the public. However, much research does not lead to worthwhile achievements, partly because some studies are done to improve understanding of basic mechanisms that might not have relevance for human health. Additionally, good research ideas often do not yield the anticipated results. As long as the way in which these ideas are prioritised for research is transparent and warranted, these disappointments should not be deemed wasteful; they are simply an inevitable feature of the way science works. However, some sources of waste cannot be justified. In this report, we discuss how avoidable waste can be considered when research priorities are set. We have four recommendations. First, ways to improve the yield from basic research should be investigated. Second, the transparency of processes by which funders prioritise important uncertainties should be increased, making clear how they take account of the needs of potential users of research. Third, investment in additional research should always be preceded by systematic assessment of existing evidence. Fourth, sources of information about research that is in progress should be strengthened and developed and used by researchers. Research funders have primary responsibility for reductions in waste resulting from decisions about what research to do.

    View details for DOI 10.1016/S0140-6736(13)62229-1

    View details for PubMedID 24411644

  • Biomedical research: increasing value, reducing waste. Lancet Macleod, M. R., Michie, S., Roberts, I., Dirnagl, U., Chalmers, I., Ioannidis, J. P., Al-Shahi Salman, R., Chan, A., Glasziou, P. 2014; 383 (9912): 101-104

    View details for DOI 10.1016/S0140-6736(13)62329-6

    View details for PubMedID 24411643

  • Protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants. Neurobiology of aging Heckman, M. G., Elbaz, A., Soto-Ortolaza, A. I., Serie, D. J., Aasly, J. O., Annesi, G., Auburger, G., Bacon, J. A., Boczarska-Jedynak, M., Bozi, M., Brighina, L., Chartier-Harlin, M., Dardiotis, E., Destée, A., Ferrarese, C., Ferraris, A., Fiske, B., Gispert, S., Hadjigeorgiou, G. M., Hattori, N., Ioannidis, J. P., Jasinska-Myga, B., Jeon, B. S., Kim, Y. J., Klein, C., Kruger, R., Kyratzi, E., Lin, C., Lohmann, K., Loriot, M., Lynch, T., Mellick, G. D., Mutez, E., Opala, G., Park, S. S., Petrucci, S., Quattrone, A., Sharma, M., Silburn, P. A., Sohn, Y. H., Stefanis, L., Tadic, V., Tomiyama, H., Uitti, R. J., Valente, E. M., Vassilatis, D. K., Vilariño-Güell, C., White, L. R., Wirdefeldt, K., Wszolek, Z. K., Wu, R., Xiromerisiou, G., Maraganore, D. M., Farrer, M. J., Ross, O. A. 2014; 35 (1): 266 e5-14

    Abstract

    The best validated susceptibility variants for Parkinson's disease are located in the α-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined 4 SNCA variants (rs181489, rs356219, rs11931074, and rs2583988), the MAPT H1-haplotype-defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (n = 10,322) and Asian (n = 2289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all p ≥ 0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with Parkinson's disease is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations.

    View details for DOI 10.1016/j.neurobiolaging.2013.07.013

    View details for PubMedID 23962496

  • Estimates of the continuously publishing core in the scientific workforce. PloS one Ioannidis, J. P., Boyack, K. W., Klavans, R. 2014; 9 (7)

    Abstract

    The ability of a scientist to maintain a continuous stream of publication may be important, because research requires continuity of effort. However, there is no data on what proportion of scientists manages to publish each and every year over long periods of time.Using the entire Scopus database, we estimated that there are 15,153,100 publishing scientists (distinct author identifiers) in the period 1996-2011. However, only 150,608 (<1%) of them have published something in each and every year in this 16-year period (uninterrupted, continuous presence [UCP] in the literature). This small core of scientists with UCP are far more cited than others, and they account for 41.7% of all papers in the same period and 87.1% of all papers with >1000 citations in the same period. Skipping even a single year substantially affected the average citation impact. We also studied the birth and death dynamics of membership in this influential UCP core, by imputing and estimating UCP-births and UCP-deaths. We estimated that 16,877 scientists would qualify for UCP-birth in 1997 (no publication in 1996, UCP in 1997-2012) and 9,673 scientists had their UCP-death in 2010. The relative representation of authors with UCP was enriched in Medical Research, in the academic sector and in Europe/North America, while the relative representation of authors without UCP was enriched in the Social Sciences and Humanities, in industry, and in other continents.The proportion of the scientific workforce that maintains a continuous uninterrupted stream of publications each and every year over many years is very limited, but it accounts for the lion's share of researchers with high citation impact. This finding may have implications for the structure, stability and vulnerability of the scientific workforce.

    View details for DOI 10.1371/journal.pone.0101698

    View details for PubMedID 25007173

    View details for PubMedCentralID PMC4090124

  • Authors' reply to Boucher. BMJ (Clinical research ed.) Theodoratou, E., Ioannidis, J. P. 2014; 348: g2927-?

    View details for DOI 10.1136/bmj.g2927

    View details for PubMedID 24780520

  • What Is Wrong with Clinical Proteomics? Clinical chemistry Meo, A. D., Diamandis, E. P., Rodriguez, H., Hoofnagle, A. N., Ioannidis, J., Lopez, M. 2014

    View details for DOI 10.1373/clinchem.2014.225185

    View details for PubMedID 24831563

  • Studying the elusive environment in large scale. JAMA : the journal of the American Medical Association Patel, C. J., Ioannidis, J. P. 2014; 311 (21): 2173–74

    View details for DOI 10.1001/jama.2014.4129

    View details for PubMedID 24893084

  • Errors (my very own) and the fearful uncertainty of numbers. European journal of clinical investigation Ioannidis, J. P. 2014

    View details for DOI 10.1111/eci.12277

    View details for PubMedID 24785138

  • The diagnostic accuracy of the Patient Health Questionnaire-2 (PHQ-2), Patient Health Questionnaire-8 (PHQ-8), and Patient Health Questionnaire-9 (PHQ-9) for detecting major depression: protocol for a systematic review and individual patient data meta-analyses. Systematic reviews Thombs, B. D., Benedetti, A., Kloda, L. A., Levis, B., Nicolau, I., Cuijpers, P., Gilbody, S., Ioannidis, J. P., McMillan, D., Patten, S. B., Shrier, I., Steele, R. J., Ziegelstein, R. C. 2014; 3: 124-?

    Abstract

    Major depressive disorder (MDD) may be present in 10%-20% of patients in medical settings. Routine depression screening is sometimes recommended to improve depression management. However, studies of the diagnostic accuracy of depression screening tools have typically used data-driven, exploratory methods to select optimal cutoffs. Often, these studies report results from a small range of cutoff points around whatever cutoff score is most accurate in that given study. When published data are combined in meta-analyses, estimates of accuracy for different cutoff points may be based on data from different studies, rather than data from all studies for each possible cutoff point. As a result, traditional meta-analyses may generate exaggerated estimates of accuracy. Individual patient data (IPD) meta-analyses can address this problem by synthesizing data from all studies for each cutoff score to obtain diagnostic accuracy estimates. The nine-item Patient Health Questionnaire-9 (PHQ-9) and the shorter PHQ-2 and PHQ-8 are commonly recommended for depression screening. Thus, the primary objectives of our IPD meta-analyses are to determine the diagnostic accuracy of the PHQ-9, PHQ-8, and PHQ-2 to detect MDD among adults across all potentially relevant cutoff scores. Secondary analyses involve assessing accuracy accounting for patient factors that may influence accuracy (age, sex, medical comorbidity).Data sources will include MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, PsycINFO, and Web of Science. We will include studies that included a Diagnostic and Statistical Manual or International Classification of Diseases diagnosis of MDD based on a validated structured or semi-structured clinical interview administered within 2 weeks of the administration of the PHQ. Two reviewers will independently screen titles and abstracts, perform full article review, and extract study data. Disagreements will be resolved by consensus. Risk of bias will be assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Bivariate random-effects meta-analysis will be conducted for the full range of plausible cutoff values.The proposed IPD meta-analyses will allow us to obtain estimates of the diagnostic accuracy of the PHQ-9, PHQ-8, and PHQ-2.PROSPERO CRD42014010673.

    View details for DOI 10.1186/2046-4053-3-124

    View details for PubMedID 25348422

  • Simple, standardized incorporation of genetic risk into non-genetic risk prediction tools for complex traits: coronary heart disease as an example. Frontiers in genetics Goldstein, B. A., Knowles, J. W., Salfati, E., Ioannidis, J. P., Assimes, T. L. 2014; 5: 254-?

    Abstract

    Genetic risk assessment is becoming an important component of clinical decision-making. Genetic Risk Scores (GRSs) allow the composite assessment of genetic risk in complex traits. A technically and clinically pertinent question is how to most easily and effectively combine a GRS with an assessment of clinical risk derived from established non-genetic risk factors as well as to clearly present this information to patient and health care providers.We illustrate a means to combine a GRS with an independent assessment of clinical risk using a log-link function. We apply the method to the prediction of coronary heart disease (CHD) in the Atherosclerosis Risk in Communities (ARIC) cohort. We evaluate different constructions based on metrics of effect change, discrimination, and calibration.The addition of a GRS to a clinical risk score (CRS) improves both discrimination and calibration for CHD in ARIC. RESULTS are similar regardless of whether external vs. internal coefficients are used for the CRS, risk factor single nucleotide polymorphisms (SNPs) are included in the GRS, or subjects with diabetes at baseline are excluded. We outline how to report the construction and the performance of a GRS using our method and illustrate a means to present genetic risk information to subjects and/or their health care provider.The proposed method facilitates the standardized incorporation of a GRS in risk assessment.

    View details for DOI 10.3389/fgene.2014.00254

    View details for PubMedID 25136350

  • The protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants. Neurobiology of aging Heckman, M. G., Elbaz, A., Soto-Ortolaza, A. I., Serie, D. J., Aasly, J. O., Annesi, G., Auburger, G., Bacon, J. A., Boczarska-Jedynak, M., Bozi, M., Brighina, L., Chartier-Harlin, M., Dardiotis, E., Destée, A., Ferrarese, C., Ferraris, A., Fiske, B., Gispert, S., Hadjigeorgiou, G. M., Hattori, N., Ioannidis, J. P., Jasinska-Myga, B., Jeon, B. S., Kim, Y. J., Klein, C., Kruger, R., Kyratzi, E., Lin, C., Lohmann, K., Loriot, M., Lynch, T., Mellick, G. D., Mutez, E., Opala, G., Park, S. S., Petrucci, S., Quattrone, A., Sharma, M., Silburn, P. A., Sohn, Y. H., Stefanis, L., Tadic, V., Tomiyama, H., Uitti, R. J., Valente, E. M., Vassilatis, D. K., Vilariño-Güell, C., White, L. R., Wirdefeldt, K., Wszolek, Z. K., Wu, R., Xiromerisiou, G., Maraganore, D. M., Farrer, M. J., Ross, O. A. 2014; 35 (1): 266 e5-266 e14
  • The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method. BMC medical research methodology Inthout, J., Ioannidis, J. P., Borm, G. F. 2014; 14: 25-?

    Abstract

    The DerSimonian and Laird approach (DL) is widely used for random effects meta-analysis, but this often results in inappropriate type I error rates. The method described by Hartung, Knapp, Sidik and Jonkman (HKSJ) is known to perform better when trials of similar size are combined. However evidence in realistic situations, where one trial might be much larger than the other trials, is lacking. We aimed to evaluate the relative performance of the DL and HKSJ methods when studies of different sizes are combined and to develop a simple method to convert DL results to HKSJ results.We evaluated the performance of the HKSJ versus DL approach in simulated meta-analyses of 2-20 trials with varying sample sizes and between-study heterogeneity, and allowing trials to have various sizes, e.g. 25% of the trials being 10-times larger than the smaller trials. We also compared the number of "positive" (statistically significant at p < 0.05) findings using empirical data of recent meta-analyses with > = 3 studies of interventions from the Cochrane Database of Systematic Reviews.The simulations showed that the HKSJ method consistently resulted in more adequate error rates than the DL method. When the significance level was 5%, the HKSJ error rates at most doubled, whereas for DL they could be over 30%. DL, and, far less so, HKSJ had more inflated error rates when the combined studies had unequal sizes and between-study heterogeneity. The empirical data from 689 meta-analyses showed that 25.1% of the significant findings for the DL method were non-significant with the HKSJ method. DL results can be easily converted into HKSJ results.Our simulations showed that the HKSJ method consistently results in more adequate error rates than the DL method, especially when the number of studies is small, and can easily be applied routinely in meta-analyses. Even with the HKSJ method, extra caution is needed when there are = <5 studies of very unequal sizes.

    View details for DOI 10.1186/1471-2288-14-25

    View details for PubMedID 24548571

    View details for PubMedCentralID PMC4015721

  • Non-publication and delayed publication of randomized trials on vaccines: survey. BMJ (Clinical research ed.) Manzoli, L., Flacco, M. E., D'Addario, M., Capasso, L., De Vito, C., Marzuillo, C., Villari, P., Ioannidis, J. P. 2014; 348: g3058-?

    Abstract

    To evaluate the extent of non-publication or delayed publication of registered randomized trials on vaccines, and to investigate potential determinants of delay to publication.Survey.Trials registry websites, Scopus, PubMed, Google.Randomized controlled trials evaluating the safety or the efficacy or immunogenicity of human papillomavirus (HPV), pandemic A/H1N1 2009 influenza, and meningococcal, pneumococcal, and rotavirus vaccines that were registered in ClinicalTrials.gov, Current Controlled Trials, WHO International Clinical Trials Registry Platform, Clinical Study Register, or Indian, Australian-New Zealand, and Chinese trial registries in 2006-12. Electronic databases were searched up to February 2014 to identify published manuscripts containing trial results. These were reviewed and classified as positive, mixed, or negative. We also reviewed the results available in ClinicalTrials.gov.Publication status of trial results and time from completion to publication in peer reviewed journals.Cox proportional hazards regression was used to evaluate potential predictors of publication delay.We analysed 384 trials (85% sponsored by industry). Of 355 trials (404 758 participants) that were completed, 176 (n=151 379) had been published in peer reviewed journals. Another 42 trials (total sample 62 765) remained unpublished but reported results in ClinicalTrials.gov. The proportion of trials published 12, 24, 36, and 48 months after completion was 12%, 29%, 53%, and 73%, respectively. Including results posted in ClinicalTrials.gov, 48 months after study completion results were available for 82% of the trials and 90% of the participants. Delay to publication between non-industry and industry sponsored trials did not differ, but non-industry sponsored trials were 4.42-fold (P=0.008) more likely to report negative or mixed findings. Negative results were reported by only 2% of the published trials.Most vaccine trials are published eventually or the results posted in ClinicalTrials.gov, but delays to publication of several years are common. Actions should focus on the timely dissemination of data from vaccine trials to the public.

    View details for DOI 10.1136/bmj.g3058

    View details for PubMedID 24838102

  • Guidelines for cardiovascular risk assessment and cholesterol treatment--reply. JAMA : the journal of the American Medical Association Ioannidis, J. P. 2014; 311 (21): 2235–36

    View details for DOI 10.1001/jama.2014.4075

    View details for PubMedID 24893099

  • Attention to local health burden and the global disparity of health research. PloS one Evans, J. A., Shim, J., Ioannidis, J. P. 2014; 9 (4)

    Abstract

    Most studies on global health inequality consider unequal health care and socio-economic conditions but neglect inequality in the production of health knowledge relevant to addressing disease burden. We demonstrate this inequality and identify likely causes. Using disability-adjusted life years (DALYs) for 111 prominent medical conditions, assessed globally and nationally by the World Health Organization, we linked DALYs with MEDLINE articles for each condition to assess the influence of DALY-based global disease burden, compared to the global market for treatment, on the production of relevant MEDLINE articles, systematic reviews, clinical trials and research using animal models vs. humans. We then explored how DALYs, wealth, and the production of research within countries correlate with this global pattern. We show that global DALYs for each condition had a small, significant negative relationship with the production of each type of MEDLINE articles for that condition. Local processes of health research appear to be behind this. Clinical trials and animal studies but not systematic reviews produced within countries were strongly guided by local DALYs. More and less developed countries had very different disease profiles and rich countries publish much more than poor countries. Accordingly, conditions common to developed countries garnered more clinical research than those common to less developed countries. Many of the health needs in less developed countries do not attract attention among developed country researchers who produce the vast majority of global health knowledge--including clinical trials--in response to their own local needs. This raises concern about the amount of knowledge relevant to poor populations deficient in their own research infrastructure. We recommend measures to address this critical dimension of global health inequality.

    View details for DOI 10.1371/journal.pone.0090147

    View details for PubMedID 24691431

    View details for PubMedCentralID PMC3972174

  • Registering Diagnostic and Prognostic Trials of Tests: Is it the Right Thing to Do? Clinical chemistry Rifai, N., Bossuyt, P. M., Ioannidis, J. P., Bray, K. R., McShane, L. M., Golub, R. M., Hooft, L. 2014

    View details for DOI 10.1373/clinchem.2014.226100

    View details for PubMedID 24855278

  • A vision for chronic disease prevention intervention research: Report from a workshop. Canadian journal of public health = Revue canadienne de santé publique Ashbury, F. D., Little, J., Ioannidis, J. P., Kreiger, N., Palmer, L. J., Relton, C., Taylor, P. 2014; 105 (2): e150–3

    Abstract

    The Population Studies Research Network of Cancer Care Ontario hosted a strategic planning workshop to establish an agenda for a prevention intervention research program in Ontario, including priority topics for investigation and design considerations. The two-day workshop included: presentations on background papers developed to facilitate participants' preparation for and discussions in the workshop; keynote presentations on intervention research concerning primary prevention of chronic diseases, design and study implementation considerations; a dedicated session on critical and creative thinking to stimulate participation and discussion topics; breakout groups to identify, discuss and present study ideas, designs, implementation considerations; and a consensus process to discuss and identify recommendations for research priorities and next steps. The retreat yielded the following recommendations: 1) develop an intervention research agenda that includes working with existing large-scale cohorts; 2) develop an intervention research agenda that includes novel research designs that could target individuals or groups; and 3) develop an intervention research agenda in which studies collect data on costs, define stakeholders, and ensure clear strategies for stakeholder engagement and knowledge transfer. The Population Studies Research Network will develop options from these recommendations and release a call for proposals in 2014 for intervention research pilot projects that reflect these recommendations. Pilot projects will be evaluated based on their fit with the retreat's recommendations, and their potential to scale up to full studies and application in practice.

    View details for PubMedID 24886853

  • Discussion: Why "An estimate of the science-wise false discovery rate and application to the top medical literature" is false BIOSTATISTICS Ioannidis, J. P. 2014; 15 (1): 28-36

    Abstract

    Jager and Leek have tried to estimate a false-discovery rate (FDR) in abstracts of articles published in five medical journals during 2000-2010. Their approach is flawed in sampling, calculations, and conclusions. It uses a tiny portion of select papers in highly select journals. Randomized controlled trials and systematic reviews (designs with the lowest anticipated false-positive rates) are 52% of the analyzed papers, while these designs account for only 4% in PubMed in the same period. The FDR calculations consider the entire published literature as equivalent to a single genomic experiment where all performed analyses are reported without selection or distortion. However, the data used are the P-values reported in the abstracts of published papers; these P-values are a highly distorted, highly select sample. Besides selective reporting biases, all other biases, in particular confounding in observational studies, are also ignored, while these are often the main drivers for high false-positive rates in the biomedical literature. A reproducibility check of the raw data shows that much of the data Jager and Leek used are either wrong or make no sense: most of the usable data were missed by their script, 94% of the abstracts that reported ≥2 P-values had high correlation/overlap between reported outcomes, and only a minority of P-values corresponded to relevant primary outcomes. The Jager and Leek paper exemplifies the dreadful combination of using automated scripts with wrong methods and unreliable data. Sadly, this combination is common in the medical literature.

    View details for DOI 10.1093/biostatistics/kxt036

    View details for Web of Science ID 000328286700006

    View details for PubMedID 24068251

  • Potential increased risk of cancer from commonly used medications: an umbrella review of meta-analyses. Annals of oncology Ioannidis, J. P., Zhou, Y., Chang, C. Q., Schully, S. D., Khoury, M. J., Freedman, A. N. 2014; 25 (1): 16-23

    Abstract

    Several commonly used medications have been associated with increased cancer risk in the literature. Here, we evaluated the strength and consistency of these claims in published meta-analyses. We carried out an umbrella review of 74 meta-analysis articles addressing the association of commonly used medications (antidiabetics, antihyperlipidemics, antihypertensives, antirheumatics, drugs for osteoporosis, and others) with cancer risk where at least one meta-analysis in the medication class included some data from randomized trials. Overall, 51 articles found no statistically significant differences, 13 found some decreased cancer risk, and 11 found some increased risk (one reported both increased and decreased risks). The 11 meta-analyses that found some increased risks reported 16 increased risk estimates, of which 5 pertained to overall cancer and 11 to site-specific cancer. Six of the 16 estimates were derived from randomized trials and 10 from observational data. Estimates of increased risk were strongly inversely correlated with the amount of evidence (number of cancer cases) (Spearman's correlation coefficient = -0.77, P < 0.001). In 4 of the 16 topics, another meta-analysis existed that was larger (n = 2) or included better controlled data (n = 2) and in all 4 cases there was no statistically significantly increased risk of malignancy. No medication or class had substantial and consistent evidence for increased risk of malignancy. However, for most medications we cannot exclude small risks or risks in population subsets. Such risks are unlikely to be possible to document robustly unless very large, collaborative studies with standardized analyses and no selective reporting are carried out.

    View details for DOI 10.1093/annonc/mdt372

    View details for PubMedID 24310915

    View details for PubMedCentralID PMC3868319

  • Evidence-based de-implementation for contradicted, unproven, and aspiring healthcare practices. Implementation science Prasad, V., Ioannidis, J. P. 2014; 9 (1): 1-?

    Abstract

    Abandoning ineffective medical practices and mitigating the risks of untested practices are important for improving patient health and containing healthcare costs. Historically, this process has relied on the evidence base, societal values, cultural tensions, and political sway, but not necessarily in that order. We propose a conceptual framework to guide and prioritize this process, shifting emphasis toward the principles of evidence-based medicine, acknowledging that evidence may still be misinterpreted or distorted by recalcitrant proponents of entrenched practices and other biases.

    View details for DOI 10.1186/1748-5908-9-1

    View details for PubMedID 24398253

    View details for PubMedCentralID PMC3892018

  • Research accomplishments that are too good to be true: reply to Ting. Intensive care medicine Ioannidis, J. P. 2014

    View details for DOI 10.1007/s00134-014-3220-0

    View details for PubMedID 24477457

  • Research accomplishments that are too good to be true INTENSIVE CARE MEDICINE Ioannidis, J. P. 2014; 40 (1): 99-101

    View details for DOI 10.1007/s00134-013-3100-z

    View details for Web of Science ID 000328198600013

    View details for PubMedID 24129497

  • Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ (Clinical research ed.) Theodoratou, E., Tzoulaki, I., Zgaga, L., Ioannidis, J. P. 2014; 348: g2035-?

    Abstract

    To evaluate the breadth, validity, and presence of biases of the associations of vitamin D with diverse outcomes.Umbrella review of the evidence across systematic reviews and meta-analyses of observational studies of plasma 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D concentrations and randomised controlled trials of vitamin D supplementation.Medline, Embase, and screening of citations and references.Three types of studies were eligible for the umbrella review: systematic reviews and meta-analyses that examined observational associations between circulating vitamin D concentrations and any clinical outcome; and meta-analyses of randomised controlled trials assessing supplementation with vitamin D or active compounds (both established and newer compounds of vitamin D).107 systematic literature reviews and 74 meta-analyses of observational studies of plasma vitamin D concentrations and 87 meta-analyses of randomised controlled trials of vitamin D supplementation were identified. The relation between vitamin D and 137 outcomes has been explored, covering a wide range of skeletal, malignant, cardiovascular, autoimmune, infectious, metabolic, and other diseases. Ten outcomes were examined by both meta-analyses of observational studies and meta-analyses of randomised controlled trials, but the direction of the effect and level of statistical significance was concordant only for birth weight (maternal vitamin D status or supplementation). On the basis of the available evidence, an association between vitamin D concentrations and birth weight, dental caries in children, maternal vitamin D concentrations at term, and parathyroid hormone concentrations in patients with chronic kidney disease requiring dialysis is probable, but further studies and better designed trials are needed to draw firmer conclusions. In contrast to previous reports, evidence does not support the argument that vitamin D only supplementation increases bone mineral density or reduces the risk of fractures or falls in older people.Despite a few hundred systematic reviews and meta-analyses, highly convincing evidence of a clear role of vitamin D does not exist for any outcome, but associations with a selection of outcomes are probable.

    View details for DOI 10.1136/bmj.g2035

    View details for PubMedID 24690624

    View details for PubMedCentralID PMC3972415

  • John P. A. Ioannidis. Nature reviews. Drug discovery Ioannidis, J. P., Mullard, A. 2014; 13 (5): 328–29

    View details for DOI 10.1038/nrd4317

    View details for PubMedID 24751817

  • There are no randomized controlled trials that support the United States Preventive Services Task Force guideline on screening for depression in primary care: a systematic review. BMC medicine Thombs, B. D., Ziegelstein, R. C., Roseman, M., Kloda, L. A., Ioannidis, J. P. 2014; 12 (1): 13-?

    Abstract

    The United States Preventive Services Task Force (USPSTF) recommends screening adults for depression in primary care settings when staff-assisted depression management programs are available. This recommendation, however, is based on evidence from depression management programs conducted with patients already identified as depressed, even though screening is intended to identify depressed patients not already recognized or treated. The objective of this systematic review was to evaluate whether there is evidence from randomized controlled trials (RCTs) that depression screening benefits patients in primary care, using an explicit definition of screening.We re-evaluated RCTs included in the 2009 USPSTF evidence review on depression screening, including only trials that compared depression outcomes between screened and non-screened patients and met the following three criteria: determined patient eligibility and randomized prior to screening; excluded patients already diagnosed with a recent episode of depression or already being treated for depression; and provided the same level of depression treatment services to patients identified as depressed in the screening and non-screening trial arms. We also reviewed studies included in a recent Cochrane systematic review, but not the USPSTF review; conducted a focused search to update the USPSTF review; and reviewed trial registries.Of the nine RCTs included in the USPSTF review, four fulfilled none of three criteria for a test of depression screening, four fulfilled one of three criteria, and one fulfilled two of three criteria. There were two additional RCTs included only in the Cochrane review, and each fulfilled one of three criteria. No eligible RCTs were found via the updated review.The USPSTF recommendation to screen adults for depression in primary care settings when staff-assisted depression management programs are available is not supported by evidence from any RCTs that are directly relevant to the recommendation. The USPSTF should re-evaluate this recommendation.Registration: PROSPERO (#CRD42013004276).

    View details for DOI 10.1186/1741-7015-12-13

    View details for PubMedID 24472580

  • Association between pediatric clinical trials and global burden of disease. Pediatrics Bourgeois, F. T., Olson, K. L., Ioannidis, J. P., Mandl, K. D. 2014; 133 (1): 78-87

    Abstract

    The allocation of research resources should favor conditions responsible for the greatest disease burden. This is particularly important in pediatric populations, which have been underrepresented in clinical research. Our aim was to measure the association between the focus of pediatric clinical trials and burden of disease and to identify neglected clinical domains.We performed a cross-sectional study of clinical trials by using trial records in ClinicalTrials.gov. All trials started in 2006 or after and studying patient-level interventions in pediatric populations were included. Age-specific measures of disease burden were obtained for 21 separate conditions for high-, middle-, and low-income countries. We measured the correlation between number of pediatric clinical trials and disease burden for each condition.Neuropsychiatric conditions and infectious diseases were the most studied conditions globally in terms of number of trials (874 and 847 trials, respectively), while intentional injuries (5 trials) and maternal conditions (4 trials) were the least studied. Clinical trials were only moderately correlated with global disease burden (r = 0.58, P = .006). Correlations were also moderate within each of the country income levels, but lowest in low-income countries (r = .47, P = .03). Globally, the conditions most understudied relative to disease burden were injuries (-260 trials for unintentional injuries and -160 trials for intentional injuries), nutritional deficiencies (-175 trials), and respiratory infections (-171 trials).Pediatric clinical trial activity is only moderately associated with pediatric burden of disease, and least associated in low-income countries. The mismatch between clinical trials and disease burden identifies key clinical areas for focus and investment.

    View details for DOI 10.1542/peds.2013-2567

    View details for PubMedID 24344112

    View details for PubMedCentralID PMC3876184

  • Autonomic Denervation Added to Pulmonary Vein Isolation for Paroxysmal Atrial Fibrillation A Randomized Clinical Trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Katritsis, D. G., Pokushalov, E., Romanov, A., Giazitzoglou, E., Siontis, G. C., Po, S. S., Camm, A. J., Ioannidis, J. P. 2013; 62 (24): 2318-2325

    Abstract

    The aim of this study was to investigate whether the combination of conventional pulmonary vein isolation (PVI) by circumferential antral ablation with ganglionated plexi (GP) modification in a single ablation procedure, yields higher success rates than PVI or GP ablation alone, in patients with paroxysmal atrial fibrillation (PAF).Conventional PVI transects the major left atrial GP, and it is possible that autonomic denervation by inadvertent GP ablation plays a central role in the efficacy of PVI.A total of 242 patients with symptomatic PAF were recruited and randomized as follows: 1) circumferential PVI (n = 78); 2) anatomic ablation of the main left atrial GP (n = 82); or 3) circumferential PVI followed by anatomic ablation of the main left atrial GP (n = 82). The primary endpoint was freedom from atrial fibrillation (AF) or other sustained atrial tachycardia (AT), verified by monthly visits, ambulatory electrocardiographic monitoring, and implantable loop recorders, during a 2-year follow-up period.Freedom from AF or AT was achieved in 44 (56%), 39 (48%), and 61 (74%) patients in the PVI, GP, and PVI+GP groups, respectively (p = 0.004 by log-rank test). PVI+GP ablation strategy compared with PVI alone yielded a hazard ratio of 0.53 (95% confidence interval: 0.31 to 0.91; p = 0.022) for recurrence of AF or AT. Fluoroscopy duration was 16 ± 3 min, 20 ± 5 min, and 23 ± 5 min for PVI, GP, and PVI+GP groups, respectively (p < 0.001). Post-ablation atrial flutter did not differ between groups: 5.1% in PVI, 4.9% in GP, and 6.1% in PVI+GP. No serious adverse procedure-related events were encountered.Addition of GP ablation to PVI confers a significantly higher success rate compared with either PVI or GP alone in patients with PAF.

