Academic Appointments


Boards, Advisory Committees, Professional Organizations


  • Board Member, Bay Area Chapter, Society of Catholic Scientists (2022 - Present)
  • Member, Stanford Academic Freedom Alliance (2022 - Present)
  • Genomics Advisory Panel, Stanford University School of Medicine (2017 - Present)
  • Associate Editor, Statistical Applications in Genetics and Molecular Biology (2002 - Present)

Professional Education


  • PhD, UCLA, Biostatistics (1994)

Current Research and Scholarly Interests


Dr. Lazzeroni is a statistician and data scientist who develops and implements models, methods and algorithms for complex, and sometimes not-so-complex, data in medical science and biology. She is also interested in the interplay between fundamental statistical properties (such as variability, bias, p-values, and replication) and how scientists use and interpret data in practice. Much of her research has been in methodological and applied statistical genetics: including the invention of the Plaid bi-clustering model for gene expression data; methods for twin, genetic association, and family studies; and the problem of large-scale multiple testing and estimation in high dimensional biological arrays.

Projects


  • Integrating MultiOmic Data in Coronary Heart Disease: A Pilot Study for New Statistical Methods, Stanford Cardiovascular Institute

    Location

    Stanford University

All Publications


  • Modifying the Emotion Regulation Brain Network in Depression: Mechanistic Insights From a Clinical Trial of Cognitive-Behavioral Therapy for Insomnia Krause, A., Izabel, S., Osorno, R., Solomon, N., Ahmadi, M., Lam, P., Magana, O., Blozyte, E., Cirelli, A., Harris, L., Bernert, R., Williams, L., Gross, J., Ma, J., Lazzeroni, L., Yesavage, J., Manber, R., Saletin, J., Goldstein-Piekarski, A. SPRINGERNATURE. 2023: 208-209
  • Personalized digital behaviour interventions increase short-term physical activity: a randomized control crossover trial substudy of the MyHeart Counts Cardiovascular Health Study. European heart journal. Digital health Javed, A., Kim, D. S., Hershman, S. G., Shcherbina, A., Johnson, A., Tolas, A., O'Sullivan, J. W., McConnell, M. V., Lazzeroni, L., King, A. C., Christle, J. W., Oppezzo, M., Mattsson, C. M., Harrington, R. A., Wheeler, M. T., Ashley, E. A. 2023; 4 (5): 411-419

    Abstract

    Physical activity is associated with decreased incidence of the chronic diseases associated with aging. We previously demonstrated that digital interventions delivered through a smartphone app can increase short-term physical activity.We offered enrolment to community-living iPhone-using adults aged ≥18 years in the USA, UK, and Hong Kong who downloaded the MyHeart Counts app. After completion of a 1-week baseline period, e-consented participants were randomized to four 7-day interventions. Interventions consisted of: (i) daily personalized e-coaching based on the individual's baseline activity patterns, (ii) daily prompts to complete 10 000 steps, (iii) hourly prompts to stand following inactivity, and (iv) daily instructions to read guidelines from the American Heart Association (AHA) website. After completion of one 7-day intervention, participants subsequently randomized to the next intervention of the crossover trial. The trial was completed in a free-living setting, where neither the participants nor investigators were blinded to the intervention. The primary outcome was change in mean daily step count from baseline for each of the four interventions, assessed in a modified intention-to-treat analysis (modified in that participants had to complete 7 days of baseline monitoring and at least 1 day of an intervention to be included in analyses). This trial is registered with ClinicalTrials.gov, NCT03090321.Between 1 January 2017 and 1 April 2022, 4500 participants consented to enrol in the trial (a subset of the approximately 50 000 participants in the larger MyHeart Counts study), of whom 2458 completed 7 days of baseline monitoring (mean daily steps 4232 ± 73) and at least 1 day of one of the four interventions. Personalized e-coaching prompts, tailored to an individual based on their baseline activity, increased step count significantly (+402 ± 71 steps from baseline, P = 7.1⨯10-8). Hourly stand prompts (+292 steps from baseline, P = 0.00029) and a daily prompt to read AHA guidelines (+215 steps from baseline, P = 0.021) were significantly associated with increased mean daily step count, while a daily reminder to complete 10 000 steps was not (+170 steps from baseline, P = 0.11). Digital studies have a significant advantage over traditional clinical trials in that they can continuously recruit participants in a cost-effective manner, allowing for new insights provided by increased statistical power and refinement of prior signals. Here, we present a novel finding that digital interventions tailored to an individual are effective in increasing short-term physical activity in a free-living cohort. These data suggest that participants are more likely to react positively and increase their physical activity when prompts are personalized. Further studies are needed to determine the effects of digital interventions on long-term outcomes.

    View details for DOI 10.1093/ehjdh/ztad047

    View details for PubMedID 37794870

    View details for PubMedCentralID PMC10545510

  • A Twin Study of Altered White Matter Heritability in Youth With Autism Spectrum Disorder. Journal of the American Academy of Child and Adolescent Psychiatry Hegarty, J. P., Monterrey, J. C., Tian, Q., Cleveland, S. C., Gong, X., Phillips, J. M., Wolke, O., McNab, J. A., Hallmayer, J., Reiss, A. L., Hardan, A. Y., Lazzeroni, L. C. 2023

    Abstract

    OBJECTIVE: White matter alterations are frequently reported in autism spectrum disorder (ASD), yet the etiology is currently unknown. The objective of this investigation was to examine, for the first time, the impact of genetic and environmental factors on white matter microstructure in twins with ASD compared to control twins without ASD.METHOD: Diffusion-weighted MRIs were obtained from same-sex twin pairs (aged 6-15 years) in which at least one twin was diagnosed with ASD or neither twin exhibited a history of neurological or psychiatric disorders. Fractional anisotropy (FA) and mean diffusivity (MD) were examined across different white matter tracts in the brain and statistical and twin modeling were completed to assess the proportion of variation associated with additive genetic (A) and common/shared (C) or unique (E) environmental factors. We also developed a new version of the twin-pair difference score analysis method that estimates the contribution of genetic and environmental factors to shared covariance between different brain and behavioral traits.RESULTS: Good quality data were available from 84 twin pairs, 50 ASD pairs [32 concordant for ASD (16 monozygotic; 16 dizygotic), 16 discordant for ASD (3 monozygotic; 13 dizygotic), and 2 pairs in which one twin had ASD and the other exhibited some subthreshold symptoms (1 monozygotic; 1 dizygotic)] and 34 control pairs (20 monozygotic; 14 dizygotic). Average FA and MD across the brain, respectively, were primarily genetically mediated in both control twins (A=0.80 [0.57,1.02]; A=0.80 [0.55,1.04]) and twins concordant for having ASD (A=0.71 [0.33,1.09]; A= 0.84 [0.32,1.36]). However, there were also significant tract-specific differences between groups. For instance, genetic effects on commissural fibers were primarily associated with differences in general cognitive abilities and perhaps some diagnostic differences for ASD, e.g., our new twin-pair difference-scores analysis indicated that genetic factors may have contributed to 40-50% of the covariation between IQ scores and FA of the corpus callosum. Conversely, the increased impact of environmental factors on some projection and association fibers were primarily associated with differences in symptom severity in twins with ASD, e.g., twin-pair difference-scores suggested that unique environmental factors may have contributed to 10-20% of the covariation between autism-related symptom severity and FA of the cerebellar peduncles and external capsule.CONCLUSION: White matter alterations in youth with ASD are associated with both genetic contributions and potentially increased vulnerability or responsivity to environmental influences.DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. One or more of the authors of this paper self-identifies as living with a disability. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

    View details for DOI 10.1016/j.jaac.2023.05.030

    View details for PubMedID 37406770

  • Plasma proteomic signatures of a direct measure of insulin sensitivity in two population cohorts. Diabetologia Zanetti, D., Stell, L., Gustafsson, S., Abbasi, F., Tsao, P. S., Knowles, J. W., Zethelius, B., Ärnlöv, J., Balkau, B., Walker, M., Lazzeroni, L. C., Lind, L., Petrie, J. R., Assimes, T. L. 2023

    Abstract

    The euglycaemic-hyperinsulinaemic clamp (EIC) is the reference standard for the measurement of whole-body insulin sensitivity but is laborious and expensive to perform. We aimed to assess the incremental value of high-throughput plasma proteomic profiling in developing signatures correlating with the M value derived from the EIC.We measured 828 proteins in the fasting plasma of 966 participants from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study and 745 participants from the Uppsala Longitudinal Study of Adult Men (ULSAM) using a high-throughput proximity extension assay. We used the least absolute shrinkage and selection operator (LASSO) approach using clinical variables and protein measures as features. Models were tested within and across cohorts. Our primary model performance metric was the proportion of the M value variance explained (R2).A standard LASSO model incorporating 53 proteins in addition to routinely available clinical variables increased the M value R2 from 0.237 (95% CI 0.178, 0.303) to 0.456 (0.372, 0.536) in RISC. A similar pattern was observed in ULSAM, in which the M value R2 increased from 0.443 (0.360, 0.530) to 0.632 (0.569, 0.698) with the addition of 61 proteins. Models trained in one cohort and tested in the other also demonstrated significant improvements in R2 despite differences in baseline cohort characteristics and clamp methodology (RISC to ULSAM: 0.491 [0.433, 0.539] for 51 proteins; ULSAM to RISC: 0.369 [0.331, 0.416] for 67 proteins). A randomised LASSO and stability selection algorithm selected only two proteins per cohort (three unique proteins), which improved R2 but to a lesser degree than in standard LASSO models: 0.352 (0.266, 0.439) in RISC and 0.495 (0.404, 0.585) in ULSAM. Reductions in improvements of R2 with randomised LASSO and stability selection were less marked in cross-cohort analyses (RISC to ULSAM R2 0.444 [0.391, 0.497]; ULSAM to RISC R2 0.348 [0.300, 0.396]). Models of proteins alone were as effective as models that included both clinical variables and proteins using either standard or randomised LASSO. The single most consistently selected protein across all analyses and models was IGF-binding protein 2.A plasma proteomic signature identified using a standard LASSO approach improves the cross-sectional estimation of the M value over routine clinical variables. However, a small subset of these proteins identified using a stability selection algorithm affords much of this improvement, especially when considering cross-cohort analyses. Our approach provides opportunities to improve the identification of insulin-resistant individuals at risk of insulin resistance-related adverse health consequences.

    View details for DOI 10.1007/s00125-023-05946-z

    View details for PubMedID 37329449

    View details for PubMedCentralID 5866840

  • Improvements in Immediate and Delayed Memory With Insomnia Therapy and Their Associations With SWA in Older Adults Ahmadi, M., Krause, A. J., O'Hora, K. P., Hernandez, B., Lazzeroni, L., Zeitzer, J. M., Friedman, L. F., Posner, D., Kushida, C. A., Yesavage, J. A., Saletin, J., Goldstein-Piekarski, A. ELSEVIER SCIENCE INC. 2023: S301
  • ADULTS WITH AND WITHOUT MILD COGNITIVE IMPAIRMENT SHOW SIMILAR TREATMENT ADHERENCE AND SLEEP IMPROVEMENT AFTER INSOMNIA THERAPY Morehouse, A., O'Hora, K., Hernandez, B., Lazzeroni, L., Zeitzer, J., Friedman, L., Posner, D., Kushida, C., Yesavage, J., Goldstein-Piekarski, A. OXFORD UNIV PRESS INC. 2023
  • Sensitivity of Schizophrenia Endophenotype Biomarkers to Anticholinergic Medication Burden. The American journal of psychiatry Joshi, Y. B., Molina, J. L., Braff, D. L., Green, M. F., Gur, R. C., Gur, R. E., Nuechterlein, K. H., Stone, W. S., Greenwood, T. A., Lazzeroni, L. C., Radant, A. D., Silverman, J. M., Sprock, J., Sugar, C. A., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Swerdlow, N. R., Light, G. A. 2023: appiajp20220649

    View details for DOI 10.1176/appi.ajp.20220649

    View details for PubMedID 37038743

  • Repetitive Transcranial Magnetic Stimulation for Depression and Posttraumatic Stress Disorder in Veterans With Mild Traumatic Brain Injury. Neuromodulation : journal of the International Neuromodulation Society Philip, N. S., Ramanathan, D., Gamboa, B., Brennan, M. C., Kozel, F. A., Lazzeroni, L., Madore, M. R. 2023

    Abstract

    OBJECTIVES: Mild traumatic brain injury (mTBI) is a signature injury of military conflicts and is prevalent in veterans with major depressive disorder (MDD) and posttraumatic stress disorder (PTSD). Although therapeutic transcranial magnetic stimulation (TMS) can reduce symptoms of depression and PTSD, whether traumatic brain injury (TBI) affects TMS responsiveness is not yet known. We hypothesized mTBI would be associated with higher pretreatment symptom burden and poorer TMS response.MATERIALS AND METHODS: We investigated a registry of veterans (N= 770) who received TMS for depression across the US Veterans Affairs system. Of these, 665 (86.4%) had data on TBI and lifetime number of head injuries while 658 had complete data related to depression outcomes. Depression symptoms were assessed using the nine-item Patient Health Questionnaire and PTSD symptoms using the PTSD Checklist for DSM-5. Linear mixed effects models and t-tests evaluated whether head injuries predicted symptom severity before treatment, and how TBI status affected clinical TMS outcomes.RESULTS: Of the 658 veterans included, 337 (50.7%) reported previous mTBI, with a mean of three head injuries (range 1-20). TBI status did not predict depressive symptom severity or TMS-associated changes in depression (all p's > 0.1). TBI status was associated with a modest attenuation of TMS-associated improvement in PTSD (in patients with PTSD Checklist for DSM-5 scores > 33). There was no correlation between the number of head injuries and TMS response (p > 0.1).CONCLUSIONS: Contrary to our hypothesis, presence of mTBI did not meaningfully change TMS outcomes. Veterans with mTBI had greater PTSD symptoms, yet neither TBI status nor cumulative head injuries reduced TMS effectiveness. Limitations include those inherent to retrospective registry studies and self-reporting. Although these findings are contrary to our hypotheses, they support the safety and effectiveness of TMS for MDD and PTSD in patients who have comorbid mTBI.

    View details for DOI 10.1016/j.neurom.2022.11.015

    View details for PubMedID 36737300

  • Impact of PTSD and Obstructive Sleep Apnea on Cognition in Older Adult Veterans. Journal of geriatric psychiatry and neurology Noland, M. D., Paolillo, E. W., Noda, A., Lazzeroni, L. C., Holty, J. C., Kuschner, W. G., Yesavage, J., Kinoshita, L. M. 2023: 8919887221149132

    Abstract

    Background: Posttraumatic stress disorder (PTSD) and obstructive sleep apnea (OSA) are highly prevalent and comorbid among older adult male veterans. Both PTSD and OSA are independently associated with cognitive deficits in older adults, but little research regarding the impact of comorbid PTSD and OSA among older adults exists. Purpose: The current study aimed to examine the independent and interactive effects of PTSD and OSA on cognitive functioning in older adult veterans. Study Sample: Older adult male veterans with (n= 106) and without PTSD (n= 69), ranging in age from 55 to 89 (M= 63.35). Data Collection: Participants underwent polysomnography evaluation to assess severity of OSA symptoms and comprehensive neuropsychological evaluation to assess cognitive functioning in 3 domains: attention and processing speed, learning and memory, and executive functioning. Results: Multiple regression analyses showed that the interaction between PTSD and OSA did not predict cognitive performance. However, PTSD significantly predicted poorer attention and processing speed, and increased OSA severity predicted poorer learning and memory. Conclusions: While PTSD and OSA did not have a synergistic detrimental impact on cognition, each independently predicted poorer cognitive functioning within certain domains, suggesting that older adults with these comorbid conditions may experience a wider array of cognitive difficulties.

    View details for DOI 10.1177/08919887221149132

    View details for PubMedID 36592096

  • Cognitive Improvement Following Physical Exercise and Cognitive Training Intervention for Older Adults with MCI. The journals of gerontology. Series A, Biological sciences and medical sciences Campbell, E. B., Delgadillo, M., Lazzeroni, L. C., Louras, P. N., Myers, J., Yesavage, J., Fairchild, J. K. 2022

    Abstract

    BACKGROUND: The diagnosis of mild cognitive impairment (MCI) presents a critical period for intervention. Although exercise and cognitive training (CT) interventions have reported independent success for improving cognition, some meta-analyses have suggested combined interventions provide maximal benefits. Much previous research has studied land-based as opposed to water-based exercise, which places potential barriers on older adults. The purpose of the current study was to examine the impact of combined exercise (water- or land-based) and CT treatment on cognition for older adults with MCI.METHODS: Participants were 67 adults ages 54 to 86 years classified with MCI who engaged in six months of land or in aquatic with subsequent CT over four weeks. Primary outcome variables were performance measures of several cognitive domains across three time points (baseline, following exercise intervention, and following CT intervention). Linear mixed effects modeling examined exercise group differences across time periods in an intention-to-treat analysis.RESULTS: Both aquatic- and land-based exercise with CT interventions resulted significant in improvement in learning and memory outcomes, though improvement in executive functioning, processing speed, language, and visuospatial abilities was limited to water-based and CT treatment group. Differences in linear growth patterns between groups were non-significant.CONCLUSIONS: Results suggest that for older adults with MCI to obtain global cognitive benefits (i.e., Learning and Memory, Executive Functioning, Processing Speed, Language, and Visuospatial abilities) using combined exercise and CT interventions, they must be able to fully engage in exercise, and aquatic-based activities should be further considered.

    View details for DOI 10.1093/gerona/glac189

    View details for PubMedID 36099058

  • Randomised clinical non-inferiority trial of breathing-based meditation and cognitive processing therapy for symptoms of post-traumatic stress disorder in military veterans. BMJ open Bayley, P. J., Schulz-Heik, R. J., Tang, J. S., Mathersul, D. C., Avery, T., Wong, M., Zeitzer, J. M., Rosen, C. S., Burn, A. S., Hernandez, B., Lazzeroni, L. C., Seppala, E. M. 2022; 12 (8): e056609

    Abstract

    OBJECTIVE: Test whether Sudarshan Kriya Yoga (SKY) was non-inferior to cognitive processing therapy (CPT) for treating symptoms of post-traumatic stress disorder (PTSD) among veterans via a parallel randomised controlled non-inferiority trial.SETTING: Outpatient Veterans Affairs healthcare centre.PARTICIPANTS: 85 veterans (75 men, 61% white, mean age 56.9) with symptoms of PTSD participated between October 2015 and March 2020: 59 participants completed the study.INTERVENTIONS: SKY emphasises breathing routines and was delivered in group format in a 15-hour workshop followed by two 1-hour sessions per week for 5 weeks. CPT is an individual psychotherapy which emphasises shifting cognitive appraisals and was delivered in two 1-hour sessions per week for 6 weeks.MEASURES: The primary outcome measure was the PTSD Checklist-Civilian Version (PCL-C). The secondary measures were the Beck Depression Inventory-II (BDI-II) and Positive and Negative Affect Scale (PANAS).RESULTS: Mean PCL-C at baseline was 56.5 (±12.6). Intent-to-treat analyses showed that PCL-C scores were reduced at 6weeks (end of treatment) relative to baseline (SKY, -5.6, d=0.41, n=41: CPT, -6.8, d=0.58, n=44). The between-treatment difference in change scores was within the non-inferiority margin of 10 points (-1.2, 95%CI -5.7 to 3.3), suggesting SKY was not inferior to CPT. SKY was also non-inferior at 1-month (CPT-SKY: -2.1, 95%CI -6.9 to 2.8) and 1-year (CPT-SKY: -1.8, 95%CI -6.6 to 2.9) assessments. SKY was also non-inferior to CPT on the BDI-II and PANAS at end of treatment and 1month, but SKY was inferior to CPT on both BDI-II and PANAS at 1year. Dropout rates were similar (SKY, 27%, CPT, 34%: OR=1.36, 95%CI 0.51 to 3.62, p=0.54).CONCLUSIONS: SKY may be non-inferior to CPT for treating symptoms of PTSD and merits further consideration as a treatment for PTSD.TRIAL REGISTRATION NUMBER: NCT02366403.

    View details for DOI 10.1136/bmjopen-2021-056609

    View details for PubMedID 36008059

  • Understanding Connections and Boundaries Between Positive Symptoms, Negative Symptoms, and Role Functioning Among Individuals With Schizophrenia: A Network Psychometric Approach. JAMA psychiatry Abplanalp, S. J., Braff, D. L., Light, G. A., Nuechterlein, K. H., Green, M. F., Consortium on the Genetics of Schizophrenia-2, Gur, R. C., Gur, R. E., Stone, W. S., Greenwood, T. A., Lazzeroni, L. C., Radant, A. D., Seidman, L. J., Siever, L. J., Silverman, J. M., Sprock, J., Sugar, C. A., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I. 2022

    Abstract

    Importance: Improved understanding of the boundaries and connections between positive symptoms, negative symptoms, and role functioning in schizophrenia is critical, given limited empirical support for clear distinctions among these clinical areas. This study's use of network psychometrics to investigate differential associations and structural overlap between positive symptoms, negative symptoms, and functional domains in schizophrenia may contribute to such understanding.Objective: To apply network analysis and community detection methods to examine the interplay and structure of positive symptoms, negative symptoms, and functional domains in individuals with schizophrenia.Design, Setting, and Participants: Cross-sectional study in 5 geographically distributed research centers in the US as part of the Consortium on the Genetics of Schizophrenia-2 from July 1, 2010, through January 31, 2014. Data were analyzed from November 2021 to June 2022. Clinically stable outpatients with schizophrenia or schizoaffective disorder were included. Participants were excluded if they had evidence of neurologic or additional Axis I psychiatric disorders. Other exclusion criteria included head injury, stroke, and substance abuse. Of 1415 patients approached, 979 were included in the final analysis.Main Outcomes and Measures: Measures included the Scale for the Assessment of Positive Symptoms, the Scale for the Assessment of Negative Symptoms, and the Role Functioning Scale. Main outcomes were expected influence, which assesses the relative importance of items to the network and is defined as the association of an item with all others, and community detection and stability, defined as the presence of statistical clusters and their replicability.Results: Participants with complete data included 979 outpatients (mean [SD] age, 46 [11] years; 663 male [67.7%]; 390 participants [40%] self-identified as African American, 30 [3%] as Asian, 7 [0.7%] as Native American, 8 [0.8%] as Pacific Islander, 412 [42.1%] as White, 125 [12.8%] as more than 1 race, and 5 [0.5%] did not identify). Anhedonia had the highest expected influence in the most comprehensive network analysis, showing connections with negative and positive symptoms and functional domains. Positive symptoms had the lowest expected influence. Community detection analyses indicated the presence of 3 clusters corresponding to positive symptoms; negative symptoms and work functioning; functional domains, including independent living, family relationships, and social network; and avolition, anhedonia, and work functioning. Hallucinations and delusions replicated in 1000 bootstrapped samples (100%), while bizarre behavior and thought disorder replicated in 390 (39%) and 570 (57%), respectively. In contrast, negative symptoms and work functioning replicated between 730 (73%) and 770 (77%) samples, respectively, and the remaining functional domains in 940 samples (94%).Conclusions and Relevance: The high centrality of anhedonia and its connections with multiple functional domains suggest that it could be a treatment target for global functioning. Interventions for work functioning may benefit from a specialized approach that focuses primarily on avolition.

    View details for DOI 10.1001/jamapsychiatry.2022.2386

    View details for PubMedID 35976655

  • The Benton Visual Form Discrimination Test as a Predictor of Neurocognitive Disorder in Older Veterans. Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists Maruyama, B. A., Alipio Jocson, V. Z., Gretler, J., Doudell, K., Lazzeroni, L. C., Hernandez, B., Noda, A., Yesavage, J. A., Kinoshita, L. M. 2022

    Abstract

    OBJECTIVE: The Benton Visual Form Discrimination Test (VFDT) is a commonly used measure of visual discrimination and visual recognition memory and has shown promise in distinguishing between different levels of cognitive impairment. We assess the predictive diagnostic utility of the VFDT in a sample of older Veterans with cognitive concerns.METHOD: Subjects included a total of 172 mostly male Veterans over the age of 64 (mean=76.0; SD=7.6) recruited from a VA clinic specializing in neuropsychological assessment of older Veterans. The clinical sample included 56 subjects diagnosed with Major Neurocognitive Disorder, 74 diagnosed with Mild Neurocognitive Disorder, and 42 with No Neurocognitive Impairment. Impairment categories were modeled in separate multinomial logistic regressions with two versions of the VFDT as predictors: the Visual Form Discrimination Test-Recognition Subtest (VFDT-Rec) test (visual recognition memory) and the Visual Form Discrimination Test-Matching Subtest VFDT-Mat test (visual form discrimination). Years of education were included as a covariate.RESULTS: After adjusting for education, higher VFDT-Rec total scores were associated with lower odds of being categorized with a greater degree of cognitive/functional impairment (OR 0.66-0.83, p<.001). VFDT-Mat scores showed a similar pattern, but only reached statistical significance for the Major versus No Neurocognitive Impairment (OR=0.77, p=.0010) and Major versus Mild comparisons (OR=0.89, p=.0233).CONCLUSIONS: The VFDT may enhance the confidence of differential diagnosis of dementia in older adult Veterans. Formal education-adjusted norms need to be established for clinical use.

    View details for DOI 10.1093/arclin/acac067

    View details for PubMedID 35965251

  • Valued living among veterans in breath-based meditation treatment or cognitive processing therapy for posttraumatic stress disorder: Exploratory outcome of a randomized controlled trial. Global advances in health and medicine Schulz-Heik, R. J., Lazzeroni, L. C., Hernandez, B., Avery, T. J., Mathersul, D. C., Tang, J. S., Hugo, E., Bayley, P. J. 2022; 11: 2164957X221108376

    Abstract

    Valued living is the extent to which an individual's behavior is consistent with what they believe is important or good. It is unknown whether many complementary and integrative treatments and psychotherapies for posttraumatic stress disorder enhance valued living, and for whom.Measure within- and between-group changes in valued living in Veterans who completed cognitive processing therapy (CPT) and sudarshan kriya yoga (SKY) for posttraumatic stress disorder (PTSD); evaluate moderators of improvement.Participants with clinically significant symptoms of PTSD were assigned to CPT, a first line, evidence-based psychotherapy for PTSD or SKY, an emerging breath-based meditation with strong preliminary empirical support in a parallel-groups randomized controlled trial at a single Veterans Affairs healthcare center. The Valuing Questionnaire subscales for progress in valued living (VQ-P) and obstruction in valued living (VQ-O) were exploratory outcome measures. Assessors were blind to treatment assignment.59 participants completed treatment (29 CPT, 30 SKY). Participants in the CPT group improved from baseline to end of treatment in both VQ-Progress (d=0.55, p=0.02) and VQ-Obstruction (d=-0.51, p=0.03), while the SKY group did not improve on either subscale (d=0.08, p=0.69; d=0.00, p=1.00). However, differences between treatments were not statistically significant (p=0.16, 0.11, respectively). Participants reporting less valued living and more depression symptoms at baseline reported greater improvements in valued living following treatment.CPT may have a positive effect on valued living. Individuals lower in valued living and with more depression may derive relatively more benefit.

    View details for DOI 10.1177/2164957X221108376

    View details for PubMedID 35770246

    View details for PubMedCentralID PMC9234823

  • THE IMPACT OF NON-PHARMACOLOGICAL INSOMNIA THERAPY ON MOOD AND SLEEP IN MORNING AND EVENING CHRONOTYPES IN OLDER ADULTS Lopez, M., Krause, A., O'Hora, K., Hernandez, B., Lazzeroni, L., Zeitzer, J., Friedman, L., Posner, D., Kushida, C., Yesavage, J., Goldstein-Piekarski, A. OXFORD UNIV PRESS INC. 2022: A211-A212
  • NON-PHARMACOLOGICAL INSOMNIA THERAPY IS ROBUST TO CO-OCCURRING PAIN IN OLDER ADULTS Krause, A., Ahmadi, M., O'Hora, K., Hernandez, B., Lazzeroni, L., Zeitzer, J., Friedman, L., Posner, D., Kushida, C., Yesavage, J., Saletin, J., Goldstein-Piekarski, A. OXFORD UNIV PRESS INC. 2022: A197-A198
  • THE EFFECT OF DISTINCT COMPONENTS OF CBT-I ON SLOW WAVE POWER AND ENERGY Ahmadi, M., Krause, A., O'Hora, K., Hernandez, B., Lazzeroni, L., Zeitzer, J., Friedman, L., Posner, D., Kushida, C., Yesavage, J., Saletin, J., Goldstein-Piekarski, A. OXFORD UNIV PRESS INC. 2022: A197
  • THE EFFECTS OF INSOMNIA THERAPY ON DEPRESSION, ANXIETY, AND DAILY FUNCTIONING IN INDIVIDUALS WITH INSOMNIA AND MILD COGNITIVE IMPAIRMENT Morehouse, A., O'Hora, K., Hernandez, B., Lazzeroni, L., Zeitzer, J., Friedman, L., Posner, D., Kushida, C., Yesavage, J., Goldstein-Piekarski, A. OXFORD UNIV PRESS INC. 2022: A275-A276
  • Non-Pharmacological Insomnia Therapy is Robust to Co-Occurring Pain in Older Adults Krause, A., Ahmadi, M., O'Hora, K., Hernandez, B., Lazzeroni, L., Zeitzer, J., Friedman, L., Posner, D., Kushida, C., Yesavage, J., Saletin, J., Goldstein-Piekarski, A. ELSEVIER SCIENCE INC. 2022: S370
  • The Effect of Distinct Components of CBT-I on Slow Wave Power and Energy Ahmadi, M., Krause, A. J., O'Hora, K., Hernandez, B., Lazzeroni, L., Zeitzer, J., Friedman, L., Posner, D., Kushida, C., Yesavage, J. A., Saletin, J., Goldstein-Piekarski, A. ELSEVIER SCIENCE INC. 2022: S369-S370
  • Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature Trubetskoy, V., Pardinas, A. F., Qi, T., Panagiotaropoulou, G., Awasthi, S., Bigdeli, T. B., Bryois, J., Chen, C., Dennison, C. A., Hall, L. S., Lam, M., Watanabe, K., Frei, O., Ge, T., Harwood, J. C., Koopmans, F., Magnusson, S., Richards, A. L., Sidorenko, J., Wu, Y., Zeng, J., Grove, J., Kim, M., Li, Z., Voloudakis, G., Zhang, W., Adams, M., Agartz, I., Atkinson, E. G., Agerbo, E., Al Eissa, M., Albus, M., Alexander, M., Alizadeh, B. Z., Alptekin, K., Als, T. D., Amin, F., Arolt, V., Arrojo, M., Athanasiu, L., Azevedo, M. H., Bacanu, S. A., Bass, N. J., Begemann, M., Belliveau, R. A., Bene, J., Benyamin, B., Bergen, S. E., Blasi, G., Bobes, J., Bonassi, S., Braun, A., Bressan, R. A., Bromet, E. J., Bruggeman, R., Buckley, P. F., Buckner, R. L., Bybjerg-Grauholm, J., Cahn, W., Cairns, M. J., Calkins, M. E., Carr, V. J., Castle, D., Catts, S. V., Chambert, K. D., Chan, R. 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T., van Os, J., Vawter, M. P., Weinberger, D. R., Werge, T., Wildenauer, D. B., Yu, X., Yue, W., Holmans, P. A., Pocklington, A. J., Roussos, P., Vassos, E., Verhage, M., Visscher, P. M., Yang, J., Posthuma, D., Andreassen, O. A., Kendler, K. S., Owen, M. J., Wray, N. R., Daly, M. J., Huang, H., Neale, B. M., Sullivan, P. F., Ripke, S., Walters, J. T., O'Donovan, M. C., Schizophrenia Working Group of the Psychiatric Genomics Consortium, Dai, N., Wenwen, Q., Wildenauer, D. B., Agiananda, F., Amir, N., Antoni, R., Arsianti, T., Asmarahadi, A., Diatri, H., Djatmiko, P., Irmansyah, I., Khalimah, S., Kusumadewi, I., Kusumaningrum, P., Lukman, P. R., Nasrun, M. W., Safyuni, N. S., Prasetyawan, P., Semen, G., Siste, K., Tobing, H., Widiasih, N., Wiguna, T., Wulandari, D., Evalina, N., Hananto, A. J., Ismoyo, J. H., Marini, T. M., Henuhili, S., Reza, M., Yusnadewi, S., Abyzov, A., Akbarian, S., Ashley-Koch, A., van Bakel, H., Breen, M., Brown, M., Bryois, J., Carlyle, B., Charney, A., Coetzee, G., Crawford, G., Dracheva, S., Emani, P., Farnham, P., Fromer, M., Galeev, T., Gandal, M., Gerstein, M., Giase, G., Girdhar, K., Goes, F., Grennan, K., Gu, M., Guerra, B., Gursoy, G., Hoffman, G., Hyde, T., Jaffe, A., Jiang, S., Jiang, Y., Kefi, A., Kim, Y., Kitchen, R., Knowles, J. A., Lay, F., Lee, D., Li, M., Liu, C., Liu, S., Mattei, E., Navarro, F., Pan, X., Peters, M. A., Pinto, D., Pochareddy, S., Polioudakis, D., Purcaro, M., Purcell, S., Pratt, H., Reddy, T., Rhie, S., Roussos, P., Rozowsky, J., Sanders, S., Sestan, N., Sethi, A., Shi, X., Shieh, A., Swarup, V., Szekely, A., Wang, D., Warrell, J., Weissman, S., Weng, Z., White, K., Wiseman, J., Witt, H., Won, H., Wood, S., Wu, F., Xu, X., Yao, L., Zandi, P., Arranz, M. J., Bakker, S., Bender, S., Bramon, E., Collier, D. A., Crepo-Facorro, B., Hall, J., Iyegbe, C., Kahn, R., Lawrie, S., Lewis, C., Lin, K., Linszen, D. H., Mata, I., McIntosh, A., Murray, R. M., Ophoff, R. A., van Os, J., Powell, J., Rujescu, D., Walshe, M., Weisbrod, M., Achsel, T., Andres-Alonso, M., Bagni, C., Bayes, A., Biederer, T., Brose, N., Brown, T. C., Chua, J. J., Coba, M. P., Cornelisse, L. N., de Jong, A. P., de Juan-Sanz, J., Dieterich, D. C., Feng, G., Goldschmidt, H. L., Gundelfinger, E. D., Hoogenraad, C., Huganir, R. L., Hyman, S. E., Imig, C., Jahn, R., Jung, H., Kaeser, P. S., Kim, E., Koopmans, F., Kreutz, M. R., Lipstein, N., MacGillavry, H. D., Malenka, R., McPherson, P. S., O'Connor, V., Pielot, R., Ryan, T. A., Sahasrabudhe, D., Sala, C., Sheng, M., Smalla, K., Smit, A. B., Sudhof, T. C., Thomas, P. D., Toonen, R. F., van Weering, J. R., Verhage, M., Verpelli, C., de Haan, L., van Amelsvoort, T., van Winkel, R., Gareeva, A., Sham, P. C., Shi, Y., St Clair, D., van Os, J. 2022

    Abstract

    Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.