    View details for DOI 10.1016/j.jacc.2013.06.053

    View details for Web of Science ID 000328073300012

    View details for PubMedID 23973694

  • Concordance of effects of medical interventions on hospital admission and readmission rates with effects on mortality. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne Hemkens, L. G., Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2013; 185 (18): E827-37

    Abstract

    Many clinical trials examine a composite outcome of admission to hospital and death, or infer a relationship between hospital admission and survival benefit. This assumes concordance of the outcomes "hospital admission" and "death." However, whether the effects of a treatment on hospital admissions and readmissions correlate to its effect on serious outcomes such as death is unknown. We aimed to assess the correlation and concordance of effects of medical interventions on admission rates and mortality.We searched the Cochrane Database of Systematic Reviews from its inception to January 2012 (issue 1, 2012) for systematic reviews of treatment comparisons that included meta-analyses for both admission and mortality outcomes. For each meta-analysis, we synthesized treatment effects on admissions and death, from respective randomized trials reporting those outcomes, using random-effects models. We then measured the concordance of directions of effect sizes and the correlation of summary estimates for the 2 outcomes.We identified 61 meta-analyses including 398 trials reporting mortality and 182 trials reporting admission rates; 125 trials reported both outcomes. In 27.9% of comparisons, the point estimates of treatment effects for the 2 outcomes were in opposite directions; in 8.2% of trials, the 95% confidence intervals did not overlap. We found no significant correlation between effect sizes for admission and death (Pearson r = 0.07, p = 0.6). Our results were similar when we limited our analysis to trials reporting both outcomes.In this metaepidemiological study, admission and mortality outcomes did not correlate, and discordances occurred in about one-third of the treatment comparisons included in our analyses. Both outcomes convey useful information and should be reported separately, but extrapolating the benefits of admission to survival is unreliable and should be avoided.

    View details for DOI 10.1503/cmaj.130430

    View details for PubMedID 24144601

  • Concordance of effects of medical interventions on hospital admission and readmission rates with effects on mortality CANADIAN MEDICAL ASSOCIATION JOURNAL Hemkens, L. G., Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2013; 185 (18): E827-E837

    Abstract

    Many clinical trials examine a composite outcome of admission to hospital and death, or infer a relationship between hospital admission and survival benefit. This assumes concordance of the outcomes "hospital admission" and "death." However, whether the effects of a treatment on hospital admissions and readmissions correlate to its effect on serious outcomes such as death is unknown. We aimed to assess the correlation and concordance of effects of medical interventions on admission rates and mortality.We searched the Cochrane Database of Systematic Reviews from its inception to January 2012 (issue 1, 2012) for systematic reviews of treatment comparisons that included meta-analyses for both admission and mortality outcomes. For each meta-analysis, we synthesized treatment effects on admissions and death, from respective randomized trials reporting those outcomes, using random-effects models. We then measured the concordance of directions of effect sizes and the correlation of summary estimates for the 2 outcomes.We identified 61 meta-analyses including 398 trials reporting mortality and 182 trials reporting admission rates; 125 trials reported both outcomes. In 27.9% of comparisons, the point estimates of treatment effects for the 2 outcomes were in opposite directions; in 8.2% of trials, the 95% confidence intervals did not overlap. We found no significant correlation between effect sizes for admission and death (Pearson r = 0.07, p = 0.6). Our results were similar when we limited our analysis to trials reporting both outcomes.In this metaepidemiological study, admission and mortality outcomes did not correlate, and discordances occurred in about one-third of the treatment comparisons included in our analyses. Both outcomes convey useful information and should be reported separately, but extrapolating the benefits of admission to survival is unreliable and should be avoided.

    View details for DOI 10.1503/cmaj.130430

    View details for Web of Science ID 000327902600014

    View details for PubMedID 24144601

    View details for PubMedCentralID PMC3855143

  • Joint Linkage and Association Analysis with Exome Sequence Data Implicates SLC25A40 in Hypertriglyceridemia. American journal of human genetics Rosenthal, E. A., Ranchalis, J., Crosslin, D. R., Burt, A., Brunzell, J. D., Motulsky, A. G., Nickerson, D. A., Wijsman, E. M., Jarvik, G. P. 2013; 93 (6): 1035-1045

    Abstract

    Hypertriglyceridemia (HTG) is a heritable risk factor for cardiovascular disease. Investigating the genetics of HTG may identify new drug targets. There are ~35 known single-nucleotide variants (SNVs) that explain only ~10% of variation in triglyceride (TG) level. Because of the genetic heterogeneity of HTG, a family study design is optimal for identification of rare genetic variants with large effect size because the same mutation can be observed in many relatives and cosegregation with TG can be tested. We considered HTG in a five-generation family of European American descent (n = 121), ascertained for familial combined hyperlipidemia. By using Bayesian Markov chain Monte Carlo joint oligogenic linkage and association analysis, we detected linkage to chromosomes 7 and 17. Whole-exome sequence data revealed shared, highly conserved, private missense SNVs in both SLC25A40 on chr7 and PLD2 on chr17. Jointly, these SNVs explained 49% of the genetic variance in TG; however, only the SLC25A40 SNV was significantly associated with TG (p = 0.0001). This SNV, c.374A>G, causes a highly disruptive p.Tyr125Cys substitution just outside the second helical transmembrane region of the SLC25A40 inner mitochondrial membrane transport protein. Whole-gene testing in subjects from the Exome Sequencing Project confirmed the association between TG and SLC25A40 rare, highly conserved, coding variants (p = 0.03). These results suggest a previously undescribed pathway for HTG and illustrate the power of large pedigrees in the search for rare, causal variants.

    View details for DOI 10.1016/j.ajhg.2013.10.019

    View details for PubMedID 24268658

  • Narrow band imaging to differentiate neoplastic and non-neoplastic colorectal polyps in real time: a meta-analysis of diagnostic operating characteristics GUT Mcgill, S. K., Evangelou, E., Ioannidis, J. P., Soetikno, R. M., Kaltenbach, T. 2013; 62 (12): 1704-1713

    Abstract

    PURPOSE: Many studies have reported on the use of narrow band imaging (NBI) colonoscopy to differentiate neoplastic from non-neoplastic colorectal polyps. It has potential to replace pathological diagnosis of diminutive polyps. We aimed to perform a systematic review and meta-analysis on the real-time diagnostic operating characteristics of NBI colonoscopy. METHODS: We searched PubMed, SCOPUS and Cochrane databases and abstracts. We used a two-level bivariate meta-analysis following a random effects model to summarise the data and fit hierarchical summary receiver-operating characteristic (HSROC) curves. The area under the HSROC curve serves as an indicator of the diagnostic test strength. We calculated summary sensitivity, specificity and negative predictive value (NPV). We assessed agreement of surveillance interval recommendations based on endoscopic diagnosis compared to pathology. RESULTS: For NBI diagnosis of colorectal polyps, the area under the HSROC curve was 0.92 (95% CI 0.90 to 0.94), based on 28 studies involving 6280 polyps in 4053 patients. The overall sensitivity was 91.0% (95% CI 87.6% to 93.5%) and specificity was 82.6% (95% CI 79.0% to 85.7%). In eight studies (n=2146 polyps) that used high-confidence diagnostic predictions, sensitivity was 93.8% and specificity was 83.3%. The NPVs exceeded 90% when 60% or less of all polyps were neoplastic. Surveillance intervals based on endoscopic diagnosis agreed with those based on pathology in 92.6% of patients (95% CI 87.9% to 96.3%). CONCLUSIONS: NBI diagnosis of colorectal polyps is highly accurate-the area under the HSROC curve exceeds 0.90. High-confidence predictions provide >90% sensitivity and NPV. It shows high potential for real-time endoscopic diagnosis.

    View details for DOI 10.1136/gutjnl-2012-303965

    View details for Web of Science ID 000326877200007

    View details for PubMedID 23300139

  • WHAT'S TO KNOW ABOUT THE CREDIBILITY OF EMPIRICAL ECONOMICS? JOURNAL OF ECONOMIC SURVEYS Ioannidis, J., Doucouliagos, C. 2013; 27 (5): 997–1004

    View details for DOI 10.1111/joes.12032

    View details for Web of Science ID 000325148400008

  • Collaborative cancer epidemiology in the 21st century: the model of cancer consortia. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Burgio, M. R., Ioannidis, J. P., Kaminski, B. M., Derycke, E., Rogers, S., Khoury, M. J., Seminara, D. 2013; 22 (12): 2148-2160

    Abstract

    During the last two decades, epidemiology has undergone a rapid evolution toward collaborative research. The proliferation of multi-institutional, interdisciplinary consortia has acquired particular prominence in cancer research. Herein, we describe the characteristics of a network of 49 established cancer epidemiology consortia (CEC) currently supported by the Epidemiology and Genomics Research Program (EGRP) at the National Cancer Institute (NCI). This collection represents the largest disease-based research network for collaborative cancer research established in population sciences. We describe the funding trends, geographic distribution, and areas of research focus. The CEC have been partially supported by 201 grants and yielded 3,876 publications between 1995 and 2011. We describe this output in terms of interdisciplinary collaboration and translational evolution. We discuss challenges and future opportunities in the establishment and conduct of large-scale team science within the framework of CEC, review future prospects for this approach to large-scale, interdisciplinary cancer research, and describe a model for the evolution of an integrated Network of Cancer Consortia optimally suited to address and support 21st-century epidemiology.

    View details for DOI 10.1158/1055-9965.EPI-13-0591

    View details for PubMedID 24045926

  • Geometry of the Randomized Evidence for Treatments of Pulmonary Hypertension CARDIOVASCULAR THERAPEUTICS Tonelli, A. R., Zein, J., Ioannidis, J. P. 2013; 31 (6): E138-E146

    Abstract

    We studied the entire agenda of randomized clinical trials in pulmonary hypertension (PH) using sociological methods. We explored the geometry of the PH network to interpret the evidence on multiple competing treatments for the same indication.We searched MEDLINE, Embase and Cochrane Library Databases for published studies. We queried clinicaltrials.gov and WHO International Clinical Trials Registry platform for non-published studies.We found 75 randomized trials (41 published [n = 4136 participants] and 34 registered unpublished [planned n = 3470 participants]). Of the published randomized studies, all used placebo as the comparator arm except for two nonindustry-sponsored comparisons between phosphodiestearase-5 (PDE-5) inhibitors and endothelin receptor antagonists (ERA), and one study comparing two different regimens of treprostinil. Similarly, only five unpublished/ongoing trials used an active PH treatment as comparator (PDE-5 inhibitors versus ERA (n = 3), different doses of sildenafil (n = 1) and two formulations of epoprostenol (n = 1). Of the 75 trials, 47 were sponsored by the manufacturer of the tested active product(s), and only two trials were sponsored by two companies comparing their products.The relative merits of different treatment options are not directly known, as there are very few head-to-head comparisons. A limited number of ongoing studies are using active FDA-approved PH-treatments for comparison. This lack of information can be overcome by carefully designing comparative effectiveness trials.

    View details for DOI 10.1111/1755-5922.12050

    View details for Web of Science ID 000327423800012

    View details for PubMedID 24112824

  • A list of highly influential biomedical researchers, 1996-2011. European journal of clinical investigation Boyack, K. W., Klavans, R., Sorensen, A. A., Ioannidis, J. P. 2013; 43 (12): 1339-1365

    Abstract

    We have generated a list of highly influential biomedical researchers based on Scopus citation data from the period 1996-2011. Of the 15,153,100 author identifiers in Scopus, approximately 1% (n=149,655) have an h-index >=20. Of those, we selected 532 authors who belonged to the 400 with highest total citation count (>=25,142 citations) and/or the 400 with highest h-index (>=76). Of those, we selected the top-400 living core biomedical researchers based on a normalized score combining total citations and h-index. Another 62 authors whose focus is outside biomedicine had a normalized score that was at least as high as the score of the 400th core biomedical researcher. We provide information on the profile of these most influential authors, including the most common Medical Subject Heading terms in their articles that are also specific to their work, most common journals where they publish, number of papers with over 100 citations that they have published as first/single, last, or middle authors, and impact score adjusted for authorship positions, given that crude citation indices and authorship positions are almost totally orthogonal. We also show for each researcher the distribution of their papers across 4 main levels (basic-to-applied) of research. We discuss technical issues, limitations and caveats, comparisons against other lists of highly-cited researchers, and potential uses of this resource.

    View details for DOI 10.1111/eci.12171

    View details for PubMedID 24134636

  • Systematic evaluation of environmental and behavioural factors associated with all-cause mortality in the United States National Health and Nutrition Examination Survey. International journal of epidemiology Patel, C. J., Rehkopf, D. H., Leppert, J. T., Bortz, W. M., Cullen, M. R., Chertow, G. M., Ioannidis, J. P. 2013; 42 (6): 1795-1810

    Abstract

    Environmental and behavioural factors are thought to contribute to all-cause mortality. Here, we develop a method to systematically screen and validate the potential independent contributions to all-cause mortality of 249 environmental and behavioural factors in the National Health and Nutrition Examination Survey (NHANES).We used Cox proportional hazards regression to associate 249 factors with all-cause mortality while adjusting for sociodemographic factors on data in the 1999-2000 and 2001-02 surveys (median 5.5 follow-up years). We controlled for multiple comparisons with the false discovery rate (FDR) and validated significant findings in the 2003-04 survey (median 2.8 follow-up years). We selected 249 factors from a set of all possible factors based on their presence in both the 1999-2002 and 2003-04 surveys and linkage with at least 20 deceased participants. We evaluated the correlation pattern of validated factors and built a multivariable model to identify their independent contribution to mortality.We identified seven environmental and behavioural factors associated with all-cause mortality, including serum and urinary cadmium, serum lycopene levels, smoking (3-level factor) and physical activity. In a multivariable model, only physical activity, past smoking, smoking in participant's home and lycopene were independently associated with mortality. These three factors explained 2.1% of the variance of all-cause mortality after adjusting for demographic and socio-economic factors.Our association study suggests that, of the set of 249 factors in NHANES, physical activity, smoking, serum lycopene and serum/urinary cadmium are associated with all-cause mortality as identified in previous studies and after controlling for multiple hypotheses and validation in an independent survey. Whereas other NHANES factors may be associated with mortality, they may require larger cohorts with longer time of follow-up to detect. It is possible to use a systematic association study to prioritize risk factors for further investigation.

    View details for DOI 10.1093/ije/dyt208

    View details for PubMedID 24345851

    View details for PubMedCentralID PMC3887569

  • Empirical evidence for low reproducibility indicates low pre-study odds. Nature reviews. Neuroscience Button, K. S., Ioannidis, J. P., Mokrysz, C., Nosek, B. A., Flint, J., Robinson, E. S., Munafò, M. R. 2013; 14 (12): 877-?

    View details for DOI 10.1038/nrn3475-c6

    View details for PubMedID 24149186

  • Raw data from clinical trials: within reach? Trends in pharmacological sciences Doshi, P., Goodman, S. N., Ioannidis, J. P. 2013; 34 (12): 645-647

    Abstract

    Making raw data from clinical trials widely publically available should reduce selective reporting biases and enhance the reproducibility of and trust in clinical research. The optimal procedures for data sharing are hotly debated. Some of the caveats and limitations in proposed data-sharing policies are potentially restrictive, and we argue in favor of more widespread availability of data from clinical research.

    View details for DOI 10.1016/j.tips.2013.10.006

    View details for PubMedID 24295825

  • Endgame: engaging the tobacco industry in its own elimination. European journal of clinical investigation Ioannidis, J. P., Henriksen, L., Prochaska, J. J. 2013; 43 (12): 1366-1370

    Abstract

    A billion deaths from tobacco are expected by 2100. Many policy interventions such as increased taxation, restrictions on advertisement, smoking bans, as well as behavioral interventions, such as pharmacological and psychological treatments for smoking cessation, decrease tobacco use, but they reach their limits. Endgame scenarios focusing on tobacco supply rather than demand are increasingly discussed, but meet with resistance by the industry and even by many tobacco control experts. A main stumbling block that requires more attention is what to do with the tobacco industry in endgame scenarios. This industry has employed notoriously talented experts in law, business, organization, marketing, advertising, strategy, policy, and statistics and has tremendous lobbying power. Performance-based regulatory approaches can pose a legal obligation on manufacturers to decrease - and eventually - eliminate tobacco products according to specified schedules. Penalties and rewards can make such plans both beneficial for public health and attractive to the companies that do the job well. We discuss caveats and reality checks of engaging the tobacco industry to eliminate its current market and change focus. Brainstorming is warranted to entice the industry to abandon tobacco for other profit goals. To get the dialogue started, we propose the wild possibility of hiring former tobacco companies to reduce the costs of healthcare, thereby addressing concurrently two major challenges to public health.

    View details for DOI 10.1111/eci.12172

    View details for PubMedID 24117211

  • Implausible results in human nutrition research BMJ-BRITISH MEDICAL JOURNAL Ioannidis, J. P. 2013; 347

    View details for DOI 10.1136/bmj.f6698

    View details for Web of Science ID 000327155000004

    View details for PubMedID 24231028

  • Prevention and Management of Non-Communicable Disease: The IOC Consensus Statement, Lausanne 2013. Sports medicine Matheson, G. O., Klügl, M., Engebretsen, L., Bendiksen, F., Blair, S. N., Börjesson, M., Budgett, R., Derman, W., Erdener, U., Ioannidis, J. P., Khan, K. M., Martinez, R., van Mechelen, W., Mountjoy, M., Sallis, R. E., Schwellnus, M., Shultz, R., Soligard, T., Steffen, K., Sundberg, C. J., Weiler, R., Ljungqvist, A. 2013; 43 (11): 1075-1088

    Abstract

    Morbidity and mortality from preventable, non-communicable chronic disease (NCD) threatens the health of our populations and our economies. The accumulation of vast amounts of scientific knowledge has done little to change this. New and innovative thinking is essential to foster new creative approaches that leverage and integrate evidence through the support of big data, technology, and design thinking. The purpose of this paper is to summarize the results of a consensus meeting on NCD prevention sponsored by the International Olympic Committee (IOC) in April, 2013. Within the context of advocacy for multifaceted systems change, the IOC's focus is to create solutions that gain traction within health care systems. The group of participants attending the meeting achieved consensus on a strategy for the prevention and management of chronic disease that includes the following: 1. Focus on behavioural change as the core component of all clinical programs for the prevention and management of chronic disease. 2. Establish actual centres to design, implement, study, and improve preventive programs for chronic disease. 3. Use human-centered design in the creation of prevention programs with an inclination to action, rapid prototyping and multiple iterations. 4. Extend the knowledge and skills of Sports and Exercise Medicine (SEM) professionals to build new programs for the prevention and treatment of chronic disease focused on physical activity, diet and lifestyle. 5. Mobilize resources and leverage networks to scale and distribute programs of prevention. True innovation lies in the ability to align thinking around these core strategies to ensure successful implementation of NCD prevention and management programs within health care. The IOC and SEM community are in an ideal position to lead this disruptive change. The outcome of the consensus meeting was the creation of the IOC Non-Communicable Diseases ad-hoc Working Group charged with the responsibility of moving this agenda forward.

    View details for DOI 10.1007/s40279-013-0104-3

    View details for PubMedID 24129783

  • ADHERENCE INTERVENTIONS TO IMPROVE ADHERENCE TO ANTIRETROVIRAL THERAPY IN LOW INCOME SETTINGS: AN INDIVIDUAL PATIENT DATA NETWORK META-ANALYSIS Mills, E. J., Nachega, J., Lester, R., Thorlund, K., Ioannidis, J., Linnemayr, S., Gross, R., Calderone, Y., Amico, R., Thirumurthy, H., Pearson, C., Remien, R., Mbuagbaw, L., Thabane, L., Chung, M., Wilson, Liu, A., Uthman, O., Ford, N. ELSEVIER SCIENCE INC. 2013: A361
  • Prevention and Management of Noncommunicable Disease: The IOC Consensus Statement, Lausanne 2013 CLINICAL JOURNAL OF SPORT MEDICINE Matheson, G. O., Kluegl, M., Engebretsen, L., Bendiksen, F., Blair, S. N., Boerjesson, M., Budgett, R., Derman, W., Erdener, U., Ioannidis, J. P., Khan, K. M., Martinez, R., van Mechelen, W., Mountjoy, M., Sallis, R. E., Schwellnus, M., Shultz, R., Soligard, T., Steffen, K., Sundberg, C. J., Weiler, R., Ljungqvist, A. 2013; 23 (6): 419-429
  • Biologic agents in rheumatology: unmet issues after 200 trials and $200 billion sales. Nature reviews. Rheumatology Ioannidis, J. P., Karassa, F. B., Druyts, E., Thorlund, K., Mills, E. J. 2013; 9 (11): 665-673

    Abstract

    Anti-TNF agents and other biologic therapies are widely prescribed for a variety of indications, with total sales that exceed $200 billion to date. In rheumatic diseases, biologic agents have now been studied in more than 200 randomized clinical trials and over 100 subsequent meta-analyses; however, the information obtained does not always meet the needs of patients and clinicians. In this Review, we discuss the current issues concerning the evidence derived from such studies: potential biases favouring positive results; a paucity of head-to-head comparisons between biologically active agents; overwhelming involvement of manufacturer sponsors in trials and in the synthesis of the evidence; the preference for trials with limited follow-up; and the potential for spurious findings on adverse events, leading to endless debates about malignancy risk. We debate the responsibilities of regulatory authorities, the pharmaceutical industry and academia in attempting to solve these shortcomings and challenges. We propose that improvements in the evidence regarding biologic treatments that are continually being added to the therapeutic armamentarium for rheumatic diseases might require revisiting the design and conduct of studies. For example, trials with long-term follow-up that are independent of the pharmaceutical industry, head-to-head comparisons of therapeutic agents and the use of rigorous clinical outcomes should be considered, and public availability of raw data endorsed.

    View details for DOI 10.1038/nrrheum.2013.134

    View details for PubMedID 23999553

  • Prevention and management of non-communicable disease: the IOC consensus statement, Lausanne 2013 BRITISH JOURNAL OF SPORTS MEDICINE Matheson, G. O., Kluegl, M., Engebretsen, L., Bendiksen, F., Blair, S. N., Borjesson, M., Budgett, R., Derman, W., Erdener, U., Ioannidis, J. P., Khan, K. M., Martinez, R., van Mechelen, W., Mountjoy, M., Sallis, R. E., Schwellnus, M., Shultz, R., Soligard, T., Steffen, K., Sundberg, C. J., Weiler, R., Ljungqvist, A. 2013; 47 (16): 1003-U56

    Abstract

    Morbidity and mortality from preventable, non-communicable chronic disease (NCD) threatens the health of our populations and our economies. The accumulation of vast amounts of scientific knowledge has done little to change this. New and innovative thinking is essential to foster new creative approaches that leverage and integrate evidence through the support of big data, technology and design thinking. The purpose of this paper is to summarise the results of a consensus meeting on NCD prevention sponsored by the IOC in April 2013. Within the context of advocacy for multifaceted systems change, the IOC's focus is to create solutions that gain traction within healthcare systems. The group of participants attending the meeting achieved consensus on a strategy for the prevention and management of chronic disease that includes the following: (1) Focus on behavioural change as the core component of all clinical programmes for the prevention and management of chronic disease. (2) Establish actual centres to design, implement, study and improve preventive programmes for chronic disease. (3) Use human-centred design in the creation of prevention programmes with an inclination to action, rapid prototyping and multiple iterations. (4) Extend the knowledge and skills of Sports and Exercise Medicine (SEM) professionals to build new programmes for the prevention and treatment of chronic disease focused on physical activity, diet and lifestyle. (5) Mobilise resources and leverage networks to scale and distribute programmes of prevention. True innovation lies in the ability to align thinking around these core strategies to ensure successful implementation of NCD prevention and management programmes within healthcare. The IOC and SEM community are in an ideal position to lead this disruptive change. The outcome of the consensus meeting was the creation of the IOC Non-Communicable Diseases ad hoc Working Group charged with the responsibility of moving this agenda forward.

    View details for DOI 10.1136/bjsports-2013-093034

    View details for Web of Science ID 000325530900002

    View details for PubMedID 24115479

  • Genome-wide Association Study for Radiographic Vertebral Fractures: A Potential Role for the 16q24 BMD Locus versus Lessons Learned from Challenging Phenotype Definition. Bone Oei, L., Estrada, K., Duncan, E. L., Christiansen, C., Liu, C., Langdahl, B. L., Obermayer-Pietsch, B., Riancho, J. A., Prince, R. L., van Schoor, N. M., McCloskey, E., Hsu, Y., Evangelou, E., Ntzani, E., Evans, D. M., Alonso, N., Husted, L. B., Valero, C., Hernandez, J. L., Lewis, J. R., Kaptoge, S. K., Zhu, K., Cupples, L. A., Medina-Gómez, C., Vandenput, L., Kim, G. S., Lee, S. H., Castaño-Betancourt, M. C., Oei, E. H., Martinez, J., Daroszewska, A., van der Klift, M., Mellström, D., Herrera, L., Karlsson, M. K., Hofman, A., Ljunggren, O., Pols, H. A., Stolk, L., van Meurs, J. B., Ioannidis, J. P., Zillikens, M. C., Lips, P., Karasik, D., Uitterlinden, A. G., Styrkarsdottir, U., Brown, M. A., Koh, J., Richards, J. B., Reeve, J., Ohlsson, C., Ralston, S. H., Kiel, D. P., Rivadeneira, F. 2013

    Abstract

    Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fractures applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged >55years; and comprising 329 cases and 2,666 controls with radiographic scoring (McCloskey-Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey-Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han-Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at P<5x10(-8). In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p=4.6 x 10(-8). However, the association was not significant across 5,720 cases and 21,791 controls from 14 studies. Fixed-effects meta analyses summary estimate was 1.06 (95% CI: 0.98-1.14; P=0.17), displaying high degree of heterogeneity (I(2)=57%; Qhet p= 0.0006). Under Han-Eskin alternative random effects model the summary effect was significant (P=0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size > 1.25) may still be consistent with an effect size <1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions are needed to confirm or reject the involvement of this locus on the risk for vertebral fractures.

    View details for DOI 10.1016/j.bone.2013.10.015

    View details for PubMedID 24513584

  • Mortality in persons with mental disorders is substantially overestimated using inpatient psychiatric diagnoses. Journal of psychiatric research Crump, C., Ioannidis, J. P., Sundquist, K., Winkleby, M. A., Sundquist, J. 2013; 47 (10): 1298-1303

    Abstract

    Mental disorders are associated with premature mortality, and the magnitudes of risk have commonly been estimated using hospital data. However, psychiatric patients who are hospitalized have more severe illness and do not adequately represent mental disorders in the general population. We conducted a national cohort study using outpatient and inpatient diagnoses for the entire Swedish adult population (N = 7,253,516) to examine the extent to which mortality risks are overestimated using inpatient diagnoses only. Outcomes were all-cause and suicide mortality during 8 years of follow-up (2001-2008). There were 377,339 (5.2%) persons with any inpatient psychiatric diagnosis, vs. 680,596 (9.4%) with any inpatient or outpatient diagnosis, hence 44.6% of diagnoses were missed using inpatient data only. When including and accounting for prevalent psychiatric cases, all-cause mortality risk among persons with any mental disorder was overestimated by 15.3% using only inpatient diagnoses (adjusted hazard ratio [aHR], 5.89; 95% CI, 5.85-5.92) vs. both inpatient and outpatient diagnoses (aHR, 5.11; 95% CI, 5.08-5.14). Suicide risk was overestimated by 18.5% (aHRs, 23.91 vs. 20.18), but this varied widely by specific disorders, from 4.4% for substance use to 49.1% for anxiety disorders. The sole use of inpatient diagnoses resulted in even greater overestimation of all-cause or suicide mortality risks when prevalent cases were unidentified (∼20-30%) or excluded (∼25-40%). However, different methods for handling prevalent cases resulted in only modest variation in risk estimates when using both inpatient and outpatient diagnoses. These findings have important implications for the interpretation of hospital-based studies and the design of future studies.

    View details for DOI 10.1016/j.jpsychires.2013.05.034

    View details for PubMedID 23806577

  • Clarifications on the application and interpretation of the test for excess significance and its extensions JOURNAL OF MATHEMATICAL PSYCHOLOGY Ioannidis, J. A. 2013; 57 (5): 184–87
  • A common biological basis of obesity and nicotine addiction TRANSLATIONAL PSYCHIATRY Thorgeirsson, T. E., Gudbjartsson, D. F., Sulem, P., Besenbacher, S., Styrkarsdottir, U., Thorleifsson, G., Walters, G. B., Furberg, H., Sullivan, P. F., Marchini, J., McCarthy, M. I., Steinthorsdottir, V., Thorsteinsdottir, U., Stefansson, K. 2013; 3

    Abstract

    Smoking influences body weight such that smokers weigh less than non-smokers and smoking cessation often leads to weight increase. The relationship between body weight and smoking is partly explained by the effect of nicotine on appetite and metabolism. However, the brain reward system is involved in the control of the intake of both food and tobacco. We evaluated the effect of single-nucleotide polymorphisms (SNPs) affecting body mass index (BMI) on smoking behavior, and tested the 32 SNPs identified in a meta-analysis for association with two smoking phenotypes, smoking initiation (SI) and the number of cigarettes smoked per day (CPD) in an Icelandic sample (N=34,216 smokers). Combined according to their effect on BMI, the SNPs correlate with both SI (r=0.019, P=0.00054) and CPD (r=0.032, P=8.0 × 10(-7)). These findings replicate in a second large data set (N=127,274, thereof 76,242 smokers) for both SI (P=1.2 × 10(-5)) and CPD (P=9.3 × 10(-5)). Notably, the variant most strongly associated with BMI (rs1558902-A in FTO) did not associate with smoking behavior. The association with smoking behavior is not due to the effect of the SNPs on BMI. Our results strongly point to a common biological basis of the regulation of our appetite for tobacco and food, and thus the vulnerability to nicotine addiction and obesity.

    View details for DOI 10.1038/tp.2013.81

    View details for Web of Science ID 000327472800001

    View details for PubMedID 24084939

  • Comparative effectiveness of exercise and drug interventions on mortality outcomes: metaepidemiological study BMJ-BRITISH MEDICAL JOURNAL Naci, H., Ioannidis, J. P. 2013; 347

    Abstract

    To determine the comparative effectiveness of exercise versus drug interventions on mortality outcomes.Metaepidemiological study.Meta-analyses of randomised controlled trials with mortality outcomes comparing the effectiveness of exercise and drug interventions with each other or with control (placebo or usual care).Medline and Cochrane Database of Systematic Reviews, May 2013.Mortality.We combined study level death outcomes from exercise and drug trials using random effects network meta-analysis.We included 16 (four exercise and 12 drug) meta-analyses. Incorporating an additional three recent exercise trials, our review collectively included 305 randomised controlled trials with 339,274 participants. Across all four conditions with evidence on the effectiveness of exercise on mortality outcomes (secondary prevention of coronary heart disease, rehabilitation of stroke, treatment of heart failure, prevention of diabetes), 14,716 participants were randomised to physical activity interventions in 57 trials. No statistically detectable differences were evident between exercise and drug interventions in the secondary prevention of coronary heart disease and prediabetes. Physical activity interventions were more effective than drug treatment among patients with stroke (odds ratios, exercise v anticoagulants 0.09, 95% credible intervals 0.01 to 0.70 and exercise v antiplatelets 0.10, 0.01 to 0.62). Diuretics were more effective than exercise in heart failure (exercise v diuretics 4.11, 1.17 to 24.76). Inconsistency between direct and indirect comparisons was not significant.Although limited in quantity, existing randomised trial evidence on exercise interventions suggests that exercise and many drug interventions are often potentially similar in terms of their mortality benefits in the secondary prevention of coronary heart disease, rehabilitation after stroke, treatment of heart failure, and prevention of diabetes.

    View details for DOI 10.1136/bmj.f5577

    View details for Web of Science ID 000325426300002

    View details for PubMedID 24473061

  • Population-specific frequencies for LRRK2 susceptibility variants in the genetic epidemiology of Parkinson's disease (GEO-PD) consortium. Movement disorders Heckman, M. G., Soto-Ortolaza, A. I., Aasly, J. O., Abahuni, N., Annesi, G., Bacon, J. A., Bardien, S., Bozi, M., Brice, A., Brighina, L., Carr, J., Chartier-Harlin, M., Dardiotis, E., Dickson, D. W., Diehl, N. N., Elbaz, A., Ferrarese, C., Fiske, B., Gibson, J. M., Gibson, R., Hadjigeorgiou, G. M., Hattori, N., Ioannidis, J. P., Boczarska-Jedynak, M., Jasinska-Myga, B., Jeon, B. S., Kim, Y. J., Klein, C., Kruger, R., Kyratzi, E., Lesage, S., Lin, C., Lynch, T., Maraganore, D. M., Mellick, G. D., Mutez, E., Nilsson, C., Opala, G., Park, S. S., Petrucci, S., Puschmann, A., Quattrone, A., Sharma, M., Silburn, P. A., Sohn, Y. H., Stefanis, L., Tadic, V., Theuns, J., Tomiyama, H., Uitti, R. J., Valente, E. M., Van Broeckhoven, C., van de Loo, S., Vassilatis, D. K., Vilariño-Güell, C., White, L. R., Wirdefeldt, K., Wszolek, Z. K., Wu, R., Hentati, F., Farrer, M. J., Ross, O. A. 2013; 28 (12): 1740-1744

    Abstract

    Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late-onset sporadic disorders like Parkinson's disease.The Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries.Herein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups.Establishing individual patient-based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies. © 2013 International Parkinson and Movement Disorder Society.

    View details for DOI 10.1002/mds.25600

    View details for PubMedID 23913756

  • In reply II-Reversal of Medical Practices MAYO CLINIC PROCEEDINGS Ioannidis, J. P. 2013; 88 (10): 1184-1184

    View details for DOI 10.1016/j.mayocp.2013.08.014

    View details for Web of Science ID 000325470800029

    View details for PubMedID 24079693

  • Mining the human phenome using allelic scores that index biological intermediates. PLoS genetics Evans, D. M., Brion, M. J., Paternoster, L., Kemp, J. P., McMahon, G., Munafò, M., Whitfield, J. B., Medland, S. E., Montgomery, G. W., Timpson, N. J., St Pourcain, B., Lawlor, D. A., Martin, N. G., Dehghan, A., Hirschhorn, J., Davey Smith, G. 2013; 9 (10)

    Abstract

    It is common practice in genome-wide association studies (GWAS) to focus on the relationship between disease risk and genetic variants one marker at a time. When relevant genes are identified it is often possible to implicate biological intermediates and pathways likely to be involved in disease aetiology. However, single genetic variants typically explain small amounts of disease risk. Our idea is to construct allelic scores that explain greater proportions of the variance in biological intermediates, and subsequently use these scores to data mine GWAS. To investigate the approach's properties, we indexed three biological intermediates where the results of large GWAS meta-analyses were available: body mass index, C-reactive protein and low density lipoprotein levels. We generated allelic scores in the Avon Longitudinal Study of Parents and Children, and in publicly available data from the first Wellcome Trust Case Control Consortium. We compared the explanatory ability of allelic scores in terms of their capacity to proxy for the intermediate of interest, and the extent to which they associated with disease. We found that allelic scores derived from known variants and allelic scores derived from hundreds of thousands of genetic markers explained significant portions of the variance in biological intermediates of interest, and many of these scores showed expected correlations with disease. Genome-wide allelic scores however tended to lack specificity suggesting that they should be used with caution and perhaps only to proxy biological intermediates for which there are no known individual variants. Power calculations confirm the feasibility of extending our strategy to the analysis of tens of thousands of molecular phenotypes in large genome-wide meta-analyses. We conclude that our method represents a simple way in which potentially tens of thousands of molecular phenotypes could be screened for causal relationships with disease without having to expensively measure these variables in individual disease collections.

    View details for DOI 10.1371/journal.pgen.1003919

    View details for PubMedID 24204319

  • US studies may overestimate effect sizes in softer research PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Fanelli, D., Ioannidis, J. P. 2013; 110 (37): 15031-15036

    Abstract

    Many biases affect scientific research, causing a waste of resources, posing a threat to human health, and hampering scientific progress. These problems are hypothesized to be worsened by lack of consensus on theories and methods, by selective publication processes, and by career systems too heavily oriented toward productivity, such as those adopted in the United States (US). Here, we extracted 1,174 primary outcomes appearing in 82 meta-analyses published in health-related biological and behavioral research sampled from the Web of Science categories Genetics & Heredity and Psychiatry and measured how individual results deviated from the overall summary effect size within their respective meta-analysis. We found that primary studies whose outcome included behavioral parameters were generally more likely to report extreme effects, and those with a corresponding author based in the US were more likely to deviate in the direction predicted by their experimental hypotheses, particularly when their outcome did not include additional biological parameters. Nonbehavioral studies showed no such "US effect" and were subject mainly to sampling variance and small-study effects, which were stronger for non-US countries. Although this latter finding could be interpreted as a publication bias against non-US authors, the US effect observed in behavioral research is unlikely to be generated by editorial biases. Behavioral studies have lower methodological consensus and higher noise, making US researchers potentially more likely to express an underlying propensity to report strong and significant findings.

    View details for DOI 10.1073/pnas.1302997110

    View details for Web of Science ID 000324125100053

    View details for PubMedID 23980165

    View details for PubMedCentralID PMC3773789

  • The effects of excluding treatments from network meta-analyses: survey BMJ-BRITISH MEDICAL JOURNAL Mills, E. J., Kanters, S., Thorlund, K., Chaimani, A., Veroniki, A., Ioannidis, J. P. 2013; 347

    Abstract

    To examine whether the exclusion of individual treatment comparators, including placebo/no treatment, affects the results of network meta-analysis.Survey of networks with individual trial data.PubMed and communication with authors of network meta-analyses.We included networks that had five or more treatments, contained at least two closed loops, had at least twice as many studies as treatments, and had trial level data available. Investigators abstracted information about study design, participants, outcomes, network geometry, and the exclusion of eligible treatments.Among 18 eligible networks involving 757 randomised controlled trials with 750 possible treatment comparisons, 11 had upfront decided not to consider all treatment comparators and only 10 included placebo/no treatment nodes. In 7/18 networks, there was at least one node whose removal caused a more than 1.10-fold average relative change in the estimated treatments effects, and switches in the top three treatments were observed in 9/18 networks. Removal of placebo/no treatment caused large relative changes of the treatment effects (average change 1.16-3.10-fold) for four of the 10 networks that had originally included placebo/no treatment nodes. Exclusion of current uncommonly used drugs resulted in substantial changes of the treatment effects (average 1.21-fold) in one of three networks on systemic treatments for advanced malignancies.Excluding treatments in network meta-analyses sometimes can have important effects on their results and can diminish the usefulness of the research to clinicians if important comparisons are missing.

    View details for DOI 10.1136/bmj.f5195

    View details for Web of Science ID 000324216500001

    View details for PubMedID 24009242

    View details for PubMedCentralID PMC3763846

  • Association Between Obesity and Postoperative Atrial Fibrillation in Patients Undergoing Cardiac Operations: A Systematic Review and Meta-Analysis ANNALS OF THORACIC SURGERY Hernandez, A. V., Kaw, R., Pasupuleti, V., Bina, P., Ioannidis, J. P., Bueno, H., Boersma, E., Gillinov, M. 2013; 96 (3): 1104-1116

    Abstract

    In a systematic review and random-effects meta-analysis, we evaluated whether obesity is associated with postoperative atrial fibrillation (POAF) in patients undergoing cardiac operations. We selected 18 observational studies until December 2011 that excluded patients with preoperative AF (n=36,147). Obese patients had a modest higher risk of POAF compared with nonobese (odds ratio, 1.12; 95% confidence interval, 1.04 to 1.21; p=0.002). The association between obesity and POAF did not vary substantially by type of cardiac operation, study design, or year of publication. POAF was significantly associated with a higher risk of stroke, respiratory failure, and operative death.

    View details for DOI 10.1016/j.athoracsur.2013.04.029

    View details for Web of Science ID 000323940200076

    View details for PubMedID 23932258

  • Optimal type I and type II error pairs when the available sample size is fixed JOURNAL OF CLINICAL EPIDEMIOLOGY Ioannidis, J. P., Hozo, I., Djulbegovic, B. 2013; 66 (8): 903-910

    Abstract

    OBJECTIVE: To model how to select the optimal pair of type I and type II errors that maximize study value when there are constrains on the available study sample size. STUDY DESIGN AND SETTING: Correct inferences [true positives (TPs) and true negatives (TNs)] increase and wrong inferences (false positives and false negatives) decrease the value of a study. We model the composite value of a study based on these four inferences, their relative importance, and relative frequency using multiplicative and additive models. Numerical examples are presented for randomized trials, epidemiologic studies, and agnostic omics investigations with massive testing and variable sample size constraints. RESULTS: The optimal choice of type I and type II errors varies a lot according to the available sample size and the plausible effect sizes in each field. We show how equations can be streamlined for special applications: when the value of all four inferences is considered equal, when the identification of TNs carries no value, and when a study carries no value unless at least one TP is discovered. CONCLUSION: The proposed optimization equations can be used to guide the selection of the optimal type I and type II errors of future studies in which sample size is constrained.

    View details for DOI 10.1016/j.jclinepi.2013.03.002

    View details for Web of Science ID 000322207300013

    View details for PubMedID 23664493

  • Confidence and precision increase with high statistical power. Nature reviews. Neuroscience Button, K. S., Ioannidis, J. P., Mokrysz, C., Nosek, B. A., Flint, J., Robinson, E. S., Munafò, M. R. 2013; 14 (8): 585-586

    View details for DOI 10.1038/nrn3475-c4

    View details for PubMedID 23820778

  • To Replicate or Not to Replicate: The Case of Pharmacogenetic Studies Have Pharmacogenomics Failed, or Do They Just Need Larger-Scale Evidence and More Replication? CIRCULATION-CARDIOVASCULAR GENETICS Ioannidis, J. P. 2013; 6 (4): 413-418
  • Expressing Death Risk as Condensed Life Experience and Death Intensity MEDICAL DECISION MAKING Ioannidis, J. P. 2013; 33 (6): 853-859

    Abstract

    Some risk exposures, including many medical and surgical procedures, typically carry hazards of death that are difficult to convey and appreciate in absolute terms. I propose presenting the death risk as a condensed life experience (i.e., the equivalent amount of life T that would carry the same cumulative mortality hazard for a person of the same age and sex based on life tables). For example, if the risk of death during an elective 1-hour procedure is 0.01%, and same-age and same-sex people have a 0.01% death risk over 1 month, one can inform the patient that "this procedure carries the same death risk as living 1 month of normal life." Comparative standards from other risky activities or from a person with the same disease at the same stage and same predictive profile could also be used. A complementary metric that may be useful to consider is the death intensity. The death intensity λ is the hazard function that shows the fold-risk estimate of dying compared with the reference person. The death intensity can vary substantially for different phases of the event, operation, or procedure (e.g., intraoperative, early postoperative, late postoperative), and this variability may also be useful to convey. T will vary depending on the time window for which it is computed. I present examples for calculating T and λ using literature data on accidents, ascent to Mount Everest, and medical and surgical procedures.

    View details for DOI 10.1177/0272989X13484389

    View details for Web of Science ID 000327813000010

    View details for PubMedID 23579043

  • Overlapping meta-analyses on the same topic: survey of published studies BMJ-BRITISH MEDICAL JOURNAL Siontis, K. C., Hernandez-Boussard, T., Ioannidis, J. P. 2013; 347

    Abstract

    To assess how common it is to have multiple overlapping meta-analyses of randomized trials published on the same topic.Survey of published meta-analyses.PubMed.Meta-analyses published in 2010 were identified, and 5% of them were randomly selected. We further selected those that included randomized trials and examined effectiveness of any medical intervention. For eligible meta-analyses, we searched for other meta-analyses on the same topic (covering the same comparisons, indications/settings, and outcomes or overlapping subsets of them) published until February 2013.Of 73 eligible meta-analyses published in 2010, 49 (67%) had at least one other overlapping meta-analysis (median two meta-analyses per topic, interquartile range 1-4, maximum 13). In 17 topics at least one author was involved in at least two of the overlapping meta-analyses. No characteristics of the index meta-analyses were associated with the potential for overlapping meta-analyses. Among pairs of overlapping meta-analyses in 20 randomly selected topics, 13 of the more recent meta-analyses did not include any additional outcomes. In three of the four topics with eight or more published meta-analyses, many meta-analyses examined only a subset of the eligible interventions or indications/settings covered by the index meta-analysis. Conversely, for statins in the prevention of atrial fibrillation after cardiac surgery, 11 meta-analyses were published with similar eligibility criteria for interventions and setting: there was still variability on which studies were included, but the results were always similar or even identical across meta-analyses.While some independent replication of meta-analyses by different teams is possibly useful, the overall picture suggests that there is a waste of efforts with many topics covered by multiple overlapping meta-analyses.

    View details for DOI 10.1136/bmj.f4501

    View details for Web of Science ID 000322247400002

    View details for PubMedID 23873947

    View details for PubMedCentralID PMC3716360

  • Practices and impact of primary outcome adjustment in randomized controlled trials: meta-epidemiologic study BMJ-BRITISH MEDICAL JOURNAL Saquib, N., Saquib, J., Ioannidis, J. P. 2013; 347

    Abstract

    To assess adjustment practices for primary outcomes of randomized controlled trials and their impact on the results.Meta-epidemiologic study.25 biomedical journals with the highest impact factor according to Journal Citation Reports 2009.Randomized controlled trials published in print in 2009 that reported primary outcomes. The search yielded 684 eligible papers of randomized controlled trials, of which 200 were randomly selected.Two researchers independently extracted data on study population, intervention, primary outcome, and the adjustment plan for primary outcomes. They also recorded the magnitude and statistical significance of the intervention effect with and without adjustments, and estimated whether adjustment made a difference in the level of nominal significance. They also compared the analysis plan for model adjustment in the published trial versus the trial protocol with information on the protocol collected from registries, design papers, and communication with all corresponding authors.54% of the trials used stratified randomization, 96% presented baseline characteristics in the compared arms, and 46% also evaluated differences in baseline factors with statistical testing. Half of the trials performed adjusted analyses for the main outcome, as the sole analysis (29%) or along with unadjusted analyses (21%). Adjustment for stratification variables and for baseline variables was performed in 39% (42/108) and 42% (84/199) of the trials, respectively. Among 40 comparisons with both adjusted and unadjusted analyses, 43% had statistically significant effects, 40% had non-significant effects, and 18% had significant effects with only one of the two analyses, but not with the other. Information on analysis plan regarding model adjustment was available in 6% (9/162) of trial registry entries, 78% (21/27) of design papers, and 74% (40/54) of protocols obtained from authors. The analysis plan disagreed between the published trial and the registry, protocol, or design paper in 47% (28/60) of the studies.There is large diversity on whether and how analyses of primary outcomes are adjusted in randomized controlled trials and these choices can sometimes change the nominal significance of the results. Registered protocols should explicitly specify adjustments plans for main outcomes and analysis should follow these plans.

    View details for DOI 10.1136/bmj.f4313

    View details for Web of Science ID 000321895300001

    View details for PubMedID 23851720

    View details for PubMedCentralID PMC3709831

  • Evaluation of excess significance bias in animal studies of neurological diseases. PLoS biology Tsilidis, K. K., Panagiotou, O. A., Sena, E. S., Aretouli, E., Evangelou, E., Howells, D. W., Al-Shahi Salman, R., Macleod, M. R., Ioannidis, J. P. 2013; 11 (7)

    Abstract

    Animal studies generate valuable hypotheses that lead to the conduct of preventive or therapeutic clinical trials. We assessed whether there is evidence for excess statistical significance in results of animal studies on neurological disorders, suggesting biases. We used data from meta-analyses of interventions deposited in Collaborative Approach to Meta-Analysis and Review of Animal Data in Experimental Studies (CAMARADES). The number of observed studies with statistically significant results (O) was compared with the expected number (E), based on the statistical power of each study under different assumptions for the plausible effect size. We assessed 4,445 datasets synthesized in 160 meta-analyses on Alzheimer disease (n = 2), experimental autoimmune encephalomyelitis (n = 34), focal ischemia (n = 16), intracerebral hemorrhage (n = 61), Parkinson disease (n = 45), and spinal cord injury (n = 2). 112 meta-analyses (70%) found nominally (p≤0.05) statistically significant summary fixed effects. Assuming the effect size in the most precise study to be a plausible effect, 919 out of 4,445 nominally significant results were expected versus 1,719 observed (p<10(-9)). Excess significance was present across all neurological disorders, in all subgroups defined by methodological characteristics, and also according to alternative plausible effects. Asymmetry tests also showed evidence of small-study effects in 74 (46%) meta-analyses. Significantly effective interventions with more than 500 animals, and no hints of bias were seen in eight (5%) meta-analyses. Overall, there are too many animal studies with statistically significant results in the literature of neurological disorders. This observation suggests strong biases, with selective analysis and outcome reporting biases being plausible explanations, and provides novel evidence on how these biases might influence the whole research domain of neurological animal literature.

    View details for DOI 10.1371/journal.pbio.1001609

    View details for PubMedID 23874156

  • Evaluation of Excess Significance Bias in Animal Studies of Neurological Diseases PLOS BIOLOGY Tsilidis, K. K., Panagiotou, O. A., Sena, E. S., Aretouli, E., Evangelou, E., Howells, D. W., Salman, R. A., Macleod, M. R., Ioannidis, J. P. 2013; 11 (7)

    Abstract

    Animal studies generate valuable hypotheses that lead to the conduct of preventive or therapeutic clinical trials. We assessed whether there is evidence for excess statistical significance in results of animal studies on neurological disorders, suggesting biases. We used data from meta-analyses of interventions deposited in Collaborative Approach to Meta-Analysis and Review of Animal Data in Experimental Studies (CAMARADES). The number of observed studies with statistically significant results (O) was compared with the expected number (E), based on the statistical power of each study under different assumptions for the plausible effect size. We assessed 4,445 datasets synthesized in 160 meta-analyses on Alzheimer disease (n = 2), experimental autoimmune encephalomyelitis (n = 34), focal ischemia (n = 16), intracerebral hemorrhage (n = 61), Parkinson disease (n = 45), and spinal cord injury (n = 2). 112 meta-analyses (70%) found nominally (p≤0.05) statistically significant summary fixed effects. Assuming the effect size in the most precise study to be a plausible effect, 919 out of 4,445 nominally significant results were expected versus 1,719 observed (p<10(-9)). Excess significance was present across all neurological disorders, in all subgroups defined by methodological characteristics, and also according to alternative plausible effects. Asymmetry tests also showed evidence of small-study effects in 74 (46%) meta-analyses. Significantly effective interventions with more than 500 animals, and no hints of bias were seen in eight (5%) meta-analyses. Overall, there are too many animal studies with statistically significant results in the literature of neurological disorders. This observation suggests strong biases, with selective analysis and outcome reporting biases being plausible explanations, and provides novel evidence on how these biases might influence the whole research domain of neurological animal literature.

    View details for DOI 10.1371/journal.pbio.1001609

    View details for Web of Science ID 000322592700013

    View details for PubMedCentralID PMC3712913

  • The DOT1L rs12982744 polymorphism is associated with osteoarthritis of the hip with genome-wide statistical significance in males. Annals of the rheumatic diseases Evangelou, E., Valdes, A. M., Castano-Betancourt, M. C., Doherty, M., Doherty, S., Esko, T., Ingvarsson, T., Ioannidis, J. P., Kloppenburg, M., Metspalu, A., Ntzani, E. E., Panoutsopoulou, K., Slagboom, P. E., Southam, L., Spector, T. D., Styrkarsdottir, U., Stefanson, K., Uitterlinden, A. G., wheeler, M., Zeggini, E., Meulenbelt, I., van Meurs, J. B. 2013; 72 (7): 1264-1265

    View details for DOI 10.1136/annrheumdis-2012-203182

    View details for PubMedID 23505243

  • Meta-analysis methods for genome-wide association studies and beyond. Nature reviews. Genetics Evangelou, E., Ioannidis, J. P. 2013; 14 (6): 379-389

    Abstract

    Meta-analysis of genome-wide association studies (GWASs) has become a popular method for discovering genetic risk variants. Here, we overview both widely applied and newer statistical methods for GWAS meta-analysis, including issues of interpretation and assessment of sources of heterogeneity. We also discuss extensions of these meta-analysis methods to complex data. Where possible, we provide guidelines for researchers who are planning to use these methods. Furthermore, we address special issues that may arise for meta-analysis of sequencing data and rare variants. Finally, we discuss challenges and solutions surrounding the goals of making meta-analysis data publicly available and building powerful consortia.

    View details for DOI 10.1038/nrg3472

    View details for PubMedID 23657481

  • JOINT EULAR/ERA-EDTA RECOMMENDATIONS FOR THE MANAGEMENT OF ADULT AND PEDIATRIC LUPUS NEPHRITIS Bertsias, G., Tektonidou, M., Amoura, Z., Aringer, M., Bajema, I., Berden, J., Boletis, J., Cervera, R., Doerner, T., Doria, A., Ferrario, F., Floege, J., Houssiau, F., Ioannidis, J. P., Isenberg, D., Kallenberg, C. G., Lightstone, L., Marks, S., Martini, A., Moroni, G., Neumann, I., Niaudet, P., Praga, M., Schneider, M., Tesar, V., Vasconcelos, C., van Vollenhoven, R., Zakharova, E., Haubitz, M., Gordon, C., Jayne, D., Boumpas, D. BMJ PUBLISHING GROUP. 2013: 74–75
  • Systematic identification of interaction effects between genome- and environment-wide associations in type 2 diabetes mellitus HUMAN GENETICS Patel, C. J., Chen, R., Kodama, K., Ioannidis, J. P., Butte, A. J. 2013; 132 (5): 495-508

    Abstract

    Diseases such as type 2 diabetes (T2D) result from environmental and genetic factors, and risk varies considerably in the population. T2D-related genetic loci discovered to date explain only a small portion of the T2D heritability. Some heritability may be due to gene-environment interactions. However, documenting these interactions has been difficult due to low availability of concurrent genetic and environmental measures, selection bias, and challenges in controlling for multiple hypothesis testing. Through genome-wide association studies (GWAS), investigators have identified over 90 single nucleotide polymorphisms (SNPs) associated to T2D. Using a method analogous to GWAS [environment-wide association study (EWAS)], we found five environmental factors associated with the disease. By focusing on risk factors that emerge from GWAS and EWAS, it is possible to overcome difficulties in uncovering gene-environment interactions. Using data from the National Health and Nutrition Examination Survey (NHANES), we screened 18 SNPs and 5 serum-based environmental factors for interaction in association to T2D. We controlled for multiple hypotheses using false discovery rate (FDR) and Bonferroni correction and found four interactions with FDR <20 %. The interaction between rs13266634 (SLC30A8) and trans-β-carotene withstood Bonferroni correction (corrected p = 0.006, FDR <1.5 %). The per-risk-allele effect sizes in subjects with low levels of trans-β-carotene were 40 % greater than the marginal effect size [odds ratio (OR) 1.8, 95 % CI 1.3-2.6]. We hypothesize that impaired function driven by rs13266634 increases T2D risk when combined with serum levels of nutrients. Unbiased consideration of environmental and genetic factors may help identify larger and more relevant effect sizes for disease associations.

    View details for DOI 10.1007/s00439-012-1258-z

    View details for Web of Science ID 000317691100002

    View details for PubMedID 23334806

    View details for PubMedCentralID PMC3625410

  • Undue industry influences that distort healthcare research, strategy, expenditure and practice: a review EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Stamatakis, E., Weiler, R., Ioannidis, J. P. 2013; 43 (5): 469-475

    Abstract

    Expenditure on industry products (mostly drugs and devices) has spiraled over the last 15 years and accounts for substantial part of healthcare expenditure. The enormous financial interests involved in the development and marketing of drugs and devices may have given excessive power to these industries to influence medical research, policy, and practice.Review of the literature and analysis of the multiple pathways through which the industry has directly or indirectly infiltrated the broader healthcare systems. We present the analysis of the industry influences at the following levels: (i) evidence base production, (ii) evidence synthesis, (iii) understanding of safety and harms issues, (iv) cost-effectiveness evaluation, (v) clinical practice guidelines formation, (vi) healthcare professional education, (vii) healthcare practice, (viii) healthcare consumer's decisions.We located abundance of consistent evidence demonstrating that the industry has created means to intervene in all steps of the processes that determine healthcare research, strategy, expenditure, practice and education. As a result of these interferences, the benefits of drugs and other products are often exaggerated and their potential harms are downplayed, and clinical guidelines, medical practice, and healthcare expenditure decisions are biased.To serve its interests, the industry masterfully influences evidence base production, evidence synthesis, understanding of harms issues, cost-effectiveness evaluations, clinical practice guidelines and healthcare professional education and also exerts direct influences on professional decisions and health consumers. There is an urgent need for regulation and other action towards redefining the mission of medicine towards a more objective and patient-, population- and society-benefit direction that is free from conflict of interests.

    View details for DOI 10.1111/eci.12074

    View details for Web of Science ID 000317983300005

    View details for PubMedID 23521369

  • Pancreatitis Potentially Associated Drugs as a Risk Factor for Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis A Prospective Cohort Study PANCREAS Sigounas, D. E., Christodoulou, D. K., Tatsioni, A., Katsanos, K. H., Baltayiannis, G., Kappas, A., Ioannidis, J. P., Tsianos, E. V. 2013; 42 (4): 601-606

    Abstract

    The aim of this study was to assess the role of known risk factors and specifically evaluate the role of pancreatitis potentially associated drugs as potential risk factors for post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP).This was a prospective, single-center cohort study conducted in a tertiary university hospital. All eligible ERCP procedures within a 16-month period were evaluated, and all interventions, patient characteristics, and medications used were documented. The association of potential risk factor with PEP was investigated with univariable analyses. Those statistically significant were entered in a multivariable regression model.Three hundred eighteen ERCP procedures were studied. Post-ERCP pancreatitis occurred in 28 patients (8.8%). Twenty-three potential risk factors were studied in univariable analyses, and 3 of them were found to be nominally statistically significant. These 3 factors were independently associated with PEP in the multivariable model and included the use of pancreatitis potentially associated drugs, belonging to Badalov classes I or II, during the last month before ERCP (odds ratio [OR], 4.39; 95% confidence interval [CI], 1.70-5.47; P = 0.003), more than 1 guide-wire insertions in the pancreatic duct (OR, 5.00; 95% CI, 1.97-12.81; P = 0.001) and bile duct stone extraction (OR, 0.12; CI, 0.05-0.32; P < 0.001).Pancreatitis potentially associated drugs used before ERCP seem to increase the risk for PEP.

    View details for DOI 10.1097/MPA.0b013e31827309fd

    View details for Web of Science ID 000317655200007

    View details for PubMedID 23548878

  • Power failure: why small sample size undermines the reliability of neuroscience NATURE REVIEWS NEUROSCIENCE Button, K. S., Ioannidis, J. P., Mokrysz, C., Nosek, B. A., Flint, J., Robinson, E. S., Munafo, M. R. 2013; 14 (5): 365-376

    Abstract

    A study with low statistical power has a reduced chance of detecting a true effect, but it is less well appreciated that low power also reduces the likelihood that a statistically significant result reflects a true effect. Here, we show that the average statistical power of studies in the neurosciences is very low. The consequences of this include overestimates of effect size and low reproducibility of results. There are also ethical dimensions to this problem, as unreliable research is inefficient and wasteful. Improving reproducibility in neuroscience is a key priority and requires attention to well-established but often ignored methodological principles.