    View details for DOI 10.1038/s41586-022-04434-5

    View details for PubMedID 35396580

  • Repetitive Transcranial Magnetic Stimulation as a Treatment for Veterans with Cognitive Impairment and Multiple Comorbidities. Journal of Alzheimer's disease : JAD Cheng, J., Fairchild, J. K., McNerney, M. W., Noda, A., Ashford, J. W., Suppes, P., Chao, S. Z., Taylor, J., Rosen, A., Durazzo, T., Lazzeroni, L. C., Yesavage, J. 1800

    Abstract

    BACKGROUND: Despite decades of research efforts, current treatments for Alzheimer's disease (AD) are of limited effectiveness and do not halt the progression of the disease and associated cognitive decline. Studies have shown that repetitive transcranial magnetic stimulation (rTMS) may improve cognition.OBJECTIVE: We conducted a pilot study to investigate the effect of rTMS on cognitive function in Veterans with numerous medical comorbidities.METHODS: Participants underwent 20 sessions, over the course of approximately 4 weeks, of 10 Hz rTMS at the left dorsolateral prefrontal cortex with intensity of 120% resting motor threshold. Outcome measures including memory, language, verbal fluency, and executive functions were acquired at baseline, end of treatment, and 4 months after the last rTMS session. Twenty-six Veterans completed the study (13 in the active rTMS group, 13 in the sham rTMS group).RESULTS: The study protocol was well-tolerated. Active, compared to sham, rTMS showed improved auditory-verbal memory at the end of treatment and at 4-month follow-up. However, the active rTMS group demonstrated a trend in decreased semantic verbal fluency at the end of treatment and at 4-month follow up.CONCLUSION: These preliminary results show rTMS is safe in general in this elderly Veteran population with multiple co-morbidities. Patients in the sham group showed an expected, slight decline in the California Verbal Learning Test scores over the course of the study, whereas the active treatment group showed a slight improvement at the 4-month post-treatment follow up. These effects need to be confirmed by studies of larger sample sizes.

    View details for DOI 10.3233/JAD-210349

    View details for PubMedID 34958013

  • Anticholinergic Medication Burden-Associated Cognitive Impairment in Schizophrenia. The American journal of psychiatry Joshi, Y. B., Thomas, M. L., Braff, D. L., Green, M. F., Gur, R. C., Gur, R. E., Nuechterlein, K. H., Stone, W. S., Greenwood, T. A., Lazzeroni, L. C., MacDonald, L. R., Molina, J. L., Nungaray, J. A., Radant, A. D., Silverman, J. M., Sprock, J., Sugar, C. A., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Swerdlow, N. R., Light, G. A. 2021: appiajp202020081212

    Abstract

    OBJECTIVE: Many psychotropic medications used to treat schizophrenia have significant anticholinergic properties, which are linked to cognitive impairment and dementia risk in healthy subjects. Clarifying the impact of cognitive impairment attributable to anticholinergic medication burden may help optimize cognitive outcomes in schizophrenia. The aim of this study was to comprehensively characterize how this burden affects functioning across multiple cognitive domains in schizophrenia outpatients.METHODS: Cross-sectional data were analyzed using inferential statistics and exploratory structural equation modeling to determine the relationship between anticholinergic medication burden and cognition. Patients with a diagnosis of schizophrenia or schizoaffective disorder (N=1,120) were recruited from the community at five U.S. universities as part of the Consortium on the Genetics of Schizophrenia-2. For each participant, prescribed medications were rated and summed according to a modified Anticholinergic Cognitive Burden (ACB) scale. Cognitive functioning was assessed by performance on domains of the Penn Computerized Neurocognitive Battery (PCNB).RESULTS: ACB score was significantly associated with cognitive performance, with higher ACB groups scoring worse than lower ACB groups on all domains tested on the PCNB. Similar effects were seen on other cognitive tests. Effects remained significant after controlling for demographic characteristics and potential proxies of illness severity, including clinical symptoms and chlorpromazine-equivalent antipsychotic dosage.CONCLUSIONS: Anticholinergic medication burden in schizophrenia is substantial, common, conferred by multiple medication classes, and associated with cognitive impairments across all cognitive domains. Anticholinergic medication burden from all medication classes-including psychotropics used in usual care-should be considered in treatment decisions and accounted for in studies of cognitive functioning in schizophrenia.

    View details for DOI 10.1176/appi.ajp.2020.20081212

    View details for PubMedID 33985348

  • RELATIVE EFFECTIVENESS OF COGNITIVE BEHAVIORAL THERAPY AND ITS COMPONENTS IN IMPROVING INSOMNIA SYMPTOMS IN OLDER ADULTS O'Hora, K., Hernandez, B., Lazzeroni, L., Zeitzer, J., Friedman, L., Posner, D., Kushida, C., Yesavage, J., Goldstein-Piekarski, A. OXFORD UNIV PRESS INC. 2021: A144
  • EFFICACY OF CBT-I AND ITS COMPONENTS ON HEALTH-RELATED QUALITY OF LIFE OUTCOMES IN OLDER ADULTS Showen, K., O'Hora, K., Hernandez, B., Lazzeroni, L., Zeitzer, J., Friedman, L., Posner, D., Kushida, C., Yesavage, J., Goldstein-Piekarski, A. OXFORD UNIV PRESS INC. 2021: A143-A144
  • Plasma Proteomics to Predict Insulin-mediated Glucose Disposal/Uptake Zanetti, D., Gustafsson, S., Lazzeroni, L. C., Walker, M., Lind, L., Petrie, J., Assimes, T. L. W B SAUNDERS CO-ELSEVIER INC. 2021: 41
  • Posttraumatic Stress Disorder-Associated Cognitive Deficits on the Repeatable Battery for the Assessment of Neuropsychological Status in a Veteran Population. Federal practitioner : for the health care professionals of the VA, DoD, and PHS Hantke, N. n., Adamson, M. M., Noda, A. n., Lazzeroni, L. C., Beaudreau, S. A., Yutsis, M. n., Fairchild, J. K., Kinoshita, L. M., Kong, J. n., Sheng, T. n., Waltzman, D. n., Ashford, J. W., Yesavage, J. A. 2021; 38 (1): 28–34

    Abstract

    Posttraumatic stress disorder (PTSD) is a frequent problem of veterans receiving care and is often associated with cognitive deficits. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a well-validated cognitive screening measure often used in the US Department of Veterans Affairs (VA), particularly in neurorehabilitation settings. However, the influence of PTSD on RBANS performance is unclear, particularly within a heterogeneous VA outpatient population in which PTSD and traumatic brain injury (TBI) may not be the primary focus of care.Participants included 153 veterans with complex deployment-related health problems, including a diagnosis of PTSD (n = 98) and a history of TBI (n = 92). All veterans completed a targeted cognitive battery that included the Wechsler Test of Adult Reading, the Wechsler Adults Intelligence Scale, measure assessing processing speed, attention, and cognitive flexibility, and RBANS.A diagnosis of PTSD was associated with worse performance on the Story Recall subtest of the RBANS, but not on any other cognitive measures. A diagnosis of mild TBI, or co-occurring PTSD and TBI did not predict cognitive performance on any measures.The RBANS best captured cognitive deficits associated with PTSD compared with a history of mild TBI or co-occurring mild TBI and PTSD. These findings may provide insight into the interpretation and attribution of cognitive deficits in the veteran population.

    View details for DOI 10.12788/fp.0083

    View details for PubMedID 33574646

    View details for PubMedCentralID PMC7870275

  • Heritability of acoustic startle magnitude and latency from the consortium on the genetics of schizophrenia. Schizophrenia research Greenwood, T. A., Swerdlow, N. R., Sprock, J., Calkins, M. E., Freedman, R., Green, M. F., Gur, R. E., Gur, R. C., Lazzeroni, L. C., Light, G. A., Nuechterlein, K. H., Radant, A. D., Silverman, J. M., Stone, W. S., Sugar, C. A., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Braff, D. L., Duncan, E. 2020

    Abstract

    BACKGROUND: Latency of the acoustic startle reflex is the time from presentation of the startling stimulus until the response, and provides an index of neural processing speed. Schizophrenia subjects exhibit slowed latency compared to healthy controls. One prior publication reported significant heritability of latency. The current study was undertaken to replicate and extend this solitary finding in a larger cohort.METHODS: Schizophrenia probands, their relatives, and control subjects from the Consortium on the Genetics of Schizophrenia (COGS-1) were tested in a paradigm to ascertain magnitude, latency, and prepulse inhibition of startle. Trial types in the paradigm were: pulse-alone, and trials with 30, 60, or 120ms between the prepulse and pulse. Comparisons of subject groups were conducted with ANCOVAs to assess startle latency and magnitude. Heritability of startle magnitude and latency was analyzed with a variance component method implemented in SOLAR v.4.3.1.RESULTS: 980 subjects had analyzable startle results: 199 schizophrenia probands, 456 of their relatives, and 325 controls. A mixed-design ANCOVA on startle latency in the four trial types was significant for subject group (F(2,973)=4.45, p=0.012) such that probands were slowest, relatives were intermediate and controls were fastest. Magnitude to pulse-alone trials differed significantly between groups by ANCOVA (F(2,974)=3.92, p=0.020) such that controls were lowest, probands highest, and relatives intermediate. Heritability was significant (p<0.0001), with heritability of 34-41% for latency and 45-59% for magnitude.CONCLUSION: Both startle latency and magnitude are significantly heritable in the COGS-1 cohort. Startle latency is a strong candidate for being an endophenotype in schizophrenia.

    View details for DOI 10.1016/j.schres.2020.11.003

    View details for PubMedID 33189519

  • Genetic and environmental influences on structural brain measures in twins with autism spectrum disorder MOLECULAR PSYCHIATRY Hegarty, J. P., Pegoraro, L. L., Lazzeroni, L. C., Raman, M. M., Hallmayer, J. F., Monterrey, J. C., Cleveland, S. C., Wolke, O. N., Phillips, J. M., Reiss, A. L., Hardan, A. Y. 2020; 25 (10): 2556–66
  • Default Mode Network Connectivity and Brain Derived Trophic Factor in Brain Stimulation of TBI patients Adamson, M., McNerney, M., Siddiqi, S., Swaminath, G., Wu, L., Hernandez, B., Lazzeroni, L., Yesavage, J. ELSEVIER SCIENCE INC. 2020: S158
  • A NOVEL COGNITIVE-BEHAVIORAL THERAPY TO INCREASE PAP ADHERENCE IN VETERANS WITH POSTTRAUMATIC STRESS DISORDER: PRELIMINARY RESULTS Kinoshita, L., Blank, E., Chen, M., Doudell, K., Day, Y., Jocson, A., Lazzeroni, L., Noda, A., Hernandez, B., Holty, J., Kuschner, W., Kushida, C., Yaffe, K., Cheng, J., Yesavage, J. A. OXFORD UNIV PRESS INC. 2020: A249
  • The effects of age and sex on cognitive impairment in schizophrenia: Findings from the Consortium on the Genetics of Schizophrenia (COGS) study. PloS one Lee, J., Green, M. F., Nuechterlein, K. H., Swerdlow, N. R., Greenwood, T. A., Hellemann, G. S., Lazzeroni, L. C., Light, G. A., Radant, A. D., Seidman, L. J., Siever, L. J., Silverman, J. M., Sprock, J., Stone, W. S., Sugar, C. A., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Gur, R. C., Gur, R. E., Braff, D. L. 2020; 15 (5): e0232855

    Abstract

    Recently emerging evidence indicates accelerated age-related changes in the structure and function of the brain in schizophrenia, raising a question about its potential consequences on cognitive function. Using a large sample of schizophrenia patients and controls and a battery of tasks across multiple cognitive domains, we examined whether patients show accelerated age-related decline in cognition and whether an age-related effect differ between females and males. We utilized data of 1,415 schizophrenia patients and 1,062 healthy community collected by the second phase of the Consortium on the Genetics of Schizophrenia (COGS-2). A battery of cognitive tasks included the Letter-Number Span Task, two forms of the Continuous Performance Test, the California Verbal Learning Test, Second Edition, the Penn Emotion Identification Test and the Penn Facial Memory Test. The effect of age and gender on cognitive performance was examined with a general linear model. We observed age-related changes on most cognitive measures, which was similar between males and females. Compared to controls, patients showed greater deterioration in performance on attention/vigilance and greater slowness of processing social information with increasing age. However, controls showed greater age-related changes in working memory and verbal memory compared to patients. Age-related changes (eta2p of 0.001 to .008) were much smaller than between-group differences (eta2p of 0.005 to .037). This study found that patients showed continued decline of cognition on some domains but stable impairment or even less decline on other domains with increasing age. These findings indicate that age-related changes in cognition in schizophrenia are subtle and not uniform across multiple cognitive domains.

    View details for DOI 10.1371/journal.pone.0232855

    View details for PubMedID 32401791

  • Genome-wide association study of cognitive performance in US veterans with schizophrenia or bipolar disorder AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS Harvey, P. D., Sun, N., Bigdeli, T. B., Fanous, A. H., Aslan, M., Malhotra, A. K., Lu, Q., Hu, Y., Li, B., Chen, Q., Mane, S., Miller, P., Rajeevan, N., Sayward, F., Cheung, K., Li, Y., Greenwood, T. A., Gur, R. E., Braff, D. L., Brophy, M., Pyarajan, S., O'Leary, T. J., Gleason, T., Przygodszki, R., Muralidhar, S., Gaziano, J., Concato, J., Zhao, H., Siever, L. J., Braff, D. L., Calkins, M. E., Freedman, R., Green, M. F., Greenwood, T. A., Gur, R. E., Gur, R. C., Lazzeroni, L. C., Light, G. A., Nuechterlein, K. H., Radant, A. D., Seidman, L. J., Siever, L. J., Silverman, J. M., Stone, W. S., Sugar, C. A., Swerdlow, N. R., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Consortium Genetics Schizophrenia 2019

    Abstract

    Cognitive impairment is a frequent and serious problem in patients with various forms of severe mental illnesses (SMI), including schizophrenia (SZ) and bipolar disorder (BP). Recent research suggests genetic links to several cognitive phenotypes in both SMI and in the general population. Our goal in this study was to identify potential genomic signatures of cognitive functioning in veterans with severe mental illness and compare them to previous findings for cognition across different populations. Veterans Affairs (VA) Cooperative Studies Program (CSP) Study #572 evaluated cognitive and functional capacity measures among SZ and BP patients. In conjunction with the VA Million Veteran Program, 3,959 European American (1,095 SZ, 2,864 BP) and 2,601 African American (1,095 SZ, 2,864 BP) patients were genotyped using a custom Affymetrix Axiom Biobank array. We performed a genome-wide association study of global cognitive functioning, constructed polygenic scores for SZ and cognition in the general population, and examined genetic correlations with 2,626 UK Biobank traits. Although no single locus attained genome-wide significance, observed allelic effects were strongly consistent with previous studies. We observed robust associations between global cognitive functioning and polygenic scores for cognitive performance, intelligence, and SZ risk. We also identified significant genetic correlations with several cognition-related traits in UK Biobank. In a diverse cohort of U.S. veterans with SZ or BP, we demonstrate broad overlap of common genetic effects on cognition in the general population, and find that greater polygenic loading for SZ risk is associated with poorer cognitive performance.

    View details for DOI 10.1002/ajmg.b.32775

    View details for Web of Science ID 000504114200001

    View details for PubMedID 31872970

  • The Effects of Age and Sex on Cognitive Impairment in Schizophrenia: Findings From Cognitive From the Consortium on the Genetics of Schizophrenia (COGS) Study Lee, J., Green, M., Nuechterlein, K. H., Swerdlow, N., Greenwood, T., Lazzeroni, L., Light, G., Radant, A. D., Seidman, L., Siever, L., Silverman, J., Sprock, J., Stone, W., Sugar, C., Tsuang, D., Tsuang, M., Turetsky, B., Gur, R., Gur, R., Braff, D. NATURE PUBLISHING GROUP. 2019: 343
  • The effect of digital physical activity interventions on daily step count: a randomised controlled crossover substudy of the MyHeart Counts Cardiovascular Health Study. The Lancet. Digital health Shcherbina, A., Hershman, S. G., Lazzeroni, L., King, A. C., O'Sullivan, J. W., Hekler, E., Moayedi, Y., Pavlovic, A., Waggott, D., Sharma, A., Yeung, A., Christle, J. W., Wheeler, M. T., McConnell, M. V., Harrington, R. A., Ashley, E. A. 2019; 1 (7): e344-e352

    Abstract

    Smartphone apps might enable interventions to increase physical activity, but few randomised trials testing this hypothesis have been done. The MyHeart Counts Cardiovascular Health Study is a longitudinal smartphone-based study with the aim of elucidating the determinants of cardiovascular health. We aimed to investigate the effect of four different physical activity coaching interventions on daily step count in a substudy of the MyHeart Counts Study.In this randomised, controlled crossover trial, we recruited adults (aged ≥18 years) in the USA with access to an iPhone smartphone (Apple, Cupertino, CA, USA; version 5S or newer) who had downloaded the MyHeart Counts app (version 2.0). After completion of a 1 week baseline period of interaction with the MyHeart Counts app, participants were randomly assigned to receive one of 24 permutations (four combinations of four 7 day interventions) in a crossover design using a random number generator built into the app. Interventions consisted of either daily prompts to complete 10 000 steps, hourly prompts to stand following 1 h of sitting, instructions to read the guidelines from the American Heart Association website, or e-coaching based upon the individual's personal activity patterns from the baseline week of data collection. Participants completed the trial in a free-living setting. Due to the nature of the interventions, participants could not be masked from the intervention. Investigators were not masked to intervention allocation. The primary outcome was change in mean daily step count from baseline for each of the four interventions, assessed in the modified intention-to-treat analysis set, which included all participants who had completed 7 days of baseline monitoring and at least 1 day of one of the four interventions. This trial is registered with ClinicalTrials.gov, NCT03090321.Between Dec 12, 2016, and June 6, 2018, 2783 participants consented to enrol in the coaching study, of whom 1075 completed 7 days of baseline monitoring and at least 1 day of one of the four interventions and thus were included in the modified intention-to-treat analysis set. 493 individuals completed the full set of assigned interventions. All four interventions significantly increased mean daily step count from baseline (mean daily step count 2914 [SE 74]): mean step count increased by 319 steps (75) for participants in the American Heart Association website prompt group (p<0·0001), 267 steps (74) for participants in the hourly stand prompt group (p=0·0003), 254 steps (74) for participants in the cluster-specific prompts group (p=0·0006), and by 226 steps (75) for participants in the 10 000 daily step prompt group (p=0·0026 vs baseline).Four smartphone-based physical activity coaching interventions significantly increased daily physical activity. These findings suggests that digital interventions delivered via a mobile app have the ability to increase short-term physical activity levels in a free-living cohort.Stanford Data Science Initiative.

    View details for DOI 10.1016/S2589-7500(19)30129-3

    View details for PubMedID 33323209

  • The effect of digital physical activity interventions on daily step count: a randomised controlled crossover substudy of the MyHeart Counts Cardiovascular Health Study LANCET DIGITAL HEALTH Shcherbina, A., Hershman, S. G., Lazzeroni, L., King, A. C., O'Sullivan, J. W., Hekler, E., Moayedi, Y., Pavlovic, A., Waggott, D., Sharma, A., Yeung, A., Christle, J. W., Wheeler, M. T., McConnell, M. V., Harrington, R. A., Ashley, E. A. 2019; 1 (7): E344–E352
  • Genetic and environmental influences on corticostriatal circuits in twins with autism Journal of psychiatry & neuroscience : JPN Hegarty II, J. P., Lazzeroni, L. C., Raman, M. M., Hallmayer, J. F., Cleveland, S. C., Wolke, O. N., Phillips, J. M., Reiss, A. L., Hardan, A. Y. 2019; 44 (6): 190030

    Abstract

    Corticostriatal circuits (CSC) have been implicated in the presentation of some restricted and repetitive behaviours (RRBs) in children with autism-spectrum disorder (ASD), and preliminary evidence suggests that disruptions in these pathways may be associated with differences in genetic and environmental influences on brain development. The objective of this investigation was to examine the impact of genetic and environmental factors on CSC regions in twins with and without ASD and to evaluate their relationship with the severity of RRBs.We obtained T1-weighted MRIs from same-sex monozygotic and dizygotic twin pairs, aged 6–15 years. Good-quality data were available from 48 ASD pairs (n = 96 twins; 30 pairs concordant for ASD, 15 monozygotic and 15 dizygotic; 18 pairs discordant for ASD, 4 monozygotic and 14 dizygotic) and 34 typically developing control pairs (n = 68 twins; 20 monozygotic and 14 dizygotic pairs). We generated structural measures of the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), caudate, putamen, pallidum and thalamus using FreeSurfer. Twin pair comparisons included intraclass correlation analyses and ACE modelling (a2 = additive genetics; c2 = common or shared environment; e2 = unique or nonshared environment). We also assessed correlations with RRB severity.Structural variation in CSC regions was predominantly genetically mediated in typically developing twins (a2 = 0.56 to 0.87), except for ACC white matter volume (a2 = 0.42, 95% confidence interval [CI] 0.08 to 0.77). We also observed similar magnitudes of genetic influence in twins with ASD (a2 = 0.65 to 0.97), but the cortical thickness of the ACC (c2 = 0.44, 95% CI 0.22 to 0.66) and OFC (c2 = 0.60, 95% CI 0.25 to 0.95) was primarily associated with environmental factors in only twins with ASD. Twin pair differences in OFC grey matter volume were also correlated with RRB severity and were predominantly environmentally mediated.We obtained MRIs on 2 scanners, and analytical approaches could not identify specific genetic and environmental factors.Genetic factors primarily contribute to structural variation in subcortical CSC regions, regardless of ASD, but environmental factors may exert a greater influence on the development of grey matter thickness in the OFC and ACC in children with ASD. The increased vulnerability of OFC grey matter to environmental influences may also mediate some heterogeneity in RRB severity in children with ASD.

    View details for DOI 10.1503/jpn.190030

    View details for PubMedID 31603639

  • Genome-wide Association of Endophenotypes for Schizophrenia From the Consortium on the Genetics of Schizophrenia (COGS) Study. JAMA psychiatry Greenwood, T. A., Lazzeroni, L. C., Maihofer, A. X., Swerdlow, N. R., Calkins, M. E., Freedman, R., Green, M. F., Light, G. A., Nievergelt, C. M., Nuechterlein, K. H., Radant, A. D., Siever, L. J., Silverman, J. M., Stone, W. S., Sugar, C. A., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Gur, R. C., Gur, R. E., Braff, D. L. 2019

    Abstract

    Importance: The Consortium on the Genetics of Schizophrenia (COGS) uses quantitative neurophysiological and neurocognitive endophenotypes with demonstrated deficits in schizophrenia as a platform from which to explore the underlying neural circuitry and genetic architecture. Many of these endophenotypes are associated with poor functional outcome in schizophrenia. Some are also endorsed as potential treatment targets by the US Food and Drug Administration.Objective: To build on prior assessments of heritability, association, and linkage in the COGS phase 1 (COGS-1) families by reporting a genome-wide association study (GWAS) of 11 schizophrenia-related endophenotypes in the independent phase 2 (COGS-2) cohort of patients with schizophrenia and healthy comparison participants (HCPs).Design, Setting, and Participants: A total of 1789 patients with schizophrenia and HCPs of self-reported European or Latino ancestry were recruited through a collaborative effort across the COGS sites and genotyped using the PsychChip. Standard quality control filters were applied, and more than 6.2 million variants with a genotyping call rate of greater than 0.99 were available after imputation. Association was performed for data sets stratified by diagnosis and ancestry using linear regression and adjusting for age, sex, and 5 principal components, with results combined through weighted meta-analysis. Data for COGS-1 were collected from January 6, 2003, to August 6, 2008; data for COGS-2, from June 30, 2010, to February 14, 2014. Data were analyzed from October 28, 2016, to May 4, 2018.Main Outcomes and Measures: A genome-wide association study was performed to evaluate association for 11 neurophysiological and neurocognitive endophenotypes targeting key domains of schizophrenia related to inhibition, attention, vigilance, learning, working memory, executive function, episodic memory, and social cognition.Results: The final sample of 1533 participants included 861 male participants (56.2%), and the mean (SD) age was 41.8 (13.6) years. In total, 7 genome-wide significant regions (P<5*10-8) and 2 nearly significant regions (P<9*10-8) containing several genes of interest, including NRG3 and HCN1, were identified for 7 endophenotypes. For each of the 11 endophenotypes, enrichment analyses performed at the level of P<10-4 compared favorably with previous association results in the COGS-1 families and showed extensive overlap with regions identified for schizophrenia diagnosis.Conclusions and Relevance: These analyses identified several genomic regions of interest that require further exploration and validation. These data seem to demonstrate the utility of endophenotypes for resolving the genetic architecture of schizophrenia and characterizing the underlying biological dysfunctions. Understanding the molecular basis of these endophenotypes may help to identify novel treatment targets and pave the way for precision-based medicine in schizophrenia and related psychotic disorders.

    View details for DOI 10.1001/jamapsychiatry.2019.2850

    View details for PubMedID 31596458

  • Contributions of common genetic variants to risk of schizophrenia among individuals of African and Latino ancestry. Molecular psychiatry Bigdeli, T. B., Genovese, G., Georgakopoulos, P., Meyers, J. L., Peterson, R. E., Iyegbe, C. O., Medeiros, H., Valderrama, J., Achtyes, E. D., Kotov, R., Stahl, E. A., Abbott, C., Azevedo, M. H., Belliveau, R. A., Bevilacqua, E., Bromet, E. J., Byerley, W., Carvalho, C. B., Chapman, S. B., DeLisi, L. E., Dumont, A. L., O'Dushlaine, C., Evgrafov, O. V., Fochtmann, L. J., Gage, D., Kennedy, J. L., Kinkead, B., Macedo, A., Moran, J. L., Morley, C. P., Dewan, M. J., Nemesh, J., Perkins, D. O., Purcell, S. M., Rakofsky, J. J., Scolnick, E. M., Sklar, B. M., Sklar, P., Smoller, J. W., Sullivan, P. F., Macciardi, F., Marder, S. R., Gur, R. C., Gur, R. E., Braff, D. L., Consortium on the Genetics of Schizophrenia (COGS) Investigators, Nicolini, H., Escamilla, M. A., Vawter, M. P., Sobell, J. L., Malaspina, D., Lehrer, D. S., Buckley, P. F., Rapaport, M. H., Knowles, J. A., Genomic Psychiatry Cohort (GPC) Consortium, Fanous, A. H., Pato, M. T., McCarroll, S. A., Pato, C. N., Calkins, M. E., Freedman, R. R., Green, M. F., Greenwood, T. A., Lazzeroni, L. C., Light, G. A., Nuechterlein, K. H., Radant, A. D., Seidman, L. J., Siever, L. J., Silverman, J. M., Stone, W. S., Sugar, C. A., Swerdlow, N. R., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I. 2019

    Abstract

    Schizophrenia is a common, chronic and debilitating neuropsychiatric syndrome affecting tens of millions of individuals worldwide. While rare genetic variants play a role in the etiology of schizophrenia, most of the currently explained liability is within common variation, suggesting that variation predating the human diaspora out of Africa harbors a large fraction of the common variant attributable heritability. However, common variant association studies in schizophrenia have concentrated mainly on cohorts of European descent. We describe genome-wide association studies of 6152 cases and 3918 controls of admixed African ancestry, and of 1234 cases and 3090 controls of Latino ancestry, representing the largest such study in these populations to date. Combining results from the samples with African ancestry with summary statistics from the Psychiatric Genomics Consortium (PGC) study of schizophrenia yielded seven newly genome-wide significant loci, and we identified an additional eight loci by incorporating the results from samples with Latino ancestry. Leveraging population differences in patterns of linkage disequilibrium, we achieve improved fine-mapping resolution at 22 previously reported and 4 newly significant loci. Polygenic risk score profiling revealed improved prediction based on trans-ancestry meta-analysis results for admixed African (Nagelkerke's R2=0.032; liability R2=0.017; P<10-52), Latino (Nagelkerke's R2=0.089; liability R2=0.021; P<10-58), and European individuals (Nagelkerke's R2=0.089; liability R2=0.037; P<10-113), further highlighting the advantages of incorporating data from diverse human populations.

    View details for DOI 10.1038/s41380-019-0517-y

    View details for PubMedID 31591465

  • Characterization of Pre-Deviant Standard Effects on MMN and P3a in Schizophrenia: Findings From Consortium on the Genetics of Schizophrenia (COGS) Joshi, Y., Molina, J., Sharp, R., Light, G., COGS Investigators ELSEVIER SCIENCE INC. 2019: S285
  • Regional Variation in RBM20 Causes a Highly Penetrant Arrhythmogenic Cardiomyopathy CIRCULATION-HEART FAILURE Parikh, V. N., Caleshu, C., Reuter, C., Lazzeroni, L. C., Ingles, J., Garcia, J., McCaleb, K., Adesiyun, T., Sedaghat-Hamedani, F., Kumar, S., Graw, S., Gigli, M., Stolfo, D., Dal Ferro, M., Ing, A. Y., Nussbaum, R., Funke, B., Wheeler, M. T., Hershberger, R. E., Cook, S., Steinmetz, L. M., Lakdawala, N. K., Taylor, M. G., Mestroni, L., Merlo, M., Sinagra, G., Semsarian, C., Meder, B., Judge, D. P., Ashley, E. 2019; 12 (3)
  • Nonlinear dynamics underlying sensory processing dysfunction in schizophrenia. Proceedings of the National Academy of Sciences of the United States of America Lainscsek, C., Sampson, A. L., Kim, R., Thomas, M. L., Man, K., Lainscsek, X., COGS Investigators, Swerdlow, N. R., Braff, D. L., Sejnowski, T. J., Light, G. A., Light, G. A., Swerdlow, N. R., Thomas, M. L., Green, M. F., Greenwood, T. A., Gur, R. E., Gur, R. C., Lazzeroni, L. C., Nuechterlein, K. H., Radant, A. D., Seidman, L. J., Sharp, R. F., Siever, L. J., Silverman, J. M., Sprock, J., Stone, W. S., Sugar, C. A., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Braff, D. L. 2019; 116 (9): 3847–52

    Abstract

    Natural systems, including the brain, often seem chaotic, since they are typically driven by complex nonlinear dynamical processes. Disruption in the fluid coordination of multiple brain regions contributes to impairments in information processing and the constellation of symptoms observed in neuropsychiatric disorders. Schizophrenia (SZ), one of the most debilitating mental illnesses, is thought to arise, in part, from such a network dysfunction, leading to impaired auditory information processing as well as cognitive and psychosocial deficits. Current approaches to neurophysiologic biomarker analyses predominantly rely on linear methods and may, therefore, fail to capture the wealth of information contained in whole EEG signals, including nonlinear dynamics. In this study, delay differential analysis (DDA), a nonlinear method based on embedding theory from theoretical physics, was applied to EEG recordings from 877 SZ patients and 753 nonpsychiatric comparison subjects (NCSs) who underwent mismatch negativity (MMN) testing via their participation in the Consortium on the Genetics of Schizophrenia (COGS-2) study. DDA revealed significant nonlinear dynamical architecture related to auditory information processing in both groups. Importantly, significant DDA changes preceded those observed with traditional linear methods. Marked abnormalities in both linear and nonlinear features were detected in SZ patients. These results illustrate the benefits of nonlinear analysis of brain signals and underscore the need for future studies to investigate the relationship between DDA features and pathophysiology of information processing.

    View details for DOI 10.1073/pnas.1810572116

    View details for PubMedID 30808768

  • Genetic and environmental influences on structural brain measures in twins with autism spectrum disorder. Molecular psychiatry Hegarty, J. P., Pegoraro, L. F., Lazzeroni, L. C., Raman, M. M., Hallmayer, J. F., Monterrey, J. C., Cleveland, S. C., Wolke, O. N., Phillips, J. M., Reiss, A. L., Hardan, A. Y. 2019

    Abstract

    Atypical growth patterns of the brain have been previously reported in autism spectrum disorder (ASD) but these alterations are heterogeneous across individuals, which may be associated with the variable effects of genetic and environmental influences on brain development. Monozygotic (MZ) and dizygotic (DZ) twin pairs with and without ASD (aged 6-15 years) were recruited to participate in this study. T1-weighted MRIs (n=164) were processed with FreeSurfer to evaluate structural brain measures. Intra-class correlations were examined within twin pairs and compared across diagnostic groups. ACE modeling was also completed. Structural brain measures, including cerebral and cerebellar gray matter (GM) and white matter (WM) volume, surface area, and cortical thickness, were primarily influenced by genetic factors in TD twins; however, mean curvature appeared to be primarily influenced by environmental factors. Similarly, genetic factors accounted for the majority of variation in brain size in twins with ASD, potentially to a larger extent regarding curvature and subcortical GM; however, there were also more environmental contributions in twins with ASD on some structural brain measures, such that cortical thickness and cerebellar WM volume were primarily influenced by environmental factors. These findings indicate potential neurobiological outcomes of the genetic and environmental risk factors that have been previously associated with ASD and, although preliminary, may help account for some of the previously outlined neurobiological heterogeneity across affected individuals. This is especially relevant regarding the role of genetic and environmental factors in the development of ASD, in which certain brain structures may be more sensitive to specific influences.

    View details for PubMedID 30659287

  • The effects of repetitive transcranial magnetic stimulation in older adults with mild cognitive impairment: a protocol for a randomized, controlled three-arm trial. BMC neurology Taylor, J. L., Hambro, B. C., Strossman, N. D., Bhatt, P. n., Hernandez, B. n., Ashford, J. W., Cheng, J. J., Iv, M. n., Adamson, M. M., Lazzeroni, L. C., McNerney, M. W. 2019; 19 (1): 326

    Abstract

    Mild Cognitive Impairment (MCI) carries a high risk of progression to Alzheimer's disease (AD) dementia. Previous clinical trials testing whether cholinesterase inhibitors can slow the rate of progression from MCI to AD dementia have yielded disappointing results. However, recent studies of the effects of repetitive transcranial magnetic stimulation (rTMS) in AD have demonstrated improvements in cognitive function. Because few rTMS trials have been conducted in MCI, we designed a trial to test the short-term efficacy of rTMS in MCI. Yet, in both MCI and AD, we know little about what site of stimulation would be ideal for improving cognitive function. Therefore, two cortical sites will be investigated in this trial: (1) the dorsolateral prefrontal cortex (DLPFC), which has been well studied for treatment of major depressive disorder; and (2) the lateral parietal cortex (LPC), a novel site with connectivity to AD-relevant limbic regions.In this single-site trial, we plan to enroll 99 participants with single or multi-domain amnestic MCI. We will randomize participants to one of three groups: (1) Active DLPFC rTMS; (2) Active LPC rTMS; and (3) Sham rTMS (evenly split between DLPFC and LPC locations). After completing 20 bilateral rTMS treatment sessions, participants will be followed for 6 months to test short-term efficacy and track durability of effects. The primary efficacy measure is the California Verbal Learning Test-II (CVLT-II), assessed 1 week after intervention. Secondary analyses will examine effects of rTMS on other cognitive measures, symptoms of depression, and brain function with respect to the site of stimulation. Finally, selected biomarkers will be analyzed to explore predictors of response and mechanisms of action.The primary aim of this trial is to test the short-term efficacy of rTMS in MCI. Additionally, the project will provide information on the durability of cognitive effects and potentially distinct effects of stimulating DLPFC versus LPC regions. Future efforts would be directed toward better understanding therapeutic mechanisms and optimizing rTMS for treatment of MCI. Ultimately, if rTMS can be utilized to slow the rate of progression to AD dementia, this will be a significant advancement in the field.Clinical Trials NCT03331796. Registered 6 November 2017, https://clinicaltrials.gov/ct2/show/NCT03331796. All items from the World Health Organization Trial Registration Data Set are listed in Appendix A.This report is based on version 1, approved by the DSMB on 30 November, 2017 and amended on 14 August, 2018 and 19 September, 2019.

    View details for DOI 10.1186/s12883-019-1552-7

    View details for PubMedID 31842821

  • Genetic and Environmental Influences on Lobar Brain Structures in Twins With Autism. Cerebral cortex (New York, N.Y. : 1991) Hegarty, J. P., Lazzeroni, L. C., Raman, M. M., Pegoraro, L. F., Monterrey, J. C., Cleveland, S. C., Hallmayer, J. F., Wolke, O. N., Phillips, J. M., Reiss, A. L., Hardan, A. Y. 2019

    Abstract

    This investigation examined whether the variation of cerebral structure is associated with genetic or environmental factors in children with autism spectrum disorder (ASD) compared with typically developing (TD) controls. T1-weighted magnetic resonance imaging scans were obtained from twin pairs (aged 6-15 years) in which at least one twin was diagnosed with ASD or both were TD. Good quality data were available from 30 ASD, 18 discordant, and 34 TD pairs (n = 164). Structural measures (volume, cortical thickness, and surface area) were generated with FreeSurfer, and ACE modeling was completed. Lobar structures were primarily genetically mediated in TD twins (a2 = 0.60-0.89), except thickness of the temporal (a2 = 0.33 [0.04, 0.63]) and occipital lobes (c2 = 0.61 [0.45, 0.77]). Lobar structures were also predominantly genetically mediated in twins with ASD (a2 = 0.70-1.00); however, thickness of the frontal (c2 = 0.81 [0.71, 0.92]), temporal (c2 = 0.77 [0.60, 0.93]), and parietal lobes (c2 = 0.87 [0.77, 0.97]), and frontal gray matter (GM) volume (c2 = 0.79 [0.63, 0.95]), were associated with environmental factors. Conversely, occipital thickness (a2 = 0.93 [0.75, 1.11]) did not exhibit the environmental contributions that were found in controls. Differences in GM volume were associated with social communication impairments for the frontal (r = 0.52 [0.18, 0.75]), temporal (r = 0.61 [0.30, 0.80]), and parietal lobes (r = 0.53 [0.19, 0.76]). To our knowledge, this is the first investigation to suggest that environmental factors influence GM to a larger extent in children with ASD, especially in the frontal lobe.

    View details for DOI 10.1093/cercor/bhz215

    View details for PubMedID 31711118

  • Impact of race/ethnicity on insulin resistance and hypertriglyceridaemia. Diabetes & vascular disease research Raygor, V. n., Abbasi, F. n., Lazzeroni, L. C., Kim, S. n., Ingelsson, E. n., Reaven, G. M., Knowles, J. W. 2019; 16 (2): 153–59

    Abstract

    Insulin sensitivity affects plasma triglyceride concentration and both differ by race/ethnicity. The purpose of this study was to provide a comprehensive assessment of the variation in insulin sensitivity and its relationship to hypertriglyceridaemia between five race/ethnic groups.In this cross-sectional study, clinical data for 1025 healthy non-Hispanic White, Hispanic White, East Asian, South Asian and African American individuals were analysed. Insulin-mediated glucose disposal (a direct measure of peripheral insulin sensitivity) was measured using the modified insulin suppression test. Statistical analysis was performed using analysis of co-variance.Of the study participants, 63% were non-Hispanic White, 9% were Hispanic White, 11% were East Asian, 11% were South Asian and 6% were African American. Overall, non-Hispanic Whites and African Americans displayed greater insulin sensitivity than East Asians and South Asians. Triglyceride concentration was positively associated with insulin resistance in all groups, including African Americans. Nevertheless, for any given level of insulin sensitivity, African Americans had the lowest triglyceride concentrations.Insulin sensitivity, as assessed by a direct measure of insulin-mediated glucose disposal, and its relationship to triglyceride concentration vary across five race/ethnic groups. Understanding these relationships is crucial for accurate cardiovascular risk stratification and prevention.

    View details for PubMedID 31014093

  • The Myheart Counts Cardiovascular Health Study: A Randomized Controlled Trial of Digital Health Coaching for Physical Activity Promotion Shcherbina, A., Hershman, S., King, A. C., Hekler, E., Pavlovic, A., Waggott, D., McConnell, M. V., Ashley, E. A., Harrington, R. A. LIPPINCOTT WILLIAMS & WILKINS. 2018: E767
  • Regional Variation in RBM20 Causes a Highly Penetrant Arrhythmogenic Cardiomyopathy. Parikh, V. N., Caleshu, C., Reuter, C., Lazzeroni, L., Ingles, J., Kumar, S., Garcia, J., McCaleb, K., Adesiyun, T., Dedaghat-Hamedani, F., Graw, S., Gigli, M., Stolfo, D., Dal Ferro, M., Ing, A., Nussbaum, R., Funke, B., Wheeler, M. T., Hershberger, R. E., Cook, S., Steinmetz, L., Lakdawala, N. K., Taylor, M. R., Mestroni, L., Merlo, M., Sinagra, G., Semsarian, C., Meder, B., Judge, D. P., Ashley, E. A. LIPPINCOTT WILLIAMS & WILKINS. 2018
  • Deficient prepulse inhibition in schizophrenia in a multi-site cohort: Internal replication and extension SCHIZOPHRENIA RESEARCH Swerdlow, N. R., Light, G. A., Thomas, M. L., Sprock, J., Calkins, M. E., Green, M. F., Greenwood, T. A., Gur, R. E., Gur, R. C., Lazzeroni, L. C., Nuechterlein, K. H., Radant, A. D., Seidman, L. J., Siever, L. J., Silverman, J. M., Stone, W. S., Sugar, C. A., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Braff, D. L. 2018; 198: 6–15
  • Genome-Wide Association of Endophenotypes for Schizophrenia From the Consortium On the Genetics of Schizophrenia (COGS) Study Greenwood, T., Lazzeroni, L., Calkins, M., Freedman, R., Green, M., Gur, R., Gur, R., Light, G., Nuechterlein, K., Olincy, A., Radant, A., Seidman, L., Siever, L., Silverman, J., Stone, W., Sugar, C., Swerdlow, N., Tsuang, D., Tsuang, M., Turetsky, B., Braff, D. ELSEVIER SCIENCE INC. 2018: S428–S429
  • Genome-Wide Association of Endophenotypes for Schizophrenia From the Consortium on the Genetics of Schizophrenia (COGS) Study Greenwood, T., Lazzeroni, L., Calkins, M. E., Freedman, R., Green, M. F., Gur, R. E., Gur, R. C., Light, G., Nuechterlein, K., Olincy, A., Radant, A., Seidman, L., Siever, L., Silverman, J., Stone, W., Sugar, C., Swerdlow, N., Tsuang, D., Tsuang, M., Turetsky, B., Braff, D. ELSEVIER SCIENCE INC. 2018: S44
  • History of Cannabis Use is Associated With Greater Impairment in Neurophysiological, Clinical and Functional Measures in Schizophrenia Patients Molina, J., Swerdlow, N. R., Joshi, Y. B., Thomas, M. L., Sprock, J., Calkins, M. E., Green, M. F., Greenwood, T. A., Gur, R. E., Gur, R. C., Lazzeroni, L. C., Nuechterlein, K. H., Radant, A. D., Seidman, L. J., Siever, L. J., Silverman, J. M., Stone, W. S., Sugar, C. A., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Braff, D. L., Light, G. A. NATURE PUBLISHING GROUP. 2017: S423–S424
  • Genome-Wide Association of Endophenotypes for Schizophrenia Greenwood, T., Lazzeroni, L., Calkins, M., Freedman, R., Green, M., Gur, R., Gur, R., Light, G., Nuechterlein, K., Olincy, A., Radant, A., Seidman, L., Siever, L., Silverman, J., Stone, W., Sugar, C., Swerdlow, N., Tsuang, D., Tsuang, M., Turetsky, B., Braff, D. NATURE PUBLISHING GROUP. 2017: S433
  • Deficient prepulse inhibition in schizophrenia in a multi-site cohort: Internal replication and extension. Schizophrenia research Swerdlow, N. R., Light, G. A., Thomas, M. L., Sprock, J., Calkins, M. E., Green, M. F., Greenwood, T. A., Gur, R. E., Gur, R. C., Lazzeroni, L. C., Nuechterlein, K. H., Radant, A. D., Seidman, L. J., Siever, L. J., Silverman, J. M., Stone, W. S., Sugar, C. A., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Braff, D. L. 2017

    Abstract

    The Consortium on the Genetics of Schizophrenia (COGS) collected case-control endophenotype and genetic information from 2457 patients and healthy subjects (HS) across 5 test sites over 3.5 years. Analysis of the first "wave" (W1) of 1400 subjects identified prepulse inhibition (PPI) deficits in patients vs. HS. Data from the second COGS "wave" (W2), and the combined W(1+2), were used to assess: 1) the replicability of PPI deficits in this design; 2) the impact of response criteria on PPI deficits; and 3) PPI in a large cohort of antipsychotic-free patients.PPI in W2 HS (n=315) and schizophrenia patients (n=326) was compared to findings from W1; planned analyses assessed the impact of diagnosis, "wave" (1 vs. 2), and startle magnitude criteria. Combining waves allowed us to assess PPI in 120 antipsychotic-free patients, including many in the early course of illness.ANOVA of all W(1+2) subjects revealed robust PPI deficits in patients across "waves" (p<0.0004). Strict response criteria excluded almost 39% of all subjects, disproportionately impacting specific subgroups; ANOVA in this smaller cohort confirmed no significant effect of "wave" or "wave x diagnosis" interaction, and a significant effect of diagnosis (p<0.002). Antipsychotic-free, early-illness patients had particularly robust PPI deficits.Schizophrenia-linked PPI deficits were replicable across two multi-site "waves" of subjects collected over 3.5years. Strict response criteria disproportionately excluded older, male, non-Caucasian patients with low-normal hearing acuity. These findings set the stage for genetic analyses of PPI using the combined COGS wave 1 and 2 cohorts.

    View details for DOI 10.1016/j.schres.2017.05.013

    View details for PubMedID 28549722

  • Results from a clinical yoga program for veterans: yoga via telehealth provides comparable satisfaction and health improvements to in-person yoga BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE Schulz-Heik, R. J., Meyer, H., Mahoney, L., Stanton, M. V., Cho, R. H., Moore-Downing, D. P., Avery, T. J., Lazzeroni, L. C., Varni, J. M., Collery, L. M., Bayley, P. J. 2017; 17

    Abstract

    Yoga is increasingly popular, though little data regarding its implementation in healthcare settings is available. Similarly, telehealth is being utilized more frequently to increase access to healthcare; however we know of no research on the acceptability or effectiveness of yoga delivered through telehealth. Therefore, we evaluated the feasibility, acceptability, and patient-reported effectiveness of a clinical yoga program at a Veterans Affairs Medical Center and assessed whether these outcomes differed between those participating in-person and those participating via telehealth.Veterans who attended a yoga class at the VA Palo Alto Health Care System were invited to complete an anonymous program evaluation survey.64 Veterans completed the survey. Participants reported high satisfaction with the classes and the instructors. More than 80% of participants who endorsed a problem with pain, energy level, depression, or anxiety reported improvement in these symptoms. Those who participated via telehealth did not differ from those who participated in-person in any measure of satisfaction, overall improvement (p = .40), or improvement in any of 16 specific health problems.Delivering yoga to a wide range of patients within a healthcare setting appears to be feasible and acceptable, both when delivered in-person and via telehealth. Patients in this clinical yoga program reported high levels of satisfaction and improvement in multiple problem areas. This preliminary evidence for the effectiveness of a clinical yoga program complements prior evidence for the efficacy of yoga and supports the use of yoga in healthcare settings.

    View details for DOI 10.1186/s12906-017-1705-4

    View details for Web of Science ID 000398770400012

    View details for PubMedID 28376861

    View details for PubMedCentralID PMC5381127

  • HPA axis in major depression: cortisol, clinical symptomatology and genetic variation predict cognition MOLECULAR PSYCHIATRY Keller, J., Gomez, R., Williams, G., Lembke, A., Lazzeroni, L., urphy, G. M., Schatzberg, A. F. 2017; 22 (4): 527-536

    Abstract

    The hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathophysiology of a variety of mood and cognitive disorders. Neuroendocrine studies have demonstrated HPA axis overactivity in major depression, a relationship of HPA axis activity to cognitive performance and a potential role of HPA axis genetic variation in cognition. The present study investigated the simultaneous roles HPA axis activity, clinical symptomatology and HPA genetic variation play in cognitive performance. Patients with major depression with psychotic major depression (PMD) and with nonpsychotic major depression (NPMD) and healthy controls (HC) were studied. All participants underwent a diagnostic interview and psychiatric ratings, a comprehensive neuropsychological battery, overnight hourly blood sampling for cortisol and genetic assessment. Cognitive performance differed as a function of depression subtype. Across all subjects, cognitive performance was negatively correlated with higher cortisol, and PMD patients had higher cortisol than did NPMDs and HCs. Cortisol, clinical symptoms and variation in genes, NR3C1 (glucocorticoid receptor; GR) and NR3C2 (mineralocorticoid receptor; MR) that encode for GRs and MRs, predicted cognitive performance. Beyond the effects of cortisol, demographics and clinical symptoms, NR3C1 variation predicted attention and working memory, whereas NR3C2 polymorphisms predicted memory performance. These findings parallel the distribution of GR and MR in primate brain and their putative roles in specific cognitive tasks. HPA axis genetic variation and activity were important predictors of cognition across the entire sample of depressed subjects and HR. GR and MR genetic variation predicted unique cognitive functions, beyond the influence of cortisol and clinical symptoms. GR genetic variation was implicated in attention and working memory, whereas MR was implicated in verbal memory.Molecular Psychiatry advance online publication, 16 August 2016; doi:10.1038/mp.2016.120.

    View details for DOI 10.1038/mp.2016.120

    View details for Web of Science ID 000397099900006

  • Volume of subclinical embolic infarct correlates to long-term cognitive changes after carotid revascularization. Journal of vascular surgery Zhou, W., Baughman, B. D., Soman, S., Wintermark, M., Lazzeroni, L. C., Hitchner, E., Bhat, J., Rosen, A. 2017; 65 (3): 686-694

    Abstract

    Carotid intervention is safe and effective in stroke prevention in appropriately selected patients. Despite minimal neurologic complications, procedure-related subclinical microemboli are common and their cognitive effects are largely unknown. In this prospective longitudinal study, we sought to determine long-term cognitive effects of embolic infarcts.The study recruited 119 patients including 46% symptomatic patients who underwent carotid revascularization. Neuropsychological testing was administered preoperatively and at 1 month, 6 months, and 12 months postoperatively. Rey Auditory Verbal Learning Test (RAVLT) was the primary cognitive measure with parallel forms to avoid practice effect. All patients also received 3T brain magnetic resonance imaging with a diffusion-weighted imaging (DWI) sequence preoperatively and within 48 hours postoperatively to identify procedure-related new embolic lesions. Each DWI lesion was manually traced and input into a neuroimaging program to define volume. Embolic infarct volumes were correlated with cognitive measures. Regression models were used to identify relationships between infarct volumes and cognitive measures.A total of 587 DWI lesions were identified on 3T magnetic resonance imaging in 81.7% of carotid artery stenting (CAS) and 36.4% of carotid endarterectomy patients with a total volume of 29,327 mm(3). Among them, 54 DWI lesions were found in carotid endarterectomy patients and 533 in the CAS patients. Four patients had transient postoperative neurologic symptoms and one had a stroke. CAS was an independent predictor of embolic infarction (odds ratio, 6.6 [2.1-20.4]; P < .01) and infarct volume (P = .004). Diabetes and contralateral carotid severe stenosis or occlusion had a trend of positive association with infarct volume, whereas systolic blood pressure ≥140 mm Hg had a negative association (P = .1, .09, and .1, respectively). There was a trend of improved RAVLT scores overall after carotid revascularization. Significantly higher infarct volumes were observed among those with RAVLT decline. Within the CAS cohort, infarct volume was negatively correlated with short- and long-term RAVLT changes (P < .05).Cognitive assessment of procedure-related subclinical microemboli is challenging. Volumes of embolic infarct correlate with long-term cognitive changes, suggesting that microembolization should be considered a surrogate measure for carotid disease management.

    View details for DOI 10.1016/j.jvs.2016.09.057

    View details for PubMedID 28024850

  • Incidental brain MRI findings in an autism twin study. Autism research Monterrey, J. C., Philips, J., Cleveland, S., Tanaka, S., Barnes, P., Hallmayer, J. F., Reiss, A. L., Lazzeroni, L. C., Hardan, A. Y. 2017; 10 (1): 113-120

    Abstract

    Brain magnetic resonance imaging (MRI) studies suggest the prevalence of asymptomatic "incidental" findings (IF) in autism spectrum disorder (ASD) is similar to that of neurotypically developing (NT) controls. However, given the causes of IF may include both genetic and environmental factors, a twin study would facilitate comparing brain IF between ASD and NT subjects. MRI scans were examined to assess the prevalence of brain IF in twin "case pairs" (at least one twin with diagnosis of ASD) and twin "control pairs" (NT). Fifty case pairs and thirty-two control pairs were analyzed. IF were found in 68% of subjects with ASD, 71% of unaffected ASD siblings, and in 58% of control subjects (P = 0.4). IF requiring clinical follow-up occurred more frequently in subjects with ASD compared to NT controls (17% vs. 5%, respectively; P = 0.02). The concordance rate of IF in twins was 83%. A mixed effects model found younger age, male sex, and "family environment" to be significantly associated with IF. There was no difference in the prevalence rate of IF between ASD subjects and NT controls. More IF required clinical follow-up in ASD subjects compared to NT controls. The prevalence rate of IF observed in this twin study was higher than rates previously reported in singleton studies. Our results suggest the shared environment of twins - perhaps in utero - increases the risk of brain IF. Brain MRI in the initial work-up of ASD may be indicated in twins, especially in males. Autism Res 2016. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

    View details for DOI 10.1002/aur.1720

    View details for PubMedID 27874265

  • A proton MR spectroscopy study of the thalamus in twins with autism spectrum disorder. Progress in neuro-psychopharmacology & biological psychiatry Hegarty, J. P., Gu, M. n., Spielman, D. M., Cleveland, S. C., Hallmayer, J. F., Lazzeroni, L. C., Raman, M. M., Frazier, T. W., Phillips, J. M., Reiss, A. L., Hardan, A. Y. 2017

    Abstract

    Multiple lines of research have reported thalamic abnormalities in individuals with autism spectrum disorder (ASD) that are associated with social communication impairments (SCI), restricted and repetitive behaviors (RRB), or sensory processing abnormalities (SPA). Thus, the thalamus may represent a common neurobiological structure that is shared across symptom domains in ASD. Same-sex monozygotic (MZ) and dizygotic (DZ) twin pairs with and without ASD underwent cognitive/behavioral evaluation and magnetic resonance imaging to assess the thalamus. Neurometabolites were measured with (1)H magnetic resonance spectroscopy (MRS) utilizing a multi-voxel PRESS sequence and were referenced to creatine+phosphocreatine (tCr). N-acetyl aspartate (NAA), a marker of neuronal integrity, was reduced in twins with ASD (n=47) compared to typically-developing (TD) controls (n=33), and this finding was confirmed in a sub-sample of co-twins discordant for ASD (n=11). NAA in the thalamus was correlated to a similar extent with SCI, RRB, and SPA, such that reduced neuronal integrity was associated with greater symptom severity. Glutamate+glutamine (Glx) was also reduced in affected versus unaffected co-twins. Additionally, NAA and Glx appeared to be primarily genetically-mediated, based on comparisons between MZ and DZ twin pairs. Thus, thalamic abnormalities may be influenced by genetic susceptibility for ASD but are likely not domain-specific.

    View details for PubMedID 28941767

  • EHRs and RCTs: Outcome Predictions vs. Optimal Treatment Selection Statistical Thinking http://www.fharrell.com/2017/06/ehrs-and-rcts-outcome-prediction-vs.html (blog article) Harrell, F., Lazzeroni, L. C. 2017
  • Modeling Deficits From Early Auditory Information Processing to Psychosocial Functioning in Schizophrenia JAMA PSYCHIATRY Thomas, M. L., Green, M. F., Hellemann, G., Sugar, C. A., Tarasenko, M., Calkins, M. E., Greenwood, T. A., Gur, R. E., Gur, R. C., Lazzeroni, L. C., Nuechterlein, K. H., Radant, A. D., Seidman, L. J., Shiluk, A. L., Siever, L. J., Silverman, J., Sprock, J., Stone, W. S., Swerdlow, N. R., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Braff, D. L., Light, G. A. 2017; 74 (1): 37-46

    Abstract

    Neurophysiologic measures of early auditory information processing (EAP) are used as endophenotypes in genomic studies and biomarkers in clinical intervention studies. Research in schizophrenia has established correlations among measures of EAP, cognition, clinical symptoms, and functional outcome. Clarifying these associations by determining the pathways through which deficits in EAP affect functioning would suggest when and where to therapeutically intervene.To characterize the pathways from EAP to outcome and to estimate the extent to which enhancement of basic information processing might improve cognition and psychosocial functioning in schizophrenia.Cross-sectional data were analyzed using structural equation modeling to examine the associations among EAP, cognition, negative symptoms, and functional outcome. Participants were recruited from the community at 5 geographically distributed laboratories as part of the Consortium on the Genetics of Schizophrenia 2 from July 1, 2010, through January 31, 2014. This well-characterized cohort of 1415 patients with schizophrenia underwent EAP, cognitive, and thorough clinical and functional assessment.Mismatch negativity, P3a, and reorienting negativity were used to measure EAP. Cognition was measured by the Letter Number Span test and scales from the California Verbal Learning Test-Second Edition, the Wechsler Memory Scale-Third Edition, and the Penn Computerized Neurocognitive Battery. Negative symptoms were measured by the Scale for the Assessment of Negative Symptoms. Functional outcome was measured by the Role Functioning Scale.Participants included 1415 unrelated outpatients diagnosed with schizophrenia or schizoaffective disorder (mean [SD] age, 46 [11] years; 979 males [69.2%] and 619 white [43.7%]). Early auditory information processing had a direct effect on cognition (β = 0.37, P < .001), cognition had a direct effect on negative symptoms (β = -0.16, P < .001), and both cognition (β = 0.26, P < .001) and experiential negative symptoms (β = -0.75, P < .001) had direct effects on functional outcome. The indirect effect of EAP on functional outcome was significant as well (β = 0.14, P < .001). Overall, EAP had a fully mediated effect on functional outcome, engaging general rather than modality-specific cognition, with separate pathways that involved or bypassed negative symptoms.The data support a model in which EAP deficits lead to poor functional outcome via impaired cognition and increased negative symptoms. Results can be used to help guide mechanistically informed, personalized treatments and support the strategy of using EAP measures as surrogate end points in early-stage procognitive intervention studies.