    View details for DOI 10.1038/nrn3475

    View details for Web of Science ID 000317913900012

    View details for PubMedID 23571845

  • Mega-Randomized Clinical Trials for Blockbuster Drugs Reply JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P. 2013; 309 (16): 1683-1683

    View details for Web of Science ID 000317906700018

    View details for PubMedID 23613069

  • Bias in associations of emerging biomarkers with cardiovascular disease. JAMA internal medicine Tzoulaki, I., Siontis, K. C., Evangelou, E., Ioannidis, J. P. 2013; 173 (8): 664-671

    Abstract

    IMPORTANCE Numerous cardiovascular biomarkers are proposed as potential predictors of cardiovascular risk. OBJECTIVE To evaluate whether there is evidence for biases favoring statistically significant results and inflating associations in this literature. DESIGN AND SETTING PubMed search for meta-analyses of cardiovascular biomarkers that are not part of the Framingham Risk Score. MAIN OUTCOME MEASURES We estimated summary effects and between-study heterogeneity (considered "very large" for I2 > 75%). We evaluated whether large studies had significantly more conservative results than smaller studies (small-study effects) and whether there were too many studies with statistically significant results compared with what would be expected on the basis of the findings of the largest study in each meta-analysis. RESULTS Of 56 eligible meta-analyses, 49 had statistically significant results. Very large heterogeneity and small-study effects were seen in 9 and 13 meta-analyses, respectively. In 29 meta-analyses (52%), there was a significant excess of studies with statistically significant results. Only 13 of the statistically significant meta-analyses had more than 1000 cases and no hints of large heterogeneity, small-study effects, or excess significance. These included the associations of glomerular filtration rate and albumin to creatinine ratio in general and high-risk populations with cardiovascular disease mortality and of non-high-density lipoprotein cholesterol, serum albumin, Chlamydia pneumoniae IgG, glycosylated hemoglobin, nonfasting insulin, apolipoprotein B/AI ratio, erythrocyte sedimentation rate, and lipoprotein-associated phospholipase mass or activity with coronary heart disease. CONCLUSIONS AND RELEVANCE Selective reporting biases may be common in the evidence on emerging cardiovascular biomarkers. Most of the proposed associations of these biomarkers may be inflated.

    View details for DOI 10.1001/jamainternmed.2013.3018

    View details for PubMedID 23529078

  • Are Mortality Differences Detected by Administrative Data Reliable and Actionable? JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P. 2013; 309 (13): 1410-1411

    View details for Web of Science ID 000316934500032

    View details for PubMedID 23549588

  • Seven new loci associated with age-related macular degeneration. Nature genetics Fritsche, L. G., Chen, W., Schu, M., Yaspan, B. L., Yu, Y., Thorleifsson, G., Zack, D. J., Arakawa, S., Cipriani, V., Ripke, S., Igo, R. P., Buitendijk, G. H., Sim, X., Weeks, D. E., Guymer, R. H., Merriam, J. E., Francis, P. J., Hannum, G., Agarwal, A., Armbrecht, A. M., Audo, I., Aung, T., Barile, G. R., Benchaboune, M., Bird, A. C., Bishop, P. N., Branham, K. E., Brooks, M., Brucker, A. J., Cade, W. H., Cain, M. S., Campochiaro, P. A., Chan, C., Cheng, C., Chew, E. Y., Chin, K. A., Chowers, I., Clayton, D. G., Cojocaru, R., Conley, Y. P., Cornes, B. K., Daly, M. J., Dhillon, B., Edwards, A. O., Evangelou, E., Fagerness, J., Ferreyra, H. A., Friedman, J. S., Geirsdottir, A., George, R. J., Gieger, C., Gupta, N., Hagstrom, S. A., Harding, S. P., Haritoglou, C., Heckenlively, J. R., Holz, F. G., Hughes, G., Ioannidis, J. P., Ishibashi, T., Joseph, P., Jun, G., Kamatani, Y., Katsanis, N., N Keilhauer, C., Khan, J. C., Kim, I. K., Kiyohara, Y., Klein, B. E., Klein, R., Kovach, J. L., Kozak, I., Lee, C. J., Lee, K. E., Lichtner, P., Lotery, A. J., Meitinger, T., Mitchell, P., Mohand-Saïd, S., Moore, A. T., Morgan, D. J., Morrison, M. A., Myers, C. E., Naj, A. C., Nakamura, Y., Okada, Y., Orlin, A., Ortube, M. C., Othman, M. I., Pappas, C., Park, K. H., Pauer, G. J., Peachey, N. S., Poch, O., Priya, R. R., Reynolds, R., Richardson, A. J., Ripp, R., Rudolph, G., Ryu, E., Sahel, J., Schaumberg, D. A., Scholl, H. P., Schwartz, S. G., Scott, W. K., Shahid, H., Sigurdsson, H., Silvestri, G., Sivakumaran, T. A., Smith, R. T., Sobrin, L., Souied, E. H., Stambolian, D. E., Stefansson, H., Sturgill-Short, G. M., Takahashi, A., Tosakulwong, N., Truitt, B. J., Tsironi, E. E., Uitterlinden, A. G., van Duijn, C. M., Vijaya, L., Vingerling, J. R., Vithana, E. N., Webster, A. R., Wichmann, H., Winkler, T. W., Wong, T. Y., Wright, A. F., Zelenika, D., Zhang, M., Zhao, L., Zhang, K., Klein, M. L., Hageman, G. S., Lathrop, G. M., Stefansson, K., Allikmets, R., Baird, P. N., Gorin, M. B., Wang, J. J., Klaver, C. C., Seddon, J. M., Pericak-Vance, M. A., Iyengar, S. K., Yates, J. R., Swaroop, A., Weber, B. H., Kubo, M., DeAngelis, M. M., Léveillard, T., Thorsteinsdottir, U., Haines, J. L., Farrer, L. A., Heid, I. M., Abecasis, G. R. 2013; 45 (4): 433-?

    Abstract

    Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 × 10(-8). These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P < 5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.

    View details for DOI 10.1038/ng.2578

    View details for PubMedID 23455636

  • Seven new loci associated with age-related macular degeneration NATURE GENETICS Fritsche, L. G., Chen, W., Schu, M., Yaspan, B. L., Yu, Y., Thorleifsson, G., Zack, D. J., Arakawa, S., Cipriani, V., Ripke, S., Igo, R. P., Buitendijk, G. H., Sim, X., Weeks, D. E., Guymer, R. H., Merriam, J. E., Francis, P. J., Hannum, G., Agarwal, A., Armbrecht, A. M., Audo, I., Aung, T., Barile, G. R., Benchaboune, M., Bird, A. C., Bishop, P. N., Branham, K. E., Brooks, M., Brucker, A. J., Cade, W. H., Cain, M. S., Campochiaroll, P. A., Chan, C., Cheng, C., Chew, E. Y., Chin, K. A., Chowers, I., Clayton, D. G., Cojocaru, R., Conley, Y. P., Cornes, B. K., Daly, M. J., Dhillon, B., Edwards, A., Evangelou, E., Fagemess, J., Ferreyra, H. A., Friedman, J. S., Geirsdottir, A., George, R. J., Gieger, C., Gupta, N., Hagstrom, S. A., Harding, S. P., Haritoglou, C., Heckenlively, J. R., Hoz, F. G., Hughes, G., Ioannidis, J. P., Ishibashi, T., Joseph, P., Jun, G., Kamatani, Y., Katsanis, N., Keilhauer, C. N., Khan, J. C., Kim, I. K., Kiyohara, Y., Klein, B. E., Klein, R., Kovach, J. L., Kozak, I., Lee, C. J., Lee, K. E., Lichtner, P., Lotery, A. J., Meitinger, T., Mitchell, P., Mohand-Saied, S., Moore, A. T., Morgan, D. J., Morrison, M. A., Myers, C. E., Naj, A. C., Nakamura, Y., Okada, Y., Orlin, A., Ortube, M. C., Othman, M. I., Pappas, C., Park, K. H., Pauer, G. J., Peachey, N. S., Poch, O., Priya, R. R., Reynolds, R., Richardson, A. J., Ripp, R., Rudolph, G., Ryu, E., Sahel, J., Schaumberg, D. A., Scholl, H. P., Schwartz, S. G., Scott, W. K., Shahid, H., Sigurdsson, H., Silvestri, G., Sivakumaran, T. A., Smith, R. T., Sobrin, L., Souied, E. H., Stambolian, D. E., Stefansson, H., Sturgill-Short, G. M., Takahashi, A., Tosakulwong, N., Truitt, B. J., Tsironi, E. E., Uitterlinden, A. G., van Duijn, C. M., Vijaya, L., Vingerling, J. R., Vithana, E. N., Webster, A. R., Wichmann, H., Winkler, T. W., Wong, T. Y., Wright, A. F., Zelenika, D., Zhang, M., Zhao, L., Zhang, K., Klein, M. L., Hageman, G. S., Lathrop, G. M., Stefansson, K., Allikmets, R., Baird, P. N., Gorin, M. B., Wang, J. J., Klaver, C. C., Seddon, J. M., Pericak-Vance, M. A., Iyengar, S. K., Yates, J. R., Swaroop, A., Weber, B. H., Kubo, M., DeAngelis, M. M., Leveillard, T., Thorsteinsdottir, U., Haines, J. L., Farrer, L. A., Heid, I. M., Abecasis, G. R. 2013; 45 (4): 433-439

    Abstract

    Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 × 10(-8). These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P < 5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.

    View details for DOI 10.1038/ng.2578

    View details for Web of Science ID 000316840600015

    View details for PubMedID 23455636

  • Technical aspects and inter-laboratory variability in native peptide profiling: The CE-MS experience CLINICAL BIOCHEMISTRY Mischak, H., Vlahou, A., Ioannidis, J. P. 2013; 46 (6): 432-443

    Abstract

    Mass spectrometry platforms have attracted a lot of interest in the last 2 decades as profiling tools for native peptides and proteins with clinical potential. However, limitations associated with reproducibility and analytical robustness, especially pronounced with the initial SELDI systems, hindered the application of such platforms in biomarker qualification and clinical implementation. The scope of this article is to give a short overview on data available on performance and on analytical robustness of the different platforms for peptide profiling. Using the CE-MS platform as a paradigm, data on analytical performance are described including reproducibility (short-term and intermediate repeatability), stability, interference, quantification capabilities (limits of detection), and inter-laboratory variability. We discuss these issues by using as an example our experience with the development of a 273-peptide marker for chronic kidney disease. Finally, we discuss pros and cons and means for improvement and emphasize the need to test in terms of comparative clinical performance and impact, different platforms that pass reasonably well analytical validation tests.

    View details for DOI 10.1016/j.clinbiochem.2012.09.025

    View details for Web of Science ID 000317155800005

    View details for PubMedID 23041249

  • Transforming Epidemiology for 21st Century Medicine and Public Health CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Khoury, M. J., Lam, T. K., Ioannidis, J. P., Hartge, P., Spitz, M. R., Buring, J. E., Chanock, S. J., Croyle, R. T., Goddard, K. A., Ginsburg, G. S., Herceg, Z., Hiatt, R. A., Hoover, R. N., Hunter, D. J., Kramer, B. S., Lauer, M. S., Meyerhardt, J. A., Olopade, O. I., Palmer, J. R., Sellers, T. A., Seminara, D., Ransohoff, D. F., Rebbeck, T. R., Tourassi, G., Winn, D. M., Zauber, A., Schully, S. D. 2013; 22 (4): 508-516

    Abstract

    In 2012, the National Cancer Institute (NCI) engaged the scientific community to provide a vision for cancer epidemiology in the 21st century. Eight overarching thematic recommendations, with proposed corresponding actions for consideration by funding agencies, professional societies, and the research community emerged from the collective intellectual discourse. The themes are (i) extending the reach of epidemiology beyond discovery and etiologic research to include multilevel analysis, intervention evaluation, implementation, and outcomes research; (ii) transforming the practice of epidemiology by moving toward more access and sharing of protocols, data, metadata, and specimens to foster collaboration, to ensure reproducibility and replication, and accelerate translation; (iii) expanding cohort studies to collect exposure, clinical, and other information across the life course and examining multiple health-related endpoints; (iv) developing and validating reliable methods and technologies to quantify exposures and outcomes on a massive scale, and to assess concomitantly the role of multiple factors in complex diseases; (v) integrating "big data" science into the practice of epidemiology; (vi) expanding knowledge integration to drive research, policy, and practice; (vii) transforming training of 21st century epidemiologists to address interdisciplinary and translational research; and (viii) optimizing the use of resources and infrastructure for epidemiologic studies. These recommendations can transform cancer epidemiology and the field of epidemiology, in general, by enhancing transparency, interdisciplinary collaboration, and strategic applications of new technologies. They should lay a strong scientific foundation for accelerated translation of scientific discoveries into individual and population health benefits.

    View details for DOI 10.1158/1055-9965.EPI-13-0146

    View details for Web of Science ID 000317960900005

    View details for PubMedID 23462917

    View details for PubMedCentralID PMC3625652

  • Most meta-analyses of drug interventions have narrow scopes and many focus on specific agents JOURNAL OF CLINICAL EPIDEMIOLOGY Haidich, A., Pilalas, D., Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2013; 66 (4): 371-378

    Abstract

    To assess the extent to which meta-analysis publications of drugs and biologics focus on specific named agents or even only a single agent, and identify characteristics associated with such focus.We evaluated 499 articles with meta-analyses published in 2010 and estimated how many did not cover all the available comparisons of tested interventions for a given condition (not all-inclusive); focused on specific named agent(s), or focused strictly on comparisons of only one specific active agent vs. placebo/no treatment or different doses/schedules.Of 499 eligible articles, 403 (80.8%) were not all-inclusive, 214 (42.9%) covered only specific named agent(s), and 74 (14.8%) examined only comparisons with one active agent vs. placebo/no treatment or different doses/schedules. Only 39 articles (7.8%) covered all possible indications for the examined agent(s). After adjusting for type of treatment/field, focus on specific named agent(s) was associated with publication in journal venues (odds ratio [OR]: 1.95; 95% confidence interval [CI]: 1.17-3.26) vs. Cochrane, industry sponsoring (OR: 3.94; 95% CI: 1.66-10.66), and individual patient data analyses (OR: 6.59; 95% CI: 2.24-19.39). Individual patient data analyses primarily (29/34) focused on specific named agent(s).The scope of meta-analysis publications frequently is narrow and shaped to serve particular agents.

    View details for DOI 10.1016/j.jclinepi.2012.10.014

    View details for Web of Science ID 000315935100006

    View details for PubMedID 23384590

  • Limitations of Medical Research and Evidence at the Patient-Clinician Encounter Scale CHEST Morris, A. H., Ioannidis, J. P. 2013; 143 (4): 1127-1135

    Abstract

    We explore some philosophical and scientific underpinnings of clinical research and evidence at the patient-clinician encounter scale. Insufficient evidence and a common failure to use replicable and sound research methods limit us. Both patients and health care may be, in part, complex nonlinear chaotic systems, and predicting their outcomes is a challenge. When trustworthy (credible) evidence is lacking, making correct clinical choices is often a low-probability exercise. Thus, human (clinician) error and consequent injury to patients appear inevitable. Individual clinician decision-makers operate under the philosophical influence of Adam Smith's "invisible hand" with resulting optimism that they will eventually make the right choices and cause health benefits. The presumption of an effective "invisible hand" operating in health-care delivery has supported a model in which individual clinicians struggle to practice medicine, as they see fit based on their own intuitions and preferences (and biases) despite the obvious complexity, errors, noise, and lack of evidence pervading the system. Not surprisingly, the "invisible hand" does not appear to produce the desired community health benefits. Obtaining a benefit at the patient-clinician encounter scale requires human (clinician) behavior modification. We believe that serious rethinking and restructuring of the clinical research and care delivery systems is necessary to assure the profession and the public that we continue to do more good than harm. We need to evaluate whether, and how, detailed decision-support tools may enable reproducible clinician behavior and beneficial use of evidence.

    View details for DOI 10.1378/chest.12-1908

    View details for Web of Science ID 000317871500037

    View details for PubMedID 23546485

    View details for PubMedCentralID PMC3616682

  • Informed Consent, Big Data, and the Oxymoron of Research That Is Not Research AMERICAN JOURNAL OF BIOETHICS Ioannidis, J. P. 2013; 13 (4): 40-42

    View details for DOI 10.1080/15265161.2013.768864

    View details for Web of Science ID 000316391200014

    View details for PubMedID 23514395

  • Observational studies often make clinical practice recommendations: an empirical evaluation of authors' attitudes JOURNAL OF CLINICAL EPIDEMIOLOGY Prasad, V., Jorgenson, J., Ioannidis, J. P., Cifu, A. 2013; 66 (4): 361-366

    Abstract

    Although observational studies provide useful descriptive and correlative information, their role in the evaluation of medical interventions remains contentious. There has been no systematic evaluation of authors' attitudes toward their own nonrandomized studies and how often they recommend specific medical practices.We reviewed all original articles of nonrandomized studies published in 2010 in New England Journal of Medicine, Lancet, Journal of the American Medical Association, and Annals of Internal Medicine. We classified articles based on whether authors recommend a medical practice and whether they state that a randomized trial is needed to support their recommendation. We also examined the types of logical extrapolations used by authors who did advance recommendations.Of the 631 original articles published in 2010, 298 (47%) articles were eligible observational studies. In 167 (56%) of 298 studies, authors recommended a medical practice based on their results. Only 24 (14%) of 167 studies stated that a randomized controlled trial (RCT) should be done to validate the recommendation, whereas the other 143 articles made a total of 149 logical extrapolations to recommend specific medical practices. Recommendations without a call for a randomized trial were most common in studies of modifiable factors (59%), but they were also common in studies reporting incidence or prevalence (51%), studies examining novel tests (41%), and association studies of nonmodifiable factors (32%).The authors of observational studies often extrapolate their results to make recommendations concerning a medical practice, typically without first calling for a RCT.

    View details for DOI 10.1016/j.jclinepi.2012.11.005

    View details for Web of Science ID 000315935100004

    View details for PubMedID 23384591

  • Patient safety strategies targeted at diagnostic errors: a systematic review. Annals of internal medicine McDonald, K. M., Matesic, B., Contopoulos-Ioannidis, D. G., Lonhart, J., Schmidt, E., Pineda, N., Ioannidis, J. P. 2013; 158 (5): 381-389

    Abstract

    Missed, delayed, or incorrect diagnosis can lead to inappropriate patient care, poor patient outcomes, and increased cost. This systematic review analyzed evaluations of interventions to prevent diagnostic errors. Searches used MEDLINE (1966 to October 2012), the Agency for Healthcare Research and Quality's Patient Safety Network, bibliographies, and prior systematic reviews. Studies that evaluated any intervention to decrease diagnostic errors in any clinical setting and with any study design were eligible, provided that they addressed a patient-related outcome. Two independent reviewers extracted study data and rated study quality. There were 109 studies that addressed 1 or more intervention categories: personnel changes (n = 6), educational interventions (n = 11), technique (n = 23), structured process changes (n = 27), technology-based systems interventions (n = 32), and review methods (n = 38). Of 14 randomized trials, which were rated as having mostly low to moderate risk of bias, 11 reported interventions that reduced diagnostic errors. Evidence seemed strongest for technology-based systems (for example, text message alerting) and specific techniques (for example, testing equipment adaptations). Studies provided no information on harms, cost, or contextual application of interventions. Overall, the review showed a growing field of diagnostic error research and categorized and identified promising interventions that warrant evaluation in large studies across diverse settings.

    View details for DOI 10.7326/0003-4819-158-5-201303051-00004

    View details for PubMedID 23460094

  • Patient Safety Strategies Targeted at Diagnostic Errors A Systematic Review ANNALS OF INTERNAL MEDICINE McDonald, K. M., Matesic, B., Contopoulos-Ioannidis, D. G., Lonhart, J., Schmidt, E., Pineda, N., Ioannidis, J. P. 2013; 158 (5): 381-?

    Abstract

    Missed, delayed, or incorrect diagnosis can lead to inappropriate patient care, poor patient outcomes, and increased cost. This systematic review analyzed evaluations of interventions to prevent diagnostic errors. Searches used MEDLINE (1966 to October 2012), the Agency for Healthcare Research and Quality's Patient Safety Network, bibliographies, and prior systematic reviews. Studies that evaluated any intervention to decrease diagnostic errors in any clinical setting and with any study design were eligible, provided that they addressed a patient-related outcome. Two independent reviewers extracted study data and rated study quality. There were 109 studies that addressed 1 or more intervention categories: personnel changes (n = 6), educational interventions (n = 11), technique (n = 23), structured process changes (n = 27), technology-based systems interventions (n = 32), and review methods (n = 38). Of 14 randomized trials, which were rated as having mostly low to moderate risk of bias, 11 reported interventions that reduced diagnostic errors. Evidence seemed strongest for technology-based systems (for example, text message alerting) and specific techniques (for example, testing equipment adaptations). Studies provided no information on harms, cost, or contextual application of interventions. Overall, the review showed a growing field of diagnostic error research and categorized and identified promising interventions that warrant evaluation in large studies across diverse settings.

    View details for Web of Science ID 000316058600004

    View details for PubMedID 23460094

  • Emergence of Large Treatment Effects From Small Trials Reply JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P., Pereira, T. V., Horwitz, R. I. 2013; 309 (8): 768-769

    View details for Web of Science ID 000315332200015

    View details for PubMedID 23443435

  • Comparative effect sizes in randomised trials from less developed and more developed countries: meta-epidemiological assessment BRITISH MEDICAL JOURNAL Panagiotou, O. A., Contopoulos-Ioannidis, D. G., Ioannidis, J. P., Rehnborg, C. F. 2013; 346

    Abstract

    To compare treatment effects from randomised trials conducted in more developed versus less developed countries.Meta-epidemiological study.Cochrane Database of Systematic Reviews (August 2012).Meta-analyses with mortality outcomes including data from at least one randomised trial conducted in a less developed country and one in a more developed country. Relative risk estimates of more versus less developed countries were compared by calculating the relative relative risks for each topic and the summary relative relative risks across all topics. Similar analyses were performed for the primary binary outcome of each topic.139 meta-analyses with mortality outcomes were eligible. No nominally significant differences between more developed and less developed countries were found for 128 (92%) meta-analyses. However, differences were beyond chance in 11 (8%) cases, always showing more favourable treatment effects in trials from less developed countries. The summary relative relative risk was 1.12 (95% confidence interval 1.06 to 1.18; P<0.001; I(2)=0%), suggesting significantly more favourable mortality effects in trials from less developed countries. Results were similar for meta-analyses with nominally significant treatment effects for mortality (1.15), meta-analyses with recent trials (1.14), and when excluding trials from less developed countries that subsequently became more developed (1.12). For the primary binary outcomes (127 meta-analyses), 20 topics had differences in treatment effects beyond chance (more favourable in less developed countries in 15/20 cases).Trials from less developed countries in a few cases show significantly more favourable treatment effects than trials in more developed countries and, on average, treatment effects are more favourable in less developed countries. These discrepancies may reflect biases in reporting or study design as well as genuine differences in baseline risk or treatment implementation and should be considers when generalising evidence across different settings.

    View details for DOI 10.1136/bmj.f707

    View details for Web of Science ID 000315087700003

    View details for PubMedID 23403829

    View details for PubMedCentralID PMC3570069

  • Replication and Predictive Value of SNPs Associated with Melanoma and Pigmentation Traits in a Southern European Case-Control Study PLOS ONE Stefanaki, I., Panagiotou, O. A., Kodela, E., Gogas, H., Kypreou, K. P., Chatzinasiou, F., Nikolaou, V., Plaka, M., Kalfa, I., Antoniou, C., Ioannidis, J. P., Evangelou, E., Stratigos, A. J. 2013; 8 (2)

    Abstract

    Genetic association studies have revealed numerous polymorphisms conferring susceptibility to melanoma. We aimed to replicate previously discovered melanoma-associated single-nucleotide polymorphisms (SNPs) in a Greek case-control population, and examine their predictive value.Based on a field synopsis of genetic variants of melanoma (MelGene), we genotyped 284 patients and 284 controls at 34 melanoma-associated SNPs of which 19 derived from GWAS. We tested each one of the 33 SNPs passing quality control for association with melanoma both with and without accounting for the presence of well-established phenotypic risk factors. We compared the risk allele frequencies between the Greek population and the HapMap CEU sample. Finally, we evaluated the predictive ability of the replicated SNPs.Risk allele frequencies were significantly lower compared to the HapMap CEU for eight SNPs (rs16891982--SLC45A2, rs12203592--IRF4, rs258322--CDK10, rs1805007--MC1R, rs1805008--MC1R, rs910873--PIGU, rs17305573--PIGU, and rs1885120--MTAP) and higher for one SNP (rs6001027--PLA2G6) indicating a different profile of genetic susceptibility in the studied population. Previously identified effect estimates modestly correlated with those found in our population (r = 0.72, P<0.0001). The strongest associations were observed for rs401681-T in CLPTM1L (odds ratio [OR] 1.60, 95% CI 1.22-2.10; P = 0.001), rs16891982-C in SCL45A2 (OR 0.51, 95% CI 0.34-0.76; P = 0.001), and rs1805007-T in MC1R (OR 4.38, 95% CI 2.03-9.43; P = 2×10⁻⁵). Nominally statistically significant associations were seen also for another 5 variants (rs258322-T in CDK10, rs1805005-T in MC1R, rs1885120-C in MYH7B, rs2218220-T in MTAP and rs4911442-G in the ASIP region). The addition of all SNPs with nominal significance to a clinical non-genetic model did not substantially improve melanoma risk prediction (AUC for clinical model 83.3% versus 83.9%, p = 0.66).Overall, our study has validated genetic variants that are likely to contribute to melanoma susceptibility in the Greek population.

    View details for DOI 10.1371/journal.pone.0055712

    View details for Web of Science ID 000314692800051

    View details for PubMedID 23393597

    View details for PubMedCentralID PMC3564929

  • Assessment of systematic effects of methodological characteristics on candidate genetic associations HUMAN GENETICS Aljasir, B., Ioannidis, J. P., Yurkiewich, A., Moher, D., Higgins, J. P., Arora, P., Little, J. 2013; 132 (2): 167-178

    Abstract

    Candidate genetic association studies have been found to have a low replication rate in the past. Here, we aimed to assess whether aspects of reported methodological characteristics in genetic association studies may be related to the magnitude of effects observed. An observational, literature-based investigation of 511 case-control studies of genetic association studies indexed in 2007, was undertaken. Meta-regression analyses were used to assess the relationship between 23 reported methodological characteristics and the magnitude of genetic associations. The 511 studies had been conducted in 52 countries and were published in 220 journals (median impact factor 5.1). The multivariate meta-regression model of methodological characteristics plus disease category accounted for 17.2 % of the between-study variance in the magnitude of the reported genetic associations. Our findings are consistent with the view that better conducted and better reported genetic association research may lead to less inflated results.

    View details for DOI 10.1007/s00439-012-1237-4

    View details for Web of Science ID 000313518900006

    View details for PubMedID 23095857

  • The genetic basis of cross-phenotype correlation with bone fracture risk: the GEFOS consortium Oei, L., Nordstrom, P., Ntzani, E., Zheng, H., Estrada, K., Duncan, E., Medina-Gomez, C., Kaptoge, S., Hsu, Y., Yang, J., Nielson, C., Styrkarsdottir, U., Ridker, P., Garcia, M., Aragaki, A., Enneman, A., Lehtimaki, T., Esko, T., Trompet, S., Eriksson, J., Amin, N., Kung, A., Tsilidis, K., Thorleifsson, G., Rose, L., Zmuda, J., Liu, C., Vernon-Smith, A., Srikanth, P., Wilson, S., Clark, G., Viikari, J., Mihailov, E., Moayyeri, A., Li, G., Kammerer, C., Lorentzon, M., Rivera, N., Xiao, S., Tranah, G., Evans, D., Siggeirsdottir, K., Oei, E., Stefansson, K., Aalto, V., Willner, D., Wareham, N., Minster, R., Bis, J., van Duijn, C., Boyle, A., Snyder, M., Herrera, L., Cupples, L., Aspelund, T., Raitakari, O., Leo, P., Khaw, K., Robbins, J., Liu, Y., Breda, S., Luben, R., Cauley, J., Arnold, A., Reppe, S., Hibbs, M., Stolk, L., Pasco, J., Grundberg, E., Gautvik, K., Ackert-Bicknell, C., Yadav, V., Choi, K., van de Peppel, J., Van Leeuwen, J., Pols, H., Hofman, A., Shen, J., van Meurs, J., Atanasovska, B., Sham, P., Ohlsson, C., Psaty, B., Harris, T., Reeve, J., Jukema, J., Metspalu, A., Kahonen, M., van der Velde, N., Brown, M., Gudnason, V., Ioannidis, J., Uitterlinden, A., Cummings, S., Spector, T., Kiel, D., Jackson, R., Thorsteinsdottir, U., Chasman, D., Orwoll, E., Karasik, D., Zillikens, M., Evangelou, E., Richards, B., Visscher, P., Michaelsson, K., Rivadeneira, F. WILEY-BLACKWELL. 2013
  • Functional characterization of GWAS loci associated with fracture risk Oei, L., Reppe, S., Ntzani, E., Hibbs, M., Choi, K., Zheng, H., Estrada, K., van de Peppel, J., Nielson, C., Styrkarsdottir, U., Ridker, P., Hsu, Y., Garcia, M., Aragaki, A., Duncan, E., Enneman, A., Lehtimaki, T., Esko, T., Trompet, S., Kaptoge, S., Eriksson, J., Amin, N., Kung, A., Medina-Gomez, C., Tsilidis, K., Thorleifsson, G., Rose, L., Zmuda, J., Liu, C., Vernon-Smith, A., Srikanth, P., Wilson, S., Clark, G., Viikari, J., Mihailov, E., Moayyeri, A., Li, G., Kammerer, C., Lorentzon, M., Rivera, N., Xiao, S., Yang, J., Visscher, P., Tranah, G., Evans, D., Karasik, D., Siggeirsdottir, K., Oei, E., Stefansson, K., Aalto, V., Willner, D., Wareham, N., Minster, R., Bis, J., van Duijn, C., Boyle, A., Snyder, M., Herrera, L., Cupples, L., Aspelund, T., Raitakari, O., Leo, P., Khaw, K., Robbins, J., Liu, Y., Breda, S., Luben, R., Cauley, J., Arnold, A., Stolk, L., Pols, H., Hofman, A., Shen, J., Van Meurs, J., Sham, P., Zillikens, M., Ohlsson, C., Psaty, B., Harris, T., Reeve, J., Jukema, J., Metspalu, A., Kahonen, M., van der Velde, N., Brown, M., Gudnason, V., Ioannidis, J., Uitterlinden, A., Cummings, S., Spector, T., Kiel, D., Jackson, R., Thorsteinsdottir, U., Chasman, D., Orwoll, E., Yadav, V., Van Leeuwen, J., Evangelou, E., Grundberg, E., Richards, B., Gautvik, K., Rivadeneira, F., Ackert-Bicknell, C., GEFOS Consortium WILEY-BLACKWELL. 2013
  • Distinguishing true from false positives in genomic studies: p values EUROPEAN JOURNAL OF EPIDEMIOLOGY Broer, L., Lill, C. M., Schuur, M., Amin, N., Roehr, J. T., Bertram, L., Ioannidis, J. P., van Duijn, C. M. 2013; 28 (2): 131-138

    Abstract

    Distinguishing true from false positive findings is a major challenge in human genetic epidemiology. Several strategies have been devised to facilitate this, including the positive predictive value (PPV) and a set of epidemiological criteria, known as the "Venice" criteria. The PPV measures the probability of a true association, given a statistically significant finding, while the Venice criteria grade the credibility based on the amount of evidence, consistency of replication and protection from bias. A vast majority of journals use significance thresholds to identify the true positive findings. We studied the effect of p value thresholds on the PPV and used the PPV and Venice criteria to define usable thresholds of statistical significance. Theoretical and empirical analyses of data published on AlzGene show that at a nominal p value threshold of 0.05 most "positive" findings will turn out to be false if the prior probability of association is below 0.10 even if the statistical power of the study is higher than 0.80. However, in underpowered studies (0.25) with a low prior probability of 1 × 10(-3), a p value of 1 × 10(-5) yields a high PPV (>96 %). Here we have shown that the p value threshold of 1 × 10(-5) gives a very strong evidence of association in almost all studies. However, in the case of a very high prior probability of association (0.50) a p value threshold of 0.05 may be sufficient, while for studies with very low prior probability of association (1 × 10(-4); genome-wide association studies for instance) 1 × 10(-7) may serve as a useful threshold to declare significance.