    View details for DOI 10.1001/jamapsychiatry.2016.2980

    View details for PubMedID 27926742

  • THALAMIC METABOLITE LEVELS AND SENSORY PROCESSING IN TWINS WITH AUTISM SPECTRUM DISORDER Hegarty, J. P., Gu, M., Spielman, D., Cleveland, S., Hallmayer, J. J., Lazzeroni, L. C., Raman, M., Monterrey, J., Frazier, T., Phillips, J. M., Reiss, A. L., Hardan, A. ELSEVIER SCIENCE INC. 2016: S102
  • Principal components analysis of agitation outcomes in Alzheimer's disease JOURNAL OF PSYCHIATRIC RESEARCH Yesavage, J. A., Taylor, J. L., Friedman, L., Rosenberg, P. B., Lazzeroni, L. C., Leoutsakos, J. S., Kinoshita, L. M., Perlow, M. J., Munro, C. A., Devanand, D. P., Drye, L. T., Mintzer, J. E., Pollock, B. G., Porsteinsson, A. P., Schneider, L. S., Shade, D. M., Weintraub, D., Lyketsos, C. G., Noda, A. 2016; 79: 4-7

    Abstract

    We developed a composite measure of agitation as a secondary outcome of change over time in the Citalopram for Agitation in Alzheimer's disease study (CitAD). CitAD demonstrated a positive effect of citalopram on agitation on the Neurobehavioral Rating Scale agitation subscale (NBRS-A). CitAD included additional agitation measures such as the Cohen-Mansfield Agitation Inventory and the Neuropsychiatric Inventory.We performed principal components analyses on change in individual item of these scales for the same, original CitAD subjects.The first principal component accounted for 12.6% of the observed variance and was composed of items that appear to reflect agitation. The effect size for citalopram calculated using this component was 0.53 (95% CI 0.22-0.83) versus 0.32 for the NBRS-A (95% CI 0.01-0.62).Results suggest that a composite measure of change in agitation might be more sensitive than change in a single primary agitation measure.

    View details for DOI 10.1016/j.jpsychires.2016.04.004

    View details for Web of Science ID 000378179000002

    View details for PubMedID 27115509

  • Prioritizing schizophrenia endophenotypes for future genetic studies: An example using data from the COGS-1 family study SCHIZOPHRENIA RESEARCH Millard, S. P., Shofer, J., Braff, D., Calkins, M., Cadenhead, K., Freedman, R., Green, M. F., Greenwood, T. A., Gur, R., Gur, R., Lazzeroni, L. C., Light, G. A., Olincy, A., Nuechterlein, K., Seidman, L., Siever, L., Silverman, J., Stone, W. S., Sprock, J., Sugar, C. A., Swerdlow, N. R., Tsuang, M., Turetsky, B., Radant, A., Tsuang, D. 2016; 174 (1-3): 1-9

    Abstract

    Past studies describe numerous endophenotypes associated with schizophrenia (SZ), but many endophenotypes may overlap in information they provide, and few studies have investigated the utility of a multivariate index to improve discrimination between SZ and healthy community comparison subjects (CCS). We investigated 16 endophenotypes from the first phase of the Consortium on the Genetics of Schizophrenia, a large, multi-site family study, to determine whether a subset could distinguish SZ probands and CCS just as well as using all 16. Participants included 345 SZ probands and 517 CCS with a valid measure for at least one endophenotype. We used both logistic regression and random forest models to choose a subset of endophenotypes, adjusting for age, gender, smoking status, site, parent education, and the reading subtest of the Wide Range Achievement Test. As a sensitivity analysis, we re-fit models using multiple imputations to determine the effect of missing values. We identified four important endophenotypes: antisaccade, Continuous Performance Test-Identical Pairs 3-digit version, California Verbal Learning Test, and emotion identification. The logistic regression model that used just these four endophenotypes produced essentially the same results as the model that used all 16 (84% vs. 85% accuracy). While a subset of endophenotypes cannot replace clinical diagnosis nor encompass the complexity of the disease, it can aid in the design of future endophenotypic and genetic studies by reducing study cost and subject burden, simplifying sample enrichment, and improving the statistical power of locating those genetic regions associated with schizophrenia that may be the easiest to identify initially.

    View details for DOI 10.1016/j.schres.2016.04.011

    View details for Web of Science ID 000377934800001

    View details for PubMedID 27132484

  • Gating Deficit Heritability and Correlation With Increased Clinical Severity in Schizophrenia Patients With Positive Family History. American journal of psychiatry Greenwood, T. A., Light, G. A., Swerdlow, N. R., Calkins, M. E., Green, M. F., Gur, R. E., Gur, R. C., Lazzeroni, L. C., Nuechterlein, K. H., Olincy, A., Radant, A. D., Seidman, L. J., Siever, L. J., Silverman, J. M., Stone, W. S., Sugar, C. A., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Freedman, R., Braff, D. L. 2016; 173 (4): 385-391

    Abstract

    The Consortium on the Genetics of Schizophrenia Family Study evaluated 12 primary and other supplementary neurocognitive and neurophysiological endophenotypes in schizophrenia probands and their families. Previous analyses of prepulse inhibition (PPI) and P50 gating measures in this sample revealed heritability estimates that were lower than expected based on earlier family studies. Here the authors investigated whether gating measures were more heritable in multiply affected families with a positive family history compared with families with only a single affected proband (singleton).A total of 296 nuclear families consisting of a schizophrenia proband, at least one unaffected sibling, and both parents underwent a comprehensive endophenotype and clinical characterization. The Family Interview for Genetic Studies was administered to all participants and used to obtain convergent psychiatric symptom information for additional first-degree relatives. Among the families, 97 were multiply affected, and 96 were singletons.Both PPI and P50 gating displayed substantially increased heritability in the 97 multiply affected families (47% and 36%, respectively) compared with estimates derived from the entire sample of 296 families (29% and 20%, respectively). However, no evidence for heritability was observed for either measure in the 96 singleton families. Schizophrenia probands derived from the multiply affected families also displayed a significantly increased severity of clinical symptoms compared with those from singleton families.PPI and P50 gating measures demonstrate substantially increased heritability in schizophrenia families with a higher genetic vulnerability for illness, providing further support for the commonality of genes underlying both schizophrenia and gating measures.

    View details for DOI 10.1176/appi.ajp.2015.15050605

    View details for PubMedID 26441157

  • Solutions for quantifying P-value uncertainty and replication power. Nature methods Lazzeroni, L. C., Lu, Y., Belitskaya-Lévy, I. 2016; 13 (2): 107-108

    View details for DOI 10.1038/nmeth.3741

    View details for PubMedID 26820540

  • Genetic assessment of additional endophenotypes from the Consortium on the Genetics of Schizophrenia Family Study SCHIZOPHRENIA RESEARCH Greenwood, T. A., Lazzeroni, L. C., Calkins, M. E., Freedman, R., Green, M. F., Gur, R. E., Gur, R. C., Light, G. A., Nuechterlein, K. H., Olincy, A., Radant, A. D., Seidman, L. J., Siever, L. J., Silverman, J. M., Stone, W. S., Sugar, C. A., Swerdlow, N. R., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Braff, D. L. 2016; 170 (1): 30-40

    Abstract

    The Consortium on the Genetics of Schizophrenia Family Study (COGS-1) has previously reported our efforts to characterize the genetic architecture of 12 primary endophenotypes for schizophrenia. We now report the characterization of 13 additional measures derived from the same endophenotype test paradigms in the COGS-1 families. Nine of the measures were found to discriminate between schizophrenia patients and controls, were significantly heritable (31 to 62%), and were sufficiently independent of previously assessed endophenotypes, demonstrating utility as additional endophenotypes. Genotyping via a custom array of 1536 SNPs from 94 candidate genes identified associations for CTNNA2, ERBB4, GRID1, GRID2, GRIK3, GRIK4, GRIN2B, NOS1AP, NRG1, and RELN across multiple endophenotypes. An experiment-wide p value of 0.003 suggested that the associations across all SNPs and endophenotypes collectively exceeded chance. Linkage analyses performed using a genome-wide SNP array further identified significant or suggestive linkage for six of the candidate endophenotypes, with several genes of interest located beneath the linkage peaks (e.g., CSMD1, DISC1, DLGAP2, GRIK2, GRIN3A, and SLC6A3). While the partial convergence of the association and linkage likely reflects differences in density of gene coverage provided by the distinct genotyping platforms, it is also likely an indication of the differential contribution of rare and common variants for some genes and methodological differences in detection ability. Still, many of the genes implicated by COGS through endophenotypes have been identified by independent studies of common, rare, and de novo variation in schizophrenia, all converging on a functional genetic network related to glutamatergic neurotransmission that warrants further investigation.

    View details for DOI 10.1016/j.schres.2015.11.008

    View details for Web of Science ID 000367535500003

  • Genetic Variation in the IL-6 and HLA-DQB1 Genes Is Associated with Spontaneous Clearance of Hepatitis C Virus Infection JOURNAL OF IMMUNOLOGY RESEARCH Waldron, P. R., Belitskaya-Levy, I., Chary, A., Won, J., Winters, M., Monto, A., Ryan, J., Lazzeroni, L. C., Holodniy, M. 2016

    Abstract

    Background. Millions of people are infected with hepatitis C virus (HCV) worldwide and 30% spontaneously clear the infection. Reasons for HCV clearance without antiviral treatment are not well understood. Methods. Blood was collected for DNA analysis from patients with chronic HCV infection or evidence of spontaneous clearance. To overcome anticipated limitations of small sample size, primary analyses consisted of a candidate gene analysis of 12 preselected genes based on known association with host immunologic response to HCV infection. To further reduce the impact of multiple testing on power, a single likelihood ratio test was conducted for each gene using all associated SNPs assayed on the Illumina Quad 610/660W chip. Step-down permutation methods were used to adjust for multiple testing in all analyses. Results. Ninety-five and 62 patients with HCV chronic infection or spontaneous clearance, respectively, were included for analysis. HLA-DQB1 (p = 1.76⁎10(-5)) and IL-6 (p = 0.0007) genes were significantly associated with spontaneous HCV clearance. IL-28B was not significantly associated with spontaneous clearance (p = 0.17). Conclusion. Our whole-gene analytic strategy identified a previously unreported association of IL-6 with spontaneous clearance of HCV infection. We also confirmed the finding that HLA-DQB1 is associated with spontaneous resolution of HCV infection.

    View details for DOI 10.1155/2016/6530436

    View details for Web of Science ID 000377874400001

    View details for PubMedID 27340680

    View details for PubMedCentralID PMC4909898

  • Prioritizing schizophrenia endophenotypes for future genetic studies: An example using data from the COGS-1 family study Schizophrenia Research Millard, S. P., Shofer, J., Braff, D., Calkins, M., Cadenhead, K., Freedman, R., Green, M. F., Greenwood, T. A., Gur, R. E., Gur, R. C., Lazzeroni, L. C., Light, G. A., Olincy, A., Nuechterlein, K., Seidman, L. J., Siever, L. J., Silverman, J., Stone, W., Sprock, J., Sugar, C. A., Swerdlow, N. R., Tsuang, M., Turetsky, B., Radant, A., Tsuang, D. W. 2016; in press
  • Response to Transdermal Selegiline Smoking Cessation Therapy and Markers in the 15q24 Chromosomal Region. Nicotine & tobacco research Sarginson, J. E., Killen, J. D., Lazzeroni, L. C., Fortmann, S. P., Ryan, H. S., Ameli, N., Schatzberg, A. F., Murphy, G. M. 2015; 17 (9): 1126-1133

    Abstract

    Current treatments for smoking cessation have limited efficacy. A potential pharmaceutical treatment for smoking cessation is selegiline, a selective and irreversible monoamine oxidase B inhibitor. A few clinical trials have been carried out using selegiline but the results have been mixed. We sought to determine if genetic markers in cholinergic loci in the 15q24 chromosomal region predict response to smoking cessation therapy with selegiline.We performed an 8-week double-blind, placebo-controlled clinical trial of the selegiline transdermal system (STS) in heavy smokers, with follow-up at weeks 25 and 52. Eight single nucleotide polymorphisms (SNPs) in the 15q24 region, which contains the genes for the nicotinic acetylcholine receptor subunits CHRNA5, CHRNA3, and CHRNB4, were investigated for association with treatment response.The CHRNB4 promoter SNP rs3813567 was associated with both point prevalence abstinence (PPA) and post-quit craving. Carriers of the minor C allele treated with selegiline showed lower rates of abstinence and higher levels of craving than selegiline-treated non-carriers, indicating that the rs3813567 C allele adversely affects abstinence in selegiline-treated smokers. This effect was not present among placebo-treated smokers. Selegiline-treated smokers with the CHRNA5 rs680244 GG genotype had lower post-quit craving, and unlike placebo-treated GG-carrying smokers, did not experience a post-quit increase in depressive symptoms.Variants in genes encoding cholinergic receptors affect abstinence, craving and mood in selegiline-treated smokers. Selegiline primarily affects dopamine levels in the brain, but cholinergic input affects nicotine-induced dopaminergic activity. These markers may have value in identifying those likely to respond to selegiline for smoking cessation.

    View details for DOI 10.1093/ntr/ntu273

    View details for PubMedID 25572450

  • The STEP model: Characterizing simultaneous time effects on practice for flight simulator performance among middle-aged and older pilots. Psychology and aging Kennedy, Q., Taylor, J., Noda, A., Yesavage, J., Lazzeroni, L. C. 2015; 30 (3): 699-711

    Abstract

    Understanding the possible effects of the number of practice sessions (practice) and time between practice sessions (interval) among middle-aged and older adults in real-world tasks has important implications for skill maintenance. Prior training and cognitive ability may impact practice and interval effects on real-world tasks. In this study, we took advantage of existing practice data from 5 simulated flights among 263 middle-aged and older pilots with varying levels of flight expertise (defined by U.S. Federal Aviation Administration proficiency ratings). We developed a new Simultaneous Time Effects on Practice (STEP) model: (a) to model the simultaneous effects of practice and interval on performance of the 5 flights, and (b) to examine the effects of selected covariates (i.e., age, flight expertise, and 3 composite measures of cognitive ability). The STEP model demonstrated consistent positive practice effects, negative interval effects, and predicted covariate effects. Age negatively moderated the beneficial effects of practice. Additionally, cognitive processing speed and intraindividual variability (IIV) in processing speed moderated the benefits of practice and/or the negative influence of interval for particular flight performance measures. Expertise did not interact with practice or interval. Results indicated that practice and interval effects occur in simulated flight tasks. However, processing speed and IIV may influence these effects, even among high-functioning adults. Results have implications for the design and assessment of training interventions targeted at middle-aged and older adults for complex real-world tasks. (PsycINFO Database Record

    View details for DOI 10.1037/pag0000043

    View details for PubMedID 26280383

    View details for PubMedCentralID PMC4556540

  • The STEP Model: Characterizing Simultaneous Time Effects on Practice for Flight Simulator Performance Among Middle-Aged and Older Pilots PSYCHOLOGY AND AGING Kennedy, Q., Taylor, J., Noda, A., Yesavage, J., Lazzeroni, L. C. 2015; 30 (3): 699-711

    Abstract

    Understanding the possible effects of the number of practice sessions (practice) and time between practice sessions (interval) among middle-aged and older adults in real-world tasks has important implications for skill maintenance. Prior training and cognitive ability may impact practice and interval effects on real-world tasks. In this study, we took advantage of existing practice data from 5 simulated flights among 263 middle-aged and older pilots with varying levels of flight expertise (defined by U.S. Federal Aviation Administration proficiency ratings). We developed a new Simultaneous Time Effects on Practice (STEP) model: (a) to model the simultaneous effects of practice and interval on performance of the 5 flights, and (b) to examine the effects of selected covariates (i.e., age, flight expertise, and 3 composite measures of cognitive ability). The STEP model demonstrated consistent positive practice effects, negative interval effects, and predicted covariate effects. Age negatively moderated the beneficial effects of practice. Additionally, cognitive processing speed and intraindividual variability (IIV) in processing speed moderated the benefits of practice and/or the negative influence of interval for particular flight performance measures. Expertise did not interact with practice or interval. Results indicated that practice and interval effects occur in simulated flight tasks. However, processing speed and IIV may influence these effects, even among high-functioning adults. Results have implications for the design and assessment of training interventions targeted at middle-aged and older adults for complex real-world tasks. (PsycINFO Database Record

    View details for DOI 10.1037/pag0000043

    View details for Web of Science ID 000360585600020

    View details for PubMedCentralID PMC4556540

  • ABCB1 (MDR1) predicts remission on P-gp substrates in chronic depression PHARMACOGENOMICS JOURNAL Ray, A., Tennakoon, L., Keller, J., Sarginson, J. E., Ryan, H. S., Murphy, G. M., Lazzeroni, L. C., Trivedi, M. H., Kocsis, J. H., Debattista, C., Schatzberg, A. F. 2015; 15 (4): 332-339

    Abstract

    The hypothesis that allelic variation in the multidrug resistance-1 (MDR1 or ABCB1) gene encoding the P-glycoprotein (P-gp) blood-brain barrier efflux pump is associated with remission and side effects was tested in chronic major depression patients treated with P-gp substrates. In 83 patients from the REVAMP trial, frequency of and time to remission as well as side effects was tested among genotype groups at 6 ABCB1 single nucleotide polymorphisms (SNPs). These six SNPs are significantly associated with remission and time to remission, with minor allele carriers on rs2235040 and rs9282564 attaining statistical significance after controlling for the other ABCB1 SNPs. The six ABCB1 SNPs are also significantly associated with the average side effects. However, here common homozygotes on rs2235040 and rs9282564 demonstrated significantly higher side effects after controlling for the effects of the other ABCB1 SNPs. These findings confirm and extend previous observations that minor alleles of two ABCB1 SNPs predict remission to treatment with substrates and demonstrate that common homozygotes on these SNPs experience greater side effects. Results point to the potential importance of ABCB1 variation for personalized medicine approaches to treating depression.The Pharmacogenomics Journal advance online publication, 9 December 2014; doi:10.1038/tpj.2014.72.

    View details for DOI 10.1038/tpj.2014.72

    View details for Web of Science ID 000358448500007

  • ABCB1 Genetic Effects on Antidepressant Outcomes: A Report From the iSPOT-D Trial AMERICAN JOURNAL OF PSYCHIATRY Schatzberg, A. F., DeBattista, C., Lazzeroni, L. C., Etkin, A., Murphy, G. M., Williams, L. M. 2015; 172 (8): 751-759

    Abstract

    The ABCB1 gene encodes P-glycoprotein, which limits brain concentrations of certain antidepressants. ABCB1 variation has been associated with antidepressant efficacy and side effects in small-sample studies. Cognitive impairment in major depressive disorder predicts poor treatment outcome, but ABCB1 genetic effects in patients with cognitive impairment are untested. The authors examined ABCB1 genetic variants as predictors of remission and side effects in a large clinical trial that also incorporated cognitive assessment.The authors genotyped 10 ABCB1 single-nucleotide polymorphisms (SNPs) in 683 patients with major depressive disorder treated for at least 2 weeks, of whom 576 completed 8 weeks of treatment with escitalopram, sertraline, or extended-release venlafaxine (all substrates for P-glycoprotein) in a large randomized, prospective, pragmatic trial. Antidepressant efficacy was assessed with the 16-item Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR), and side effects with a rating scale for frequency, intensity, and burden of side effects. General and emotional cognition was assessed with a battery of 13 tests.The functional SNP rs10245483 upstream from ABCB1 had a significant effect on remission and side effect ratings that was differentially related to medication and cognitive status. Common homozygotes responded better and had fewer side effects with escitalopram and sertraline. Minor allele homozygotes responded better and had fewer side effects with venlafaxine, with the better response most apparent for patients with cognitive impairment.The functional polymorphism rs10245483 differentially affects remission and side effect outcomes depending on the antidepressant. The predictive power of the SNP for response or side effects was not lessened by the presence of cognitive impairment.

    View details for DOI 10.1176/appi.ajp.2015.14050680

    View details for Web of Science ID 000359274700015

    View details for PubMedID 25815420

  • The utility of P300 as a schizophrenia endophenotype and predictive biomarker: Clinical and socio-demographic modulators in COGS-2 SCHIZOPHRENIA RESEARCH Turetsky, B. I., Dress, E. M., Braff, D. L., Calkins, M. E., Green, M. F., Greenwood, T. A., Gur, R. E., Gur, R. C., Lazzeroni, L. C., Nuechterlein, K. H., Radant, A. D., Seidman, L. J., Siever, L. J., Silverman, J. M., Sprock, J., Stone, W. S., Sugar, C. A., Swerdlow, N. R., Tsuang, D. W., Tsuang, M. T., Light, G. 2015; 163 (1-3): 53-62

    Abstract

    Reduced auditory P300 amplitude is a robust schizophrenia deficit exhibiting the qualities of a viable genetic endophenotype. These include heritability, test-retest reliability, and trait-like stability. Recent evidence suggests that P300 may also serve as a predictive biomarker for transition to psychosis during the schizophrenia prodrome. Historically, the utility of the P300 has been limited by its clinical nonspecificity, cross-site measurement variability, and required EEG expertise. The Consortium on the Genetics of Schizophrenia (COGS-2) study provided an opportunity to examine the consistency of the measure across multiple sites with varying degrees of EEG experience, and to identify important modulating factors that contribute to measurement variability. Auditory P300 was acquired from 649 controls and 587 patients at 5 sites. An overall patient deficit was observed with effect size 0.62. Each site independently observed a significant patient deficit, but site differences also existed. In patients, site differences reflected clinical differences in positive symptomatology and functional capacity. In controls, site differences reflected differences in racial stratification, smoking and substance use history. These factors differentially suppressed the P300 response, but only in control subjects. This led to an attenuated patient-control difference among smokers and among African Americans with history of substance use. These findings indicate that the P300 can be adequately assessed quantitatively, across sites, without substantial EEG expertise. Measurements are suitable for both genetic endophenotype analyses and studies of psychosis risk and conversion. However, careful attention must be given to selection of appropriate comparison samples to avoid misleading false negative results.

    View details for DOI 10.1016/j.schres.2014.09.024

    View details for Web of Science ID 000351928600008

    View details for PubMedID 25306203

  • Neurocognitive performance in family-based and case-control studies of schizophrenia SCHIZOPHRENIA RESEARCH Gur, R. C., Braff, D. L., Calkins, M. E., Dobie, D. J., Freedman, R., Green, M. F., Greenwood, T. A., Lazzeroni, L. C., Light, G. A., Nuechterlein, K. H., Olincy, A., Radant, A. D., Seidman, L. J., Siever, L. J., Silverman, J. M., Sprock, J., Stone, W. S., Sugar, C. A., Swerdlow, N. R., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Gur, R. E. 2015; 163 (1-3): 17-23

    Abstract

    Neurocognitive deficits in schizophrenia (SZ) are established and the Consortium on the Genetics of Schizophrenia (COGS) investigated such measures as endophenotypes in family-based (COGS-1) and case-control (COGS-2) studies. By requiring family participation, family-based sampling may result in samples that vary demographically and perform better on neurocognitive measures.The Penn computerized neurocognitive battery (CNB) evaluates accuracy and speed of performance for several domains and was administered across sites in COGS-1 and COGS-2. Most tests were included in both studies. COGS-1 included 328 patients with SZ and 497 healthy comparison subjects (HCS) and COGS-2 included 1195 patients and 1009 HCS.Demographically, COGS-1 participants were younger, more educated, with more educated parents and higher estimated IQ compared to COGS-2 participants. After controlling for demographics, the two samples produced very similar performance profiles compared to their respective controls. As expected, performance was better and with smaller effect sizes compared to controls in COGS-1 relative to COGS-2. Better performance was most pronounced for spatial processing while emotion identification had large effect sizes for both accuracy and speed in both samples. Performance was positively correlated with functioning and negatively with negative and positive symptoms in both samples, but correlations were attenuated in COGS-2, especially with positive symptoms.Patients ascertained through family-based design have more favorable demographics and better performance on some neurocognitive domains. Thus, studies that use case-control ascertainment may tap into populations with more severe forms of illness that are exposed to less favorable factors compared to those ascertained with family-based designs.

    View details for DOI 10.1016/j.schres.2014.10.049

    View details for Web of Science ID 000351928600003

  • Attention/vigilance in schizophrenia: Performance results from a large multi-site study of the Consortium on the Genetics of Schizophrenia (COGS) SCHIZOPHRENIA RESEARCH Nuechterlein, K. H., Green, M. F., Calkins, M. E., Greenwood, T. A., Gur, R. E., Gur, R. C., Lazzeroni, L. C., Light, G. A., Radant, A. D., Seidman, L. J., Siever, L. J., Silverman, J. M., Sprock, J., Stone, W. S., Sugar, C. A., Swerdlow, N. R., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Braff, D. L. 2015; 163 (1-3): 38-46

    Abstract

    Attention/vigilance impairments are present in individuals with schizophrenia across psychotic and remitted states and in their first-degree relatives. An important question is whether deficits in attention/vigilance can be consistently and reliably measured across sites varying in many participant demographic, clinical, and functional characteristics, as needed for large-scale genetic studies of endophenotypes. We examined Continuous Performance Test (CPT) data from phase 2 of the Consortium on the Genetics of Schizophrenia (COGS-2), the largest-scale assessment of cognitive and psychophysiological endophenotypes relevant to schizophrenia. The CPT data from 2251 participants from five sites were examined. A perceptual-load vigilance task (the Degraded Stimulus CPT or DS-CPT) and a memory-load vigilance task (CPT-Identical Pairs or CPT-IP) were utilized. Schizophrenia patients performed more poorly than healthy comparison subjects (HCS) across sites, despite significant site differences in participant age, sex, education, and racial distribution. Patient-HCS differences in signal/noise discrimination (d') in the DS-CPT varied significantly across sites, but averaged a medium effect size. CPT-IP performance showed large patient-HCS differences across sites. Poor CPT performance was independent of or weakly correlated with symptom severity, but was significantly associated with lower educational achievement and functional capacity. Current smoking was associated with poorer CPT-IP d'. Patients taking both atypical and typical antipsychotic medication performed more poorly than those on no or atypical antipsychotic medications, likely reflecting their greater severity of illness. We conclude that CPT deficits in schizophrenia can be reliably detected across sites, are relatively independent of current symptom severity, and are related to functional capacity.

    View details for DOI 10.1016/j.schres.2015.01.017

    View details for Web of Science ID 000351928600006

    View details for PubMedID 25749017

  • Factor structure and heritability of endophenotypes in schizophrenia: Findings from the Consortium on the Genetics of Schizophrenia (COGS-1) SCHIZOPHRENIA RESEARCH Seidman, L. J., Hellemann, G., Nuechterlein, K. H., Greenwood, T. A., Braff, D. L., Cadenhead, K. S., Calkins, M. E., Freedman, R., Gur, R. E., Gur, R. C., Lazzeroni, L. C., Light, G. A., Olincy, A., Radant, A. D., Siever, L. J., Silverman, J. M., Sprock, J., Stone, W. S., Sugar, C., Swerdlowe, N. R., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Green, M. F. 2015; 163 (1-3): 73-79

    Abstract

    Although many endophenotypes for schizophrenia have been studied individually, few studies have examined the extent to which common neurocognitive and neurophysiological measures reflect shared versus unique endophenotypic factors. It may be possible to distill individual endophenotypes into composite measures that reflect dissociable, genetically informative elements.The first phase of the Consortium on the Genetics of Schizophrenia (COGS-1) is a multisite family study that collected neurocognitive and neurophysiological data between 2003 and 2008. For these analyses, participants included schizophrenia probands (n=83), their nonpsychotic siblings (n=151), and community comparison subjects (n=209) with complete data on a battery of 12 neurocognitive tests (assessing domains of working memory, declarative memory, vigilance, spatial ability, abstract reasoning, facial emotion processing, and motor speed) and 3 neurophysiological tasks reflecting inhibitory processing (P50 gating, prepulse inhibition and antisaccade tasks). Factor analyses were conducted on the measures for each subject group and across the entire sample. Heritability analyses of factors were performed using SOLAR.Analyses yielded 5 distinct factors: 1) Episodic Memory, 2) Working Memory, 3) Perceptual Vigilance, 4) Visual Abstraction, and 5) Inhibitory Processing. Neurophysiological measures had low associations with these factors. The factor structure of endophenotypes was largely comparable across probands, siblings and controls. Significant heritability estimates for the factors ranged from 22% (Episodic Memory) to 39% (Visual Abstraction).Neurocognitive measures reflect a meaningful amount of shared variance whereas the neurophysiological measures reflect largely unique contributions as endophenotypes for schizophrenia. Composite endophenotype measures may inform our neurobiological and genetic understanding of schizophrenia.

    View details for DOI 10.1016/j.schres.2015.01.027

    View details for Web of Science ID 000351928600010

    View details for PubMedID 25682549

  • Robust differences in antisaccade performance exist between COGS schizophrenia cases and controls regardless of recruitment strategies SCHIZOPHRENIA RESEARCH Radant, A. D., Millard, S. P., Braff, D. L., Calkins, M. E., Dobie, D. J., Freedman, R., Green, M. F., Greenwood, T. A., Gur, R. E., Gur, R. C., Lazzeroni, L. C., Light, G. A., Meichle, S. P., Nuechterlein, K. H., Olincy, A., Seidman, L. J., Siever, L. J., Silverman, J. M., Stone, W. S., Swerdlow, N. R., Sugar, C. A., Tsuang, M. T., Turetsky, B. I., Tsuang, D. W. 2015; 163 (1-3): 47-52

    Abstract

    The impaired ability to make correct antisaccades (i.e., antisaccade performance) is well documented among schizophrenia subjects, and researchers have successfully demonstrated that antisaccade performance is a valid schizophrenia endophenotype that is useful for genetic studies. However, it is unclear how the ascertainment biases that unavoidably result from recruitment differences in schizophrenia subjects identified in family versus case-control studies may influence patient-control differences in antisaccade performance. To assess the impact of ascertainment bias, researchers from the Consortium on the Genetics of Schizophrenia (COGS) compared antisaccade performance and antisaccade metrics (latency and gain) in schizophrenia and control subjects from COGS-1, a family-based schizophrenia study, to schizophrenia and control subjects from COGS-2, a corresponding case-control study. COGS-2 schizophrenia subjects were substantially older; had lower education status, worse psychosocial function, and more severe symptoms; and were three times more likely to be a member of a multiplex family than COGS-1 schizophrenia subjects. Despite these variations, which were likely the result of ascertainment differences (as described in the introduction to this special issue), the effect sizes of the control-schizophrenia differences in antisaccade performance were similar in both studies (Cohen's d effect size of 1.06 and 1.01 in COGS-1 and COGS-2, respectively). This suggests that, in addition to the robust, state-independent schizophrenia-related deficits described in endophenotype studies, group differences in antisaccade performance do not vary based on subject ascertainment and recruitment factors.

    View details for DOI 10.1016/j.schres.2014.12.016

    View details for Web of Science ID 000351928600007

    View details for PubMedID 25553977

  • California Verbal Learning Test-II performance in schizophrenia as a function of ascertainment strategy: Comparing the first and second phases of the Consortium on the Genetics of Schizophrenia (COGS) SCHIZOPHRENIA RESEARCH Stone, W. S., Mesholam-Gately, R. I., Braff, D. L., Calkins, M. E., Freedman, R., Green, M. F., Greenwood, T. A., Gur, R. E., Gur, R. C., Lazzeroni, L. C., Light, G. A., Nuechterlein, K. H., Olincy, A., Radant, A. D., Siever, L. J., Silverman, J. M., Sprock, J., Sugar, C. A., Swerdlow, N. R., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Seidman, L. J. 2015; 163 (1-3): 32-37

    Abstract

    The first phase of the Consortium on the Genetics of Schizophrenia (COGS-1) showed performance deficits in learning and memory on the California Verbal Learning Test, Second Edition (CVLT-II) in individuals with schizophrenia (SZ), compared to healthy comparison subjects (HCS). A question is whether the COGS-1 study, which used a family study design (i.e. studying relatively intact families), yielded "milder" SZ phenotypes than those acquired subsequently in the COGS-2 case-control design that did not recruit unaffected family members. CVLT-II performance was compared for the COGS-1 and COGS-2 samples. Analyses focused on learning, recall and recognition variables, with age, gender and education as covariates. Analyses of COGS-2 data explored effects of additional covariates and moderating factors in CVLT-II performance. 324 SZ subjects and 510 HCS had complete CVLT-II and covariate data in COGS-1, while 1356 SZ and 1036 HCS had complete data in COGS-2. Except for recognition memory, analysis of covariance showed significantly worse performance in COGS-2 on all CVLT-II variables for SZ and HCS, and remained significant in the presence of the covariates. Performance in each of the 5 learning trials differed significantly. However, effect sizes comparing cases and controls were comparable across the two studies. COGS-2 analyses confirmed SZ performance deficits despite effects of multiple significant covariates and moderating factors. CVLT-II performance was worse in COGS-2 than in COGS-1 for both the SZ and the HCS in this large cohort, likely due to cohort effects. Demographically corrected data yield a consistent pattern of performance across the two studies in SZ.

    View details for DOI 10.1016/j.schres.2014.10.029

    View details for Web of Science ID 000351928600005

    View details for PubMedID 25497440

  • Validation of mismatch negativity and P3a for use inmulti-site studies of schizophrenia: Characterization of demographic, clinical, cognitive, and functional correlates in COGS-2 SCHIZOPHRENIA RESEARCH Light, G. A., Swerdlowa, N. R., Thomas, M. L., Calkins, M. E., Green, M. F., Greenwood, T. A., Gur, R. E., Gur, R. C., Lazzeroni, L. C., Nuechterlein, K. H., Pela, M., Radant, A. D., Seidman, L. J., Sharp, R. F., Siever, L. J., Silverman, J. M., Sprock, J., Stone, W. S., Sugar, C. A., Tsuang, D. W., Tsuang, M. T., Braff, D. L., Turetsky, B. I. 2015; 163 (1-3): 63-72

    Abstract

    Mismatch negativity (MMN) and P3a are auditory event-related potential (ERP) components that show robust deficits in schizophrenia (SZ) patients and exhibit qualities of endophenotypes, including substantial heritability, test-retest reliability, and trait-like stability. These measures also fulfill criteria for use as cognition and function-linked biomarkers in outcome studies, but have not yet been validated for use in large-scale multi-site clinical studies. This study tested the feasibility of adding MMN and P3a to the ongoing Consortium on the Genetics of Schizophrenia (COGS) study. The extent to which demographic, clinical, cognitive, and functional characteristics contribute to variability in MMN and P3a amplitudes was also examined. Participants (HCS n=824, SZ n=966) underwent testing at 5 geographically distributed COGS laboratories. Valid ERP recordings were obtained from 91% of HCS and 91% of SZ patients. Highly significant MMN (d=0.96) and P3a (d=0.93) amplitude reductions were observed in SZ patients, comparable in magnitude to those observed in single-lab studies with no appreciable differences across laboratories. Demographic characteristics accounted for 26% and 18% of the variance in MMN and P3a amplitudes, respectively. Significant relationships were observed among demographically-adjusted MMN and P3a measures and medication status as well as several clinical, cognitive, and functional characteristics of the SZ patients. This study demonstrates that MMN and P3a ERP biomarkers can be feasibly used in multi-site clinical studies. As with many clinical tests of brain function, demographic factors contribute to MMN and P3a amplitudes and should be carefully considered in future biomarker-informed clinical studies.

    View details for DOI 10.1016/j.schres.2014.09.042

    View details for PubMedID 25449710

  • Verbal working memory in schizophrenia from the Consortium on the Genetics of Schizophrenia (COGS) Study: The moderating role of smoking status and antipsychotic medications SCHIZOPHRENIA RESEARCH Lee, J., Green, M. F., Calkins, M. E., Greenwood, T. A., Gur, R. E., Gur, R. C., Lazzeroni, L. C., Light, G. A., Nuechterlein, K. H., Radant, A. D., Seidman, L. J., Siever, L. J., Silverman, J. M., Sprock, J., Stone, W. S., Sugar, C. A., Swerdlow, N. R., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Braff, D. L. 2015; 163 (1-3): 24-31

    Abstract

    Working memory impairment has been extensively studied in schizophrenia, but less is known about moderators of the impairment. Using the Consortium on the Genetics of Schizophrenia case-control study (COGS-2), we examined smoking status, types of antipsychotic medication, and history of substance as moderators for working memory impairment in schizophrenia.From 5 sites, 1377 patients with schizophrenia or schizoaffective, depressed type and 1037 healthy controls completed the letter-number span (LNS) task. The LNS uses intermixed letter and digit stimuli that increase from 2 up to 8 stimuli. In the forward condition, participants repeated the letters and numbers in the order they were presented. In the reorder condition, participants repeated the digits in ascending order followed by letters in alphabetical order.Schizophrenia patients performed more poorly than controls, with a larger difference on reorder than forward conditions. Deficits were associated with symptoms, functional capacity, and functional outcome. Patients who smoked showed larger impairment than nonsmoking patients, primarily due to deficits on the reorder condition. The impairing association of smoking was more pronounced among patients taking first-generation than those taking second-generation antipsychotic medications. Correlations between working memory and community functioning were stronger for nonsmokers. History of substance use did not moderate working memory impairment.Results confirm the working memory impairment in schizophrenia, and indicate smoking status as an important moderator for these deficits. The greater impairment in smokers may reflect added burden of smoking on general health or that patients with greater deficits are more likely to smoke.

    View details for DOI 10.1016/j.schres.2014.08.014

    View details for Web of Science ID 000351928600004

    View details for PubMedID 25248939

  • GENETIC ASSESSMENT OF CANDIDATE ENDOPHENOTYPES FROM THE CONSORTIUM ON THE GENETICS OF SCHIZOPHRENIA FAMILY STUDY 15th International Congress on Schizophrenia Research (ICOSR) Greenwood, T. A., Lazzeroni, L. C., Calkins, M. E., Freedman, R., Green, M. F., Gur, R. E., Gur, R. C., Light, G. A., Nuechterlein, K. H., Olincy, A., Radant, A. D., Seidman, L. J., Siever, L. J., Silverman, J. M., Stone, W. S., Sugar, C. A., Swerdlow, N. R., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Braff, D. L. OXFORD UNIV PRESS. 2015: S203–S203
  • Findings from the National Memory Screening Day Program JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Bayley, P. J., Kong, J. Y., Mendiondo, M., Lazzeroni, L. C., Borson, S., Buschke, H., Dean, M., Fillit, H., Frank, L., Schmitt, F. A., Peschin, S., Finkel, S., Austen, M., Steinberg, C., Ashford, J. W. 2015; 63 (2): 309-314

    Abstract

    To report experience with a large, nation-wide public memory screening program.Descriptive study of community-dwelling elderly adults.Local community sites (48 sites agreed to provide data) throughout the United States participating in National Memory Screening Day in November 2010.Of 4,369 reported participants, 3,064 had complete data records and are included in this report.Participants completed a questionnaire that included basic demographic information and a question about subjective memory concerns. Each site selected one of seven validated cognitive screening tests: Mini-Cog, General Practitioner assessment of Cognition, Memory Impairment Screen, Kokmen Short Test of Mental Status, Mini-Mental State Examination, Montreal Cognitive Assessment, Saint Louis University Mental Status Examination.Overall, 11.7% failed one of the seven screening tests. As expected, failure rates were higher in older and less-educated participants (P's < .05). Subjective memory concerns were associated with a 40% greater failure rate for persons of similar age and education but no memory concerns (odds ratio = 1.4, 95% confidence interval = 1.07-1.78), although only 11.9% of those who reported memory concerns (75% of all participants) had detectible memory problems.Screening for cognitive impairment in community settings yielded results consistent with expected effects of age and education. The event attracted a large proportion of individuals with memory concerns; 88.1% were told that they did not have memory problems detectible with the tests used. Further studies are needed to assess how participants respond to and use screening information, whether this information ultimately influences decision-making or outcomes, and whether memory screening programs outside healthcare settings have public health value.

    View details for DOI 10.1111/jgs.13234

    View details for PubMedID 25643739

  • Verbal working memory in schizophrenia from the Consortium on the Genetics of Schizophrenia (COGS) study: The moderating role of smoking status and antipsychotic medications Schizophrenia Research Lee, J., Green, M. F., Calkins, M. E., Greenwood, T. A., Gur, R. E., Gur, R. C., Lazzeroni, L. C., Light, G. A., Nuechterlein, K. H., Radant, A. D., Seidman, L. J., Siever, L. J., Silverman, J. M., Sprock, J., Stone, W. S., Sugar, C. A., Swerdlow, N. R., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Braff, D. L. 2015; in press
  • Robust differences in antisaccade performance exist between COGS schizophrenia cases and controls regardless of recruitment strategies Schizophrenia Research Radant, A. D., Millard, S. P., Braff, D., Calkins, M. E., Dobie, D. J., Freedman, R., Green, M. F., Greenwood, T. A., Gur, R. E., Gur, R. C., Lazzeroni, L. C., Light, G. A., Meichle, S., Nuechterlein, K. H., Olincy, A., Seidman, L. J., Siever, L. J., Silverman, J. M., Stone, W. S., Swerdlow, N. R., Sugar, C. A., Tsuang, M. T., Turetsky, B. I., Tsuang, D. W. 2015; in press
  • The utility of P300 as a schizophrenia endophenotype and predictive biomarker: Clilnical and socio-demographic modulators in COGS-2 Schizophrenia.Research Turetsky, B. I., Dress, E. M., Braff, D. L., Calkins, M. E., Green, M. F., Greenwood, T. A., Gur, R. E., Gur, R. C., Lazzeroni, L. C., Nuechterlein, K. H., Radant, A. D., Seidman, L. J., Siever, L. J., Silverman, J. L., Sprock, J., Stone, W. S., Sugar, C. A., Swerdlow, N. R., Tsuang, D. W., Tsuang, M. T., Light, G. 2015; in press
  • ABCB1 (MDR1) predicts remission on P-gp substrates in chronic depression. The pharmacogenomics journal Ray, A., Tennakoon, L., Keller, J., Sarginson, J. E., Ryan, H. S., Murphy, G. M., Lazzeroni, L. C., Trivedi, M. H., Kocsis, J. H., DeBattista, C., Schatzberg, A. F. 2014

    Abstract

    The hypothesis that allelic variation in the multidrug resistance-1 (MDR1 or ABCB1) gene encoding the P-glycoprotein (P-gp) blood-brain barrier efflux pump is associated with remission and side effects was tested in chronic major depression patients treated with P-gp substrates. In 83 patients from the REVAMP trial, frequency of and time to remission as well as side effects was tested among genotype groups at 6 ABCB1 single nucleotide polymorphisms (SNPs). These six SNPs are significantly associated with remission and time to remission, with minor allele carriers on rs2235040 and rs9282564 attaining statistical significance after controlling for the other ABCB1 SNPs. The six ABCB1 SNPs are also significantly associated with the average side effects. However, here common homozygotes on rs2235040 and rs9282564 demonstrated significantly higher side effects after controlling for the effects of the other ABCB1 SNPs. These findings confirm and extend previous observations that minor alleles of two ABCB1 SNPs predict remission to treatment with substrates and demonstrate that common homozygotes on these SNPs experience greater side effects. Results point to the potential importance of ABCB1 variation for personalized medicine approaches to treating depression.The Pharmacogenomics Journal advance online publication, 9 December 2014; doi:10.1038/tpj.2014.72.

    View details for DOI 10.1038/tpj.2014.72

    View details for PubMedID 25487678

  • P-values in genomics: Apparent precision masks high uncertainty MOLECULAR PSYCHIATRY Lazzeroni, L. C., Lu, Y., Belitskaya-Levy, I. 2014; 19 (12): 1336-1340

    Abstract

    Scientists often interpret P-values as measures of the relative strength of statistical findings. This is common practice in large-scale genomic studies where P-values are used to choose which of numerous hypothesis test results should be pursued in subsequent research. In this study, we examine P-value variability to assess the degree of certainty P-values provide. We develop prediction intervals for the P-value in a replication study given the P-value observed in an initial study. The intervals depend on the initial value of P and the ratio of sample sizes between the initial and replication studies, but not on the underlying effect size or initial sample size. The intervals are valid for most large-sample statistical tests in any context, and can be used in the presence of single or multiple tests. While P-values are highly variable, future P-value variability can be explicitly predicted based on a P-value from an initial study. The relative size of the replication and initial study is an important predictor of the P-value in a subsequent replication study. We provide a handy calculator implementing these results and apply them to a study of Alzheimer's disease and recent findings of the Cross-Disorder Group of the Psychiatric Genomics Consortium. This study suggests that overinterpretation of very significant, but highly variable, P-values is an important factor contributing to the unexpectedly high incidence of non-replication. Formal prediction intervals can also provide realistic interpretations and comparisons of P-values associated with different estimated effect sizes and sample sizes.Molecular Psychiatry advance online publication, 14 January 2014; doi:10.1038/mp.2013.184.

    View details for DOI 10.1038/mp.2013.184

    View details for Web of Science ID 000345423500011

    View details for PubMedID 24419042

  • The Utility of P300 as a Schizophrenia Endophenotype and Predictive Biomarker: Clinical and Socio-demographic Modulators in COGS-2 53rd Annual Meeting of the American-College-of-Neuropsychopharmacology (ACNP) Turetsky, B., Dress, E., Braff, D., Calkins, M., Green, M., Greenwood, T., Gur, R., Gur, R., Lazzeroni, L., Nuechterlein, K., Radant, A., Seidman, L., Siever, L., Silverman, J., Stone, W., Sugar, C., Swerdlow, N., Tsuang, D., Tsuang, M., Light, G. NATURE PUBLISHING GROUP. 2014: S507–S508
  • Gating Deficits Are More Heritable and Correlate with Increased Clinical Severity in Multiplex vs. Simplex Families with Schizophrenia 53rd Annual Meeting of the American-College-of-Neuropsychopharmacology (ACNP) Greenwood, T., Light, G., Swerdlow, N., Calkins, M., Green, M., Gur, R., Lazzeroni, L., Nuechterlein, K., Olincy, A., Radant, A., Seidman, L., Siever, L., Silverman, J., Stone, W., Sugar, C., Tsuang, D., Tsuang, M., Turetsky, B., Freedman, R., Braff, D. NATURE PUBLISHING GROUP. 2014: S430–S431
  • Comparison of the heritability of schizophrenia and endophenotypes in the COGS-1 family study. Schizophrenia bulletin Light, G., Greenwood, T. A., Swerdlow, N. R., Calkins, M. E., Freedman, R., Green, M. F., Gur, R. E., Gur, R. C., Lazzeroni, L. C., Nuechterlein, K. H., Olincy, A., Radant, A. D., Seidman, L. J., Siever, L. J., Silverman, J. M., Sprock, J., Stone, W. S., Sugar, C. A., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Braff, D. L. 2014; 40 (6): 1404-1411

    Abstract

    Twin and multiplex family studies have established significant heritability for schizophrenia (SZ), often summarized as 81%. The Consortium on the Genetics of Schizophrenia (COGS-1) family study was designed to deconstruct the genetic architecture of SZ using neurocognitive and neurophysiological endophenotypes, for which heritability estimates ranged from 18% to 50% (mean = 30%). This study assessed the heritability of SZ in these families to determine whether there is a "heritability gap" between the diagnosis and related endophenotypes.Nuclear families (N = 296) with a SZ proband, an unaffected sibling, and both parents (n = 1366 subjects; mean family size = 4.6) underwent comprehensive endophenotype and clinical characterization. The Family Interview for Genetic Studies was administered to all participants and used to obtain convergent psychiatric symptom information for additional first-degree relatives of interviewed subjects (N = 3304 subjects; mean family size = 11.2). Heritability estimates of psychotic disorders were computed for both nuclear and extended families.The heritability of SZ was 31% and 44% for nuclear and extended families. The inclusion of bipolar disorder increased the heritability to 37% for the nuclear families. When major depression was added, heritability estimates dropped to 34% and 20% for nuclear and extended families, respectively.Endophenotypes and psychotic disorders exhibit comparable levels of heritability in the COGS-1 family sample. The ascertainment of families with discordant sibpairs to increase endophenotypic contrast may underestimate diagnostic heritability relative to other studies. However, population-based studies also report significantly lower heritability estimates for SZ. Collectively, these findings support the importance of endophenotype-based strategies and the dimensional view of psychosis.

    View details for DOI 10.1093/schbul/sbu064

    View details for PubMedID 24903414

  • HPA axis genetic variation, cortisol and psychosis in major depression (vol 19, pg 220, 2014) MOLECULAR PSYCHIATRY Schatzberg, A. F., Keller, J., Tennakoon, L., Lembke, A., Williams, G., Kraemer, F. B., Sarginson, J. E., Lazzeroni, L. C., Murphy, G. M. 2014; 19 (10): 1151

    View details for DOI 10.1038/mp.2014.57

    View details for Web of Science ID 000343661700016

  • Paternal age of schizophrenia probands and endophenotypic differences from unaffected siblings. Psychiatry research Schmeidler, J., Lazzeroni, L. C., Swerdlow, N. R., Ferreira, R. P., Braff, D. L., Calkins, M. E., Cadenhead, K. S., Freedman, R., Green, M. F., Greenwood, T. A., Gur, R. E., Gur, R. C., Light, G. A., Olincy, A., Nuechterlein, K. H., Radant, A. D., Seidman, L. J., Siever, L. J., Stone, W. S., Sprock, J., Sugar, C. A., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Silverman, J. M. 2014; 219 (1): 67-71

    Abstract

    We evaluated the discrepancy of endophenotypic performance between probands with schizophrenia and unaffected siblings by paternal age at proband birth, a possible marker for de novo mutations. Pairs of schizophrenia probands and unaffected siblings (N=220 pairs) were evaluated on 11 neuropsychological or neurophysiological endophenotypes previously identified as heritable. For each endophenotype, the sibling-minus-proband differences were transformed to standardized scores. Then for each pair, the average discrepancy was calculated from its standardized scores. We tested the hypothesis that the discrepancy is associated with paternal age, controlling for the number of endophenotypes shared between proband and his or her sibling, and proband age, which were both associated with paternal age. The non-significant association between the discrepancy and paternal age was in the opposite direction from the hypothesis. Of the 11 endophenotypes only sensori-motor dexterity was significant, but in the opposite direction. Eight other endophenotypes were also in the opposite direction, but not significant. The results did not support the hypothesized association of increased differences between sibling/proband pairs with greater paternal age. A possible explanation is that the identification of heritable endophenotypes was based on samples for which schizophrenia was attributable to inherited rather than de novo/non-inherited causes.

    View details for DOI 10.1016/j.psychres.2014.05.035

    View details for PubMedID 24913833

  • Aberrant parietal cortex developmental trajectories in girls with Turner syndrome and related visual-spatial cognitive development: a preliminary study. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics Green, T., Chromik, L. C., Mazaika, P. K., Fierro, K., Raman, M. M., Lazzeroni, L. C., Hong, D. S., Reiss, A. L. 2014; 165B (6): 531-540

    Abstract

    Turner syndrome (TS) arises from partial or complete absence of the X-chromosome in females. Girls with TS show deficits in visual-spatial skills as well as reduced brain volume and surface area in the parietal cortex which supports these cognitive functions. Thus, measuring the developmental trajectory of the parietal cortex and the associated visual-spatial cognition in TS may provide novel insights into critical brain-behavior associations. In this longitudinal study, we acquired structural MRI data and assessed visual-spatial skills in 16 (age: 8.23 ± 2.5) girls with TS and 13 age-matched controls over two time-points. Gray and white matter volume, surface area and cortical thickness were calculated from surfaced based segmentation of bilateral parietal cortices, and the NEPSY Arrows subtest was used to assess visual-spatial ability. Volumetric and cognitive scalars were modeled to obtain estimates of age-related change. The results show aberrant growth of white matter volume (P = 0.011, corrected) and surface area (P = 0.036, corrected) of the left superior parietal regions during childhood in girls with TS. Other parietal sub-regions were significantly smaller in girls with TS at both time-points but did not show different growth trajectories relative to controls. Furthermore, we found that visual-spatial skills showed a widening deficit for girls with TS relative to controls (P = 0.003). Young girls with TS demonstrate an aberrant trajectory of parietal cortical and cognitive development during childhood. Elucidating aberrant neurodevelopmental trajectories in this population is critical for determining specific stages of brain maturation that are particularly dependent on TS-related genetic and hormonal factors. © 2014 Wiley Periodicals, Inc.

    View details for DOI 10.1002/ajmg.b.32256

    View details for PubMedID 25044604

  • Age-related atrophy of white matter tracts in veterans Adamson, M., Main, K., Kong, J., Noda, A., Hernandez, B., Taylor, J., Lazzeroni, L., Ashford, J., Bayley, P. INFORMA HEALTHCARE. 2014: 612–13
  • Aberrant Parietal Cortex Developmental Trajectories in Girls with Turner Syndrome and Related Visual-Spatial Cognitive Development: A Preliminary Study 69th Annual Scientific Convention and Meeting of the Society-of-Biological-Psychiatry Green, T., Chromik, L. C., Mazaika, P. K., Fierro, K., Raman, M. M., Lazzeroni, L., Hong, D. S., Reiss, A. L. ELSEVIER SCIENCE INC. 2014: 346S–346S
  • Serotonin transporter polymorphism is associated with increased apnea-hypopnea index in older adults. International journal of geriatric psychiatry Schröder, C. M., Primeau, M. M., Hallmayer, J. F., Lazzeroni, L. C., Hubbard, J. T., O'Hara, R. 2014; 29 (3): 227-235

    Abstract

    RATIONALE: A functional polymorphism of the serotonin transporter gene (5-HTTLPR) has previously been related to upper airway pathology, but its contribution to obstructive sleep apnea (OSA), a highly prevalent sleep disorder in older adults, remains unclear. OBJECTIVES: We aimed to investigate the relationship between apnea-hypopnea index (AHI) and genetic variations in the promoter region of the 5-HTTLPR in older adults. METHODS: DNA samples from 94 community-dwelling older adults (57% female, mean age 72 ± 8) were genotyped for the 5-HTTLPR polymorphism. All participants were assessed in their homes with full ambulatory polysomnography in order to determine AHI and related parameters such as hypoxia, sleep fragmentation, and self-reported daytime sleepiness. RESULTS: The 5-HTT l allele was significantly associated with AHI (p = 0.019), with l allele carriers displaying a higher AHI than s allele homozygotes. A single allele change in 5-HTTLPR genotype from s to l resulted in an increase of AHI by 4.46 per hour of sleep (95% CI, 0.75-8.17). The l allele was also associated with increased time during sleep spent at oxygen saturation levels below 90% (p = 0.014). CONCLUSIONS: The observed significant association between the 5-HTTLPR l allele and severity of OSA in older adults suggests that the l allele may be important to consider when assessing for OSA in this age group. This association may also explain some of the observed variability among serotonergic pharmacological treatment studies for OSA, and 5-HTT genotype status may have to be taken into account in future therapeutic trials involving serotonergic agents. Copyright © 2013 John Wiley & Sons, Ltd.

    View details for DOI 10.1002/gps.3994

    View details for PubMedID 23754303

  • HPA axis genetic variation, cortisol and psychosis in major depression. Molecular psychiatry Schatzberg, A. F., Keller, J., Tennakoon, L., Lembke, A., Williams, G., Kraemer, F. B., Sarginson, J. E., Lazzeroni, L. C., Murphy, G. M. 2014; 19 (2): 220-227

    Abstract

    Genetic variation underlying hypothalamic pituitary adrenal (HPA) axis overactivity in healthy controls (HCs) and patients with severe forms of major depression has not been well explored, but could explain risk for cortisol dysregulation. In total, 95 participants were studied: 40 patients with psychotic major depression (PMD); 26 patients with non-psychotic major depression (NPMD); and 29 HCs. Collection of genetic material was added one third of the way into a larger study on cortisol, cognition and psychosis in major depression. Subjects were assessed using the Brief Psychiatric Rating Scale, the Hamilton Depression Rating Scale and the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders. Blood was collected hourly for determination of cortisol from 1800 to 0900 h and for the assessment of alleles for six genes involved in HPA axis regulation. Two of the six genes contributed significantly to cortisol levels, psychosis measures or depression severity. After accounting for age, depression and psychosis, and medication status, only allelic variation for the glucocorticoid receptor (GR) gene accounted for a significant variance for mean cortisol levels from 1800 to 0100 h (r(2)=0.288) and from 0100 to 0900 h (r(2)=0.171). In addition, GR and corticotropin-releasing hormone receptor 1 (CRHR1) genotypes contributed significantly to psychosis measures and CRHR1 contributed significantly to depression severity rating.Molecular Psychiatry advance online publication, 29 October 2013; doi:10.1038/mp.2013.129.

    View details for DOI 10.1038/mp.2013.129

    View details for PubMedID 24166410

  • Deficient prepulse inhibition in schizophrenia detected by the multi-site COGS. Schizophrenia research Swerdlow, N. R., Light, G. A., Sprock, J., Calkins, M. E., Green, M. F., Greenwood, T. A., Gur, R. E., Gur, R. C., Lazzeroni, L. C., Nuechterlein, K. H., Radant, A. D., Ray, A., Seidman, L. J., Siever, L. J., Silverman, J. M., Stone, W. S., Sugar, C. A., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Braff, D. L. 2014; 152 (2-3): 503-512

    Abstract

    Startle inhibition by weak prepulses (PPI) is studied to understand the biology of information processing in schizophrenia patients and healthy comparison subjects (HCS). The Consortium on the Genetics of Schizophrenia (COGS) identified associations between PPI and single nucleotide polymorphisms in schizophrenia probands and unaffected relatives, and linkage analyses extended evidence for the genetics of PPI deficits in schizophrenia in the COGS-1 family study. These findings are being extended in a 5-site "COGS-2" study of 1800 patients and 1200 unrelated HCS to facilitate genetic analyses. We describe a planned interim analysis of COGS-2 PPI data.Eyeblink startle was measured in carefully screened HCS and schizophrenia patients (n=1402). Planned analyses of PPI (60ms intervals) assessed effects of diagnosis, sex and test site, PPI-modifying effects of medications and smoking, and relationships between PPI and neurocognitive measures.884 subjects met strict inclusion criteria. ANOVA of PPI revealed significant effects of diagnosis (p=0.0005) and sex (p<0.002), and a significant diagnosis×test site interaction. HCS>schizophrenia PPI differences were greatest among patients not taking 2nd generation antipsychotics, and were independent of smoking status. Modest but significant relationships were detected between PPI and performance in specific neurocognitive measures.The COGS-2 multi-site study detects schizophrenia-related PPI deficits reported in single-site studies, including patterns related to diagnosis, prepulse interval, sex, medication and other neurocognitive measures. Site differences were detected and explored. The target COGS-2 schizophrenia "endophenotype" of reduced PPI should prove valuable for identifying and confirming schizophrenia risk genes in future analyses.

    View details for DOI 10.1016/j.schres.2013.12.004

    View details for PubMedID 24405980

  • Evaluating the evidence for replication of genetic associations with schizophrenia JAMA Psychiatry Lazzeroni, L. C. 2014; in press
  • Effects of body mass index-related disorders on cognition: preliminary results DIABETES METABOLIC SYNDROME AND OBESITY-TARGETS AND THERAPY Yesavage, J. A., Kinoshita, L. M., Noda, A., Lazzeroni, L. C., Fairchild, J., Taylor, J., Kulick, D., Friedman, L., Cheng, J., Zeitzer, J. M., O'Hara, R. 2014; 7: 145–51
  • Longitudinal assessment of sleep disordered breathing in Vietnam veterans with post-traumatic stress disorder NATURE AND SCIENCE OF SLEEP Yesavage, J. A., Kinoshita, L. M., Noda, A., Lazzeroni, L. C., Fairchild, J., Friedman, L., Sekhon, G., Thompson, S., Cheng, J., Zeitzer, J. M. 2014; 6: 123–27

    View details for DOI 10.2147/NSS.S65034

    View details for Web of Science ID 000213883600014

  • Paternal age of schizophrenia probands and endophenotypic differences from unaffected siblings Psychiatry Research Schmeidler, J., Lazzeroni, L. C., Ferreira, R., Braff, D., Calkins, M., Cadenhead, K., Freedman, R., Green, M. F., Greenwood, T., Gur, R., Horanh, W., Light, G., Olincy, A., Nuechterlein, K., Radant, A., Seidman, L., Siever, L., Stone, W., Sprock, J., Sugar, C., Swerdlow, N., Tsuang, D., Tsuang, M., Turetsky, B., Silverman, J. M. 2014; in press
  • Comparison of the heritability of schizophrenia and endophenotypes in the COGS-1 family study Schizophrenia Bulletin Light, G., Greenwood, T., Swerdlow, N., Calkins, M., Freedman, R., Green, M., Gur, R., Gur, R., Lazzeroni, L., Nuechterlein, K., Olincy, A., Radant, A., Seidman, L., Siever, L., Silverman, J., Sprock, J., Stone, W., Sugar, C., Tsuang, D., Tsuang, M., Turetsky, B., Braff, D. 2014; in press
  • Evaluating the evidence of replication for genetic associations with schizophrenia. JAMA psychiatry Lazzeroni, L. C. 2014; 71 (1): 94–95

    View details for PubMedID 24382567

  • Is There an Association between Advanced Paternal Age and Endophenotype Deficit Levels in Schizophrenia? PloS one Tsuang, D., Esterberg, M., Braff, D., Calkins, M., Cadenhead, K., Dobie, D., Freedman, R., Green, M. F., Greenwood, T., Gur, R., Gur, R., Horan, W., Lazzeroni, L. C., Light, G. A., Millard, S. P., Olincy, A., Nuechterlein, K., Seidman, L., Siever, L., Silverman, J., Stone, W., Sprock, J., Sugar, C., Swerdlow, N., Tsuang, M., Turetsky, B., Radant, A. 2014; 9 (2)

    Abstract

    The children of older fathers have increased risks of developing schizophrenia spectrum disorders, and among those who develop these disorders, those with older fathers present with more severe clinical symptoms. However, the influence of advanced paternal age on other important domains related to schizophrenia, such as quantitative endophenotype deficit levels, remains unknown. This study investigated the associations between paternal age and level of endophenotypic impairment in a well-characterized family-based sample from the Consortium on the Genetics of Schizophrenia (COGS). All families included at least one affected subject and one unaffected sibling. Subjects met criteria for schizophrenia (probands; n = 293) or were unaffected first-degree siblings of those probands (n = 382). Paternal age at the time of subjects' birth was documented. Subjects completed a comprehensive clinical assessment and a battery of tests that measured 16 endophenotypes. After controlling for covariates, potential paternal age-endophenotype associations were analyzed using one model that included probands alone and a second model that included both probands and unaffected siblings. Endophenotype deficits in the Identical Pairs version of the 4-digit Continuous Performance Test and in the Penn Computerized Neurocognitive Battery verbal memory test showed significant associations with paternal age. However, after correcting for multiple comparisons, no endophenotype was significantly associated with paternal age. These findings suggest that factors other than advanced paternal age at birth may account for endophenotypic deficit levels in schizophrenia.