    View details for DOI 10.1007/s10654-012-9755-x

    View details for Web of Science ID 000316638900003

    View details for PubMedID 23371043

  • Effect of left ventricular ejection fraction and QRS duration on the survival benefit of implantable cardioverter-defibrillators: Meta-analysis of primary prevention trials HEART RHYTHM Katritsis, D. G., Siontis, K. C., Bigger, J. T., Kadish, A. H., Steinman, R., Zareba, W., Siontis, G. C., Bardy, G. H., Ioannidis, J. P. 2013; 10 (2): 200-206

    Abstract

    Implantable cardioverter-defibrillators (ICDs) are recommended for the primary prevention of sudden cardiac death in patients with left ventricular dysfunction, but it is unclear whether treatment benefits are diminished in patients with very low baseline left ventricular ejection fraction (LVEF) (<25%) or increased in those with prolonged QRS duration (>120 ms).To study the effects of very low LVEF and prolonged QRS duration on the mortality benefits of ICD therapy.We performed a meta-analysis of primary prevention randomized controlled trials comparing ICD and standard medical therapy. All-cause mortality hazard ratios (HRs) in subgroups according to thresholds of 25% for LVEF and 120 ms for QRS duration were extracted from published reports or contributed by trial investigators and synthesized.There was no significant difference of ICD effectiveness in LVEF subgroups of 25%-35% (random effects HR 0.81; 95% confidence interval [CI] 0.70-0.94) vs<25% (HR 0.71; 95% CI 0.55-0.93). Results were also similar in the narrow and wide QRS subgroups (HR 0.78; 95% CI 0.68-0.90 and HR 0.70; 95% CI 0.51-0.95, respectively). Within the LVEF<25% and wide QRS subgroups, there was large heterogeneity driven by the Defibrillator in Acute Myocardial Infarction Trial that included patients with early post-myocardial infarction and its results (HR 1.49; 95% CI 0.84-2.68 and HR 1.51; 95% CI 0.83-2.83, respectively) differed significantly from other trials (P = .008 and P = .01, respectively).LVEF values and QRS duration do not appear to directly modify the survival benefit of ICD in patients with baseline LVEF<35%. However, patients with a recent myocardial infarction do not benefit from ICD, especially when they have LVEF<25% and/or wide QRS.

    View details for DOI 10.1016/j.hrthm.2012.10.039

    View details for Web of Science ID 000315110500014

    View details for PubMedID 23107652

  • Opportunities and Challenges for Selected Emerging Technologies in Cancer Epidemiology: Mitochondrial, Epigenomic, Metabolomic, and Telomerase Profiling CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Verma, M., Khoury, M. J., Ioannidis, J. P. 2013; 22 (2): 189-200

    Abstract

    Remarkable progress has been made in the last decade in new methods for biologic measurements using sophisticated technologies that go beyond the established genome, proteome, and gene expression platforms. These methods and technologies create opportunities to enhance cancer epidemiologic studies. In this article, we describe several emerging technologies and evaluate their potential in epidemiologic studies. We review the background, assays, methods, and challenges and offer examples of the use of mitochondrial DNA and copy number assessments, epigenomic profiling (including methylation, histone modification, miRNAs, and chromatin condensation), metabolite profiling (metabolomics), and telomere measurements. We map the volume of literature referring to each one of these measurement tools and the extent to which efforts have been made at knowledge integration (e.g., systematic reviews and meta-analyses). We also clarify strengths and weaknesses of the existing platforms and the range of type of samples that can be tested with each of them. These measurement tools can be used in identifying at-risk populations and providing novel markers of survival and treatment response. Rigorous analytic and validation standards, transparent availability of massive data, and integration in large-scale evidence are essential in fulfilling the potential of these technologies.

    View details for DOI 10.1158/1055-9965.EPI-12-1263

    View details for Web of Science ID 000314700800002

    View details for PubMedID 23242141

    View details for PubMedCentralID PMC3565041

  • Mega-Trials for Blockbusters JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P. 2013; 309 (3): 239-240

    View details for Web of Science ID 000313546800020

    View details for PubMedID 23321760

  • Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants NATURE Fu, W., O'Connor, T. D., Jun, G., Kang, H. M., Abecasis, G., Leal, S. M., Gabriel, S., Altshuler, D., Shendure, J., Nickerson, D. A., Bamshad, M. J., Akey, J. M. 2013; 493 (7431): 216-220

    Abstract

    Establishing the age of each mutation segregating in contemporary human populations is important to fully understand our evolutionary history and will help to facilitate the development of new approaches for disease-gene discovery. Large-scale surveys of human genetic variation have reported signatures of recent explosive population growth, notable for an excess of rare genetic variants, suggesting that many mutations arose recently. To more quantitatively assess the distribution of mutation ages, we resequenced 15,336 genes in 6,515 individuals of European American and African American ancestry and inferred the age of 1,146,401 autosomal single nucleotide variants (SNVs). We estimate that approximately 73% of all protein-coding SNVs and approximately 86% of SNVs predicted to be deleterious arose in the past 5,000-10,000 years. The average age of deleterious SNVs varied significantly across molecular pathways, and disease genes contained a significantly higher proportion of recently arisen deleterious SNVs than other genes. Furthermore, European Americans had an excess of deleterious variants in essential and Mendelian disease genes compared to African Americans, consistent with weaker purifying selection due to the Out-of-Africa dispersal. Our results better delimit the historical details of human protein-coding variation, show the profound effect of recent human history on the burden of deleterious SNVs segregating in contemporary populations, and provide important practical information that can be used to prioritize variants in disease-gene discovery.

    View details for DOI 10.1038/nature11690

    View details for Web of Science ID 000313259600038

    View details for PubMedID 23201682

  • NIH funding: the critics respond NATURE Ioannidis, J. P., Nicholson, J. M. 2013; 493 (7430): 26-26

    View details for Web of Science ID 000312933800016

    View details for PubMedID 23282353

  • This I believe in genetics: discovery can be a nuisance, replication is science, implementation matters. Frontiers in genetics Ioannidis, J. P. 2013; 4: 33-?

    View details for DOI 10.3389/fgene.2013.00033

    View details for PubMedID 23505393

    View details for PubMedCentralID PMC3596761

  • Ensuring the integrity of clinical practice guidelines: a tool for protecting patients. BMJ (Clinical research ed.) Lenzer, J., Hoffman, J. R., Furberg, C. D., Ioannidis, J. P. 2013; 347: f5535-?

    View details for DOI 10.1136/bmj.f5535

    View details for PubMedID 24046286

  • Assessment of osteoarthritis candidate genes in a meta-analysis of 9 genome-wide association studies. Arthritis and rheumatism Rodriguez-Fontenla, C., Calaza, M., Evangelou, E., Valdes, A. M., Arden, N., Blanco, F. J., Carr, A., Chapman, K., Deloukas, P., Doherty, M., Esko, T., Garces, C. M., Gomez-Reino, J. J., Helgadottir, H., Hofman, A., Jonsdottir, I., Kerkhof, H. J., Kloppenburg, M., McCaskie, A., Ntzani, E. E., Ollier, W. E., Oreiro, N., Panoutsopoulou, K., Ralston, S. H., Ramos, Y. F., Riancho, J. A., Rivadeneira, F., Slagboom, P. E., Styrkarsdottir, U., Thorsteinsdottir, U., Thorleifsson, G., Tsezou, A., Uitterlinden, A. G., Wallis, G. A., Wilkinson, J. M., Zhai, G., Zhu, Y., Felson, D. T., Ioannidis, J. P., Loughlin, J., Metspalu, A., Meulenbelt, I., Stefansson, K., van Meurs, J. B., Zeggini, E., Spector, T. D., Gonzalez, A. 2013

    Abstract

    Objectives: To assess osteoarthritis (OA) candidate genes for identification of promising genetic factors and, secondarily, to assess the candidate gene approach in OA. Methods: 199 published candidate genes for OA were obtained from the HuGe Navigator. All their SNPs with allele frequency >5% were assessed with fixed effect meta-analysis of 9 genome-wide association studies (GWAS) including 5 636 knee OA patients and 16 972 controls, and 4 349 hip OA patients and 17 836 controls of European ancestry. Additional 5 921 individuals were studied for top SNPs in the meta-analysis. Significance was corrected for the number of independent tests at p < 1.58 x 10(-5) . Results: SNPs at only two of the 199 candidate genes were associated with OA in the meta-analysis. They were associated with hip OA, COL11A1 showing two independent associations in the combined analysis (rs4907986, p = 1.29 x 10(-5) , OR = 1.12; 95 % CI = 1.06-1.17; and rs1241164, p = 1.47 x 10(-5) , OR = 0.82, CI = 0.74-0.89) and a SNP in linkage disequilibrium with rs4907986 in the female-specific analysis (rs4908291, p = 1.29 x 10(-5) , OR = 0.87, CI = 0.82-0.92), and VEGF associated in male-specific analysis (rs833058, p = 1.35 x 10(-5) , OR = 0.85, CI = 0.79-0.91). After genotyping additional samples, association at one of the COL11A1 signals was reinforced, whereas association at VEGF was slightly weakened. Conclusion: Two candidate genes were significantly associated with OA in this focused meta-analysis COL11A1 and VEGF. The remaining candidate genes were not associated. © 2013 American College of Rheumatology.

    View details for DOI 10.1002/art.38300

    View details for PubMedID 24338622

  • Potential reporting bias in FMRI studies of the brain. PloS one David, S. P., Ware, J. J., Chu, I. M., Loftus, P. D., Fusar-Poli, P., Radua, J., Munafò, M. R., Ioannidis, J. P. 2013; 8 (7)

    Abstract

    Functional magnetic resonance imaging (fMRI) studies have reported multiple activation foci associated with a variety of conditions, stimuli or tasks. However, most of these studies used fewer than 40 participants.After extracting data (number of subjects, condition studied, number of foci identified and threshold) from 94 brain fMRI meta-analyses (k = 1,788 unique datasets) published through December of 2011, we analyzed the correlation between individual study sample sizes and number of significant foci reported. We also performed an analysis where we evaluated each meta-analysis to test whether there was a correlation between the sample size of the meta-analysis and the number of foci that it had identified. Correlation coefficients were then combined across all meta-analyses to obtain a summary correlation coefficient with a fixed effects model and we combine correlation coefficients, using a Fisher's z transformation.There was no correlation between sample size and the number of foci reported in single studies (r = 0.0050) but there was a strong correlation between sample size and number of foci in meta-analyses (r = 0.62, p<0.001). Only studies with sample sizes <45 identified larger (>40) numbers of foci and claimed as many discovered foci as studies with sample sizes ≥45, whereas meta-analyses yielded a limited number of foci relative to the yield that would be anticipated from smaller single studies.These results are consistent with possible reporting biases affecting small fMRI studies and suggest the need to promote standardized large-scale evidence in this field. It may also be that small studies may be analyzed and reported in ways that may generate a larger number of claimed foci or that small fMRI studies with inconclusive, null, or not very promising results may not be published at all.

    View details for DOI 10.1371/journal.pone.0070104

    View details for PubMedID 23936149

    View details for PubMedCentralID PMC3723634

  • More Than a Billion People Taking Statins?: Potential Implications of the New Cardiovascular Guidelines. JAMA : the journal of the American Medical Association Ioannidis, J. P. 2013

    View details for DOI 10.1001/jama.2013.284657

    View details for PubMedID 24296612

  • Systematic identification of interaction effects between validated genome- and environment-wide associations on Type 2 Diabetes Mellitus. AMIA Summits on Translational Science proceedings AMIA Summit on Translational Science Patel, C. J., Chen, R., Kodama, K., Ioannidis, J. P., Butte, A. J. 2013; 2013: 135-?

    View details for PubMedID 24303322

  • Is everything we eat associated with cancer? A systematic cookbook review AMERICAN JOURNAL OF CLINICAL NUTRITION Schoenfeld, J. D., Loannidis, J. P. 2013; 97 (1): 127-134

    Abstract

    Nutritional epidemiology is a highly prolific field. Debates on associations of nutrients with disease risk are common in the literature and attract attention in public media.We aimed to examine the conclusions, statistical significance, and reproducibility in the literature on associations between specific foods and cancer risk.We selected 50 common ingredients from random recipes in a cookbook. PubMed queries identified recent studies that evaluated the relation of each ingredient to cancer risk. Information regarding author conclusions and relevant effect estimates were extracted. When >10 articles were found, we focused on the 10 most recent articles.Forty ingredients (80%) had articles reporting on their cancer risk. Of 264 single-study assessments, 191 (72%) concluded that the tested food was associated with an increased (n = 103) or a decreased (n = 88) risk; 75% of the risk estimates had weak (0.05 > P ≥ 0.001) or no statistical (P > 0.05) significance. Statistically significant results were more likely than nonsignificant findings to be published in the study abstract than in only the full text (P < 0.0001). Meta-analyses (n = 36) presented more conservative results; only 13 (26%) reported an increased (n = 4) or a decreased (n = 9) risk (6 had more than weak statistical support). The median RRs (IQRs) for studies that concluded an increased or a decreased risk were 2.20 (1.60, 3.44) and 0.52 (0.39, 0.66), respectively. The RRs from the meta-analyses were on average null (median: 0.96; IQR: 0.85, 1.10).Associations with cancer risk or benefits have been claimed for most food ingredients. Many single studies highlight implausibly large effects, even though evidence is weak. Effect sizes shrink in meta-analyses.

    View details for DOI 10.3945/ajcn.112.047142

    View details for Web of Science ID 000313135600018

    View details for PubMedID 23193004

  • Demystifying trial networks and network meta-analysis. BMJ (Clinical research ed.) Mills, E. J., Thorlund, K., Ioannidis, J. P. 2013; 346: f2914-?

    View details for DOI 10.1136/bmj.f2914

    View details for PubMedID 23674332

  • Appropriate vs Clinically Useful Diagnostic Tests. JAMA internal medicine Ioannidis, J. P. 2013

    View details for DOI 10.1001/jamainternmed.2013.6582

    View details for PubMedID 23877418

  • Overlapping meta-analyses on the same topic: survey of published studies. BMJ (Clinical research ed.) Siontis, K. C., Hernandez-Boussard, T., Ioannidis, J. P. 2013; 347: f4501-?

    Abstract

    To assess how common it is to have multiple overlapping meta-analyses of randomized trials published on the same topic.Survey of published meta-analyses.PubMed.Meta-analyses published in 2010 were identified, and 5% of them were randomly selected. We further selected those that included randomized trials and examined effectiveness of any medical intervention. For eligible meta-analyses, we searched for other meta-analyses on the same topic (covering the same comparisons, indications/settings, and outcomes or overlapping subsets of them) published until February 2013.Of 73 eligible meta-analyses published in 2010, 49 (67%) had at least one other overlapping meta-analysis (median two meta-analyses per topic, interquartile range 1-4, maximum 13). In 17 topics at least one author was involved in at least two of the overlapping meta-analyses. No characteristics of the index meta-analyses were associated with the potential for overlapping meta-analyses. Among pairs of overlapping meta-analyses in 20 randomly selected topics, 13 of the more recent meta-analyses did not include any additional outcomes. In three of the four topics with eight or more published meta-analyses, many meta-analyses examined only a subset of the eligible interventions or indications/settings covered by the index meta-analysis. Conversely, for statins in the prevention of atrial fibrillation after cardiac surgery, 11 meta-analyses were published with similar eligibility criteria for interventions and setting: there was still variability on which studies were included, but the results were always similar or even identical across meta-analyses.While some independent replication of meta-analyses by different teams is possibly useful, the overall picture suggests that there is a waste of efforts with many topics covered by multiple overlapping meta-analyses.

    View details for DOI 10.1136/bmj.f4501

    View details for PubMedID 23873947

  • Are randomized trials obsolete or more important than ever in the genomic era? Genome medicine Ioannidis, J. P., Khoury, M. J. 2013; 5 (4): 32

    View details for DOI 10.1186/gm436

    View details for PubMedID 23673134

  • Comparative effect sizes in randomised trials from less developed and more developed countries: meta-epidemiological assessment. BMJ (Clinical research ed.) Panagiotou, O. A., Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2013; 346: f707-?

    Abstract

    To compare treatment effects from randomised trials conducted in more developed versus less developed countries.Meta-epidemiological study.Cochrane Database of Systematic Reviews (August 2012).Meta-analyses with mortality outcomes including data from at least one randomised trial conducted in a less developed country and one in a more developed country. Relative risk estimates of more versus less developed countries were compared by calculating the relative relative risks for each topic and the summary relative relative risks across all topics. Similar analyses were performed for the primary binary outcome of each topic.139 meta-analyses with mortality outcomes were eligible. No nominally significant differences between more developed and less developed countries were found for 128 (92%) meta-analyses. However, differences were beyond chance in 11 (8%) cases, always showing more favourable treatment effects in trials from less developed countries. The summary relative relative risk was 1.12 (95% confidence interval 1.06 to 1.18; P<0.001; I(2)=0%), suggesting significantly more favourable mortality effects in trials from less developed countries. Results were similar for meta-analyses with nominally significant treatment effects for mortality (1.15), meta-analyses with recent trials (1.14), and when excluding trials from less developed countries that subsequently became more developed (1.12). For the primary binary outcomes (127 meta-analyses), 20 topics had differences in treatment effects beyond chance (more favourable in less developed countries in 15/20 cases).Trials from less developed countries in a few cases show significantly more favourable treatment effects than trials in more developed countries and, on average, treatment effects are more favourable in less developed countries. These discrepancies may reflect biases in reporting or study design as well as genuine differences in baseline risk or treatment implementation and should be considers when generalising evidence across different settings.

    View details for DOI 10.1136/bmj.f707

    View details for PubMedID 23403829

  • Trends in citations to books on epidemiological and statistical methods in the biomedical literature. PloS one Porta, M., Vandenbroucke, J. P., Ioannidis, J. P., Sanz, S., Fernandez, E., Bhopal, R., Morabia, A., Victora, C., Lopez, T. 2013; 8 (5)

    Abstract

    There are no analyses of citations to books on epidemiological and statistical methods in the biomedical literature. Such analyses may shed light on how concepts and methods changed while biomedical research evolved. Our aim was to analyze the number and time trends of citations received from biomedical articles by books on epidemiological and statistical methods, and related disciplines.The data source was the Web of Science. The study books were published between 1957 and 2010. The first year of publication of the citing articles was 1945. We identified 125 books that received at least 25 citations. Books first published in 1980-1989 had the highest total and median number of citations per year. Nine of the 10 most cited texts focused on statistical methods. Hosmer & Lemeshow's Applied logistic regression received the highest number of citations and highest average annual rate. It was followed by books by Fleiss, Armitage, et al., Rothman, et al., and Kalbfleisch and Prentice. Fifth in citations per year was Sackett, et al., Evidence-based medicine. The rise of multivariate methods, clinical epidemiology, or nutritional epidemiology was reflected in the citation trends. Educational textbooks, practice-oriented books, books on epidemiological substantive knowledge, and on theory and health policies were much less cited. None of the 25 top-cited books had the theoretical or sociopolitical scope of works by Cochrane, McKeown, Rose, or Morris.Books were mainly cited to reference methods. Books first published in the 1980s continue to be most influential. Older books on theory and policies were rooted in societal and general medical concerns, while the most modern books are almost purely on methods.

    View details for DOI 10.1371/journal.pone.0061837

    View details for PubMedID 23667447

    View details for PubMedCentralID PMC3646840

  • The Power of Meta-Analysis in Genome-Wide Association Studies ANNUAL REVIEW OF GENOMICS AND HUMAN GENETICS, VOL 14 Panagiotou, O. A., Willer, C. J., Hirschhorn, J. N., Ioannidis, J. P. 2013; 14: 441-465

    Abstract

    Meta-analysis of multiple genome-wide association (GWA) studies has become common practice over the past few years. The main advantage of this technique is the maximization of power to detect subtle genetic effects for common traits. Moreover, one can use meta-analysis to probe and identify heterogeneity in the effect sizes across the combined studies. In this review, we systematically appraise and evaluate the characteristics of GWA meta-analyses with 10,000 or more subjects published up to June 2012. We provide an overview of the current landscape of variants discovered by GWA meta-analyses, and we discuss and assess with extrapolations from empirical data the value of larger meta-analyses for the discovery of additional genetic associations and new biology in the future. Finally, we discuss some emerging logistical and practical issues related to the conduct of meta-analysis of GWA studies. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 14 is August 31, 2013. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.

    View details for DOI 10.1146/annurev-genom-091212-153520

    View details for Web of Science ID 000326658500020

    View details for PubMedID 23724904

  • Evaluating Health System Processes With Randomized Controlled Trials. JAMA internal medicine Ioannidis, J. P., Prasad, V. 2013: 1–2

    View details for DOI 10.1001/jamainternmed.2013.1044

    View details for PubMedID 23689271

  • The geometric increase in meta-analyses from china in the genomic era. PloS one Ioannidis, J. P., Chang, C. Q., Lam, T. K., Schully, S. D., Khoury, M. J. 2013; 8 (6)

    Abstract

    Meta-analyses are increasingly popular. It is unknown whether this popularity is driven by specific countries and specific meta-analyses types. PubMed was used to identify meta-analyses since 1995 (last update 9/1/2012) and catalogue their types and country of origin. We focused more on meta-analyses from China (the current top producer of meta-analyses) versus the USA (top producer until recently). The annual number of meta-analyses from China increased 40-fold between 2003 and 2011 versus 2.4-fold for the USA. The growth of Chinese meta-analyses was driven by genetics (110-fold increase in 2011 versus 2003). The HuGE Navigator identified 612 meta-analyses of genetic association studies published in 2012 from China versus only 109 from the USA. We compared in-depth 50 genetic association meta-analyses from China versus 50 from USA in 2012. Meta-analyses from China almost always used only literature-based data (92%), and focused on one or two genes (94%) and variants (78%) identified with candidate gene approaches (88%), while many USA meta-analyses used genome-wide approaches and raw data. Both groups usually concluded favorably for the presence of genetic associations (80% versus 74%), but nominal significance (P<0.05) typically sufficed in the China group. Meta-analyses from China typically neglected genome-wide data, and often included candidate gene studies published in Chinese-language journals. Overall, there is an impressive rise of meta-analyses from China, particularly on genetic associations. Since most claimed candidate gene associations are likely false-positives, there is an urgent global need to incorporate genome-wide data and state-of-the art statistical inferences to avoid a flood of false-positive genetic meta-analyses.

    View details for DOI 10.1371/journal.pone.0065602

    View details for PubMedID 23776510

    View details for PubMedCentralID PMC3680482

  • Meta-analyses of hydroxyethyl starch for volume resuscitation. JAMA : the journal of the American Medical Association Ioannidis, J. P. 2013; 309 (21): 2209

    View details for DOI 10.1001/jama.2013.5817

    View details for PubMedID 23736722

  • Biomarker Failures CLINICAL CHEMISTRY Ioannidis, J. P. 2013; 59 (1): 202-204

    View details for DOI 10.1373/clinchem.2012.185801

    View details for Web of Science ID 000313535100033

    View details for PubMedID 22997282

  • How Many Contemporary Medical Practices Are Worse Than Doing Nothing or Doing Less? Mayo Clinic proceedings. Mayo Clinic Ioannidis, J. P. 2013

    View details for DOI 10.1016/j.mayocp.2013.05.010

    View details for PubMedID 23871231

  • Knowledge Integration in Cancer: Current Landscape and Future Prospects CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Ioannidis, J. P., Schully, S. D., Lam, T. K., Khoury, M. J. 2013; 22 (1): 3-10

    Abstract

    Knowledge integration includes knowledge management, synthesis, and translation processes. It aims to maximize the use of collected scientific information and accelerate translation of discoveries into individual and population health benefits. Accumulated evidence in cancer epidemiology constitutes a large share of the 2.7 million articles on cancer in PubMed. We examine the landscape of knowledge integration in cancer epidemiology. Past approaches have mostly used retrospective efforts of knowledge management and traditional systematic reviews and meta-analyses. Systematic searches identify 2,332 meta-analyses, about half of which are on genetics and epigenetics. Meta-analyses represent 1:89-1:1162 of published articles in various cancer subfields. Recently, there are more collaborative meta-analyses with individual-level data, including those with prospective collection of measurements [e.g., genotypes in genome-wide association studies (GWAS)]; this may help increase the reliability of inferences in the field. However, most meta-analyses are still done retrospectively with published information. There is also a flurry of candidate gene meta-analyses with spuriously prevalent "positive" results. Prospective design of large research agendas, registration of datasets, and public availability of data and analyses may improve our ability to identify knowledge gaps, maximize and accelerate translational progress or-at a minimum-recognize dead ends in a more timely fashion.

    View details for DOI 10.1158/1055-9965.EPI-12-1144

    View details for Web of Science ID 000313531900001

    View details for PubMedID 23093546

  • Research grants: Conform and be funded. Nature Nicholson, J. M., Ioannidis, J. P. 2012; 492 (7427): 34-36

    View details for DOI 10.1038/492034a

    View details for PubMedID 23222591

  • Scientific inbreeding and same-team replication: Type D personality as an example JOURNAL OF PSYCHOSOMATIC RESEARCH Ioannidis, J. P. 2012; 73 (6): 408-410

    Abstract

    Replication is essential for validating correct results, sorting out false-positive early discoveries, and improving the accuracy and precision of estimated effects. However, some types of seemingly successful replication may foster a spurious notion of increased credibility, if they are performed by the same team and propagate or extend the same errors made by the original discoveries. Besides same-team replication, replication by other teams may also succumb to inbreeding, if it cannot fiercely maintain its independence. These patterns include obedient replication and obliged replication. I discuss these replication patterns in the context of associations and effects in the psychological sciences, drawing from the criticism of Coyne and de Voogd of the proposed association between type D personality and cardiovascular mortality and other empirical examples.

    View details for DOI 10.1016/j.jpsychores.2012.09.014

    View details for Web of Science ID 000311465500002

    View details for PubMedID 23148806

  • METRADISC-XL: A program for meta-analysis of multidimensional ranked discovery oriented datasets including microarrays COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE Zintzaras, E., Ioannidis, J. P. 2012; 108 (3): 1243-1246

    Abstract

    A comprehensive software for performing meta-analysis of ranked discovery oriented datasets, such as those derived from microarrays or other high throughput technologies, and for testing between-study heterogeneity for biological variables (gene expression, microRNA, proteomic, or other high-dimensional data) is presented. The software can identify biological probes that have either very high average ranks (e.g. consistently over-expressed genes) or very low average ranks (e.g. consistently under-expressed genes). The program tests each probe's average rank and the between-study heterogeneity of the study-specific ranks. Furthermore, it performs heterogeneity analyses restricted to probes with similar average ranks. The program allows both unweighted and weighted analysis. Statistical inferences are based on Monte Carlo permutation tests.

    View details for DOI 10.1016/j.cmpb.2012.08.001

    View details for Web of Science ID 000311976100033

    View details for PubMedID 22959629

  • Reproducibility concerns NATURE MEDICINE Ioannidis, J. P., Nosek, B., Iorns, E. 2012; 18 (12): 1736-1736

    View details for DOI 10.1038/nm.3020

    View details for Web of Science ID 000311999800011

    View details for PubMedID 23223056

  • Genetic association studies in pre-eclampsia: systematic meta-analyses and field synopsis INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Staines-Urias, E., Paez, M. C., Doyle, P., Dudbridge, F., Serrano, N. C., Ioannidis, J. P., Keating, B. J., Hingorani, A. D., Casas, J. P. 2012; 41 (6): 1764-1775

    Abstract

    Pre-eclampsia is thought to have a polygenic basis, but the identification of susceptibility genes and the quantification of associated risks have been elusive owing to lack of replication from published genetic association studies.To perform a systematic review and meta-analysis of genetic association studies to evaluate the evidence for the associations of various candidate genes with pre-eclampsia.For inclusion, studies had to involve unrelated subjects and examine the associations between pre-eclampsia (excluding publications without a measurement of proteinuria) and any candidate variant. Authors were contacted to obtain unpublished data when necessary. A meta-analysis was conducted for all variants with three or more independent samples available. Summary odds ratios (ORs), 99% confidence intervals (CIs) and P-values were calculated using random effects models.Data from 192 genetic association studies met the selection criteria and were included in 25 independent meta-analyses. There was some evidence of association for F5 rs6025 (OR = 1.74; 99% CI 1.43-2.12), F2 rs1799963 (OR = 1.72; 99% CI 1.31-2.26), ACE rs4646994 (OR = 1.17; 99% CI 0.99-1.40), AGT rs699 (OR = 1.26; 99% CI 1.00-1.59) and AGTR1 rs5186 (OR = 1.22; 99% CI 0.96-1.56), but only the first two associations reached moderate epidemiological credibility. Possible bias resulting from small study size and poor reporting of individual studies were the most important factors affecting the reported associations.To date, candidate gene studies in pre-eclampsia have not robustly documented any associations with strong epidemiological credibility. Large-scale replication of the most promising associations, exhibited by two genetic variants, and incorporation of agnostic high-throughput data may improve our genetic knowledge base for this complex phenotype.

    View details for DOI 10.1093/ije/dys162

    View details for Web of Science ID 000313128000033

    View details for PubMedID 23132613

  • Perceived information gain from randomized trials correlates with publication in high-impact factor journals JOURNAL OF CLINICAL EPIDEMIOLOGY Evangelou, E., Siontis, K. C., Pfeiffer, T., Ioannidis, J. P. 2012; 65 (12): 1274-1281

    Abstract

    To examine whether perceived information gain (IG) drives the publication of randomized trials in high-impact factor (IF) journals.We estimated IG as the Kullback-Leibler divergence, quantifying how much a new finding changes established knowledge. We used 67 meta-analyses (964 randomized trials) that include one or more trials from any of the three highest IF general medical journals (NEJM, JAMA, and Lancet). We calculated IG for the presence of a non-null effect (IG(1)) and IG for the effect size magnitude (IG(2)).Across meta-analyses, the summary correlation coefficient of IF was 0.23 (95% confidence interval [CI]: 0.14, 0.31) for IG(1) and 0.35 (95% CI: 0.25, 0.46) for IG(2). IF also correlated with the P-value of the results (r=0.18), order of publication (r=-0.13), and number of events in the trial (r=0.36). Multivariate regression including IG, order of publication, P-value, and the number of events showed that IG is an independent correlate of IF. IG(2) explained a substantially larger proportion of the variance in IF than IG(1).Publication in journals with high IF is driven by how extensively the results of a study change prior perceptions of the evidence, independently of the statistical significance and size of the study.

    View details for DOI 10.1016/j.jclinepi.2012.06.009

    View details for Web of Science ID 000310669400009

    View details for PubMedID 22959593

  • Calculating additive treatment effects from multiple randomized trials provides useful estimates of combination therapies JOURNAL OF CLINICAL EPIDEMIOLOGY Mills, E. J., Thorlund, K., Ioannidis, J. P. 2012; 65 (12): 1282-1288

    Abstract

    Many clinicians and decision makers want to know the combined effects of treatments that have not been evaluated in combination. It is possible to determine such treatment effects by making assumptions about the additive effects. We discuss here the prerequisites and methods of applying additivity assumptions in synthesizing the evidence from randomized trials and multiple treatment meta-analyses.Using statistical approaches, we demonstrate the utility of additivity of both pairwise randomized trials and multiple treatment comparison meta-analyses.We present illustratively an example on estimating the treatment effects of drug combinations for chronic obstructive pulmonary disease. We confirm the additive treatment effects by comparing with direct combination treatment trial results.Additive effects may be a useful tool to estimate the effectiveness of treatment combinations.

    View details for DOI 10.1016/j.jclinepi.2012.07.012

    View details for Web of Science ID 000310669400010

    View details for PubMedID 22981250

  • Evaluation of Excess Statistical Significance in Meta-analyses of 98 Biomarker Associations with Cancer Risk JOURNAL OF THE NATIONAL CANCER INSTITUTE Tsilidis, K. K., Papatheodorou, S. I., Evangelou, E., Ioannidis, J. P. 2012; 104 (24): 1867-1878

    Abstract

    Numerous biomarkers have been associated with cancer risk. We assessed whether there is evidence for excess statistical significance in results of cancer biomarker studies, suggesting biases.We systematically searched PubMed for meta-analyses of nongenetic biomarkers and cancer risk. The number of observed studies with statistically significant results was compared with the expected number, based on the statistical power of each study under different assumptions for the plausible effect size. We also evaluated small-study effects using asymmetry tests. All statistical tests were two-sided.We included 98 meta-analyses with 847 studies. Forty-three meta-analyses (44%) found nominally statistically significant summary effects (random effects). The proportion of meta-analyses with statistically significant effects was highest for infectious agents (86%), inflammatory (67%), and insulin-like growth factor (IGF)/insulin system (52%) biomarkers. Overall, 269 (32%) individual studies observed nominally statistically significant results. A statistically significant excess of the observed over the expected number of studies with statistically significant results was seen in 20 meta-analyses. An excess of observed vs expected was observed in studies of IGF/insulin (P ≤ .04) and inflammation systems (P ≤ .02). Only 12 meta-analyses (12%) had a statistically significant summary effect size, more than 1000 case patients, and no hints of small-study effects or excess statistical significance; only four of them had large effect sizes, three of which pertained to infectious agents (Helicobacter pylori, hepatitis and human papilloma viruses).Most well-documented biomarkers of cancer risk without evidence of bias pertain to infectious agents. Conversely, an excess of statistically significant findings was observed in studies of IGF/insulin and inflammation systems, suggesting reporting biases.

    View details for DOI 10.1093/jnci/djs437

    View details for Web of Science ID 000312891200007

    View details for PubMedID 23090067

  • There is nothing personal-reply. Archives of internal medicine Ioannidis, J. P. 2012; 172 (21): 1691-1692

    View details for DOI 10.1001/2013.jamainternmed.13

    View details for PubMedID 23753076

  • There Is Nothing Personal reply ARCHIVES OF INTERNAL MEDICINE Ioannidis, J. A. 2012; 172 (21): 1692
  • A Nutrient-Wide Association Study on Blood Pressure CIRCULATION Tzoulaki, I., Patel, C. J., Okamura, T., Chan, Q., Brown, I. J., Miura, K., Ueshima, H., Zhao, L., Van Horn, L., Daviglus, M. L., Stamler, J., Butte, A. J., Ioannidis, J. P., Elliott, P. 2012; 126 (21): 2456-2464

    Abstract

    A nutrient-wide approach may be useful to comprehensively test and validate associations between nutrients (derived from foods and supplements) and blood pressure (BP) in an unbiased manner.Data from 4680 participants aged 40 to 59 years in the cross-sectional International Study of Macro/Micronutrients and Blood Pressure (INTERMAP) were stratified randomly into training and testing sets. US National Health and Nutrition Examination Survey (NHANES) four cross-sectional cohorts (1999-2000, 2001-2002, 2003-2004, 2005-2006) were used for external validation. We performed multiple linear regression analyses associating each of 82 nutrients and 3 urine electrolytes with systolic and diastolic BP in the INTERMAP training set. Significant findings were validated in the INTERMAP testing set and further in the NHANES cohorts (false discovery rate <5% in training, P<0.05 for internal and external validation). Among the validated nutrients, alcohol and urinary sodium-to-potassium ratio were directly associated with systolic BP, and dietary phosphorus, magnesium, iron, thiamin, folacin, and riboflavin were inversely associated with systolic BP. In addition, dietary folacin and riboflavin were inversely associated with diastolic BP. The absolute effect sizes in the validation data (NHANES) ranged from 0.97 mm Hg lower systolic BP (phosphorus) to 0.39 mm Hg lower systolic BP (thiamin) per 1-SD difference in nutrient variable. Inclusion of nutrient intake from supplements in addition to foods gave similar results for some nutrients, though it attenuated the associations of folacin, thiamin, and riboflavin intake with BP.We identified significant inverse associations between B vitamins and BP, relationships hitherto poorly investigated. Our analyses represent a systematic unbiased approach to the evaluation and validation of nutrient-BP associations.

    View details for DOI 10.1161/CIRCULATIONAHA.112.114058

    View details for Web of Science ID 000311342600010

    View details for PubMedID 23093587

  • Content area experts as authors: helpful or harmful for systematic reviews and meta-analyses? BRITISH MEDICAL JOURNAL Gotzsche, P. C., Ioannidis, J. P. 2012; 345

    View details for DOI 10.1136/bmj.e7031

    View details for Web of Science ID 000310779000003

    View details for PubMedID 23118303

  • Effectiveness and harms of seasonal and pandemic influenza vaccines in children, adults and elderly: a critical review and re-analysis of 15 meta-analyses Manzoli, L., Ioannidis, J. A., Flacco, M. E., De Vito, C., Villari, P. OXFORD UNIV PRESS. 2012: 57
  • Why Science Is Not Necessarily Self-Correcting PERSPECTIVES ON PSYCHOLOGICAL SCIENCE Ioannidis, J. P. 2012; 7 (6): 645-654

    Abstract

    The ability to self-correct is considered a hallmark of science. However, self-correction does not always happen to scientific evidence by default. The trajectory of scientific credibility can fluctuate over time, both for defined scientific fields and for science at-large. History suggests that major catastrophes in scientific credibility are unfortunately possible and the argument that "it is obvious that progress is made" is weak. Careful evaluation of the current status of credibility of various scientific fields is important in order to understand any credibility deficits and how one could obtain and establish more trustworthy results. Efficient and unbiased replication mechanisms are essential for maintaining high levels of scientific credibility. Depending on the types of results obtained in the discovery and replication phases, there are different paradigms of research: optimal, self-correcting, false nonreplication, and perpetuated fallacy. In the absence of replication efforts, one is left with unconfirmed (genuine) discoveries and unchallenged fallacies. In several fields of investigation, including many areas of psychological science, perpetuated and unchallenged fallacies may comprise the majority of the circulating evidence. I catalogue a number of impediments to self-correction that have been empirically studied in psychological science. Finally, I discuss some proposed solutions to promote sound replication practices enhancing the credibility of scientific results as well as some potential disadvantages of each of them. Any deviation from the principle that seeking the truth has priority over any other goals may be seriously damaging to the self-correcting functions of science.

    View details for DOI 10.1177/1745691612464056

    View details for Web of Science ID 000310852500018

  • Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis ANNALS OF THE RHEUMATIC DISEASES Bertsias, G. K., Tektonidou, M., Amoura, Z., Aringer, M., Bajema, I., Berden, J. H., Boletis, J., Cervera, R., Doerner, T., Doria, A., Ferrario, F., Floege, J., Houssiau, F. A., Ioannidis, J. P., Isenberg, D. A., Kallenberg, C. G., Lightstone, L., Marks, S. D., Martini, A., Moroni, G., Neumann, I., Praga, M., Schneider, M., Starra, A., Tesar, V., Vasconcelos, C., Van Vollenhoven, R. F., Zakharova, H., Haubitz, M., Gordon, C., Jayne, D., Boumpas, D. T. 2012; 71 (11): 1771-1782

    Abstract

    To develop recommendations for the management of adult and paediatric lupus nephritis (LN).The available evidence was systematically reviewed using the PubMed database. A modified Delphi method was used to compile questions, elicit expert opinions and reach consensus.Immunosuppressive treatment should be guided by renal biopsy, and aiming for complete renal response (proteinuria <0.5 g/24 h with normal or near-normal renal function). Hydroxychloroquine is recommended for all patients with LN. Because of a more favourable efficacy/toxicity ratio, as initial treatment for patients with class III-IV(A) or (A/C) (±V) LN according to the International Society of Nephrology/Renal Pathology Society 2003 classification, mycophenolic acid (MPA) or low-dose intravenous cyclophosphamide (CY) in combination with glucocorticoids is recommended. In patients with adverse clinical or histological features, CY can be prescribed at higher doses, while azathioprine is an alternative for milder cases. For pure class V LN with nephrotic-range proteinuria, MPA in combination with oral glucocorticoids is recommended as initial treatment. In patients improving after initial treatment, subsequent immunosuppression with MPA or azathioprine is recommended for at least 3 years; in such cases, initial treatment with MPA should be followed by MPA. For MPA or CY failures, switching to the other agent, or to rituximab, is the suggested course of action. In anticipation of pregnancy, patients should be switched to appropriate medications without reducing the intensity of treatment. There is no evidence to suggest that management of LN should differ in children versus adults.Recommendations for the management of LN were developed using an evidence-based approach followed by expert consensus.

    View details for DOI 10.1136/annrheumdis-2012-201940

    View details for Web of Science ID 000309654900004

    View details for PubMedID 22851469

    View details for PubMedCentralID PMC3465859

  • To Correct or Not to Correct-and How EPIDEMIOLOGY Ioannidis, J. P., Yu, Y., Seddon, J. M. 2012; 23 (6): 912-913

    View details for DOI 10.1097/EDE.0b013e31826cc1b3

    View details for Web of Science ID 000309965800024

    View details for PubMedID 23038115

  • Correction of Phenotype Misclassification Based on High-Discrimination Genetic Predictive Risk Models EPIDEMIOLOGY Ioannidis, J. P., Yu, Y., Seddon, J. M. 2012; 23 (6): 902-909

    Abstract

    Misclassification of phenotype status can seriously affect accuracy in association studies, including studies of genetic risk factors. A common problem is the classification of participants as nondiseased because of insufficient diagnostic workup or because participants have not been followed up long enough to develop disease. Some validated predictive models may have high discrimination in predicting disease. We suggest that information from such models can be used to predict the risk that a nondiseased participant will eventually develop disease and to recode the status of participants predicted to be at highest risk. We evaluate conditions under which recoding results in a maximal net improvement in the accuracy of phenotype classification. Net improvement is expected only when the positive likelihood ratio of the predictive model is larger than the inverse of the odds of disease among apparently nondiseased controls. We conducted simulations to probe the impact of reclassification on the power to detect new risk factors under several scenarios of classification accuracy of the previously developed models. We also apply this framework to a validated model of progression to advanced age-related macular degeneration that uses genetic and nongenetic variables (area under the curve = 0.915). In the training cohort (n = 2,937) and a separate validation cohort (n = 1,227), 195-272 and 78-91 nonprogressor participants, respectively, were reclassified as progressors. Correction of phenotype misclassification based on highly informative predictive models may be helpful in identifying additional genetic and other risk factors, when there are validated risk factors that provide strong discriminating ability.

    View details for DOI 10.1097/EDE.0b013e31826c3129

    View details for Web of Science ID 000309965800022

    View details for PubMedID 23023008

  • A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants JOURNAL OF MEDICAL GENETICS Sharma, M., Ioannidis, J. P., Aasly, J. O., Annesi, G., Brice, A., Bertram, L., Bozi, M., Barcikowska, M., Crosiers, D., Clarke, C. E., Facheris, M. F., Farrer, M., Garraux, G., Gispert, S., Auburger, G., Vilarino-Guell, C., Hadjigeorgiou, G. M., Hicks, A. A., Hattori, N., Jeon, B. S., Jamrozik, Z., Krygowska-Wajs, A., Lesage, S., Lill, C. M., Lin, J., Lynch, T., Lichtner, P., Lang, A. E., Libioulle, C., Murata, M., Mok, V., Jasinska-Myga, B., Mellick, G. D., Morrison, K. E., Meitnger, T., Zimprich, A., Opala, G., Pramstaller, P. P., Pichler, I., Park, S. S., Quattrone, A., Rogaeva, E., Ross, O. A., Stefanis, L., Stockton, J. D., Satake, W., Silburn, P. A., Strom, T. M., Theuns, J., Tan, E., Toda, T., Tomiyama, H., Uitti, R. J., Van Broeckhoven, C., Wirdefeldt, K., Wszolek, Z., Xiromerisiou, G., Yomono, H. S., Yueh, K., Zhao, Y., Gasser, T., Maraganore, D., Krueger, R. 2012; 49 (11): 721-726

    Abstract

    Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive.We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort.Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.

    View details for DOI 10.1136/jmedgenet-2012-101155

    View details for Web of Science ID 000310632800008

    View details for PubMedID 23125461

    View details for PubMedCentralID PMC3488700

  • Empirical Evaluation of Very Large Treatment Effects of Medical Interventions JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Pereira, T. V., Horwitz, R. I., Ioannidis, J. P. 2012; 308 (16): 1676-1684

    Abstract

    Most medical interventions have modest effects, but occasionally some clinical trials may find very large effects for benefits or harms.To evaluate the frequency and features of very large effects in medicine.Cochrane Database of Systematic Reviews (CDSR, 2010, issue 7).We separated all binary-outcome CDSR forest plots with comparisons of interventions according to whether the first published trial, a subsequent trial (not the first), or no trial had a nominally statistically significant (P < .05) very large effect (odds ratio [OR], ≥5). We also sampled randomly 250 topics from each group for further in-depth evaluation.We assessed the types of treatments and outcomes in trials with very large effects, examined how often large-effect trials were followed up by other trials on the same topic, and how these effects compared against the effects of the respective meta-analyses.Among 85,002 forest plots (from 3082 reviews), 8239 (9.7%) had a significant very large effect in the first published trial, 5158 (6.1%) only after the first published trial, and 71,605 (84.2%) had no trials with significant very large effects. Nominally significant very large effects typically appeared in small trials with median number of events: 18 in first trials and 15 in subsequent trials. Topics with very large effects were less likely than other topics to address mortality (3.6% in first trials, 3.2% in subsequent trials, and 11.6% in no trials with significant very large effects) and were more likely to address laboratory-defined efficacy (10% in first trials,10.8% in subsequent, and 3.2% in no trials with significant very large effects). First trials with very large effects were as likely as trials with no very large effects to have subsequent published trials. Ninety percent and 98% of the very large effects observed in first and subsequently published trials, respectively, became smaller in meta-analyses that included other trials; the median odds ratio decreased from 11.88 to 4.20 for first trials, and from 10.02 to 2.60 for subsequent trials. For 46 of the 500 selected topics (9.2%; first and subsequent trials) with a very large-effect trial, the meta-analysis maintained very large effects with P < .001 when additional trials were included, but none pertained to mortality-related outcomes. Across the whole CDSR, there was only 1 intervention with large beneficial effects on mortality, P < .001, and no major concerns about the quality of the evidence (for a trial on extracorporeal oxygenation for severe respiratory failure in newborns).Most large treatment effects emerge from small studies, and when additional trials are performed, the effect sizes become typically much smaller. Well-validated large effects are uncommon and pertain to nonfatal outcomes.

    View details for Web of Science ID 000310434100022

    View details for PubMedID 23093165

  • Neglected tropical diseases: survey and geometry of randomised evidence BRITISH MEDICAL JOURNAL Kappagoda, S., Ioannidis, J. P. 2012; 345

    Abstract

    To assess the quantity and distribution of evidence from randomised controlled trials for the treatment of the major neglected tropical diseases and to identify gaps in the evidence with network analysis.Systematic review and network analysis.Cochrane Central Register of Controlled Trials and PubMed from inception to 31 August 2011.Randomised controlled trials that examined treatment of 16 neglected tropical diseases or complications thereof published in English, French, Spanish, Portuguese, German, or Dutch.We identified 971 eligible randomised trials. Leishmaniasis (184 trials, 23,039 participants) and geohelminth infections; 160 trials, 46,887 participants) were the most studied, while dracunculiasis (nine trials, 798 participants) and Buruli ulcer (five trials, 337 participants) were least studied. Relative to its global burden of disease, lymphatic filariasis had the fewest trials and participants. Only 11% of trials were industry funded. Either a single trial or trials with fewer than 100 participants comprised the randomised evidence for first or second line treatments for Buruli ulcer, human African trypanosomiasis, American trypanosomiasis, cysticercosis, rabies, echinococcosis, New World cutaneous leishmaniasis, and each of the foodborne trematode infections. Among the 10 disease categories with more than 40 trials, five lacked sufficient head to head comparisons between first or second line treatments.There is considerable variation in the amount of evidence from randomised controlled trials for each of the 16 major neglected tropical diseases. Even in diseases with substantial evidence, such as leishmaniasis and geohelminth infections, some recommended treatments have limited supporting data and lack head to head comparisons.

    View details for DOI 10.1136/bmj.e6512

    View details for Web of Science ID 000310426900001

    View details for PubMedID 23089149

    View details for PubMedCentralID PMC3478233

  • Sex-specific differences in effect size estimates at established complex trait loci INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Orozco, G., Ioannidis, J. P., Morris, A., Zeggini, E. 2012; 41 (5): 1376-1382

    Abstract

    Genetic differences between men and women may contribute to sex differences in prevalence and progression of many common complex diseases. Using the WTCCC GWAS, we analysed whether there are sex-specific differences in effect size estimates at 142 established loci for seven complex diseases: rheumatoid arthritis, type 1 diabetes (T1D), Crohn's disease, type 2 diabetes (T2D), hypertension, coronary artery disease and bipolar disorder.For each Single nucleotide polymorphism (SNP), we calculated the per-allele odds ratio for each sex and the relative odds ratios (RORs; the effect size is higher in men with ROR greater than one). RORs were then meta-analysed across loci within each disease and across diseases.For each disease, summary RORs were not different from one, but there was between-SNP heterogeneity in the RORs for T1D and T2D. Four loci in T1D, three in Crohn's disease and three in T2D showed differences in the genetic effect between men and women (P<0.05). We probed these differences in additional independent replication samples for T1D and T2D. The differences remained for the T1D loci CTSH, 17q21 and 20p13 and the T2D locus BCL11A, when WTCCC data and replication data were meta-analysed. Only CTSH showed different genetic effect between men and women in the replication data alone.Our results exclude the presence of large and frequent differences in the effect size estimates between men and women for the established loci in the seven common diseases explored. Documenting small differences in genetic effects between men and women requires large studies and systematic evaluation.

    View details for DOI 10.1093/ije/dys104

    View details for Web of Science ID 000309922700023

    View details for PubMedID 22825589

    View details for PubMedCentralID PMC3465768

  • In-Depth Analysis of Diagnostic Operating Characteristics Shows that Narrow Band Imaging (NBI) Is an Excellent Test to Differentiate Neoplastic and Hyperplastic Colorectal Polyps McGill, S., Evangelou, E., Ioannidis, J., Soetikno, R., Kaltenbach, T. NATURE PUBLISHING GROUP. 2012: S206
  • Assessment of gene-by-sex interaction effect on bone mineral density JOURNAL OF BONE AND MINERAL RESEARCH Liu, C., Estrada, K., Yerges-Armstrong, L. M., Amin, N., Evangelou, E., Li, G., Minster, R. L., Carless, M. A., Kammerer, C. M., Oei, L., Zhou, Y., Alonso, N., Dailiana, Z., Eriksson, J., Garcia-Giralt, N., Giroux, S., Husted, L. B., Khusainova, R. I., Koromila, T., Kung, A. W., Lewis, J. R., Masi, L., Mencej-Bedrac, S., Nogues, X., Patel, M. S., Prezelj, J., Richards, J. B., Sham, P. C., Spector, T., Vandenput, L., Xiao, S., Zheng, H., Zhu, K., Balcells, S., Brandi, M. L., Frost, M., Goltzman, D., Gonzalez-Macias, J., Karlsson, M., Khusnutdinova, E. K., Kollia, P., Langdahl, B. L., Ljunggren, O., Lorentzon, M., Marc, J., Mellstroem, D., Ohlsson, C., Olmos, J. M., Ralston, S. H., Riancho, J. A., Rousseau, F., Urreizti, R., Van Hul, W., Zarrabeitia, M. T., Castano-Betancourt, M., Demissie, S., Grundberg, E., Herrera, L., Kwan, T., Medina-Gomez, C., Pastinen, T., Sigurdsson, G., Thorleifsson, G., Vanmeurs, J. B., Blangero, J., Hofman, A., Liu, Y., Mitchell, B. D., O'Connell, J. R., Oostra, B. A., Rotter, J. I., Stefansson, K., Streeten, E. A., Styrkarsdottir, U., Thorsteinsdottir, U., Tylavsky, F. A., Uitterlinden, A., Cauley, J. A., Harris, T. B., Ioannidis, J. P., Psaty, B. M., Robbins, J. A., Zillikens, M. C., Vanduijn, C. M., Prince, R. L., Karasik, D., Rivadeneira, F., Kiel, D. P., Cupples, L. A., Hsu, Y. 2012; 27 (10): 2051-2064

    Abstract

    Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 × 10(-5) ) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 × 10(-5) ; female effect = -0.007 and p = 3.3 × 10(-2) ), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 × 10(-8) ) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP. © 2012 American Society for Bone and Mineral Research.

    View details for DOI 10.1002/jbmr.1679

    View details for Web of Science ID 000308925800003

    View details for PubMedID 22692763

    View details for PubMedCentralID PMC3447125

  • How to use an article reporting a multiple treatment comparison meta-analysis. JAMA : the journal of the American Medical Association Mills, E. J., Ioannidis, J. P., Thorlund, K., Schünemann, H. J., Puhan, M. A., Guyatt, G. H. 2012; 308 (12): 1246-1253

    Abstract

    Multiple treatment comparison (MTC) meta-analysis uses both direct (head-to-head) randomized clinical trial (RCT) evidence as well as indirect evidence from RCTs to compare the relative effectiveness of all included interventions. The methodological quality of MTCs may be difficult for clinicians to interpret because the number of interventions evaluated may be large and the methodological approaches may be complex. Clinicians and others evaluating an MTC should be aware of the potential biases that can affect the interpretation of these analyses. Readers should consider whether the primary studies are sufficiently homogeneous to combine; whether the different interventions are sufficiently similar in their populations, study designs, and outcomes; and whether the direct evidence is sufficiently similar to the indirect evidence to consider combining. This article uses the existing Users' Guides format to address study validity, interpretation of results, and application to a patient scenario.

    View details for PubMedID 23011714

  • How to Use an Article Reporting a Multiple Treatment Comparison Meta-analysis JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Mills, E. J., Ioannidis, J. P., Thorlund, K., Schuenemann, H. J., Puhan, M. A., Guyatt, G. H. 2012; 308 (12): 1246-1253

    Abstract

    Multiple treatment comparison (MTC) meta-analysis uses both direct (head-to-head) randomized clinical trial (RCT) evidence as well as indirect evidence from RCTs to compare the relative effectiveness of all included interventions. The methodological quality of MTCs may be difficult for clinicians to interpret because the number of interventions evaluated may be large and the methodological approaches may be complex. Clinicians and others evaluating an MTC should be aware of the potential biases that can affect the interpretation of these analyses. Readers should consider whether the primary studies are sufficiently homogeneous to combine; whether the different interventions are sufficiently similar in their populations, study designs, and outcomes; and whether the direct evidence is sufficiently similar to the indirect evidence to consider combining. This article uses the existing Users' Guides format to address study validity, interpretation of results, and application to a patient scenario.

    View details for Web of Science ID 000309103600028

  • Influence of Reported Study Design Characteristics on Intervention Effect Estimates From Randomized, Controlled Trials ANNALS OF INTERNAL MEDICINE Savovic, J., Jones, H. E., Altman, D. G., Harris, R. J., Jueni, P., Pildal, J., Als-Nielsen, B., Balk, E. M., Gluud, C., Gluud, L. L., Ioannidis, J. P., Schulz, K. F., Beynon, R., Welton, N. J., Wood, L., Moher, D., Deeks, J. J., Sterne, J. A. 2012; 157 (6): 429-U97

    Abstract

    Published evidence suggests that aspects of trial design lead to biased intervention effect estimates, but findings from different studies are inconsistent. This study combined data from 7 meta-epidemiologic studies and removed overlaps to derive a final data set of 234 unique meta-analyses containing 1973 trials. Outcome measures were classified as "mortality," "other objective," "or subjective," and Bayesian hierarchical models were used to estimate associations of trial characteristics with average bias and between-trial heterogeneity. Intervention effect estimates seemed to be exaggerated in trials with inadequate or unclear (vs. adequate) random-sequence generation (ratio of odds ratios, 0.89 [95% credible interval {CrI}, 0.82 to 0.96]) and with inadequate or unclear (vs. adequate) allocation concealment (ratio of odds ratios, 0.93 [CrI, 0.87 to 0.99]). Lack of or unclear double-blinding (vs. double-blinding) was associated with an average of 13% exaggeration of intervention effects (ratio of odds ratios, 0.87 [CrI, 0.79 to 0.96]), and between-trial heterogeneity was increased for such studies (SD increase in heterogeneity, 0.14 [CrI, 0.02 to 0.30]). For each characteristic, average bias and increases in between-trial heterogeneity were driven primarily by trials with subjective outcomes, with little evidence of bias in trials with objective and mortality outcomes. This study is limited by incomplete trial reporting, and findings may be confounded by other study design characteristics. Bias associated with study design characteristics may lead to exaggeration of intervention effect estimates and increases in between-trial heterogeneity in trials reporting subjectively assessed outcomes.

    View details for Web of Science ID 000308912800017

    View details for PubMedID 22945832

  • Extrapolating from Animals to Humans SCIENCE TRANSLATIONAL MEDICINE Ioannidis, J. P. 2012; 4 (151)

    Abstract

    Because of a variety of caveats, the safety and effectiveness of interventions in human subjects can only be speculated from animal studies. Careful synthesis of data from multiple animal studies is needed to begin to assess the likelihood of successful cross-species translation (Fay et al., this issue).

    View details for DOI 10.1126/scitranslmed.3004631

    View details for Web of Science ID 000308806000002

    View details for PubMedID 22972841

  • Implementation of proteomic biomarkers: making it work EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Mischak, H., Ioannidis, J. P., Argiles, A., Attwood, T. K., Bongcam-Rudloff, E., Broenstrup, M., Charonis, A., Chrousos, G. P., Delles, C., Dominiczak, A., Dylag, T., Ehrich, J., Egido, J., Findeisen, P., Jankowski, J., Johnson, R. W., Julien, B. A., Lankisch, T., Leung, H. Y., Maahs, D., Magni, F., Manns, M. P., Manolis, E., Mayer, G., Navis, G., Novak, J., Ortiz, A., Persson, F., Peter, K., Riese, H. H., Rossing, P., Sattar, N., Spasovski, G., Thongboonkerd, V., Vanholder, R., Schanstra, J. P., Vlahou, A. 2012; 42 (9): 1027-1036

    Abstract

    While large numbers of proteomic biomarkers have been described, they are generally not implemented in medical practice. We have investigated the reasons for this shortcoming, focusing on hurdles downstream of biomarker verification, and describe major obstacles and possible solutions to ease valid biomarker implementation. Some of the problems lie in suboptimal biomarker discovery and validation, especially lack of validated platforms with well-described performance characteristics to support biomarker qualification. These issues have been acknowledged and are being addressed, raising the hope that valid biomarkers may start accumulating in the foreseeable future. However, successful biomarker discovery and qualification alone does not suffice for successful implementation. Additional challenges include, among others, limited access to appropriate specimens and insufficient funding, the need to validate new biomarker utility in interventional trials, and large communication gaps between the parties involved in implementation. To address this problem, we propose an implementation roadmap. The implementation effort needs to involve a wide variety of stakeholders (clinicians, statisticians, health economists, and representatives of patient groups, health insurance, pharmaceutical companies, biobanks, and regulatory agencies). Knowledgeable panels with adequate representation of all these stakeholders may facilitate biomarker evaluation and guide implementation for the specific context of use. This approach may avoid unwarranted delays or failure to implement potentially useful biomarkers, and may expedite meaningful contributions of the biomarker community to healthcare.