    View details for DOI 10.1371/journal.pone.0088379

    View details for PubMedID 24523888

  • Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell Gulsuner, S., Walsh, T., Watts, A. C., Lee, M. K., Thornton, A. M., Casadei, S., Rippey, C., Shahin, H., Nimgaonkar, V. L., Go, R. C., Savage, R. M., Swerdlow, N. R., Gur, R. E., Braff, D. L., King, M., McClellan, J. M. 2013; 154 (3): 518-529

    Abstract

    Genes disrupted in schizophrenia may be revealed by de novo mutations in affected persons from otherwise healthy families. Furthermore, during normal brain development, genes are expressed in patterns specific to developmental stage and neuroanatomical structure. We identified de novo mutations in persons with schizophrenia and then mapped the responsible genes onto transcriptome profiles of normal human brain tissues from age 13 weeks gestation to adulthood. In the dorsolateral and ventrolateral prefrontal cortex during fetal development, genes harboring damaging de novo mutations in schizophrenia formed a network significantly enriched for transcriptional coexpression and protein interaction. The 50 genes in the network function in neuronal migration, synaptic transmission, signaling, transcriptional regulation, and transport. These results suggest that disruptions of fetal prefrontal cortical neurogenesis are critical to the pathophysiology of schizophrenia. These results also support the feasibility of integrating genomic and transcriptome analyses to map critical neurodevelopmental processes in time and space in the brain.

    View details for DOI 10.1016/j.cell.2013.06.049

    View details for PubMedID 23911319

  • A Genome-Wide Association Study (GWAS) for Bronchopulmonary Dysplasia. Pediatrics Wang, H., St Julien, K. R., Stevenson, D. K., Hoffmann, T. J., Witte, J. S., Lazzeroni, L. C., Krasnow, M. A., Quaintance, C. C., Oehlert, J. W., Jelliffe-Pawlowski, L. L., Gould, J. B., Shaw, G. M., O'Brodovich, H. M. 2013; 132 (2): 290-297

    Abstract

    Twin studies suggest that heritability of moderate-severe bronchopulmonary dysplasia (BPD) is 53% to 79%, we conducted a genome-wide association study (GWAS) to identify genetic variants associated with the risk for BPD.The discovery GWAS was completed on 1726 very low birth weight infants (gestational age = 25(0)-29(6/7) weeks) who had a minimum of 3 days of intermittent positive pressure ventilation and were in the hospital at 36 weeks' postmenstrual age. At 36 weeks' postmenstrual age, moderate-severe BPD cases (n = 899) were defined as requiring continuous supplemental oxygen, whereas controls (n = 827) inhaled room air. An additional 795 comparable infants (371 cases, 424 controls) were a replication population. Genomic DNA from case and control newborn screening bloodspots was used for the GWAS. The replication study interrogated single-nucleotide polymorphisms (SNPs) identified in the discovery GWAS and those within the HumanExome beadchip.Genotyping using genomic DNA was successful. We did not identify SNPs associated with BPD at the genome-wide significance level (5 × 10(-8)) and no SNP identified in previous studies reached statistical significance (Bonferroni-corrected P value threshold .0018). Pathway analyses were not informative.We did not identify genomic loci or pathways that account for the previously described heritability for BPD. Potential explanations include causal mutations that are genetic variants and were not assayed or are mapped to many distributed loci, inadequate sample size, race ethnicity of our study population, or case-control differences investigated are not attributable to underlying common genetic variation.

    View details for DOI 10.1542/peds.2013-0533

    View details for PubMedID 23897914

  • Neuropsychiatric symptoms, apolipoprotein E gene, and risk of progression to cognitive impairment, no dementia and dementia: the Aging, Demographics, and Memory Study (ADAMS). International journal of geriatric psychiatry Beaudreau, S. A., Kaci Fairchild, J., Spira, A. P., Lazzeroni, L. C., O'Hara, R. 2013; 28 (7): 672-680

    Abstract

    OBJECTIVE: To examine the relationship of neuropsychiatric symptoms and apolipoprotein E (APOE) ε4 allele status to dementia at baseline and progression to dementia in older adults with and without cognitive impairment, no dementia (CIND). METHODS: Adults (n = 856) 71 years and older (mean age = 79.15 years), 12.8% ethnic minority and 60.6% women, completed neuropsychological tests and APOE genotyping, and a proxy informant completed the Neuropsychiatric Inventory. RESULTS: After adjusting for age and education, neuropsychiatric symptoms and APOE ε4 were independently associated with CIND and dementia status at baseline (compared with cognitively normal). Further, neuropsychiatric symptoms predicted progression to dementia at 16- to 18-month follow-up among participants with CIND at baseline; the presence of these symptoms decreased the risk of progression from normal to CIND or dementia at 36 to 48 months. CONCLUSION: Findings provide cross-sectional and longitudinal support for the role of neuropsychiatric symptoms in the prediction of cognitive impairment, particularly dementia. APOE ε4, although important, may be a less robust predictor. This investigation highlights the importance of behavioral symptoms, such as neuropsychiatric symptom status or frequency/severity, as predictors of future cognitive decline. Copyright © 2012 John Wiley & Sons, Ltd.

    View details for DOI 10.1002/gps.3868

    View details for PubMedID 22927174

    View details for PubMedCentralID PMC3665735

  • Intraindividual variability in basic reaction time predicts middle-aged and older pilots' flight simulator performance. journals of gerontology. Series B, Psychological sciences and social sciences Kennedy, Q., Taylor, J., Heraldez, D., Noda, A., Lazzeroni, L. C., Yesavage, J. 2013; 68 (4): 487-494

    Abstract

    ObjectivesIntraindividual variability (IIV) is negatively associated with cognitive test performance and is positively associated with age and some neurological disorders. We aimed to extend these findings to a real-world task, flight simulator performance. We hypothesized that IIV predicts poorer initial flight performance and increased rate of decline in performance among middle-aged and older pilots.MethodTwo-hundred and thirty-six pilots (40-69 years) completed annual assessments comprising a cognitive battery and two 75-min simulated flights in a flight simulator. Basic and complex IIV composite variables were created from measures of basic reaction time and shifting and divided attention tasks. Flight simulator performance was characterized by an overall summary score and scores on communication, emergencies, approach, and traffic avoidance components. RESULTS: Although basic IIV did not predict rate of decline in flight performance, it had a negative association with initial performance for most flight measures. After taking into account processing speed, basic IIV explained an additional 8%-12% of the negative age effect on initial flight performance.DiscussionIIV plays an important role in real-world tasks and is another aspect of cognition that underlies age-related differences in cognitive performance.

    View details for DOI 10.1093/geronb/gbs090

    View details for PubMedID 23052365

  • BDNF and CREB1 genetic variants interact to affect antidepressant treatment outcomes in geriatric depression. Pharmacogenetics and genomics Murphy, G. M., Sarginson, J. E., Ryan, H. S., O'Hara, R., Schatzberg, A. F., Lazzeroni, L. C. 2013; 23 (6): 301-313

    Abstract

    Brain-derived neurotrophic factor (BDNF) is associated with antidepressant response on the cellular level, in animal models, and in clinical studies. A common variant in the BDNF gene results in a substitution of a methionine (Met) for a valine at the amino acid position 66. Previous studies reported that the Met variant results in enhanced response to antidepressant medications. These findings may be at odds with studies indicating that on a cellular level the Met variant impairs the secretion of BDNF.We examined the effects of BDNF single nucleotide polymorphisms (SNPs) in response to the antidepressants paroxetine and mirtazapine in a sample of 246 geriatric patients with major depression, treated in a double-blind, randomized, 8-week clinical trial. We also examined the effects of genetic variation at the BDNF-related loci neurotrophic tyrosine kinase receptor 2, cyclic AMP responsive element binding protein 1 (CREB1), and CREB binding protein. A total of 53 SNPs were genotyped.BDNF genetic variation had a significant effect on the efficacy of paroxetine, with patients carrying the Met allele showing impaired response. SNPs at the CREB1 locus, which encodes a transcription factor important in BDNF signaling, also predicted response to paroxetine. Furthermore, we found a significant gene-gene interaction between BDNF and CREB1 that affected response to paroxetine. Because BDNF has been associated with cognitive function, we tested the effects of BDNF SNPs on change in a wide variety of cognitive tests over the 8-week trial, but there were no significant effects of genotype on cognition.These results provide new evidence for the importance of the BDNF pathway in antidepressant response in geriatric patients. The negative effect of the Met66 allele on antidepressant outcomes is consistent with basic science findings indicating a negative effect of this variant on BDNF activity in the brain. Further, the effect of BDNF genetic variation on antidepressant treatment is modified by variation in the gene encoding the downstream effector CREB1.

    View details for DOI 10.1097/FPC.0b013e328360b175

    View details for PubMedID 23619509

  • Sex differences in familiality effects on neurocognitive performance in schizophrenia. Biological psychiatry Calkins, M. E., Ray, A., Gur, R. C., Freedman, R., Green, M. F., Greenwood, T. A., Light, G. A., Nuechterlein, K. H., Olincy, A., Radant, A. D., Seidman, L. J., Siever, L. J., Silverman, J. M., Stone, W. S., Sugar, C., Swerdlow, N. R., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Braff, D. L., Lazzeroni, L. C., Gur, R. E. 2013; 73 (10): 976-984

    Abstract

    Numerous studies have documented that patients with schizophrenia show neurocognitive impairments, which are also heritable in schizophrenia families. In view of these findings, the current investigation tested the hypothesis that neurocognitive performance of schizophrenia probands can predict the neurocognitive performance of their unaffected family members.Participants (n=1967; schizophrenia=369; first-degree relatives=1072; community comparison subjects=526) in the Consortium on the Genetics of Schizophrenia were administered the Penn Computerized Neurocognitive Battery.Consistent with prior work, probands showed significant neurocognitive impairment, and neurocognitive ability was significantly heritable across domains. On average, unaffected relatives did not differ from community comparison subjects in their neurocognitive performance. However, in six of seven domains, proband scores predicted the performance of their unaffected siblings. Male, but not female, proband performance was predictive of their unaffected relatives' (siblings and mothers) performance, most consistently in face memory and spatial processing.Using a novel approach in which individual probands are paired with their respective unaffected relatives within each family, we found that male proband performance predicted both sister and brother performance, an effect that was most powerfully observed for face memory and spatial processing. Results suggest that the familial transmission of sexually dimorphic neurocognitive domains, in which a particular sex tends to show a performance advantage over the other, may not itself be sex specific in schizophrenia families.

    View details for DOI 10.1016/j.biopsych.2012.12.021

    View details for PubMedID 23395246

  • Genome-wide linkage analyses of 12 endophenotypes for schizophrenia from the consortium on the genetics of schizophrenia. American journal of psychiatry Greenwood, T. A., Swerdlow, N. R., Gur, R. E., Cadenhead, K. S., Calkins, M. E., Dobie, D. J., Freedman, R., Green, M. F., Gur, R. C., Lazzeroni, L. C., Nuechterlein, K. H., Olincy, A., Radant, A. D., Ray, A., Schork, N. J., Seidman, L. J., Siever, L. J., Silverman, J. M., Stone, W. S., Sugar, C. A., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Light, G. A., Braff, D. L. 2013; 170 (5): 521-532

    Abstract

    The Consortium on the Genetics of Schizophrenia has undertaken a large multisite study to characterize 12 neurophysiological and neurocognitive endophenotypic measures as a step toward understanding the complex genetic basis of schizophrenia. The authors previously demonstrated the heritability of these endophenotypes; in the present study, genetic linkage was evaluated.Each family consisted of a proband with schizophrenia, at least one unaffected sibling, and both parents. A total of 1,286 participants from 296 families were genotyped in two phases, and 1,004 individuals were also assessed for the endophenotypes. Linkage analyses of the 6,055 single-nucleotide polymorphisms that were successfully assayed, 5,760 of which were common to both phases, were conducted using both variance components and pedigree-wide regression methods.Linkage analyses of the 12 endophenotypes collectively identified one region meeting genome-wide significance criteria, with a LOD (log of odds) score of 4.0 on chromosome 3p14 for the antisaccade task, and another region on 1p36 nearly meeting genome-wide significance, with a LOD score of 3.5 for emotion recognition. Chromosomal regions meeting genome-wide suggestive criteria with LOD scores >2.2 were identified for spatial processing (2p25 and 16q23), sensorimotor dexterity (2q24 and 2q32), prepulse inhibition (5p15), the California Verbal Learning Test (8q24), the degraded-stimulus Continuous Performance Test (10q26), face memory (10q26 and 12p12), and the Letter-Number Span (14q23).Twelve regions meeting genome-wide significant and suggestive criteria for previously identified heritable, schizophrenia-related endophenotypes were observed, and several genes of potential neurobiological interest were identified. Replication and further genomic studies are needed to assess the biological significance of these results.

    View details for DOI 10.1176/appi.ajp.2012.12020186

    View details for PubMedID 23511790

  • Structural MRI Investigations in Twins with Autism 68th Annual Scientific Meeting of the Society-of-Biological-Psychiatry Hardan, A. Y., Hallmayer, J., Lazzeroni, L., Berquist, S., Raman, M. R., Patnaik, S., Phillips, J., Reiss, A. L., Cleveland, S. ELSEVIER SCIENCE INC. 2013: 88S–88S
  • Predischarge screening for severe neonatal hyperbilirubinemia identifies infants who need phototherapy. journal of pediatrics Bhutani, V. K., Stark, A. R., Lazzeroni, L. C., Poland, R., Gourley, G. R., Kazmierczak, S., Meloy, L., Burgos, A. E., Hall, J. Y., Stevenson, D. K. 2013; 162 (3): 477-482 e1

    Abstract

    To test whether the combined use of total plasma/serum bilirubin (TSB) levels and clinical risk factors more accurately identifies infants who receive phototherapy than does the use of either method alone.We recruited healthy infants of ≥35 weeks' gestation at 6 centers that practiced universal predischarge TSB screening. Transcutaneous bilirubin (TcB) was measured at 24 hours, with TSB at 24-60 hours and at 3- to 5- and 7- to 14-day follow-up visits. Clinical risk factors were identified systematically.Of 1157 infants, 1060 (92%) completed follow-up, and 982 (85%) had complete datasets for analysis. Infant characteristics included 25% were nonwhite and 55% were Hispanic/Latino; >90% were breastfed. During the first week, jaundice was documented in 84% of subjects. Predischarge TSB identified the 41 (4.2%) and 34 (3.5%) infants who received phototherapy before and after discharge, respectively. Prediction of postdischarge phototherapy was similar for combined clinical risk factors (earlier gestational age [GA], bruising, positive direct antiglobulin test, Asian race, exclusive breastfeeding, blood type incompatibility, jaundice extent) and age-adjusted TSB (area under the curve [AUC] = .86 vs .87), but combined screening was better (AUC = .95). TcB/TSB combined with GA alone was equally predictive (AUC = .95; 95% CI .93-.97).Jaundice is present in 4 of 5 (84%) healthy newborns. Predischarge TcB/TSB (adjusted for postnatal age) combined with specific clinical factors (especially GA) best predicts subsequent phototherapy use. Universal implementation of this strategy in the US should improve outcomes of healthy newborns discharged early.

    View details for DOI 10.1016/j.jpeds.2012.08.022

    View details for PubMedID 23043681

  • Memantine is Associated with Longer Survival than Donepezil in a Veterans Affairs Prescription Database, 1997 to 2008 JOURNAL OF ALZHEIMERS DISEASE Lazzeroni, L. C., Halbauer, J. D., Ashford, J. W., Noda, A., Hernandez, B., Azor, V., Hozack, N., Hasson, N., Henderson, V. W., Yesavage, J. A., Tinklenberg, J. R. 2013; 36 (4): 791-798

    Abstract

    Alzheimer's disease (AD) shortens life-expectancy, but the effects of pharmacological treatments for this disorder on mortality have not been studied. We compared two commonly prescribed medications, donepezil and memantine, with respect to the length of survival of veterans presumed to have AD. The Computerized Medical Records System at the Veterans Affairs Palo Alto Health Care System (VAPAHCS) was used to identify all patients prescribed these medications between 1997 and 2008. The VAPAHCS approved donepezil in 1997 and memantine in 2004. Kaplan-Meier and Cox regression analyses were used to test for chronological and drug-related associations with survival in 2,083 male veterans aged 55 years and older receiving prescriptions for donepezil, memantine, or both. Overall patient mortality decreased in the 2004 to 2008 era, compared with the 1997 to 2003 era, pre-memantine (HR: 0.75; 95% CI: 0.63, 0.89; p = 0.001). In analyses confined to the 2004 to 2008 era, patients prescribed memantine alone survived significantly longer (median survival 8.9 years) than those prescribed donepezil alone (HR: 2.24; 95% CI: 1.53, 3.28; p < 0.001) or both donepezil and memantine (HR: 1.83; 95% CI: 1.14, 2.94; p = 0.012). While this study has several limitations, these findings suggest that memantine treatment is associated with an increased life-expectancy relative to donepezil treatment. Additional research is needed to replicate these unexpected findings and identify potential mechanisms to explain this apparent association, to establish if the relationship applies to other cholinesterase inhibitors, and to discover whether the findings generalize to women and patient populations with characteristics different from those of the veterans in this study.

    View details for DOI 10.3233/JAD-130662

    View details for Web of Science ID 000322738000016

    View details for PubMedID 23703151

  • High Quality Genome-Wide Genotyping from Archived Dried Blood Spots without DNA Amplification. PloS one St Julien, K. R., Jelliffe-Pawlowski, L. L., Shaw, G. M., Stevenson, D. K., O'Brodovich, H. M., Krasnow, M. A. 2013; 8 (5): e64710

    Abstract

    Spots of blood are routinely collected from newborn babies onto filter paper called Guthrie cards and used to screen for metabolic and genetic disorders. The archived dried blood spots are an important and precious resource for genomic research. Whole genome amplification of dried blood spot DNA has been used to provide DNA for genome-wide SNP genotyping. Here we describe a 96 well format procedure to extract DNA from a portion of a dried blood spot that provides sufficient unamplified genomic DNA for genome-wide single nucleotide polymorphism (SNP) genotyping. We show that SNP genotyping of the unamplified DNA is more robust than genotyping amplified dried blood spot DNA, is comparable in cost, and can be done with thousands of samples. This procedure can be used for genome-wide association studies and other large-scale genomic analyses that require robust, high-accuracy genotyping of dried blood spot DNA.

    View details for DOI 10.1371/journal.pone.0064710

    View details for PubMedID 23737996

    View details for PubMedCentralID PMC3667813

  • High quality genome-wide genotyping from archived dried blood spots without DNA amplification. PloS one St Julien, K. R., Jelliffe-Pawlowski, L. L., Shaw, G. M., Stevenson, D. K., O'Brodovich, H. M., Krasnow, M. A. 2013; 8 (5)

    Abstract

    Spots of blood are routinely collected from newborn babies onto filter paper called Guthrie cards and used to screen for metabolic and genetic disorders. The archived dried blood spots are an important and precious resource for genomic research. Whole genome amplification of dried blood spot DNA has been used to provide DNA for genome-wide SNP genotyping. Here we describe a 96 well format procedure to extract DNA from a portion of a dried blood spot that provides sufficient unamplified genomic DNA for genome-wide single nucleotide polymorphism (SNP) genotyping. We show that SNP genotyping of the unamplified DNA is more robust than genotyping amplified dried blood spot DNA, is comparable in cost, and can be done with thousands of samples. This procedure can be used for genome-wide association studies and other large-scale genomic analyses that require robust, high-accuracy genotyping of dried blood spot DNA.

    View details for DOI 10.1371/journal.pone.0064710

    View details for PubMedID 23737996

  • Immune biomarker differences and changes comparing HCV mono-infected, HIV/HCV co-infected, and HCV spontaneously cleared patients. PloS one Kushner, L. E., Wendelboe, A. M., Lazzeroni, L. C., Chary, A., Winters, M. A., Osinusi, A., Kottilil, S., Polis, M. A., Holodniy, M. 2013; 8 (4)

    Abstract

    Immune biomarkers are implicated in HCV treatment response, fibrosis, and accelerated pathogenesis of comorbidities, though only D-dimer and C-reactive protein have been consistently studied. Few studies have evaluated HIV/HCV co-infection, and little longitudinal data exists describing a broader antiviral cytokine response.Fifty immune biomarkers were analyzed at baseline (BL) and HCV end of treatment follow-up(FU) time point using the Luminex 50-plex assay in plasma samples from 15 HCV-cleared, 24 HCV mono- and 49 HIV/HCV co-infected patients receiving antiretroviral treatment, who either did or did not receive pegylated-interferon/ribavirin HCV treatment. Biomarker levels were compared among spontaneous clearance patients, mono- and co-infected, untreated and HCV-treated, and sustained virologic responders (SVR) and non-responders (NR) at BL and FU using nonparametric analyses. A Bonferroni correction, adjusting for tests of 50 biomarkers, was used to reduce Type I error.Compared to HCV patients at BL, HIV/HCV patients had 22 significantly higher and 4 significantly lower biomarker levels, following correction for multiple testing. There were no significantly different BL levels when comparing SVR and NR in mono- or co-infected patients; however, FU levels changed considerably in co-infected patients, with seven becoming significantly higher and eight becoming significantly lower in SVR patients. Longitudinally between BL and FU, 13 markers significantly changed in co-infected SVR patients, while none significantly changed in co-infected NR patients. There were also no significant changes in longitudinal analyses of mono-infected patients achieving SVR or mono-infected and co-infected groups deferring treatment.Clear differences exist in pattern and quantity of plasma immune biomarkers among HCV mono-infected, HIV/HCV co-infected, and HCV-cleared patients; and with SVR in co-infected patients treated for HCV. Though >90% of patients were male and co-infected had a larger percentage of African American patients, our findings may have implications for better understanding HCV pathogenesis, treatment outcomes, and future therapeutic targets.

    View details for DOI 10.1371/journal.pone.0060387

    View details for PubMedID 23593207

    View details for PubMedCentralID PMC3617231

  • A Generalized Defries-Fulker Regression Framework for the Analysis of Twin Data BEHAVIOR GENETICS Lazzeroni, L. C., Ray, A. 2013; 43 (1): 85-96

    Abstract

    Twin studies compare the similarity between monozygotic twins to that between dizygotic twins in order to investigate the relative contributions of latent genetic and environmental factors influencing a phenotype. Statistical methods for twin data include likelihood estimation and Defries-Fulker regression. We propose a new generalization of the Defries-Fulker model that fully incorporates the effects of observed covariates on both members of a twin pair and is robust to violations of the Normality assumption. A simulation study demonstrates that the method is competitive with likelihood analysis. The Defries-Fulker strategy yields new insight into the parameter space of the twin model and provides a novel, prediction-based interpretation of twin study results that unifies continuous and binary traits. Due to the simplicity of its structure, extensions of the model have the potential to encompass generalized linear models, censored and truncated data; and gene by environment interactions.

    View details for DOI 10.1007/s10519-012-9573-7

    View details for Web of Science ID 000313804300008

    View details for PubMedID 23264207

    View details for PubMedCentralID PMC3573860

  • Refining Association Mapping in a Heterogeneous Population Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) Ray, A., Lazzeroni, L. C. WILEY-BLACKWELL. 2012: 726–27
  • An Empirical Bayes Method for Unified Association Analysis of a Gene, Region or Pathway Containing Multiple SNPs Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) Lazzeroni, L. C., Ray, A. WILEY-BLACKWELL. 2012: 762–63
  • Combinatorial Pharmacogenetic Interactions of Bucindolol and beta(1), alpha(2C) Adrenergic Receptor Polymorphisms PLOS ONE O'Connor, C. M., Fiuzat, M., Carson, P. E., Anand, I. S., Plehn, J. F., Gottlieb, S. S., Silver, M. A., Lindenfeld, J., Miller, A. B., White, M., Walsh, R., Nelson, P., Medway, A., Davis, G., Robertson, A. D., Port, J. D., Carr, J., Murphy, G. A., Lazzeroni, L. C., Abraham, W. T., Liggett, S. B., Bristow, M. R. 2012; 7 (10)

    Abstract

    Pharmacogenetics involves complex interactions of gene products affecting pharmacodynamics and pharmacokinetics, but there is little information on the interaction of multiple genetic modifiers of drug response. Bucindolol is a β-blocker/sympatholytic agent whose efficacy is modulated by polymorphisms in the primary target (β(1) adrenergic receptor [AR] Arg389 Gly on cardiac myocytes) and a secondary target modifier (α(2C) AR Ins [wild-type (Wt)] 322-325 deletion [Del] on cardiac adrenergic neurons). The major allele homozygotes and minor allele carriers of each polymorphism are respectively associated with efficacy enhancement and loss, creating the possibility for genotype combination interactions that can be measured by clinical trial methodology.In a 1,040 patient substudy of a bucindolol vs. placebo heart failure clinical trial, we tested the hypothesis that combinations of β(1)389 and α(2C)322-325 polymorphisms are additive for both efficacy enhancement and loss. Additionally, norepinephrine (NE) affinity for β(1)389 AR variants was measured in human explanted left ventricles.The combination of β(1)389 Arg+α(2C)322-325 Wt major allele homozygotes (47% of the trial population) was non-additive for efficacy enhancement across six clinical endpoints, with an average efficacy increase of 1.70-fold vs. 2.32-fold in β(1)389 Arg homozygotes+α(2C)322-325 Del minor allele carriers. In contrast, the minor allele carrier combination (13% subset) exhibited additive efficacy loss. These disparate effects are likely due to the higher proportion (42% vs. 8.7%, P = 0.009) of high-affinity NE binding sites in β(1)389 Arg vs. Gly ARs, which converts α(2C)Del minor allele-associated NE lowering from a therapeutic liability to a benefit.On combination, the two sets of AR polymorphisms 1) influenced bucindolol efficacy seemingly unpredictably but consistent with their pharmacologic interactions, and 2) identified subpopulations with enhanced (β(1)389 Arg homozygotes), intermediate (β(1)389 Gly carriers+α(2C)322-325 Wt homozygotes), and no (β(1)389 Gly carriers+α(2C)322-325 Del carriers) efficacy.

    View details for DOI 10.1371/journal.pone.0044324

    View details for Web of Science ID 000312385200002

    View details for PubMedID 23071495

    View details for PubMedCentralID PMC3468617

  • Aversive and Reinforcing Opioid Effects A Pharmacogenomic Twin Study ANESTHESIOLOGY Angst, M. S., Lazzeroni, L. C., Phillips, N. G., Drover, D. R., Tingle, M., Ray, A., Swan, G. E., Clark, J. D. 2012; 117 (1): 22-37

    Abstract

    The clinical utility of opioids is limited by adverse drug effects including respiratory depression, sedation, nausea, and pruritus. In addition, abuse of prescription opioids is problematic. Gaining a better understanding of the genetic and environmental mechanisms contributing to an individual's susceptibility to adverse opioid effects is essential to identify patients at risk.A classic twin study paradigm provided estimates for the genetic and familial (genetic and/or shared environment) contribution to acute adverse and affective opioid responses, all secondary outcomes of a larger dataset. One hundred twenty-one twin pairs were recruited in a single occasion, randomized, double-blind, and placebo-controlled study. The μ-opioid receptor agonist alfentanil and saline placebo were administered as target-controlled infusions under carefully monitored laboratory conditions. Measured outcomes included respiratory depression, sedation, nausea, pruritus, drug liking, and drug disliking. Demographic information was collected, and aspects of mood and sleep were evaluated.Significant heritability was detected for respiratory depression (30%), nausea (59%), and drug disliking (36%). Significant familial effects were detected for sedation (29%), pruritus (38%), dizziness (32%), and drug liking (26%). Significant covariates included age, sex, race, ethnicity, education, mood, and depression. Covariates affected sedation, pruritus, drug liking and disliking, and dizziness.This study demonstrates that large-scale efforts to collect quantitative and well-defined opioid response data are not only feasible but also produce data that are suitable for genetic analysis. Genetic, environmental, and demographic factors work together to control adverse and reinforcing opioid responses, but contribute differently to specific responses.

    View details for PubMedID 22713632

  • Pain sensitivity and opioid analgesia: A pharmacogenomic twin study PAIN Angst, M. S., Phillips, N. G., Drover, D. R., Tingle, M., Ray, A., Swan, G. E., Lazzeroni, L. C., Clark, J. D. 2012; 153 (7): 1397-1409

    Abstract

    Opioids are the cornerstone medication for the management of moderate to severe pain. Unfortunately, vast inter-individual differences in dose requirements complicate their effective and safe clinical use. Mechanisms underlying such differences are incompletely understood, are likely multifactorial, and include genetic and environmental contributions. While accumulating evidence suggests that variants of several genes account for some of the observed response variance, the relative contribution of these factors remains unknown. This study used a twin paradigm to provide a global estimate of the genetic and environmental contributions to inter-individual differences in pain sensitivity and analgesic opioid effects. Eighty one monozygotic and 31 dizygotic twin pairs successfully underwent a computer-controlled infusion with the μ-opioid agonist alfentanil in a single occasion, randomized, double-blind and placebo-controlled study design. Pain sensitivity and analgesic effects were assessed with experimental heat and cold pressor pain models along with important covariates including demographic factors, depression, anxiety, and sleep quality. Significant heritability was detected for cold pressor pain tolerance and opioid-mediated elevations in heat and cold pressor pain thresholds. Genetic effects accounted for 12-60% of the observed response variance. Significant familial effects accounting for 24-32% of observed variance were detected for heat and cold pressor pain thresholds and opioid-mediated elevation in cold pressor pain tolerance. Significant covariates included age, gender, race, education, and anxiety. Results provide a strong rationale for more detailed molecular genetic studies to elucidate mechanisms underlying inter-individual differences in pain sensitivity and analgesic opioid responses. Such studies will require careful consideration of the studied pain phenotype.

    View details for DOI 10.1016/j.pain.2012.02.022

    View details for PubMedID 22444188

  • Integrative Approach to Pain Genetics Identifies Pain Sensitivity Loci across Diseases PLOS COMPUTATIONAL BIOLOGY Ruau, D., Dudley, J. T., Chen, R., Phillips, N. G., Swan, G. E., Lazzeroni, L. C., Clark, J. D., Butte, A. J., Angst, M. S. 2012; 8 (6)

    Abstract

    Identifying human genes relevant for the processing of pain requires difficult-to-conduct and expensive large-scale clinical trials. Here, we examine a novel integrative paradigm for data-driven discovery of pain gene candidates, taking advantage of the vast amount of existing disease-related clinical literature and gene expression microarray data stored in large international repositories. First, thousands of diseases were ranked according to a disease-specific pain index (DSPI), derived from Medical Subject Heading (MESH) annotations in MEDLINE. Second, gene expression profiles of 121 of these human diseases were obtained from public sources. Third, genes with expression variation significantly correlated with DSPI across diseases were selected as candidate pain genes. Finally, selected candidate pain genes were genotyped in an independent human cohort and prospectively evaluated for significant association between variants and measures of pain sensitivity. The strongest signal was with rs4512126 (5q32, ABLIM3, P = 1.3×10⁻¹⁰) for the sensitivity to cold pressor pain in males, but not in females. Significant associations were also observed with rs12548828, rs7826700 and rs1075791 on 8q22.2 within NCALD (P = 1.7×10⁻⁴, 1.8×10⁻⁴, and 2.2×10⁻⁴ respectively). Our results demonstrate the utility of a novel paradigm that integrates publicly available disease-specific gene expression data with clinical data curated from MEDLINE to facilitate the discovery of pain-relevant genes. This data-derived list of pain gene candidates enables additional focused and efficient biological studies validating additional candidates.