    View details for DOI 10.1111/j.1365-2362.2012.02674.x

    View details for Web of Science ID 000307473300014

    View details for PubMedID 22519700

    View details for PubMedCentralID PMC3464367

  • Replication and meta-analysis of TMEM132D gene variants in panic disorder TRANSLATIONAL PSYCHIATRY Erhardt, A., Akula, N., Schumacher, J., Czamara, D., Karbalai, N., Mueller-Myhsok, B., Mors, O., Borglum, A., Kristensen, A. S., Woldbye, D. P., Koefoed, P., Eriksson, E., Maron, E., Metspalu, A., Nurnberger, J., Philibert, R. A., Kennedy, J., Domschke, K., Reif, A., Deckert, J., Otowa, T., Kawamura, Y., Kaiya, H., Okazaki, Y., Tanii, H., Tokunaga, K., Sasaki, T., Ioannidis, J. P., McMahon, F. J., Binder, E. B. 2012; 2

    Abstract

    A recent genome-wide association study in patients with panic disorder (PD) identified a risk haplotype consisting of two single-nucleotide polymorphisms (SNPs) (rs7309727 and rs11060369) located in intron 3 of TMEM132D to be associated with PD in three independent samples. Now we report a subsequent confirmation study using five additional PD case-control samples (n = 1670 cases and n = 2266 controls) assembled as part of the Panic Disorder International Consortium (PanIC) study for a total of 2678 cases and 3262 controls in the analysis. In the new independent samples of European ancestry (EA), the association of rs7309727 and the risk haplotype rs7309727-rs11060369 was, indeed, replicated, with the strongest signal coming from patients with primary PD, that is, patients without major psychiatric comorbidities (n = 1038 cases and n = 2411 controls). This finding was paralleled by the results of the meta-analysis across all samples, in which the risk haplotype and rs7309727 reached P-levels of P = 1.4e-8 and P = 1.1e-8, respectively, when restricting the samples to individuals of EA with primary PD. In the Japanese sample no associations with PD could be found. The present results support the initial finding that TMEM132D gene contributes to genetic susceptibility for PD in individuals of EA. Our results also indicate that patient ascertainment and genetic background could be important sources of heterogeneity modifying this association signal in different populations.

    View details for DOI 10.1038/tp.2012.85

    View details for Web of Science ID 000312900000001

    View details for PubMedID 22948381

    View details for PubMedCentralID PMC3565207

  • STrengthening the Reporting of OBservational studies in Epidemiology: Molecular Epidemiology STROBE-ME. An extension of the STROBE statement JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH Gallo, V., Egger, M., McCormack, V., Farmer, P. B., Ioannidis, J. P., Kirsch-Volders, M., Matullo, G., Phillips, D. H., Schoket, B., Stromberg, U., Vermeulen, R., Wild, C., Porta, M., Vineis, P. 2012; 66 (9): 844-854

    Abstract

    Advances in laboratory techniques have led to a rapidly increasing use of biomarkers in epidemiological studies. Biomarkers of internal dose, early biological change, susceptibility, and clinical outcomes are used as proxies for investigating the interactions between external and/or endogenous agents and the body components or processes. The need for improved reporting of scientific research led to influential statements of recommendations such as STrengthening Reporting of Observational studies in Epidemiology (STROBE) statement. The STROBE initiative established in 2004 aimed to provide guidance on how to report observational research. Its guidelines provide a user-friendly checklist of 22 items to be reported in epidemiological studies, with items specific to the three main study designs: cohort studies, case-control studies and cross-sectional studies. The present STrengthening the Reporting of OBservational studies in Epidemiology - Molecular Epidemiology (STROBE-ME) initiative builds on the STROBE Statement implementing 9 existing items of STROBE and providing 17 additional items to the 22 items of STROBE checklist. The additions relate to the use of biomarkers in epidemiological studies, concerning collection, handling and storage of biological samples; laboratory methods, validity and reliability of biomarkers; specificities of study design; and ethical considerations. The STROBE-ME recommendations are intended to complement the STROBE recommendations.

    View details for DOI 10.1136/jech-2011-200318

    View details for Web of Science ID 000307101800014

    View details for PubMedID 22025194

  • Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study LANCET Zeggini, E., Panoutsopoulou, K., Southam, L., Rayner, N. W., Day-Williams, A. G., Lopes, M. C., Boraska, V., Esko, T., Evangelou, E., Hofman, A., Houwing-Duistermaat, J. J., Ingvarsson, T., Jonsdottir, I., Jonsson, H., Kerkhof, H. J., Kloppenburg, M., Bos, S. D., Mangino, M., Metrustry, S., Slagboom, P. E., Thorleifsson, G., Raine, E. V., Ratnayake, M., Ricketts, M., Beazley, C., Blackburn, H., Bumpstead, S., Elliott, K. S., Hunt, S. E., Potter, S. C., Shin, S., Yadav, V. K., Zhai, G., Sherburn, K., Dixon, K., Arden, E., Aslam, N., Battley, P., Carluke, I., Doherty, S., Gordon, A., Joseph, J., Keen, R., Koller, N. C., Mitchell, S., O'Neill, F., Paling, E., Reed, M. R., Rivadeneira, F., Swift, D., Walker, K., Watkins, B., Wheeler, M., Birrell, F., Ioannidis, J. P., Meulenbelt, I., Metspalu, A., Rai, A., Salter, D., Stefansson, K., Styrkarsdottir, U., Uitterlinden, A. G., van Meurs, J. B., Chapman, K., Deloukas, P., Ollier, W. E., Wallis, G. A., Arden, N., Carr, A., Doherty, M., McCaskie, A., Wilkinson, J. M., Ralston, S. H., Valdes, A. M., Spector, T. D., Loughlin, J. 2012; 380 (9844): 815-823

    Abstract

    Osteoarthritis is the most common form of arthritis worldwide and is a major cause of pain and disability in elderly people. The health economic burden of osteoarthritis is increasing commensurate with obesity prevalence and longevity. Osteoarthritis has a strong genetic component but the success of previous genetic studies has been restricted due to insufficient sample sizes and phenotype heterogeneity.We undertook a large genome-wide association study (GWAS) in 7410 unrelated and retrospectively and prospectively selected patients with severe osteoarthritis in the arcOGEN study, 80% of whom had undergone total joint replacement, and 11,009 unrelated controls from the UK. We replicated the most promising signals in an independent set of up to 7473 cases and 42,938 controls, from studies in Iceland, Estonia, the Netherlands, and the UK. All patients and controls were of European descent.We identified five genome-wide significant loci (binomial test p≤5·0×10(-8)) for association with osteoarthritis and three loci just below this threshold. The strongest association was on chromosome 3 with rs6976 (odds ratio 1·12 [95% CI 1·08-1·16]; p=7·24×10(-11)), which is in perfect linkage disequilibrium with rs11177. This SNP encodes a missense polymorphism within the nucleostemin-encoding gene GNL3. Levels of nucleostemin were raised in chondrocytes from patients with osteoarthritis in functional studies. Other significant loci were on chromosome 9 close to ASTN2, chromosome 6 between FILIP1 and SENP6, chromosome 12 close to KLHDC5 and PTHLH, and in another region of chromosome 12 close to CHST11. One of the signals close to genome-wide significance was within the FTO gene, which is involved in regulation of bodyweight-a strong risk factor for osteoarthritis. All risk variants were common in frequency and exerted small effects.Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention.arcOGEN was funded by a special purpose grant from Arthritis Research UK.

    View details for DOI 10.1016/S0140-6736(12)60681-3

    View details for Web of Science ID 000308396300030

    View details for PubMedCentralID PMC3443899

  • Influence of reported study design characteristics on intervention effect estimates from randomised controlled trials: combined analysis of meta-epidemiological studies HEALTH TECHNOLOGY ASSESSMENT Savovic, J., Jones, H. E., Altman, D. G., Harris, R. J., Juni, P., Pildal, J., Als-Nielsen, B., Balk, E. M., Gluud, C., Gluud, L. L., Ioannidis, J. P., Schulz, K. F., Beynon, R., Welton, N., Wood, L., Moher, D., Deeks, J. J., Sterne, J. A. 2012; 16 (35): 1-?

    Abstract

    The design of randomised controlled trials (RCTs) should incorporate characteristics (such as concealment of randomised allocation and blinding of participants and personnel) that avoid biases resulting from lack of comparability of the intervention and control groups. Empirical evidence suggests that the absence of such characteristics leads to biased intervention effect estimates, but the findings of different studies are not consistent.To examine the influence of unclear or inadequate random sequence generation and allocation concealment, and unclear or absent double blinding, on intervention effect estimates and between-trial heterogeneity, and whether or not these influences vary with type of clinical area, intervention, comparison and outcome measure.Data were combined from seven contributing meta-epidemiological studies (collections of meta-analyses in which trial characteristics are assessed and results recorded). The resulting database was used to identify and remove overlapping meta-analyses. Outcomes were coded such that odds ratios < 1 correspond to beneficial intervention effects. Outcome measures were classified as mortality, other objective or subjective. We examined agreement between assessments of trial characteristics in trials assessed in more than one contributing study. We used hierarchical Bayesian bias models to estimate the effect of trial characteristics on average bias [quantified as ratios of odds ratios (RORs) with 95% credible intervals (CrIs) comparing trials with and without a characteristic] and in increasing between-trial heterogeneity.The analysis data set contained 1973 trials included in 234 meta-analyses. Median kappa statistics for agreement between assessments of trial characteristics were: sequence generation 0.60, allocation concealment 0.58 and blinding 0.87. Intervention effect estimates were exaggerated by an average 11% in trials with inadequate or unclear (compared with adequate) sequence generation (ROR 0.89, 95% CrI 0.82 to 0.96); between-trial heterogeneity was higher among such trials. Bias associated with inadequate or unclear sequence generation was greatest for subjective outcomes (ROR 0.83, 95% CrI 0.74 to 0.94) and the increase in heterogeneity was greatest for such outcomes [standard deviation (SD) 0.20, 95% CrI 0.03 to 0.32]. The effect of inadequate or unclear (compared with adequate) allocation concealment was greatest among meta-analyses with a subjectively assessed outcome intervention effect (ROR 0.85, 95% CrI 0.75 to 0.95), and the increase in between-trial heterogeneity was also greatest for such outcomes (SD 0.20, 95% CrI 0.02 to 0.33). Lack of, or unclear, double blinding (compared with double blinding) was associated with an average 13% exaggeration of intervention effects (ROR 0.87, 95% CrI 0.79 to 0.96), and between-trial heterogeneity was increased for such studies (SD 0.14, 95% CrI 0.02 to 0.30). Average bias (ROR 0.78, 95% CrI 0.65 to 0.92) and between-trial heterogeneity (SD 0.37, 95% CrI 0.19 to 0.53) were greatest for meta-analyses assessing subjective outcomes. Among meta-analyses with subjectively assessed outcomes, the effect of lack of blinding appeared greater than the effect of inadequate or unclear sequence generation or allocation concealment.Bias associated with specific reported study design characteristics leads to exaggeration of beneficial intervention effect estimates and increases in between-trial heterogeneity. For each of the three characteristics assessed, these effects were greatest for subjectively assessed outcomes. Assessments of the risk of bias in RCTs should account for these findings. Further research is needed to understand the effects of attrition bias, as well as the relative importance of blinding of patients, care-givers and outcome assessors, and thus separate the effects of performance and detection bias.National Institute for Health Research Health Technology Assessment programme.

    View details for DOI 10.3310/hta16350

    View details for Web of Science ID 000311662000001

    View details for PubMedID 22989478

  • Heritability and Genome-Wide Association Study to Assess Genetic Differences between Advanced Age-related Macular Degeneration Subtypes OPHTHALMOLOGY Sobrin, L., Ripke, S., Yu, Y., Fagerness, J., Bhangale, T. R., Tan, P. L., Souied, E. H., Buitendijk, G. H., Merriam, J. E., Richardson, A. J., Raychaudhuri, S., Reynolds, R., Chin, K. A., Lee, A. Y., Leveziel, N., Zack, D. J., Campochiaro, P., Smith, R. T., Barile, G. R., Hogg, R. E., Chakravarthy, U., Behrens, T. W., Uitterlinden, A. G., van Duijn, C. M., Vingerling, J. R., Brantley, M. A., Baird, P. N., Klaver, C. C., Allikmets, R., Katsanis, N., Graham, R. R., Ioannidis, J. P., Daly, M. J., Seddon, J. M. 2012; 119 (9): 1874-1885

    Abstract

    To investigate whether the 2 subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV), and geographic atrophy (GA) segregate separately in families and to identify which genetic variants are associated with these 2 subtypes.Sibling correlation study and genome-wide association study (GWAS).For the sibling correlation study, 209 sibling pairs with advanced AMD were included. For the GWAS, 2594 participants with advanced AMD subtypes and 4134 controls were included. Replication cohorts included 5383 advanced AMD participants and 15 240 controls.Participants had the AMD grade assigned based on fundus photography, examination, or both. To determine heritability of advanced AMD subtypes, a sibling correlation study was performed. For the GWAS, genome-wide genotyping was conducted and 6 036 699 single nucleotide polymorphisms (SNPs) were imputed. Then, the SNPs were analyzed with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts.Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes.The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P = 4.2 × 10(-5)), meaning that in siblings of probands with CNV or GA, the same advanced subtype is more likely to develop. In the analysis comparing participants with CNV to those with GA, a statistically significant association was observed at the ARMS2/HTRA1 locus (rs10490924; odds ratio [OR], 1.47; P = 4.3 × 10(-9)), which was confirmed in the replication samples (OR, 1.38; P = 7.4 × 10(-14) for combined discovery and replication analysis).Whether CNV versus GA develops in a patient with AMD is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes, but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations that differ for advanced AMD subtypes and deserve follow-up in additional studies.

    View details for DOI 10.1016/j.ophtha.2012.03.014

    View details for Web of Science ID 000310581200023

    View details for PubMedID 22705344

  • The Importance of Potential Studies That Have Not Existed and Registration of Observational Data Sets JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P. 2012; 308 (6): 575-576

    View details for Web of Science ID 000307228400022

    View details for PubMedID 22871867

  • TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome NATURE GENETICS Boileau, C., Guo, D., Hanna, N., Regalado, E. S., Detaint, D., Gong, L., Varret, M., Prakash, S. K., Li, A. H., d'Indy, H., Braverman, A. C., Grandchamp, B., Kwartler, C. S., Gouya, L., Santos-Cortez, R. L., Abifadel, M., Leal, S. M., Muti, C., Shendure, J., Gross, M., Rieder, M. J., Vahanian, A., Nickerson, D. A., Michel, J. B., Jondeau, G., Milewicz, D. M. 2012; 44 (8): 916-?

    Abstract

    A predisposition for thoracic aortic aneurysms leading to acute aortic dissections can be inherited in families in an autosomal dominant manner. Genome-wide linkage analysis of two large unrelated families with thoracic aortic disease followed by whole-exome sequencing of affected relatives identified causative mutations in TGFB2. These mutations-a frameshift mutation in exon 6 and a nonsense mutation in exon 4-segregated with disease with a combined logarithm of odds (LOD) score of 7.7. Sanger sequencing of 276 probands from families with inherited thoracic aortic disease identified 2 additional TGFB2 mutations. TGFB2 encodes transforming growth factor (TGF)-β2, and the mutations are predicted to cause haploinsufficiency for TGFB2; however, aortic tissue from cases paradoxically shows increased TGF-β2 expression and immunostaining. Thus, haploinsufficiency for TGFB2 predisposes to thoracic aortic disease, suggesting that the initial pathway driving disease is decreased cellular TGF-β2 levels leading to a secondary increase in TGF-β2 production in the diseased aorta.

    View details for DOI 10.1038/ng.2348

    View details for Web of Science ID 000306854700018

    View details for PubMedID 22772371

  • Large-scale replication and heterogeneity in Parkinson disease genetic loci NEUROLOGY Sharma, M., Ioannidis, J. P., Aasly, J. O., Annesi, G., Brice, A., Van Broeckhoven, C., Bertram, L., Bozi, M., Crosiers, D., Clarke, C., Facheris, M., Farrer, M., Garraux, G., Gispert, S., Auburger, G., Vilarino-Gueell, C., Hadjigeorgiou, G. M., Hicks, A. A., Hattori, N., Jeon, B., Lesage, S., Lill, C. M., Lin, J., Lynch, T., Lichtner, P., Lang, A. E., Mok, V., Jasinska-Myga, B., Mellick, G. D., Morrison, K. E., Opala, G., Pramstaller, P. P., Pichler, I., Park, S. S., Quattrone, A., Rogaeva, E., Ross, O. A., Stefanis, L., Stockton, J. D., Satake, W., Silburn, P. A., Theuns, J., Tan, E., Toda, T., Tomiyama, H., Uitti, R. J., Wirdefeldt, K., Wszolek, Z., Xiromerisiou, G., Yueh, K., Zhao, Y., Gasser, T., Maraganore, D., Krueger, R. 2012; 79 (7): 659-667

    Abstract

    Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown.Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry.In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I(2) estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD.Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.

    View details for Web of Science ID 000307475200013

    View details for PubMedID 22786590

    View details for PubMedCentralID PMC3414661

  • Exome sequencing of extreme phenotypes identifies DCTN4 as a modifier of chronic Pseudomonas aeruginosa infection in cystic fibrosis. Nature genetics Emond, M. J., Louie, T., Emerson, J., Zhao, W., Mathias, R. A., Knowles, M. R., Wright, F. A., Rieder, M. J., Tabor, H. K., Nickerson, D. A., Barnes, K. C., Gibson, R. L., Bamshad, M. J. 2012; 44 (8): 886-889

    Abstract

    Exome sequencing has become a powerful and effective strategy for the discovery of genes underlying Mendelian disorders. However, use of exome sequencing to identify variants associated with complex traits has been more challenging, partly because the sample sizes needed for adequate power may be very large. One strategy to increase efficiency is to sequence individuals who are at both ends of a phenotype distribution (those with extreme phenotypes). Because the frequency of alleles that contribute to the trait are enriched in one or both phenotype extremes, a modest sample size can potentially be used to identify novel candidate genes and/or alleles. As part of the National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP), we used an extreme phenotype study design to discover that variants in DCTN4, encoding a dynactin protein, are associated with time to first P. aeruginosa airway infection, chronic P. aeruginosa infection and mucoid P. aeruginosa in individuals with cystic fibrosis.

    View details for DOI 10.1038/ng.2344

    View details for PubMedID 22772370

  • Pediatric Versus Adult Drug Trials for Conditions With High Pediatric Disease Burden PEDIATRICS Bourgeois, F. T., Murthy, S., Pinto, C., Olson, K. L., Ioannidis, J. P., Mandl, K. D. 2012; 130 (2): 285-292

    Abstract

    Optimal treatment decisions in children require sufficient evidence on the safety and efficacy of pharmaceuticals in pediatric patients. However, there is concern that not enough trials are conducted in children and that pediatric trials differ from those performed in adults. Our objective was to measure the prevalence of pediatric studies among clinical drug trials and compare trial characteristics and quality indicators between pediatric and adult drug trials.For conditions representing a high burden of pediatric disease, we identified all drug trials registered in ClinicalTrials.gov with start dates between 2006 and 2011 and tracked the resulting publications. We measured the proportion of pediatric trials and subjects for each condition and compared pediatric and adult trial characteristics and quality indicators.For the conditions selected, 59.9% of the disease burden was attributable to children, but only 12.0% (292/2440) of trials were pediatric (P < .001). Among pediatric trials, 58.6% were conducted without industry funding compared with 35.0% of adult trials (P < .001). Fewer pediatric compared with adult randomized trials examined safety outcomes (10.1% vs 16.9%, P = .008). Pediatric randomized trials were slightly more likely to be appropriately registered before study start (46.9% vs 39.3%, P = .04) and had a modestly higher probability of publication in the examined time frame (32.8% vs 23.2%, P = .04).There is substantial discrepancy between pediatric burden of disease and the amount of clinical trial research devoted to pediatric populations. This may be related in part to trial funding, with pediatric trials relying primarily on government and nonprofit organizations.

    View details for DOI 10.1542/peds.2012-0139

    View details for Web of Science ID 000307123000049

    View details for PubMedID 22826574

    View details for PubMedCentralID PMC3408692

  • Estimating the contribution of genetic variants to difference in incidence of disease between population groups EUROPEAN JOURNAL OF HUMAN GENETICS Moonesinghe, R., Ioannidis, J. P., Flanders, W. D., Yang, Q., Truman, B. I., Khoury, M. J. 2012; 20 (8): 831-836

    Abstract

    Genome-wide association studies have identified multiple genetic susceptibility variants to several complex human diseases. However, risk-genotype frequency at loci showing robust associations might differ substantially among different populations. In this paper, we present methods to assess the contribution of genetic variants to the difference in the incidence of disease between different population groups for different scenarios. We derive expressions for the contribution of a single genetic variant, multiple genetic variants, and the contribution of the joint effect of a genetic variant and an environmental factor to the difference in the incidence of disease. The contribution of genetic variants to the difference in incidence increases with increasing difference in risk-genotype frequency, but declines with increasing difference in incidence between the two populations. The contribution of genetic variants also increases with increasing relative risk and the contribution of joint effect of genetic and environmental factors increases with increasing relative risk of the gene-environmental interaction. The contribution of genetic variants to the difference in incidence between two populations can be expressed as a function of the population attributable risks of the genetic variants in the two populations. The contribution of a group of genetic variants to the disparity in incidence of disease could change considerably by adding one more genetic variant to the group. Any estimate of genetic contribution to the disparity in incidence of disease between two populations at this stage seems to be an elusive goal.

    View details for DOI 10.1038/ejhg.2012.15

    View details for Web of Science ID 000306556600007

    View details for PubMedID 22333905

    View details for PubMedCentralID PMC3400729

  • Concordance of Sleep and Pain Outcomes of Diverse Interventions: An Umbrella Review PLOS ONE Doufas, A. G., Panagiotou, O. A., Ioannidis, J. P. 2012; 7 (7)

    Abstract

    Pain influences sleep and vice versa. We performed an umbrella review of meta-analyses on treatments for diverse conditions in order to examine whether diverse medical treatments for different conditions have similar or divergent effects on pain and sleep.We searched published systematic reviews with meta-analyses in the Cochrane Database of Systematic Reviews until October 20, 2011. We identified randomized trials (or meta-analyses thereof, when >1 trial was available) where both pain and sleep outcomes were examined. Pain outcomes were categorized as headache, musculoskeletal, abdominal, pelvic, generic or other pain. Sleep outcomes included insomnia, sleep disruption, and sleep disturbance. We estimated odds ratios for all outcomes and evaluated the concordance in the direction of effects between sleep and various types of pain and the correlation of treatment effects between sleep and pain outcomes.151 comparisons with 385 different trials met our eligibility criteria. 96 comparisons had concordant direction of effects between each pain outcome and sleep, while in 55 the effect estimates were in opposite directions (P<0.0001). In the 20 comparisons with largest amount of evidence, the experimental drug always had worse sleep outcomes and tended to have worse pain outcomes in 17/20 cases. For headache and musculoskeletal pain, 69 comparisons showed concordant direction of effects with sleep outcomes and 36 showed discordant direction (P<0.0001). For the other 4 pain types there were overall 27 vs. 19 pairs with concordant vs. discordant direction of effects (P = 0.095). There was a weak correlation of the treatment effect sizes for sleep vs. headache/musculoskeletal pain (r = 0.17, P = 0.092).Medical interventions tend to have effects in the same direction for pain and sleep outcomes, but exceptions occur. Concordance is primarily seen for sleep and headache or musculoskeletal pain where many drugs may both disturb sleep and cause pain.

    View details for DOI 10.1371/journal.pone.0040891

    View details for Web of Science ID 000306507000039

    View details for PubMedID 22815856

    View details for PubMedCentralID PMC3398909

  • Usefulness of Medical Conferences Reply JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. A. 2012; 308 (1): 32–33
  • Time to compare impact and feasibility of prediction models in real life reply BRITISH MEDICAL JOURNAL Siontis, G. C., Tzoulaki, I., Siontis, K. C., Ioannidis, J. P. 2012; 344

    View details for DOI 10.1136/bmj.e4360

    View details for Web of Science ID 000306274800015

  • Consistency of genome-wide associations across major ancestral groups HUMAN GENETICS Ntzani, E. E., Liberopoulos, G., Manolio, T. A., Ioannidis, J. P. 2012; 131 (7): 1057-1071

    Abstract

    It is not well known whether genetic markers identified through genome-wide association studies (GWAS) confer similar or different risks across people of different ancestry. We screened a regularly updated catalog of all published GWAS curated at the NHGRI website for GWAS-identified associations that had reached genome-wide significance (p ≤ 5 × 10(-8)) in at least one major ancestry group (European, Asian, African) and for which replication data were available for comparison in at least two different major ancestry groups. These groups were compared for the correlation between and differences in risk allele frequencies and genetic effects' estimates. Data on 108 eligible GWAS-identified associations with a total of 900 datasets (European, n = 624; Asian, n = 217; African, n = 60) were analyzed. Risk-allele frequencies were modestly correlated between ancestry groups, with >10% absolute differences in 75-89% of the three pairwise comparisons of ancestry groups. Genetic effect (odds ratio) point estimates between ancestry groups correlated modestly (pairwise comparisons' correlation coefficients: 0.20-0.33) and point estimates of risks were opposite in direction or differed more than twofold in 57%, 79%, and 89% of the European versus Asian, European versus African, and Asian versus African comparisons, respectively. The modest correlations, differing risk estimates, and considerable between-association heterogeneity suggest that differential ancestral effects can be anticipated and genomic risk markers may need separate further evaluation in different ancestry groups.

    View details for DOI 10.1007/s00439-011-1124-4

    View details for Web of Science ID 000305195400004

    View details for PubMedID 22183176

  • Effectiveness and harms of seasonal and pandemic influenza vaccines in children, adults and elderly A critical review and re-analysis of 15 meta-analyses HUMAN VACCINES & IMMUNOTHERAPEUTICS Manzoli, L., Ioannidis, J. P., Flacco, M. E., De Vito, C., Villari, P. 2012; 8 (7): 851-862

    Abstract

    Fifteen meta-analyses have been published between 1995 and 2011 to evaluate the efficacy/effectiveness and harms of diverse influenza vaccines--seasonal, H5N1 and 2009 (H1N1)--in various age-classes (healthy children, adults or elderly). These meta-analyses have often adopted different analyses and study selection criteria. Because it is difficult to have a clear picture of vaccine benefits and harms examining single systematic reviews, we compiled the main findings and evaluated which could be the most reasonable explanations for some differences in findings (or their interpretation) across previously published meta-analyses. For each age group, we performed analyses that included all trials that had been included in at least one relevant meta-analysis, also exploring whether effect sizes changed over time. Although we identified several discrepancies among the meta-analyses on seasonal vaccines for children and elderly, overall most seasonal influenza vaccines showed statistically significant efficacy/effectiveness, which was acceptable or high for laboratory-confirmed cases and of modest magnitude for clinically-confirmed cases. The available evidence on parenteral inactivated vaccines for children aged < 2 y remains scarce. Pre-pandemic "avian" H5N1 and pandemic 2009 (H1N1) vaccines can achieve satisfactory immunogenicity, but no meta-analysis has addressed H1N1 vaccination impact on clinical outcomes. Data on harms are overall reassuring, but their value is diminished by inconsistent reporting.

    View details for DOI 10.4161/hv.19917

    View details for Web of Science ID 000307107600010

    View details for PubMedID 22777099

    View details for PubMedCentralID PMC3495721

  • Primary study authors of significant studies are more likely to believe that a strong association exists in a heterogeneous meta-analysis compared with methodologists JOURNAL OF CLINICAL EPIDEMIOLOGY Panagiotou, O. A., Ioannidis, J. P. 2012; 65 (7): 740-747

    Abstract

    To assess the interpretation of a highly heterogeneous meta-analysis by authors of primary studies and by methodologists.We surveyed the authors of studies on the association between insulin-like growth factor 1 (IGF-1) and prostate cancer, and 20 meta-analysis methodologists. Authors and methodologists presented with the respective meta-analysis results were queried about the effect size and potential causality of the association. We evaluated whether author responses correlated with the number of IGF-related articles they had published and their study results included in the meta-analysis. We also compared authors' and methodologists' responses.Authors who had published more IGF-related papers offered more generous effect size estimates for the association (ρ(s)=0.61, P=0.01) and higher likelihood that the odds ratio (OR) was greater than 1.20 (ρ(s)=0.63, P=0.01). Authors who had published themselves studies with statistically significant effects for a positive association were more likely to believe that the true OR is greater than 1.20 compared with methodologists (median likelihood 50% versus 2.5%, P=0.01).Researchers are influenced by their own investment in the field, when interpreting a meta-analysis that includes their own study. Authors who published significant results are more likely to believe that a strong association exists compared with methodologists.

    View details for DOI 10.1016/j.jclinepi.2012.01.008

    View details for Web of Science ID 000305357300006

    View details for PubMedID 22537426

  • Systematic evaluation of environmental factors: persistent pollutants and nutrients correlated with serum lipid levels INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Patel, C. J., Cullen, M. R., Ioannidis, J. P., Butte, A. J. 2012; 41 (3): 828-843

    Abstract

    Both genetic and environmental factors contribute to triglyceride, low-density lipoprotein-cholesterol (LDL-C), and high-density lipoprotein-cholesterol (HDL-C) levels. Although genome-wide association studies are currently testing the genetic factors systematically, testing and reporting one or a few factors at a time can lead to fragmented literature for environmental chemical factors. We screened for correlation between environmental factors and lipid levels, utilizing four independent surveys with information on 188 environmental factors from the Centers of Disease Control, National Health and Nutrition Examination Survey, collected between 1999 and 2006.We used linear regression to correlate each environmental chemical factor to triglycerides, LDL-C and HDL-C adjusting for age, age(2), sex, ethnicity, socio-economic status and body mass index. Final estimates were adjusted for waist circumference, diabetes status, blood pressure and survey. Multiple comparisons were controlled for by estimating the false discovery rate and significant findings were tentatively validated in an independent survey.We identified and validated 29, 9 and 17 environmental factors correlated with triglycerides, LDL-C and HDL-C levels, respectively. Findings include hydrocarbons and nicotine associated with lower HDL-C and vitamin E (γ-tocopherol) associated with unfavourable lipid levels. Higher triglycerides and lower HDL-C were correlated with higher levels of fat-soluble contaminants (e.g. polychlorinated biphenyls and dibenzofurans). Nutrients and vitamin markers (e.g. vitamins B, D and carotenes), were associated with favourable triglyceride and HDL-C levels.Our systematic association study has enabled us to postulate about broad environmental correlation to lipid levels. Although subject to confounding and reverse causality bias, these findings merit evaluation in additional cohorts.