    View details for DOI 10.1371/journal.pcbi.1002538

    View details for PubMedID 22685391

  • Neuroanatomical Similarities and Differences in Twin Pairs with Autism 67th Annual Meeting of the Society-of-Biological-Psychiatry Harden, A. Y., Hallmayer, J., Frazier, T., Lazzeroni, L., Reiss, A. ELSEVIER SCIENCE INC. 2012: 188S–188S
  • The cost of large numbers of hypothesis tests on power, effect size and sample size MOLECULAR PSYCHIATRY Lazzeroni, L. C., Ray, A. 2012; 17 (1): 108-114

    Abstract

    Advances in high-throughput biology and computer science are driving an exponential increase in the number of hypothesis tests in genomics and other scientific disciplines. Studies using current genotyping platforms frequently include a million or more tests. In addition to the monetary cost, this increase imposes a statistical cost owing to the multiple testing corrections needed to avoid large numbers of false-positive results. To safeguard against the resulting loss of power, some have suggested sample sizes on the order of tens of thousands that can be impractical for many diseases or may lower the quality of phenotypic measurements. This study examines the relationship between the number of tests on the one hand and power, detectable effect size or required sample size on the other. We show that once the number of tests is large, power can be maintained at a constant level, with comparatively small increases in the effect size or sample size. For example at the 0.05 significance level, a 13% increase in sample size is needed to maintain 80% power for ten million tests compared with one million tests, whereas a 70% increase in sample size is needed for 10 tests compared with a single test. Relative costs are less when measured by increases in the detectable effect size. We provide an interactive Excel calculator to compute power, effect size or sample size when comparing study designs or genome platforms involving different numbers of hypothesis tests. The results are reassuring in an era of extreme multiple testing.

    View details for DOI 10.1038/mp.2010.117

    View details for Web of Science ID 000299014000015

    View details for PubMedID 21060308

    View details for PubMedCentralID PMC3252610

  • Length of prenatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants: effects on neonatal adaptation and psychomotor development PSYCHOPHARMACOLOGY Casper, R. C., Gilles, A. A., Fleisher, B. E., Baran, J., Enns, G., Lazzeroni, L. C. 2011; 217 (2): 211-219

    Abstract

    This study evaluated the question whether length of in utero exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants might affect neonatal outcome and psychomotor development in infancy.Birth outcome was determined in the offspring of 55 women with major depressive disorder who used SSRI medication for different durations during their pregnancies. At an average age of 14 months, children underwent a pediatric examination and an evaluation with the Bayley Scales of Infant Development (BSID-II).Duration of in utero exposure to SSRIs was negatively associated with total Apgar scores, specifically the activity subscale. Odds ratios for a low score (<2) on this scale were 3.8 and 6.0 at 1 and 5 min, respectively. Newborns with longer exposure were more often admitted to the Neonatal Intensive Care Unit (p < .03). Mental Development Index scores of the infants were not associated with the length of gestational exposure to SSRIs. A longer duration of exposure increased the risk for lower Psychomotor Developmental Index and Behavioral Rating Scale scores in infancy (p = 0.012 and p = 0.007, respectively) on the BSID-II.The findings provide evidence that the length of prenatal SSRI antidepressant use can affect neonatal adjustment and can have an effect on psychomotor test scores in infancy. Importantly, the children's mental development and motor function by neurological examination were within the normal range. Timing of exposure to SSRIs during susceptible periods of fetal development and variations in the severity of maternal depression may have contributed to the associations.

    View details for DOI 10.1007/s00213-011-2270-z

    View details for PubMedID 21499702

  • Analysis of 94 Candidate Genes and 12 Endophenotypes for Schizophrenia From the Consortium on the Genetics of Schizophrenia AMERICAN JOURNAL OF PSYCHIATRY Greenwood, T. A., Lazzeroni, L. C., Murray, S. S., Cadenhead, K. S., Calkins, M. E., Dobie, D. J., Green, M. F., Gur, R. E., Gur, R. C., Hardiman, G., Kelsoe, J. R., Leonard, S., Light, G. A., Nuechterlein, K. H., Olincy, A., Radant, A. D., Schork, N. J., Seidman, L. J., Siever, L. J., Silverman, J. M., Stone, W. S., Swerdlow, N. R., Tsuang, D. W., Tsuang, M. T., Turetsky, B. I., Freedman, R., Braff, D. L. 2011; 168 (9): 930-946

    Abstract

    The authors used a custom array of 1,536 single-nucleotide polymorphisms (SNPs) to interrogate 94 functionally relevant candidate genes for schizophrenia and identify associations with 12 heritable neurophysiological and neurocognitive endophenotypes in data collected by the Consortium on the Genetics of Schizophrenia.Variance-component association analyses of 534 genotyped subjects from 130 families were conducted by using Merlin software. A novel bootstrap total significance test was also developed to overcome the limitations of existing genomic multiple testing methods and robustly demonstrate significant associations in the context of complex family data and possible population stratification effects.Associations with endophenotypes were observed for 46 genes of potential functional significance, with three SNPs at p<10(-4), 27 SNPs at p<10(-3), and 147 SNPs at p<0.01. The bootstrap analyses confirmed that the 47 SNP-endophenotype combinations with the strongest evidence of association significantly exceeded that expected by chance alone, with 93% of these findings expected to be true. Many of the genes interact on a molecular level, and eight genes (e.g., NRG1 and ERBB4) displayed evidence for pleiotropy, revealing associations with four or more endophenotypes. The results collectively support a strong role for genes related to glutamate signaling in mediating schizophrenia susceptibility.This study supports use of relevant endophenotypes and the bootstrap total significance test for identifying genetic variation underlying the etiology of schizophrenia. In addition, the observation of extensive pleiotropy for some genes and singular associations for others suggests alternative, independent pathways mediating pathogenesis in the "group of schizophrenias."

    View details for DOI 10.1176/appi.ajp.2011.10050723

    View details for Web of Science ID 000294484100013

    View details for PubMedID 21498463

  • Influences of APOE epsilon 4 and Expertise on Performance of Older Pilots PSYCHOLOGY AND AGING Taylor, J. L., Kennedy, Q., Adamson, M. M., Lazzeroni, L. C., Noda, A., Murphy, G. M., Yesavage, J. A. 2011; 26 (2): 480-487

    Abstract

    Little is known about how APOE ε4-related differences in cognitive performance translate to real-life performance, where training and experience may help to sustain performance. We investigated the influences of APOE ε4 status, expertise (FAA pilot proficiency ratings), and their interaction on longitudinal flight simulator performance. Over a 2-year period, 139 pilots aged 42-69 years were tested annually. APOE ε4 carriers had lower memory performance than noncarriers (p = .019). APOE interacted with Expertise (p = .036), such that the beneficial influence of expertise (p = .013) on longitudinal flight simulator performance was more pronounced for ε4 carriers. Results suggest that relevant training and activity may help sustain middle-aged and older adults' real-world performance, especially among APOE ε4 carriers.

    View details for DOI 10.1037/a0021697

    View details for Web of Science ID 000291668800026

    View details for PubMedID 21668123

    View details for PubMedCentralID PMC3117441

  • Markers in the 15q24 Nicotinic Receptor Subunit Gene Cluster (CHRNA5-A3-B4) Predict Severity of Nicotine Addiction and Response to Smoking Cessation Therapy AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS Sarginson, J. E., Killen, J. D., Lazzeroni, L. C., Fortmann, S. P., Ryan, H. S., Schatzberg, A. F., Murphy, G. M. 2011; 156B (3): 275-284

    Abstract

    Stopping smoking is difficult even with treatment. Many patients prescribed pharmacologic treatments for smoking cessation experience side effects or lack of efficacy. We performed a pharmacogenetic study of the efficacy and tolerability of bupropion and transdermal nicotine (TN), two treatments for smoking cessation. Samples were drawn from two studies. In the first study (Maintenance 1, MT1), 301 smokers received bupropion plus TN for 11 weeks, followed by 14 weeks of placebo or bupropion. In the second study (MT2), 276 smokers received bupropion and TN for 8 weeks. We focused on eight SNPs in the 15q24 region, which contains the genes for the nicotinic cholinergic receptor subunits CHRNA5, CHRNA3, and CHRNB4, and has previously been implicated in nicotine addiction and smoking cessation. Analyses of baseline smoking quantity (SQ) identified an association between SQ and both the functional CHRNA5 SNP rs16969968 (D398N) and the CHRNA3 SNP rs1051730 (Y215Y) in a combined cohort containing MT1 and MT2. An association between SQ and ethnicity was also identified in the combined cohort. Pharmacogenetic analysis showed a significant association between rs8192475 (R37H) in CHRNA3 and both higher craving after quitting and increased withdrawal symptoms over time in MT2. Two markers for point prevalence abstinence, CHRNA5 SNP rs680244 and CHRNB4 SNP rs12914008, were also identified in MT2, with the strongest findings at week 52. These results provide further support for the role of the CHRNA5/A3/B4 subunits in determining number of cigarettes smoked and response to smoking cessation therapy.

    View details for DOI 10.1002/ajmg.b.31155

    View details for Web of Science ID 000288332600003

    View details for PubMedID 21268243

  • Analysis of 94 candidate genes and twelve endophenotypes for schizophrenia from the Consortium on the Genetics of Schizophrenia American Journal of Psychiatry Greenwood TA, Lazzeroni LC, Cadenhead KS, Calkins ME, Dobie DJ, Freedman R, Green MF, Gur RE, Kelsoe JR et al. 2011; in press
  • Opioid Pharmacogenomics Using a Twin Study Paradigm: Methods and Procedures for Determining Familial Aggregation and Heritability TWIN RESEARCH AND HUMAN GENETICS Angst, M. S., Phillips, N. G., Drover, D. R., Tingle, M., Galinkin, J. L., Christians, U., Swan, G. E., Lazzeroni, L. C., Clark, J. D. 2010; 13 (5): 412-425

    Abstract

    Opioids are the cornerstone medication for the treatment of moderate to severe pain. However, analgesic opioid requirements and the propensity to suffer from aversive opioid effects, including fatal respiratory depression and addiction, vary widely among patients. The factors underlying the substantial response variance remain largely unknown and need clarification for using opioids more effectively in appropriately selected patients. This ongoing study takes advantage of the twin paradigm to estimate the genetic and environmental contributions to inter-individual differences in opioid responses. Evidence of significant heritability will justify more detailed and extensive genomic studies. The enrollment target is 80 monozygotic and 45 dizygotic twin pairs who undergo a target-controlled infusion of the opioid alfentanil and saline placebo in sequential but randomized order. In a laboratory-type setting, well-defined pharmacodynamic endpoints are measured to quantify pain sensitivity, analgesic opioid effects, and aversive opioid effects including respiratory depression, sedation and reinforcing affective responses. First results obtained in 159 participants provide evidence for the feasibility and utility of this interventional study paradigm to estimate familial aggregation and heritability components of relevant drug effects. Areas highlighted in this report include recruitment strategies, required infrastructure and personnel, selection of relevant outcome measures, drug infusion algorithm minimizing pharmacokinetic variability, and considerations for optimizing data quality and quantity without hampering feasibility. Applying the twin paradigm to complex and potentially harmful studies comprehensively characterizing pharmacological response profiles is without much precedent. Methods and first results including heritability estimates for heat and cold pain sensitivity should be of interest to investigators considering similar studies.

    View details for PubMedID 20874462

  • Keratin Variants Predispose to Acute Liver Failure and Adverse Outcome: Race and Ethnic Associations GASTROENTEROLOGY Strnad, P., Zhou, Q., Hanada, S., Lazzeroni, L. C., Zhong, B. H., So, P., Davern, T. J., Lee, W. M., Omary, M. B. 2010; 139 (3): 828-U175

    Abstract

    Keratins 8 and 18 (K8/K18) provide anti-apoptotic functions upon liver injury. The cytoprotective function of keratins explains the overrepresentation of K8/K18 variants in patients with cirrhosis. However, K8/K18 variant-associated susceptibility to acute liver injury, which is well-described in animal models, has not been studied in humans.We analyzed the entire coding regions of KRT8 and KRT18 genes (15 total exons and their exon-intron boundaries) to determine the frequency of K8/K18 variants in 344 acute liver failure (ALF) patients (49% acetaminophen-related) and 2 control groups (African-American [n = 245] and previously analyzed white [n = 727] subjects).Forty-five ALF patients had significant amino-acid-altering K8/K18 variants, including 23 with K8 R341H and 11 with K8 G434S. K8 variants were significantly more common (total of 42 patients) than K18 variants (3 patients) (P < .001). We found increased frequency of variants in white ALF patients (9.1%) versus controls (3.7%) (P = .01). K8 R341H was more common in white (P = .01) and G434S was more common in African-American (P = .02) ALF patients versus controls. White patients with K8/K18 variants were less likely to survive ALF without transplantation (P = .02). K8 A333A and G434S variants associated exclusively with African Americans (23% combined frequency in African American but none in white controls; P < .0001), while overall, K18 variants were more common in non-white liver-disease subjects compared to whites (2.8% vs 0.6%, respectively; P = .008).KRT8 and KRT18 are important susceptibility genes for ALF development. Presence of K8/K18 variants predisposes to adverse ALF outcome, and some variants segregate with unique ethnic and race backgrounds.

    View details for DOI 10.1053/j.gastro.2010.06.007

    View details for Web of Science ID 000281365500025

    View details for PubMedID 20538000

    View details for PubMedCentralID PMC3249217

  • ABCB1 ( MDR1) polymorphisms and antidepressant response in geriatric depression PHARMACOGENETICS AND GENOMICS Sarginson, J. E., Lazzeroni, L. C., Ryan, H. S., Ershoff, B. D., Schatzberg, A. F., Murphy, G. M. 2010; 20 (8): 467-475

    Abstract

    Variation in the ATP-binding cassette, subfamily B, member 1 transporter (ABCB1) (multidrug-resistance gene 1) gene has been investigated as a predictor of response to treatment with a variety of medications such as antiarrhythmics, chemotherapeutic agents, anti-HIV medications, and some psychotropics. The ABCB1 gene product, P-glycoprotein, affects the transport of drugs out of many cell types, including endothelial cells at the blood-brain barrier. We sought to determine if ABCB1 polymorphisms predict response to antidepressant treatment in geriatric patients.We compared the effects of ABCB1 genetic variation on the therapeutic response to paroxetine, a P-glycoprotein substrate, and to mirtazapine, which is not thought to be transported by ABCB1, in a sample of 246 elderly patients with major depression treated in a clinical trial setting. A total of 15 single nucleotide polymorphisms in the ABCB1 gene were assessed in each patient. Two of these ABCB1 single nucleotide polymorphisms were earlier reported to predict treatment response in patients prescribed with P-glycoprotein substrate antidepressants.The two earlier identified ABCB1 markers for antidepressant response predicted time to remission in our paroxetine-treated patients, but not in the mirtazapine-treated patients. These results replicate the published findings of others. If a Bonferroni correction for type I error is made, our results do not reach the criteria for statistical significance. However, the Bonferroni correction may be too conservative given the strong linkage disequilibrium among some of the markers and our aim to replicate the earlier published findings.Our study provides confirmation that certain ABCB1 polymorphisms predict response to substrate medications in geriatric patients.

    View details for DOI 10.1097/FPC.0b013e32833b593a

    View details for Web of Science ID 000279865400001

    View details for PubMedID 20555295

  • FKBP5 Polymorphisms and Antidepressant Response in Geriatric Depression AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS Sarginson, J. E., Lazzeroni, L. C., Ryan, H. S., Schatzberg, A. F., Murphy, G. M. 2010; 153B (2): 554-560

    Abstract

    Genetic variation at the FKBP5 locus has been reported to affect clinical outcomes in patients treated with antidepressant medications in several studies. However, other reports have not confirmed this association. FKBP5 may regulate the sensitivity of the hypothalamic-pituitary-adrenal axis. We tested two FKBP5 single nucleotide polymorphisms (rs1360780 and rs3800373) in a sample of 246 geriatric patients treated for 8 weeks in a double-blind randomized comparison trial of paroxetine and mirtazapine. These two polymorphisms had previously been reported to predict efficacy in depressed patients treated with selective serotonin reuptake inhibitors such as paroxetine, and those treated with mirtazapine, an agent with both serotonergic and noradrenergic actions. However, we found no significant associations between these FKBP5 genetic variants and clinical outcomes. Neither mean Hamilton Depression Rating Scale scores nor time to remission or response were predicted by FKBP5 genetic variation. These results suggest that FKBP5 is unlikely to play a major role in determining antidepressant treatment outcomes in geriatric patients.

    View details for DOI 10.1002/ajmg.b.31019

    View details for Web of Science ID 000275377900023

    View details for PubMedID 19676097

    View details for PubMedCentralID PMC2897151

  • An alpha(2C)-Adrenergic Receptor Polymorphism Alters the Norepinephrine-Lowering Effects and Therapeutic Response of the beta-Blocker Bucindolol in Chronic Heart Failure CIRCULATION-HEART FAILURE Bristow, M. R., Murphy, G. A., Krause-Steinrauf, H., Anderson, J. L., Carlquist, J. F., Thaneemit-Chen, S., Krishnan, V., Abraham, W. T., Lowes, B. D., Port, J. D., Davis, G. W., Lazzeroni, L. C., Robertson, A. D., Lavori, P. W., Liggett, S. B. 2010; 3 (1): 21-28

    Abstract

    Adrenergic activation is an important determinant of outcomes in chronic heart failure. Adrenergic activity is regulated in part by prejunctional alpha(2C)-adrenergic receptors (ARs), which exhibit genetic variation in humans. Bucindolol is a novel beta-AR blocking agent that also lowers systemic norepinephrine and thus is also a sympatholytic agent. This study investigated whether alpha(2C)-AR polymorphisms affect sympatholytic effects of bucindolol in patients with heart failure.In the beta-Blocker Evaluation of Survival Trial, adrenergic activation was estimated by systemic venous norepinephrine measured at baseline, 3 months, and 12 months posttreatment in patients treated with placebo or bucindolol. In the beta-Blocker Evaluation of Survival Trial AR polymorphism substudy, DNA was collected from 1040 of the 2708 randomized patients, and alpha(2C)-AR gene polymorphisms (alpha(2C) Del322-325 or the wild-type counterpart) were measured by polymerase chain reaction and gel electrophoresis. Patients who were alpha(2C) Del carriers (heterozygotes or homozygotes) exhibited a much greater sympatholytic response to bucindolol (decrease in norepinephrine at 3 months of 153+/-57 pg/mL, P=0.012 compared with placebo versus decrease of 50+/-13 pg/mL in alpha(2C) wild type, P=0.0005 versus placebo; P=0.010 by interaction test). alpha(2C) Del carriers had no evidence of a favorable survival benefit from bucindolol (mortality compared with placebo hazard ratio, 1.09; 95% CI, 0.57 to 2.08; P=0.80), whereas bucindolol-treated subjects who were wild type for the alpha(2C)-AR had a 30% reduction in mortality (hazard ratio, 0.70; 95% CI, 0.51 to 0.96; P=0.025).In the beta-Blocker Evaluation of Survival Trial AR polymorphism substudy, the norepinephrine lowering and clinical therapeutic responses to bucindolol were strongly influenced by alpha(2C) receptor genotype.

    View details for DOI 10.1161/CIRCHEARTFAILURE.109.885962

    View details for Web of Science ID 000273735100005

    View details for PubMedID 19880803

  • immunological response in normal healthy twins across age BCB'10 Proceedings of the First ACM International Conference on Bioinformatics and Computational Biology Bhattacharya, S., Shen-Orr, S., Maecker, H., Lazzeroni, L., Swan, G. E., Clark, J. D., Angst, M. S., Butte, A. J., Davis, M. M. 2010
  • A randomized trial of computer-based reminders and audit and feedback to improve HIV screening in a primary care setting INTERNATIONAL JOURNAL OF STD & AIDS Sundaram, V., Lazzeroni, L. C., Douglass, L. R., Sanders, G. D., Tempio, P., Owens, D. K. 2009; 20 (8): 527-533

    Abstract

    Despite recommendations for voluntary HIV screening, few medical centres have implemented screening programmes. The objective of the study was to determine whether an intervention with computer-based reminders and feedback would increase screening for HIV in a Department of Veterans Affairs (VA) health-care system. The design of the study was a randomized controlled trial at five primary care clinics at the VA Palo Alto Health Care System. All primary care providers were eligible to participate in the study. The study intervention was computer-based reminders to either assess HIV risk behaviours or to offer HIV testing; feedback on adherence to reminders was provided. The main outcome measure was the difference in HIV testing rates between intervention and control group providers. The control group providers tested 1.0% (n = 67) and 1.4% (n = 106) of patients in the preintervention and intervention period, respectively; intervention providers tested 1.8% (n = 98) and 1.9% (n = 114), respectively (P = 0.75). In our random sample of 753 untested patients, 204 (27%) had documented risk behaviours. Providers were more likely to adhere to reminders to test rather than with reminders to perform risk assessment (11% versus 5%, P < 0.01). Sixty-one percent of providers felt that lack of time prevented risk assessment. In conclusion, in primary care clinics in our setting, HIV testing rates were low. Providers were unaware of the high rates of risky behaviour in their patient population and perceived important barriers to testing. Low-intensity clinical reminders and feedback did not increase rates of screening.

    View details for DOI 10.1258/ijsa.2008.008423

    View details for PubMedID 19625582

  • Identification of a Major Susceptibility Locus for Lethal Graft-versus-Host Disease in MHC-Matched Mice JOURNAL OF IMMUNOLOGY Cao, T. M., Lazzeroni, L. C., Tsai, S., Pang, W. W., Kao, A., Camp, N. J., Thomas, A., Shizuru, J. A. 2009; 183 (1): 462-469

    Abstract

    Graft-vs-host disease (GVHD) is the major cause of morbidity and mortality after allogeneic hemopoietic cell transplantation. From a genetic perspective, GVHD is a complex phenotypic trait. Although it is understood that susceptibility results from interacting polymorphisms of genes encoding histocompatibility Ags and immune regulatory molecules, a detailed and integrative understanding of the genetic background underlying GVHD remains lacking. To gain insight regarding these issues, we performed a forward genetic study. A MHC-matched mouse model was used in which irradiated recipient BALB.K and B10.BR mice demonstrate differential susceptibility to lethal GHVD when transplanted using AKR/J donors. Assessment of GVHD in (B10.BR x BALB.K)F(1) mice revealed that susceptibility is a dominant trait and conferred by deleterious alleles from the BALB.K strain. To identify the alleles responsible for GVHD susceptibility, a genome-scanning approach was taken using (B10.BR x BALB.K)F(1) x B10.BR backcross mice as recipients. A major susceptibility locus, termed the Gvh1 locus, was identified on chromosome 16 using linkage analysis (logarithm of the odds, 9.1). A second locus was found on chromosome 13, named Gvh2, which had additive but protective effects. Further identification of Gvh genes by positional cloning may yield new insight into genetic control mechanisms regulating GVHD and potentially reveal novel approaches for effective GVHD therapy.

    View details for DOI 10.4049/jimmunol.0900454

    View details for Web of Science ID 000275119400051

    View details for PubMedID 19525392

    View details for PubMedCentralID PMC2735236

  • Trends in US Autism Research Funding JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Singh, J., Illes, J., Lazzeroni, L., Hallmayer, J. 2009; 39 (5): 788-795

    Abstract

    This study shows that the number of autism research grants funded in the US from 1997 to 2006 significantly increased 15% per year. Although the majority of projects were concentrated in basic science (65%) compared to clinical (15%) and translational research (20%), there is a significant decrease in the proportion of basic research grants per year and a significant increase in the proportion of translational projects per year. The number of translational projects funded by the National Alliance for Autism Research and Cure Autism Now increased significantly, whereas the number of clinical projects significantly increased for the National Institutes of Health. In conclusion, this study demonstrates the shifting landscape of autism research from basic science to clinical and translational research.

    View details for DOI 10.1007/s10803-008-0685-0

    View details for Web of Science ID 000265820500009

    View details for PubMedID 19148735

  • Gene expression profile of the PDAPP mouse model for Alzheimer's disease with and without Apolipoprotein E NEUROBIOLOGY OF AGING Selwood, S. P., Parvathy, S., Cordell, B., Ryan, H. S., Oshidari, F., Vincent, V., Yesavage, J., Lazzeroni, L. C., Murphy, G. M. 2009; 30 (4): 574-590

    Abstract

    The APOE epsilon 4 allele is a strong risk factor for Alzheimer's disease (AD). However, the molecular basis for this effect remains unclear. We examined expression of approximately 12,000 genes and expressed sequence tags in the hippocampus and cortex of PDAPP (APP(V717)) mice modeling AD that show extensive amyloid beta (A beta) deposition, and in PDAPP mice lacking murine APOE expression, which show marked attenuation of A beta deposition in the brain. Wild type and APOE knockout animals were also examined. Expression levels were determined at the initial stage of A beta deposition, as well as in older animals showing extensive neuropathological changes. Fifty-four transcripts were identified using our statistical analysis as differentially regulated between the PDAPP and PDAPP/APOE ko mice, whereas 31 transcripts were classified as differentially regulated among PDAPP mice and WT animals, and seven transcripts were identified as regulated between the PDAPP/APOE ko animals and the APOE ko animals. Interestingly, many of the differentially regulated genes we detected can be related to biological processes previously shown to be important in AD pathophysiology, including inflammation, calcium homeostasis, cholesterol transport and uptake, kinases and phosphatases involved in tau phosphorylation and dephosphorylation, mitochondrial energy metabolism, protein degradation, neuronal growth, endoplasmic reticulum (ER) stress related proteins, antioxidant activity, cytoskeletal organization, and presenilin binding proteins. Regulated genes also included some not directly associated with AD in the past but likely to be involved in known AD pathophysiologic mechanisms, and others that may represent completely novel factors in the pathogenesis of AD. These results provide a global molecular profile of hippocampal and cortical gene expression during the initial and intermediate stages Abeta deposition, and the effects of APOE deletion on this process.

    View details for DOI 10.1016/j.neurobiolaging.2007.08.006

    View details for PubMedID 17904698

  • Purified hematopoietic stem cell allografts reconstitute immunity superior to bone marrow PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Tsao, G. J., Allen, J. A., Logronio, K. A., Lazzeroni, L. C., Shizuru, J. A. 2009; 106 (9): 3288-3293

    Abstract

    Antigen-specific immune responses are impaired after allogeneic hematopoietic cell transplantation (HCT). The events contributing to this impairment include host hematolymphoid ablation and donor cell regeneration, which is altered by pharmacologic immune suppression to prevent graft-versus-host disease (GVHD). A generally accepted concept is that graft T cell depletion performed to avoid GVHD yields poorer immune recovery because mature donor T cells are thought to be the major mediators of protective immunity early post-HCT. Our findings contradict the idea that removal of mature donor cells worsens immune recovery post-HCT. By transplantation of purified hematopoietic stem cells (HSC) compared with bone marrow (BM) across donor and recipient pairs of increasing genetic disparity, we show that grafts composed of the purified progenitor population give uniformly superior lymphoid reconstitution, both qualitatively and quantitatively. Subclinical GVHD by T cells in donor BM likely caused this lympho-depleting GVHD. We further determined in the major histocompatibility complex (MHC)-mismatched pairs, that T cell restricted proliferative responses were dictated by donor rather than host elements. We interpret these latter findings to show the importance of peripheral antigen presentation in the selection and maintenance of the T cell repertoire.

    View details for DOI 10.1073/pnas.0813335106

    View details for Web of Science ID 000263844100057

    View details for PubMedID 19223585

    View details for PubMedCentralID PMC2644259

  • Cognitive effects of memantine in postmenopausal women at risk of dementia: a pilot study ACTA NEUROLOGICA SCANDINAVICA Wroolie, T. E., Kenna, H. A., Williams, K. E., Powers, B. N., Holcomb, M., Lazzeroni, L., Rasgon, N. L. 2009; 119 (3): 172-179

    Abstract

    To determine the effects of memantine on cognition in a normal population of postmenopausal women with putative risk factors for Alzheimer's disease (AD) using a built-in control for the genetic risk factor for AD (apoE-epsilon4 status).A prospective, open-label, 6-month pilot medication trial with memantine and follow-up after discontinuance conducted at the Center for Neuroscience in Women's Health, Stanford University School of Medicine. Neuropsychological data were collected on 22 community-dwelling postmenopausal women (11 apoE-epsilon4 carriers and 11 apoE-epsilon4 non-carriers) with at least one putative risk factor for AD.ApoE-epsilon4 status was not a significant predictor of change in neuropsychological performance. Changes associated with memantine treatment for entire sample included significant declines in some variables associated with verbal learning and memory that improved upon medication withdrawal. A positive medication effect was noted with executive functions and possibly category fluency. Trend-level improvements were seen in motor dexterity of the non-dominant hand and maintained even after drug discontinuance.Treatment with memantine appeared to have differential effects on cognitive performance in a population of women with putative risk factors for AD. ApoE-epsilon4 carrier status did not account for observed changes in cognition.

    View details for DOI 10.1111/j.1600-0404.2008.01084.x

    View details for Web of Science ID 000262949100005

    View details for PubMedID 18705678

  • ADVANCES IN STATISTICAL GENETICS: APPLICATION TO SCHIZOPHRENIA AND RELATED NEUROPSYCHIATRIC DISORDERS 12th International Congress on Schizophrenia Research Schork, N., Lazzeroni, L. OXFORD UNIV PRESS. 2009: 100–101
  • Physiological Correlates of Social Avoidance Behavior in Children and Adolescents With Fragile X Syndrome JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Hall, S. S., Lightbody, A. A., Huffman, L. C., Lazzeroni, L. C., Reiss, A. L. 2009; 48 (3): 320-329

    Abstract

    To investigate whether eye-gaze avoidance, a striking phenotypic feature in fragile X syndrome (FXS), is associated with high levels of "hyperarousal" during social interactions with others. To date, almost all studies in this area have been confounded by inclusion of task demands in addition to social demands.We monitored the cardiovascular activity and eye-gaze avoidance of 50 boys and girls with FXS aged 5 to 20 years during a 25-minute intensive social interaction session with an unfamiliar experimenter. To control for possible family and genetic factors in cardiovascular activity, we compared each child with FXS with their same-sex typically developing biological sibling.Participants with FXS obtained significantly higher heart rates, lower vagal tone, and lower heart rate variability estimates both at baseline and during the social interaction session compared with their typically developing siblings. Although eye-gaze avoidance occurred at significantly higher levels in the children with FXS, this behavior decreased slightly over the course of the session (a "warm-up" effect) and did not seem to be associated with cardiovascular activity. In the girls with FXS, higher levels of the fragile X mental retardation protein were associated with higher (and more typical) heart rate variability.These data suggest that both sympathetic and parasympathetic nervous systems are dysregulated in FXS. However, given that prolonged exposure to social demands does not inevitably lead to increased anxiety or "hyperarousal," professionals should not be deterred from providing much needed social skills interventions for individuals with FXS.