    View details for DOI 10.1093/ije/dys003

    View details for Web of Science ID 000306417300030

    View details for PubMedID 22421054

    View details for PubMedCentralID PMC3396318

  • Systematic Identification of Interaction Effects Between Validated Genome- and Environment-Wide Associations on Type 2 Diabetes Mellitus Patel, C. J., Chen, R., Kodama, K., Ioannidis, J. P., Butte, A. J. AMER DIABETES ASSOC. 2012: A394
  • Randomized Trial of Personal Genomics for Preventive Cardiology Design and Challenges CIRCULATION-CARDIOVASCULAR GENETICS Knowles, J. W., Assimes, T. L., Kiernan, M., Pavlovic, A., Goldstein, B. A., Yank, V., McConnell, M. V., Absher, D., Bustamante, C., Ashley, E. A., Ioannidis, J. P. 2012; 5 (3): 368-376
  • Standard 6: Age Groups for Pediatric Trials PEDIATRICS Williams, K., Thomson, D., Seto, I., Contopoulos-Ioannidis, D. G., Ioannidis, J. P., Curtis, S., Constantin, E., Batmanabane, G., Hartling, L., Klassen, T. 2012; 129: S153-S160

    View details for DOI 10.1542/peds.2012-0055I

    View details for Web of Science ID 000307396800008

    View details for PubMedID 22661762

  • Recommendations and proposed guidelines for assessing the cumulative evidence on joint effects of genes and environments on cancer occurrence in humans INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Boffetta, P., Winn, D. M., Ioannidis, J. P., Thomas, D. C., Little, J., Smith, G. D., Cogliano, V. J., Hecht, S. S., Seminara, D., Vineis, P., Khoury, M. J. 2012; 41 (3): 686-704

    Abstract

    We propose guidelines to evaluate the cumulative evidence of gene-environment (G × E) interactions in the causation of human cancer. Our approach has its roots in the HuGENet and IARC Monographs evaluation processes for genetic and environmental risk factors, respectively, and can be applied to common chronic diseases other than cancer. We first review issues of definitions of G × E interactions, discovery and modelling methods for G × E interactions, and issues in systematic reviews of evidence for G × E interactions, since these form the foundation for appraising the credibility of evidence in this contentious field. We then propose guidelines that include four steps: (i) score the strength of the evidence for main effects of the (a) environmental exposure and (b) genetic variant; (ii) establish a prior score category and decide on the pattern of interaction to be expected; (iii) score the strength of the evidence for interaction between the environmental exposure and the genetic variant; and (iv) examine the overall plausibility of interaction by combining the prior score and the strength of the evidence and interpret results. We finally apply the scheme to the interaction between NAT2 polymorphism and tobacco smoking in determining bladder cancer risk.

    View details for DOI 10.1093/ije/dys010

    View details for Web of Science ID 000306417300018

    View details for PubMedID 22596931

    View details for PubMedCentralID PMC3481885

  • Empirical Evaluation of Age Groups and Age-Subgroup Analyses in Pediatric Randomized Trials and Pediatric Meta-analyses PEDIATRICS Contopoulos-Ioannidis, D. G., Seto, I., Hamm, M. P., Thomson, D., Hartling, L., Ioannidis, J. P., Curtis, S., Constantin, E., Batmanabane, G., Klassen, T., Williams, K. 2012; 129: S161-S184

    Abstract

    An important step toward improvement of the conduct of pediatric clinical research is the standardization of the ages of children to be included in pediatric trials and the optimal age-subgroups to be analyzed.We set out to evaluate empirically the age ranges of children, and age-subgroup analyses thereof, reported in recent pediatric randomized clinical trials (RCTs) and meta-analyses. First, we screened 24 RCTs published in Pediatrics during the first 6 months of 2011; second, we screened 188 pediatric RCTs published in 2007 in the Cochrane Central Register of Controlled Trials; third, we screened 48 pediatric meta-analyses published in the Cochrane Database of Systematic Reviews in 2011. We extracted information on age ranges and age-subgroups considered and age-subgroup differences reported.The age range of children in RCTs published in Pediatrics varied from 0.1 to 17.5 years (median age: 5; interquartile range: 1.8-10.2) and only 25% of those presented age-subgroup analyses. Large variability was also detected for age ranges in 188 RCTs from the Cochrane Central Register of Controlled Trials, and only 28 of those analyzed age-subgroups. Moreover, only 11 of 48 meta-analyses had age-subgroup analyses, and in 6 of those, only different studies were included. Furthermore, most of these observed differences were not beyond chance.We observed large variability in the age ranges and age-subgroups of children included in recent pediatric trials and meta-analyses. Despite the limited available data, some age-subgroup differences were noted. The rationale for the selection of particular age-subgroups deserves further study.

    View details for DOI 10.1542/peds.2012-0055J

    View details for Web of Science ID 000307396800009

    View details for PubMedID 22661763

  • Comparisons of established risk prediction models for cardiovascular disease: systematic review BRITISH MEDICAL JOURNAL Siontis, G. C., Tzoulaki, I., Siontis, K. C., Ioannidis, J. P. 2012; 344

    Abstract

    To evaluate the evidence on comparisons of established cardiovascular risk prediction models and to collect comparative information on their relative prognostic performance.Systematic review of comparative predictive model studies.Medline and screening of citations and references.Studies examining the relative prognostic performance of at least two major risk models for cardiovascular disease in general populations.Information on study design, assessed risk models, and outcomes. We examined the relative performance of the models (discrimination, calibration, and reclassification) and the potential for outcome selection and optimism biases favouring newly introduced models and models developed by the authors.20 articles including 56 pairwise comparisons of eight models (two variants of the Framingham risk score, the assessing cardiovascular risk to Scottish Intercollegiate Guidelines Network to assign preventative treatment (ASSIGN) score, systematic coronary risk evaluation (SCORE) score, Prospective Cardiovascular Münster (PROCAM) score, QRESEARCH cardiovascular risk (QRISK1 and QRISK2) algorithms, Reynolds risk score) were eligible. Only 10 of 56 comparisons exceeded a 5% relative difference based on the area under the receiver operating characteristic curve. Use of other discrimination, calibration, and reclassification statistics was less consistent. In 32 comparisons, an outcome was used that had been used in the original development of only one of the compared models, and in 25 of these comparisons (78%) the outcome-congruent model had a better area under the receiver operating characteristic curve. Moreover, authors always reported better area under the receiver operating characteristic curves for models that they themselves developed (in five articles on newly introduced models and in three articles on subsequent evaluations).Several risk prediction models for cardiovascular disease are available and their head to head comparisons would benefit from standardised reporting and formal, consistent statistical comparisons. Outcome selection and optimism biases apparently affect this literature.

    View details for DOI 10.1136/bmj.e3318

    View details for Web of Science ID 000304591600005

    View details for PubMedID 22628003

  • Invited commentary-Genetic prediction for common diseases. Archives of internal medicine Ioannidis, J. P. 2012; 172 (9): 744-746

    View details for DOI 10.1001/archinternmed.2012.931

    View details for PubMedID 22782208

  • Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture NATURE GENETICS Estrada, K., Styrkarsdottir, U., Evangelou, E., Hsu, Y., Duncan, E. L., Ntzani, E. E., Oei, L., Albagha, O. M., Amin, N., Kemp, J. P., Koller, D. L., Li, G., Liu, C., Minster, R. L., Moayyeri, A., Vandenput, L., Willner, D., Xiao, S., Yerges-Armstrong, L. M., Zheng, H., Alonso, N., Eriksson, J., Kammerer, C. M., Kaptoge, S. K., Leo, P. J., Thorleifsson, G., Wilson, S. G., Wilson, J. F., Aalto, V., Alen, M., Aragaki, A. K., Aspelund, T., Center, J. R., Dailiana, Z., Duggan, D. J., Garcia, M., Garcia-Giralt, N., Giroux, S., Hallmans, G., Hocking, L. J., Husted, L. B., Jameson, K. A., Khusainova, R., Kim, G. S., Kooperberg, C., Koromila, T., Kruk, M., Laaksonen, M., LaCroix, A. Z., Lee, S. H., Leung, P. C., Lewis, J. R., Masi, L., Mencej-Bedrac, S., Nguyen, T. V., Nogues, X., Patel, M. S., Prezelj, J., Rose, L. M., Scollen, S., Siggeirsdottir, K., Smith, A. V., Svensson, O., Trompet, S., Trummer, O., van Schoor, N. M., Woo, J., Zhu, K., Balcells, S., Brandi, M. L., Buckley, B. M., Cheng, S., Christiansen, C., Cooper, C., Dedoussis, G., Ford, I., Frost, M., Goltzman, D., Gonzalez-Macias, J., Kahonen, M., Karlsson, M., Khusnutdinova, E., Koh, J., Kollia, P., Langdahl, B. L., Leslie, W. D., Lips, P., Ljunggren, O., Lorenc, R. S., Marc, J., Mellstrom, D., Obermayer-Pietsch, B., Olmos, J. M., Pettersson-Kymmer, U., Reid, D. M., Riancho, J. A., Ridker, P. M., Rousseau, F., Slagboom, P. E., Tang, N. L., Urreizti, R., Van Hul, W., Viikari, J., Zarrabeitia, M. T., Aulchenko, Y. S., Castano-Betancourt, M., Grundberg, E., Herrera, L., Ingvarsson, T., Johannsdottir, H., Kwan, T., Li, R., Luben, R., Medina-Gomez, C., Palsson, S. T., Reppe, S., Rotter, J. I., Sigurdsson, G., van Meurs, J. B., Verlaan, D., Williams, F. M., Wood, A. R., Zhou, Y., Gautvik, K. M., Pastinen, T., Raychaudhuri, S., Cauley, J. A., Chasman, D. I., Clark, G. R., Cummings, S. R., Danoy, P., Dennison, E. M., Eastell, R., Eisman, J. A., Gudnason, V., Hofman, A., Jackson, R. D., Jones, G., Jukema, J. W., Khaw, K., Lehtimaki, T., Liu, Y., Lorentzon, M., McCloskey, E., Mitchell, B. D., Nandakumar, K., Nicholson, G. C., Oostra, B. A., Peacock, M., Pols, H. A., Prince, R. L., Raitakari, O., Reid, I. R., Robbins, J., Sambrook, P. N., Sham, P. C., Shuldiner, A. R., Tylavsky, F. A., van Duijn, C. M., Wareham, N. J., Cupples, L. A., Econs, M. J., Evans, D. M., Harris, T. B., Kung, A. W., Psaty, B. M., Reeve, J., Spector, T. D., Streeten, E. A., Zillikens, M. C., Thorsteinsdottir, U., Ohlsson, C., Karasik, D., Richards, J. B., Brown, M. A., Stefansson, K., Uitterlinden, A. G., Ralston, S. H., Ioannidis, J. P., Kiel, D. P., Rivadeneira, F. 2012; 44 (5): 491-?

    Abstract

    Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

    View details for DOI 10.1038/ng.2249

    View details for Web of Science ID 000303416300007

    View details for PubMedID 22504420

    View details for PubMedCentralID PMC3338864

  • STrengthening the Reporting of OBservational studies in Epidemiology - Molecular Epidemiology (STROBE-ME): An extension of the STROBE statement (vol 53, pg 377, 2011) PREVENTIVE MEDICINE Gallo, V., Egger, M., McCormack, V., Farmer, P. B., Ioannidis, J. A., Kirsch-Volders, M., Matullo, G., Phillips, D. H., Schoket, B., Stromberg, U., Vermeulen, R., Wild, C., Porta, M., Vineis, P. 2012; 54 (5): 367
  • Methodological Standards and Patient-Centeredness in Comparative Effectiveness Research The PCORI Perspective JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Basch, E., Aronson, N., Berg, A., Flum, D., Gabriel, S., Goodman, S. N., Helfand, M., Ioannidis, J. P., Lauer, M., Meltzer, D., Mittman, B., Newhouse, R., Normand, S., Schneeweiss, S., Slutsky, J., Tinetti, M., Yancy, C. 2012; 307 (15): 1636-1640

    Abstract

    Rigorous methodological standards help to ensure that medical research produces information that is valid and generalizable, and are essential in patient-centered outcomes research (PCOR). Patient-centeredness refers to the extent to which the preferences, decision-making needs, and characteristics of patients are addressed, and is the key characteristic differentiating PCOR from comparative effectiveness research. The Patient Protection and Affordable Care Act signed into law in 2010 created the Patient-Centered Outcomes Research Institute (PCORI), which includes an independent, federally appointed Methodology Committee. The Methodology Committee is charged to develop methodological standards for PCOR. The 4 general areas identified by the committee in which standards will be developed are (1) prioritizing research questions, (2) using appropriate study designs and analyses, (3) incorporating patient perspectives throughout the research continuum, and (4) fostering efficient dissemination and implementation of results. A Congressionally mandated PCORI methodology report (to be issued in its first iteration in May 2012) will begin to provide standards in each of these areas, and will inform future PCORI funding announcements and review criteria. The work of the Methodology Committee is intended to enable generation of information that is relevant and trustworthy for patients, and to enable decisions that improve patient-centered outcomes.

    View details for Web of Science ID 000302896100026

  • A Multidimensional Prognostic Index in Common Conditions Leading to Death in Older Patients reply ARCHIVES OF INTERNAL MEDICINE Siontis, G. C., Tzoulaki, I., Ioannidis, J. P. 2012; 172 (7): 594-595
  • Clinical Outcome Prediction by MicroRNAs in Human Cancer: A Systematic Review JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Nair, V. S., Maeda, L. S., Ioannidis, J. P. 2012; 104 (7): 528-540

    Abstract

    MicroRNA (miR) expression may have prognostic value for many types of cancers. However, the miR literature comprises many small studies. We systematically reviewed and synthesized the evidence.Using MEDLINE (last update December 2010), we identified English language studies that examined associations between miRs and cancer prognosis using tumor specimens for more than 10 patients during classifier development. We included studies that assessed a major clinical outcome (nodal disease, disease progression, response to therapy, metastasis, recurrence, or overall survival) in an agnostic fashion using either polymerase chain reaction or hybridized oligonucleotide microarrays.Forty-six articles presenting results on 43 studies pertaining to 20 different types of malignancy were eligible for inclusion in this review. The median study size was 65 patients (interquartile range [IQR] = 34-129), the median number of miRs assayed was 328 (IQR = 250-470), and overall survival or recurrence were the most commonly measured outcomes (30 and 19 studies, respectively). External validation was performed in 21 studies, 20 of which reported at least one nominally statistically significant result for a miR classifier. The median hazard ratio for poor outcome in externally validated studies was 2.52 (IQR = 2.26-5.40). For all classifier miRs in studies that evaluated overall survival across diverse malignancies, the miRs most frequently associated with poor outcome after accounting for differences in miR assessment due to platform type were let-7 (decreased expression in patients with cancer) and miR 21 (increased expression).MiR classifiers show promising prognostic associations with major cancer outcomes and specific miRs are consistently identified across diverse studies and platforms. These types of classifiers require careful external validation in large groups of cancer patients that have adequate protection from bias. -

    View details for DOI 10.1093/jnci/djs027

    View details for Web of Science ID 000302293200008

    View details for PubMedID 22395642

    View details for PubMedCentralID PMC3317879

  • Research needs grants, funding and money - missing something? EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Ioannidis, J. P. 2012; 42 (4): 349-351
  • Are Medical Conferences Useful? And for Whom? JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P. 2012; 307 (12): 1257-1258

    View details for Web of Science ID 000301978400018

    View details for PubMedID 22453564

  • Re-rethinking the article by Thombs and colleagues Response CANADIAN MEDICAL ASSOCIATION JOURNAL Thombs, B. D., Coyne, J. C., Cuijpers, P., de Jonge, P., Gilbody, S., Ioannidis, J. P., Johnson, B. T., Patten, S. B., Turner, E. H., Ziegelstein, R. C. 2012; 184 (4): 438-439
  • Rethinking recommendations for screening for depression in primary care CANADIAN MEDICAL ASSOCIATION JOURNAL Thombs, B. D., Coyne, J. C., Cuijpers, P., de Jonge, P., Gilbody, S., Ioannidis, J. P., Johnson, B. T., Patten, S. B., Turner, E. H., Ziegelstein, R. C. 2012; 184 (4): 413-418

    View details for DOI 10.1503/cmaj.111035

    View details for Web of Science ID 000301465400009

    View details for PubMedID 21930744

    View details for PubMedCentralID PMC3291670

  • Minimal and Null Predictive Effects for the Most Popular Blood Biomarkers of Cardiovascular Disease CIRCULATION RESEARCH Ioannidis, J. P., Tzoulaki, I. 2012; 110 (5): 658-662

    View details for DOI 10.1161/RES.0b013e31824da8ad

    View details for Web of Science ID 000301045500006

    View details for PubMedID 22383708

  • The effectiveness of long-term psychoanalytic psychotherapy-A meta-analysis of randomized controlled trials CLINICAL PSYCHOLOGY REVIEW Smit, Y., Huibers, M. J., Ioannidis, J. P., Van Dyck, R., van Tilburg, W., Arntz, A. 2012; 32 (2): 81-92

    Abstract

    The effectiveness of psychoanalysis and long-term psychoanalytic psychotherapy (LTPP) is debated. We evaluated the effectiveness of LTPP, compared to other treatments or no treatment, in patients with clearly defined metal disorders. We selected randomised or quasi-randomised controlled trials on LTPP. Two authors independently identified trials for inclusion. Eleven trials were eligible. The risk difference for recovery (primary outcome) at the longest available follow-up was 0.00 (95% CI: -0.17 to 0.17; p=0.96; I-squared: 58%). The combined Hedges' g, at the longest follow-up for each study, were: for target problems: -0.05 (95% CI -0.55 to 0.46; p=0.86; I-squared=88%); general psychiatric symptoms: 0.69 (95% CI -0.19 to 1.57; p=0.13; I-squared=96%); personality pathology: 0.17 (95% CI: -0.25 to 0.59; p=0.42; I-squared=41%); social functioning: 0.20 (95% CI -0.10 to 0.50; p=0.19; I-squared=53%); overall effectiveness: 0.33 (95% CI -0.31 to 0.96; p=0.32; I-squared=94%); and quality of life: -0.37 (95% CI: -0.78 to 0.04; p=0.08; I-squared=55%). A subgroup analysis of the domain target problem showed that LTPP did significantly better when compared to control treatments without a specialized psychotherapy component, but not when compared to various specialized psychotherapy control treatments. An exploratory meta-regression indicated that there might be a relation between the difference in treatment intensity between the intervention and control group (session ratio) and effect size. We came to conclude that the recovery rate of various mental disorders was equal after LTPP or various control treatments, including treatment as usual. The effect sizes of the individual trials varied substantially in direction and magnitude. In contrast to previous reviews, we found the evidence for the effectiveness of LTPP to be limited and at best conflicting.

    View details for DOI 10.1016/j.cpr.2011.11.003

    View details for Web of Science ID 000300033800001

    View details for PubMedID 22227111

  • First-Trimester Ductus Venosus Screening for Cardiac Defects: A Meta-Analysis EDITORIAL COMMENT OBSTETRICAL & GYNECOLOGICAL SURVEY Papatheodorou, S. I., Evangelou, E., Makrydimas, G., Ioannidis, J. A. 2012; 67 (3): 148–49
  • Comprehensive Research Synopsis and Systematic Meta-Analyses in Parkinson's Disease Genetics: The PDGene Database PLOS GENETICS Lill, C. M., Roehr, J. T., McQueen, M. B., Kavvoura, F. K., Bagade, S., Schjeide, B. M., Schjeide, L. M., Meissner, E., Zauft, U., Allen, N. C., Liu, T., Schilling, M., Anderson, K. J., Beecham, G., Berg, D., Biernacka, J. M., Brice, A., DeStefano, A. L., Do, C. B., Eriksson, N., Factor, S. A., Farrer, M. J., Foroud, T., Gasser, T., Hamza, T., Hardy, J. A., Heutink, P., Hill-Burns, E. M., Klein, C., Latourelle, J. C., Maraganore, D. M., Martin, E. R., Martinez, M., Myers, R. H., Nalls, M. A., Pankratz, N., Payami, H., Satake, W., Scott, W. K., Sharma, M., Singleton, A. B., Stefansson, K., Toda, T., Tung, J. Y., Vance, J., Wood, N. W., Zabetian, C. P., Young, P., Tanzi, R. E., Khoury, M. J., Zipp, F., Lehrach, H., Ioannidis, J. P., Bertram, L. 2012; 8 (3)

    Abstract

    More than 800 published genetic association studies have implicated dozens of potential risk loci in Parkinson's disease (PD). To facilitate the interpretation of these findings, we have created a dedicated online resource, PDGene, that comprehensively collects and meta-analyzes all published studies in the field. A systematic literature screen of -27,000 articles yielded 828 eligible articles from which relevant data were extracted. In addition, individual-level data from three publicly available genome-wide association studies (GWAS) were obtained and subjected to genotype imputation and analysis. Overall, we performed meta-analyses on more than seven million polymorphisms originating either from GWAS datasets and/or from smaller scale PD association studies. Meta-analyses on 147 SNPs were supplemented by unpublished GWAS data from up to 16,452 PD cases and 48,810 controls. Eleven loci showed genome-wide significant (P < 5 × 10(-8)) association with disease risk: BST1, CCDC62/HIP1R, DGKQ/GAK, GBA, LRRK2, MAPT, MCCC1/LAMP3, PARK16, SNCA, STK39, and SYT11/RAB25. In addition, we identified novel evidence for genome-wide significant association with a polymorphism in ITGA8 (rs7077361, OR 0.88, P  =  1.3 × 10(-8)). All meta-analysis results are freely available on a dedicated online database (www.pdgene.org), which is cross-linked with a customized track on the UCSC Genome Browser. Our study provides an exhaustive and up-to-date summary of the status of PD genetics research that can be readily scaled to include the results of future large-scale genetics projects, including next-generation sequencing studies.

    View details for DOI 10.1371/journal.pgen.1002548

    View details for Web of Science ID 000302254800024

    View details for PubMedID 22438815

    View details for PubMedCentralID PMC3305333

  • Claims for improved survival from systemic corticosteroids in diverse conditions: an umbrella review EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2012; 42 (3): 233-244

    Abstract

    Systemic corticosteroids have been proposed for numerous indications and there are many claims that corticosteroids can reduce mortality in diverse conditions.We performed an umbrella, agenda-wide review of the evidence on systemic corticosteroids and mortality, focusing primarily on large trials (defined as those with > 100 deaths) and meta-analyses. Searches were performed in PubMed and Cochrane Central Register of Controlled Trials (last update February 2011). We also examined whether spurious subset analyses may be responsible for claims of survival benefits in indications where only small trials had been available.Among 257 identified randomized trials with mortality data in their abstract, we found 14 large trials pertaining to 10 different indications. Although 10 of these 14 trials have reported statistically significant survival differences in subset analyses, none shows a nominally statistically significant (P < 0·05) decrease in death risk for any of the tested conditions when all deaths on all randomized patients are analysed. Meta-analyses for these conditions show statistically significant reductions in mortality only with antenatal corticosteroids for preterm labour (relative risk 0·77, 95% CI, 0·67-0·89) and in tuberculous meningitis (relative risk 0·78, 95% CI, 0·67-0·91). For conditions without any large trials, statistically significant reductions in mortality in meta-analyses were noted for Pneumocystis pneumonia (relative risk 0·54, 95% CI, 0·38-0·79) and alcoholic hepatitis (relative risk 0·63, 95% CI, 0·50-0·80). Many small trials that claim significant benefits, even those for classic indications such as typhoid fever and tetanus, have shown these benefits only in subset analyses.Corticosteroids have been documented to decrease mortality in some indications, in particular, antenatal use for preterm labour, tuberculous meningitis, Pneumocystis pneumonia, and alcoholic hepatitis. Many postulated benefits of corticosteroids on mortality may reflect 'vibration of treatment effects' leading to false-positive claims from spurious subset analyses and even for standard indications, such biases may have inflated the treatment effect estimates. More large trials are needed for serious, common conditions where use of corticosteroids is proposed.

    View details for DOI 10.1111/j.1365-2362.2011.02584.x

    View details for Web of Science ID 000299832800002

    View details for PubMedID 21880039

  • What should the genome-wide significance threshold be? Empirical replication of borderline genetic associations INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Panagiotou, O. A., Ioannidis, J. P. 2012; 41 (1): 273-286

    Abstract

    Robust replication is a sine qua non for the rigorous documentation of proposed associations in the genome-wide association (GWA) setting. Currently, associations of common variants reaching P ≤ 5 × 10(-8) are considered replicated. However, there is some ambiguity about the most suitable threshold for claiming genome-wide significance.We defined as 'borderline' associations those with P > 5 × 10(-8) and P ≤ 1 × 10(-7). The eligible associations were retrieved using the 'Catalog of Published Genome-Wide Association Studies'. For each association we assessed whether it reached P ≤ 5 × 10(-8) with inclusion of additional data from subsequent GWA studies.Thirty-four eligible genotype-phenotype associations were evaluated with data and clarifications contributed from diverse investigators. Replication data from subsequent GWA studies could be obtained for 26 of them. Of those, 19 associations (73%) reached P ≤ 5 × 10(-8) for the same or a related trait implicating either the exact same allele or one in very high linkage disequilibrium and 17 reached P < 10(-8). If the seven associations that did not reach P ≤ 5 × 10(-8) when additional data were considered are assumed to have been false-positives, the false-discovery rate for borderline associations is estimated to be 27% [95% confidence interval (CI) 12-48%]. For five associations, the current P-value is > 10(-6) [corresponding false-discovery rate 19% (95% CI 7-39%)].A substantial proportion, but not all, of the associations with borderline genome-wide significance represent replicable, possibly genuine associations. Our empirical evaluation suggests a possible relaxation in the current GWS threshold.

    View details for DOI 10.1093/ije/dyr178

    View details for Web of Science ID 000302026800032

    View details for PubMedID 22253303

  • STrengthening the reporting of OBservational studies in Epidemiology-Molecular Epidemiology (STROBE-ME): an extension of the STROBE statement (vol 26, pg 797, 2011) EUROPEAN JOURNAL OF EPIDEMIOLOGY Gallo, V., Egger, M., McCormack, V., Farmer, P. B., Ioannidis, J. A., Kirsch-Volders, M., Matullo, G., Phillips, D. H., Bernadette Schoket, Stromberg, U., Vermeulen, R., Wild, C., Porta, M., Vineis, P. 2012; 27 (2): 151
  • The Clinical Utility of Prognostic Indices: The Proof of the Pudding Is in the Eating reply ARCHIVES OF INTERNAL MEDICINE Siontis, G. C., Tzoulaki, I., Ioannidis, J. P. 2012; 172 (2): 195-195
  • Reversals of Established Medical Practices Evidence to Abandon Ship JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Prasad, V., Cifu, A., Ioannidis, J. P. 2012; 307 (1): 37-38

    View details for DOI 10.1001/jama.2011.1960

    View details for Web of Science ID 000298792300016

    View details for PubMedID 22215160

  • STrengthening the Reporting of OBservational studies in Epidemiology - Molecular Epidemiology (STROBE-ME): An extension of the STROBE statement EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Gallo, V., Egger, M., McCormack, V., Farmer, P. B., Ioannidis, J. P., Kirsch-Volders, M., Matullo, G., Phillips, D. H., Schoket, B., Stromberg, U., Vermeulen, R., Wild, C., Porta, M., Vineis, P. 2012; 42 (1): 1-16

    Abstract

    Advances in laboratory techniques have led to a rapidly increasing use of biomarkers in epidemiological studies. Biomarkers of internal dose, early biological change, susceptibility and clinical outcomes are used as proxies for investigating interactions between external and/or endogenous agents and body components or processes. The need for improved reporting of scientific research led to influential statements of recommendations such as the STrengthening Reporting of OBservational studies in Epidemiology (STROBE) statement. The STROBE initiative established in 2004 aimed to provide guidance on how to report observational research. Its guidelines provide a user-friendly checklist of 22 items to be reported in epidemiological studies, with items specific to the three main study designs: cohort studies, case-control studies and cross-sectional studies. The present STrengthening the Reporting of OBservational studies in Epidemiology -Molecular Epidemiology (STROBE-ME) initiative builds on the STROBE statement implementing nine existing items of STROBE and providing 17 additional items to the 22 items of STROBE checklist. The additions relate to the use of biomarkers in epidemiological studies, concerning collection, handling and storage of biological samples; laboratory methods, validity and reliability of biomarkers; specificities of study design; and ethical considerations. The STROBE-ME recommendations are intended to complement the STROBE recommendations.

    View details for DOI 10.1111/j.1365-2362.2011.02561.x

    View details for Web of Science ID 000297738500001

    View details for PubMedID 22023344

  • Scientific Communication Is Down at the Moment, Please Check Again Later PSYCHOLOGICAL INQUIRY Ioannidis, J. A. 2012; 23 (3): 267–70
  • STrengthening the Reporting of OBservational studies in Epidemiology - Molecular Epidemiology (STROBE-ME): An extension of the STROBE statement MUTAGENESIS Gallo, V., Egger, M., McCormack, V., Farmer, P. B., Ioannidis, J. P., Kirsch-Volders, M., Matullo, G., Phillips, D. H., Schoket, B., Stromberg, U., Vermeulen, R., Wild, C., Porta, M., Vineis, P. 2012; 27 (1): 17-29

    Abstract

    Advances in laboratory techniques have led to a rapidly increasing use of biomarkers in epidemiological studies. Biomarkers of internal dose, early biological change, susceptibility and clinical outcomes are used as proxies for investigating interactions between external and / or endogenous agents and body components or processes. The need for improved reporting of scientific research led to influential statements of recommendations such as the STrengthening Reporting of OBservational studies in Epidemiology (STROBE) statement. The STROBE initiative established in 2004 aimed to provide guidance on how to report observational research. Its guidelines provide a user-friendly checklist of 22 items to be reporte