    View details for DOI 10.1097/CHI.0b013e318195bd15

    View details for PubMedID 19182690

  • Pharmacogenetic effect of an endothelin-1 haplotype on response to bucindolol therapy in chronic heart failure PHARMACOGENETICS AND GENOMICS Taylor, M. R., Slavov, D., Humphrey, K., Zhao, L., Cockroft, J., Zhu, X., Lavori, P., Bristow, M. R., Mestroni, L., Lazzeroni, L. C. 2009; 19 (1): 35-43

    Abstract

    Beta-blocker therapy has become a mainstay therapy for the over 5 million patients with chronic heart failure in the United States. Variation in clinical response to beta-blockers is a well-known phenomenon and may be because of genetic differences between patients. We hypothesized that variation in genes of the endothelin system mediate the clinical response to beta-blockers in heart failure.Single nucleotide polymorphisms (SNPs) in six endothelin system genes were genotyped in 309 heart failure patients in a randomized trial of bucindolol versus placebo therapy. We adjusted for multiple comparisons and tested for association between genotype and time to two prospective endpoints.Nine SNPs were sufficiently common to undergo statistical analysis. The SNPs had no significant effect on prospective outcomes in the placebo group, or on the primary endpoint of time to death in either arm. Two SNPs (IVS-4 G/A and Lys198Asn) in the endothelin-1 gene, however, predicted time to the combined endpoint of heart failure hospitalization or all-cause death in bucindolol-treated patients. The alleles at these SNPs were in tight linkage disequilibrium appearing on either of two complementary haplotypes. A 'dose-response' trend was observed, with participants carrying the rarer haplotype having the highest hazard ratios as compared to the relative 'protective' effect of the common haplotype.A common endothelin-1 gene haplotype may be a pharmacogenetic predictor of a favorable clinical response to beta-blocker therapy in heart failure patients. The existence of a less common 'high-risk' haplotype could identify a subpopulation of heart failure patients destined to respond poorly to beta-blocker therapies.

    View details for DOI 10.1097/FPC.0b013e328317cc57

    View details for Web of Science ID 000262342500004

    View details for PubMedID 18953265

    View details for PubMedCentralID PMC3035051

  • Effect of the MTHFR C677T and A1298C polymorphisms on survival in patients with advanced CKD and ESRD: a prospective study. Am J Kidney Dis. Jamison, R. L., Shih, M. C., Humphries, D. E., Guarino, P. D., Kaufman, J. S., Goldfarb, D. S., Warren, S. R., Gaziano, J. M., Lavori, P., BEST DNA Bank 2009; 53 (5): 779-789
  • Transplantation of hematopoietic stem cells expressing diabetes-resistant loci Beilhack, G., Lazzeroni, L., Landa, R. R., Shizuru, J. A. SPRINGER WIEN. 2008: 167–167
  • Prevalence of HIV infection among inpatients and outpatients in department of veterans affairs health care systems: Implications for screening programs for HIV AMERICAN JOURNAL OF PUBLIC HEALTH Owens, D. K., Sundaram, V., Lazzeroni, L. C., Douglass, L. R., Sanders, G. D., Taylor, K., VanGroningen, R., Shadle, V. M., McWhorter, V. C., Agoncillo, T., Haren, N., Nyland, J., Tempio, P., Khayr, W., Dietzen, D. J., Jensen, P., Simberkoff, M. S., Bozzette, S. A., Holodniy, M. 2007; 97 (12): 2173-2178

    Abstract

    We sought to determine the prevalence of HIV in both inpatient and outpatient settings in 6 Department of Veterans Affairs (VA) health care sites.We collected demographic data and data on comorbid conditions and then conducted blinded, anonymous HIV testing. We conducted a multivariate analysis to determine predictors of HIV infection.We tested 4500 outpatient blood specimens and 4205 inpatient blood specimens; 326 (3.7%) patients tested positive for HIV. Inpatient HIV prevalence ranged from 1.2% to 6.9%; outpatient HIV prevalence ranged from 0.9% to 8.9%. Having a history of hepatitis B or C infection, a sexually transmitted disease, or pneumonia also predicted HIV infection. The prevalence of previously undocumented HIV infection varied from 0.1% to 2.8% among outpatients and from 0.0% to 1.7% among inpatients.The prevalence of undocumented HIV infection was sufficiently high for routine voluntary screening to be cost effective in each of the 6 sites we evaluated. Many VA health care systems should consider expanded routine voluntary HIV screening.

    View details for DOI 10.2105/AJPH.2007.110700

    View details for PubMedID 17971545

  • Pure hematopoietic stem cells reconstitute immunity in allogeneic hosts superior to bone marrow: Immunosuppression by subclinical graft-versus-host disease 49th Annual Meeting of the American-Society-of-Hematology Tsao, G. J., Allen, J. A., Logronio, K., Lazzeroni, L. C., Shizuru, J. A. AMER SOC HEMATOLOGY. 2007: 292B–292B
  • HIV testing of at risk patients in a large integrated health care system JOURNAL OF GENERAL INTERNAL MEDICINE Owens, D. K., Sundaram, V., Lazzeroni, L. C., Douglass, L. R., Tempio, P., Holodniy, M., Sanders, G. D., Shadle, V. M., McWhorter, V. C., Agoncillo, T., Haren, N., Chavis, D., Borowsky, L. H., Yano, E. M., Jensen, P., Simberkoff, M. S., Bozzette, S. A. 2007; 22 (3): 315-320

    Abstract

    Early identification of HIV infection is critical for patients to receive life-prolonging treatment and risk-reduction counseling. Understanding HIV screening practices and barriers to HIV testing is an important prelude to designing successful HIV screening programs. Our objective was to evaluate current practice patterns for identification of HIV.We used a retrospective cohort analysis of 13,991 at-risk patients seen at 4 large Department of Veterans Affairs (VA) health-care systems. We also reviewed 1,100 medical records of tested patients. We assessed HIV testing rates among at-risk patients, the rationale for HIV testing, and predictors of HIV testing and of HIV infection.Of the 13,991 patients at risk for HIV, only 36% had been HIV-tested. The prevalence of HIV ranged from 1% to 20% among tested patients at the 4 sites. Approximately 90% of patients who were tested had a documented reason for testing.One-half to two-thirds of patients at risk for HIV had not been tested within our selected VA sites. Among tested patients, the rationale for HIV testing was well documented. Further testing of at-risk patients could clearly benefit patients who have unidentified HIV infection by providing earlier access to life-prolonging therapy.

    View details for DOI 10.1007/s11606-006-0028-9

    View details for PubMedID 17356961

  • Prevalence of desmin mutations in dilated cardiomyopathy. Circulation Taylor, M. R., Slavov, D., Ku, L., Di Lenarda, A., Sinagra, G., Carniel, E., Haubold, K., Boucek, M. M., Ferguson, D., Graw, S. L., Zhu, X., Cavanaugh, J., Sucharov, C. C., Long, C. S., Bristow, M. R., Lavori, P., Mestroni, L., BEST DNA Bank 2007; 115 (10): 1244-51
  • A polymorphism within a conserved beta(1)-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Liggett, S. B., Mialet-Perez, J., Thaneemit-Chen, S., Weber, S. A., Greene, S. M., Hodne, D., Nelson, B., Morrison, J., Domanski, M. J., Wagoner, L. E., Abraham, W. T., Anderson, J. L., Carlquist, J. F., Krause-Steinrauf, H. J., Lazzeroni, L. C., Port, J. D., Lavori, P. W., Bristow, M. R. 2006; 103 (30): 11288-11293

    Abstract

    Heterogeneity of heart failure (HF) phenotypes indicates contributions from underlying common polymorphisms. We considered polymorphisms in the beta(1)-adrenergic receptor (beta(1)AR), a beta-blocker target, as candidate pharmacogenomic loci. Transfected cells, genotyped human nonfailing and failing ventricles, and a clinical trial were used to ascertain phenotype and mechanism. In nonfailing and failing isolated ventricles, beta(1)-Arg-389 had respective 2.8 +/- 0.3- and 4.3 +/- 2.1-fold greater agonist-promoted contractility vs. beta(1)-Gly-389, defining enhanced physiologic coupling under relevant conditions of endogenous expression and HF. The beta-blocker bucindolol was an inverse agonist in failing Arg, but not Gly, ventricles, without partial agonist activity at either receptor; carvedilol was a genotype-independent neutral antagonist. In transfected cells, bucindolol antagonized agonist-stimulated cAMP, with a greater absolute decrease observed for Arg-389 (435 +/- 80 vs. 115 +/- 23 fmol per well). Potential pathophysiologic correlates were assessed in a placebo-controlled trial of bucindolol in 1,040 HF patients. No outcome was associated with genotype in the placebo group, indicating little impact on the natural course of HF. However, the Arg-389 homozygotes treated with bucindolol had an age-, sex-, and race-adjusted 38% reduction in mortality (P = 0.03) and 34% reduction in mortality or hospitalization (P = 0.004) vs. placebo. In contrast, Gly-389 carriers had no clinical response to bucindolol compared with placebo. Those with Arg-389 and high baseline norepinephrine levels trended toward improved survival, but no advantage with this allele and exaggerated sympatholysis was identified. We conclude that beta(1)AR-389 variation alters signaling in multiple models and affects the beta-blocker therapeutic response in HF and, thus, might be used to individualize treatment of the syndrome.

    View details for DOI 10.1073/pnas.0509937103

    View details for Web of Science ID 000239353900034

    View details for PubMedID 16844790

    View details for PubMedCentralID PMC1523317

  • Keratin variants associate with progression of fibrosis during chronic hepatitis C infection HEPATOLOGY Strnad, P., Lienau, T. C., Tao, G., Lazzeroni, L. C., Stickel, F., Schuppan, D., Omary, M. B. 2006; 43 (6): 1354-1363

    Abstract

    Keratins 8 and 18 (K8/K18) protect the liver from various forms of injury. Studies of liver explants from a large cohort of U.S. patients showed that K8/K18 mutations confer a risk to developing end-stage liver diseases, though which diseases are preferentially involved is unknown. We tested the hypothesis that K8/K18 variants are associated with chronic hepatitis C (CHC) and that their presence correlates with progression of fibrosis. Genomic DNA was isolated from peripheral blood of a well-characterized German cohort of 329 patients with CHC infection. Exonic regions were PCR-amplified and analyzed using denaturing high-performance liquid chromatography and DNA sequencing. Our findings showed: (1) amino acid altering keratin heterozygous variants in 24 of 329 CHC patients (7.3%) and non-coding heterozygous variants in 26 patients (7.8%), and (2) 3 new exonic K8 variants (T26R/G55A/A359T); 6 novel non-coding variants and one K18 coding variant (K18 S230T; 2 patients). The most common variants were K8 R341H (10 patients), K8 G62C (6 patients) and K8 I63V (4 patients). A novel and exclusive association of an intronic KRT8 IVS7+10delC deletion in all 10 patients with K8 R341H was observed. Notably, there was a significant association of exonic, but not of intronic K8 variants with increased fibrosis. In conclusion, previously described and novel K8 variants are present in a German population and collectively associate with progression of fibrosis in CHC infection. The unique 100% segregation of the most common K8 variant, R341H, with an intronic deletion suggests that one of these two genetic changes might lead to the other.

    View details for DOI 10.1002/hep.21211

    View details for Web of Science ID 000237984500022

    View details for PubMedID 16729313

  • The effect of diagnosis with HIV infection on health-related quality of life QUALITY OF LIFE RESEARCH Honiden, S., Sundaram, V., Nease, R. F., Holodniy, M., Lazzeroni, L. C., Zolopa, A., Owens, D. K. 2006; 15 (1): 69-82

    Abstract

    We sought to understand how diagnosis with HIV affects health-related quality of life. We assessed health-related quality of life using utility-based measures in a Department of Veterans Affairs (VA) clinic and a University-based clinic. Respondents assessed health-related quality of life regarding their current health, and retrospectively assessed their health 1 month prior to and 2 months after diagnosis with HIV infection. Sixty-six patients completed the study. The overall mean utilities for health 1 month before and 2 months after diagnosis were 0.87 (standard error 0.037), and 0.80 (0.043) (p<0.005 by rank sign test), but the effect of diagnosis differed between the two clinics, with a substantial decrease in the university clinic and a small non-significant decrease in the VA clinic. The overall mean utility for current health was 0.85 (0.034), assessed on average 7.5 years after diagnosis. When asked directly whether diagnosis of HIV decreased health-related quality of life, 47% agreed, but 35% stated that HIV diagnosis positively affected health-related quality of life. Diagnosis with HIV decreased health-related quality of life at 2 months on average, but this effect diminished over time, and differed among patient populations. Years after diagnosis, although half of the patients believed that diagnosis reduced health-related quality of life, one-third reported improved health-related quality of life.

    View details for DOI 10.1007/s11136-005-8485-x

    View details for PubMedID 16411032

  • The role of a common adenosine monophosphate deaminase (AMPD)-1 polymorphism in outcomes of ischemic and nonischemic heart failure JOURNAL OF CARDIAC FAILURE Kolek, M. J., Carlquist, J. F., Thaneemit-Chen, S., Lazzeroni, L. C., Whiting, B. M., Horne, B. D., Muhlestein, J. B., Lavori, P., Anderson, J. L. 2005; 11 (9): 677-683

    Abstract

    A common variant of the adenosine monophosphate deaminase (AMPD)-1 gene (C34T) results in enzymatic inactivity and may increase adenosine in cardiac muscle and confer cardioprotection through ischemic preconditioning.We hypothesized that AMPD1 carriers with ischemic heart failure (HF) in the Beta-Blocker Evaluation of Survival Trial (BEST) might have a relative survival advantage. Patients (n = 1038, 20% black) with ischemic (58%) and nonischemic (42%) HF were followed for an average of 2.0 years for cardiovascular mortality. DNA was purified from blood using phenol/chloroform. Genotyping was performed by polymerase chain reaction with 5' exonuclease chemistry. Differences in survival were assessed by comparing Kaplan-Meier curves with the log-rank test. Genotype frequencies differed by ethnicity (P < .001) but not by disease etiology. AMPD1 genotype did not significantly modify survival in the entire study population (hazard ratio [HR] = 0.91, 95% CI = 0.61-1.37), among ischemics (HR = 0.73, CI = 0.44-1.22, P = .23), or ischemic non-blacks (HR = 0.74, CI = 0.44-1.24, P = .25). Genotype did not modify the effect of bucindolol on mortality.Results of this study failed to confirm a reported survival benefit among HF patients carrying the AMPD1 T-allele. However, further studies in larger, more homogeneous populations should explore the possibility of a modest survival advantage for patients with ischemic HF.

    View details for DOI 10.1016/j.cardfail.2005.06.437

    View details for Web of Science ID 000234655900005

    View details for PubMedID 16360962

  • Accuracy, precision, and consistency of expert HIV type 1 genotype interpretation: An international comparison (The GUESS Study) CLINICAL INFECTIOUS DISEASES Zolopa, A. R., Lazzeroni, L. C., Rinehart, A., Vezinet, F. B., Clavel, F., Collier, A., Conway, B., Gulick, R. M., Holodniy, M., Perno, C. F., Shafer, R. W., Richman, D. D., Wainberg, M. A., Kuritzkes, D. R. 2005; 41 (1): 92-99

    Abstract

    Resistance testing is considered standard of care in HIV medicine, but there is no standard interpretation system for genotype tests. We sought to determine how much agreement exists within a group of experts in the interpretation of complex genotypes.Genotypes from clinical specimens were sent to an international panel of 12 resistance experts. Phenotypic susceptibility testing of these clinical isolates was performed with antivirogram. Experts predicted phenotype fold change category (<2.5-fold change, 2.5-4.0-fold change, >4.0- to 7.0-fold change, >7.0- to 10-fold change, >10- to 20-fold change, or >20-fold change) and predicted expected drug activity for each of 16 antiretroviral drugs. Experts were also asked to make treatment recommendations on the basis of the genotype.The experts predicted the exact phenotype fold change category correctly 44% of the time, but they varied widely by antiretroviral drug (range, 25%-74%). The highest accuracy was observed for lamivudine (74%) and the nonnucleoside reverse transcriptase inhibitors (66%-69%). Experts generally predicted higher levels of resistance to the remaining nucleoside reverse transcriptase inhibitors than what was found by phenotypic testing. Agreement among experts in predicting phenotype fold change category ranged widely depending on the drug (median agreement, 42% [range, 28%-74%]); the same pattern was observed in predicting expected drug activity (median agreement, 45% [range, 32%-87%]). Experts agreed on treatment recommendations in a median of 79% of instances, and recommendations were consistent over time, with blinded retesting.Although their ability to predict phenotype from a genotype varied for individual antiretroviral drugs, this expert panel had a high degree of agreement in deriving treatment recommendations from the genotype.

    View details for Web of Science ID 000229530400015

    View details for PubMedID 15937768

  • Cost-effectiveness of screening for HIV in the era of highly active antiretroviral therapy NEW ENGLAND JOURNAL OF MEDICINE Sanders, G. D., Bayoumi, A. M., Sundaram, V., Bilir, S. P., Neukermans, C. P., Rydzak, C. E., Douglass, L. R., Lazzeroni, L. C., Holodniy, M., Owens, D. K. 2005; 352 (6): 570-585

    Abstract

    The costs, benefits, and cost-effectiveness of screening for human immunodeficiency virus (HIV) in health care settings during the era of highly active antiretroviral therapy (HAART) have not been determined.We developed a Markov model of costs, quality of life, and survival associated with an HIV-screening program as compared with current practice. In both strategies, symptomatic patients were identified through symptom-based case finding. Identified patients started treatment when their CD4 count dropped to 350 cells per cubic millimeter. Disease progression was defined on the basis of CD4 levels and viral load. The likelihood of sexual transmission was based on viral load, knowledge of HIV status, and efficacy of counseling.Given a 1 percent prevalence of unidentified HIV infection, screening increased life expectancy by 5.48 days, or 4.70 quality-adjusted days, at an estimated cost of 194 dollars per screened patient, for a cost-effectiveness ratio of 15,078 dollars per quality-adjusted life-year. Screening cost less than 50,000 dollars per quality-adjusted life-year if the prevalence of unidentified HIV infection exceeded 0.05 percent. Excluding HIV transmission, the cost-effectiveness of screening was 41,736 dollars per quality-adjusted life-year. Screening every five years, as compared with a one-time screening program, cost 57,138 dollars per quality-adjusted life-year, but was more attractive in settings with a high incidence of infection. Our results were sensitive to the efficacy of behavior modification, the benefit of early identification and therapy, and the prevalence and incidence of HIV infection.The cost-effectiveness of routine HIV screening in health care settings, even in relatively low-prevalence populations, is similar to that of commonly accepted interventions, and such programs should be expanded.

    View details for Web of Science ID 000226862100007

    View details for PubMedID 15703422

  • Genetic susceptibility loci for lethal graft-versus-host disease in MHC-identical mice: Initial results from a genome-wide scan. 46th Annual Meeting of the American-Society-of-Hematology Cao, T. M., Pang, W. W., Grumet, R. C., Lazzeroni, L. C., Shizuru, J. A. AMER SOC HEMATOLOGY. 2004: 328B–328B
  • Genome-wide identification of genes conferring resistance to the anticancer agents cisplatin, oxaliplatin, and mitomycin C CANCER RESEARCH Wu, H. I., BROWN, J. A., Dorie, M. J., Lazzeroni, L., Brown, J. M. 2004; 64 (11): 3940-3948

    Abstract

    Cisplatin is a crucial agent in the treatment of many solid tumors, yet many tumors have either acquired or intrinsic resistance to the drug. We have used the homozygous diploid deletion pool of Saccharomyces cerevisiae, containing 4728 strains with individual deletion of all nonessential genes, to systematically identify genes that when deleted confer sensitivity to the anticancer agents cisplatin, oxaliplatin, and mitomycin C. We found that deletions of genes involved in nucleotide excision repair, recombinational repair, postreplication repair including translesional synthesis, and DNA interstrand cross-link repair resulted in sensitivity to all three of the agents, although with some differences between the platinum drugs and mitomycin C in the spectrum of required translesional polymerases. Putative defective repair of oxidative damage (imp2'Delta strain) also resulted in sensitivity to platinum and oxaliplatin, but not to mitomycin C. Surprisingly in light of their different profiles of clinical activity, cisplatin and oxaliplatin have very similar sensitivity profiles. Finally, we identified three novel genes (PSY1-3, "platinum sensitivity") that, when deleted, demonstrate sensitivity to cisplatin and oxaliplatin, but not to mitomycin C. Our results emphasize the importance of multiple DNA repair pathways responsible for normal cellular resistance to all three of the agents. Also, the similarity of the sensitivity profiles of the platinum agents with that of the known DNA interstrand cross-linking agent mitomycin C, and the importance of the gene PSO2 known to be involved in DNA interstrand cross-link repair strongly suggests that interstrand cross-links are important toxic lesions for cisplatin and oxaliplatin, at least in yeast.

    View details for Web of Science ID 000221727300033

    View details for PubMedID 15173006

  • A polymorphism in the TCF7 gene, C883A, is associated with type 1 diabetes DIABETES Noble, J. A., White, A. M., Lazzeroni, L. C., Valdes, A. M., Mirel, D. B., Reynolds, R., Grupe, A., Aud, D., Peltz, G., Erlich, H. A. 2003; 52 (6): 1579-1582

    Abstract

    Type 1 diabetes is an autoimmune disease with a Th1 phenotype in which insulin-producing beta-cells in the pancreas are destroyed. The T-cell-specific transcription factor TCF7 activates genes involved in immune regulation and is a candidate locus for genetic susceptibility to type 1 diabetes. A nonsynonymous single nucleotide polymorphism (SNP) (Pro to Thr) in the TCF7 gene, C883A, was examined in samples from 282 Caucasian multiplex type 1 diabetic families. HLA-DRB1 and -DQB1 genotypes were previously determined for these samples, allowing data stratification based on HLA-associated risk. The transmission disequilibrium test showed significant overtransmission of the A allele from fathers (64.1%, P < 0.007) and nonsignificant overtransmission (57.4%, P < 0.06) of the A allele to patients who do not carry the highest-risk HLA-DR3/DR4 genotype. Elliptical sib pair analysis showed significant associations of the A allele with type 1 diabetes in paternal transmissions (P < 0.03), transmissions to male children (P < 0.04), and in the non-DR3/DR4 group (P < 0.04). These data also suggest that TCF7 C883A may affect age of disease onset. Analysis of genotype data from surrounding SNPs suggests that this TCF7 polymorphism may itself represent a risk factor for type 1 diabetes.

    View details for Web of Science ID 000183167600037

    View details for PubMedID 12765974

  • Gene expression patterns vary in clonal cell cultures from Rett syndrome females with eight different MECP2 mutations. BMC medical genetics Traynor, J., Agarwal, P., Lazzeroni, L., Francke, U. 2002; 3: 12-?

    Abstract

    Females with the neurological disorder Rett syndrome are heterozygous for mutations in X-linked MECP2 that encodes methyl-CpG binding protein 2 (MeCP2) thought to act as a transcriptional repressor. To identify target genes for MeCP2 modulation, we studied global gene expression in single cell-derived wild-type and mutant MECP2 expressing fibroblast clones with four common mutations (R106W, R306C, 705delG, 1155del32) and in lymphoblastoid cell lines (LCLs) that included four mutant MeCP2 (T158M, 803delG, R168X and 1159del28) expressing, and five (1159del28, R106W, R255X, 803delG, 803delG) wild-type MeCP2 expressing lines.Clonality and mutation status were verified by androgen receptor methylation assays for X-inactivation and by sequencing MECP2 transcripts. Expression studies were done with oligonucleotide microarrays (Affymetrix U95) and verified with real-time quantitative RT-PCR using Sybr Green.Expression of 49 transcripts was increased, and expression of 21 transcripts was decreased, in at least 3 of 4 mutant/wild-type fibroblast comparisons. Transcript levels of 11 genes, determined by quantitative RT-PCR, were highly correlated with the microarray data. Therefore, multiple additional clones from two Rett individuals were tested by RT-PCR only. Striking expression differences were found in both mutant and wildtype MeCP2 expressing clones. Comparing expression profiles of lymphoblastoid cell lines yielded 16 differentially expressed genes.MeCP2 deficiency does not lead to global deregulation of gene expression. Either MeCP2's in vivo function does not involve widespread transcriptional repression, or its function is redundant in cell types that also express other methyl-CpG binding proteins. Our data suggest that clonal fibroblast strains may show substantial inter-strain variation, making them a difficult and unstable resource for genome-wide expression profiling studies.

    View details for PubMedID 12418965

  • Association of IL4R haplotypes with type 1 diabetes DIABETES Mirel, D. B., Valdes, A. M., Lazzeroni, L. C., Reynolds, R. L., Erlich, H. A., Noble, J. A. 2002; 51 (11): 3336-3341

    Abstract

    We have investigated, in 282 multiplex Caucasian families (the Human Biological Data Interchange Repository), the association of type 1 diabetes with polymorphisms in the IL4R gene. IL4R encodes a subunit of the interleukin-4 receptor, a molecule critical to T-helper cell development. By genotyping eight different IL4R single-nucleotide polymorphisms (SNPs) and identifying haplotypes (complex alleles) in the multiplex type 1 diabetic families who were stratified for HLA genotype, we have observed significant evidence of linkage and association of the IL4R gene to type 1 diabetes. In particular, we have identified a specific haplotype that appears to be protective and observed that this protective effect is strongest among individuals not carrying the HLA DR3/DR4 genotype (which confers the strongest genetic risk for type 1 diabetes). These findings suggest an important role for the IL4R gene in immune-related disease susceptibility and illustrate the value of using multi-SNP haplotype information in association studies.

    View details for Web of Science ID 000178914900025

    View details for PubMedID 12401728

  • Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy in HIV-infected patients - Natural history and clinical predictors Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) Lin, D. Y., Warren, J. F., Lazzeroni, L. C., Wolitz, R. A., Mansour, S. E. LIPPINCOTT WILLIAMS & WILKINS. 2002: 268–77

    Abstract

    To characterize the natural course and clinical predictors of cytomegalovirus (CMV) retinitis in human immunodeficiency virus (HIV)-infected patients after initiation of highly active antiretroviral therapy (HAART).Retrospective analysis of 53 HIV-positive patients (73 eyes with CMV retinitis) treated with and without HAART. All participants continued to take anti-CMV therapy. Survival analysis was used to characterize the natural course of CMV retinitis. Proportional hazards analysis was performed to assess the correlation of the nine potential clinical predictors (baseline CD4 count, post-HAART CD4 count, post-HAART rise in CD4 count, baseline weight, post-HAART rise in weight, post-HAART percentage rise in weight, log of baseline HIV viral load, log of minimum post-HAART HIV viral load, and post-HAART log unit reduction in HIV viral load) with the duration of CMV retinitis remission.Patients receiving HAART had a median CMV retinitis remission duration of 574 days (95% confidence interval, 336-NA) whereas those not receiving HAART had a median remission duration of 80.5 days (95% confidence interval, 28-NA; P < 0.001). Within the HAART-treated population, the minimal viral load reached after HAART was the only clinical predictor to demonstrate significance (P = 0.0075). Several other clinical predictors demonstrated borderline significance; however, this was most likely due to the high correlation of these variables with the minimum post-HAART viral load. A potential secondary clinical predictor identified was the post-HAART rise in CD4 count (P = 0.085).With the introduction of HAART, HIV-infected patients have much longer remission durations from recurrent CMV retinitis. The minimum HIV viral load level reached after the initiation of HAART treatment appears to be more important than other clinical variables in the prediction of favorable CMV retinitis remission status. Furthermore, a rise in CD4 T-lymphocyte count by itself appears to be a less significant clinical predictor but may be useful in combination with the HIV viral load data. Selective discontinuation of anti-CMV therapy may be considered in patients with a favorable set of clinical predictors.

    View details for Web of Science ID 000176594200003

    View details for PubMedID 12055458

  • Genotype to phenotype: associations, errors and complexity. Trends in genetics : TIG Lazzeroni, L. C., Karlovich, C. A. 2002; 18 (6): 283-284

    Abstract

    The Keystone Symposium on Genotype to Phenotype: Focus on Disease was held in Santa Fe, New Mexico, USA, from 19 to 24 February 2002.

    View details for PubMedID 12044349

  • Allele sharing and allelic association I: Sib pair tests with increased power GENETIC EPIDEMIOLOGY Lazzeroni, L. C. 2002; 22 (4): 328-344

    Abstract

    Affected sib pair data contain information about allele sharing and allelic association. Either of these features can point to the presence of a risk-related gene. This study introduces the elliptical sib pair test, a generalization of traditional sib pair tests. The proposed test can be implemented using any of three strategies, the choice of which depends on the anticipated combination of sharing and association. The elliptical sib pair test can achieve substantial gains in power relative to traditional tests for likely alternative hypotheses at little or no cost for other alternatives. The proposed test is valid under most models of genetic risk, disease etiology, and genotype-haplotype distributions. This study also provides new insight into the trade-off between tests of allelic association and tests of allele sharing.

    View details for DOI 10.1002/gepi.0185

    View details for Web of Science ID 000175413700005

    View details for PubMedID 11984865

  • Plaid models for gene expression data STATISTICA SINICA Lazzeroni, L., Owen, A. 2002; 12 (1): 61-86
  • Accuracy, precision and consistency of expert HIV-1 genotype interpretation: an international comparison (The GUESS study) Zolopa, A. R., Lazzeroni, L. C., Rinehart, A., Kuritzkes, D. INT MEDICAL PRESS LTD. 2002: S129–S129
  • A polymorphism in the TCF7 locus is associated with type I diabetes in Caucasians. Noble, J. A., White, A., Mirel, D. B., Valdes, A. M., Reynolds, R., Zangenberg, G., Lazzeroni, L., Grupe, A., Peltz, G., Erlich, H. A. CELL PRESS. 2001: 226–26
  • Tests of allele sharing and allelic association for affected sib pairs. Lazzeroni, L. CELL PRESS. 2001: 510–10
  • A high-resolution radiation hybrid map of the human genome draft sequence SCIENCE Olivier, M., Aggarwal, A., Allen, J., Almendras, A. A., Bajorek, E. S., Beasley, E. M., Brady, S. D., Bushard, J. M., Bustos, V. I., Chu, A., Chung, T. R., de Witte, A., Denys, M. E., Dominguez, R., Fang, N. Y., Foster, B. D., Freudenberg, R. W., Hadley, D., Hamilton, L. R., Jeffrey, T. J., Kelly, L., Lazzeroni, L., Levy, M. R., Lewis, S. C., Liu, X., Lopez, F. J., Louie, B., Marquis, J. P., Martinez, R. A., Matsuura, M. K., Misherghi, N. S., NORTON, J. A., Olshen, A., Perkins, S. M., Perou, A. J., Piercy, C., Piercy, M., Qin, F., Reif, T., Sheppard, K., Shokoohi, V., Smick, G. A., Sun, W. L., Stewart, E. A., Tejeda, J. F., Tran, N. M., Trejo, T., Vo, N. T., Yan, S. C., Zierten, D. L., Zhao, S. Y., Sachidanandam, R., Trask, B. J., Myers, R. M., Cox, D. R. 2001; 291 (5507): 1298-?

    Abstract

    We have constructed a physical map of the human genome by using a panel of 90 whole-genome radiation hybrids (the TNG panel) in conjunction with 40,322 sequence-tagged sites (STSs) derived from random genomic sequences as well as expressed sequences. Of 36,678 STSs on the TNG radiation hybrid map, only 3604 (9.8%) were absent from the unassembled draft sequence of the human genome. Of 20,030 STSs ordered on the TNG map as well as the assembled human genome draft sequence and the Celera assembled human genome sequence, 36% of the STSs had a discrepant order between the working draft sequence and the Celera sequence. The TNG map order was identical to one of the two sequence orders in 60% of these discrepant cases.

    View details for Web of Science ID 000166993400040

    View details for PubMedID 11181994

  • A chronology of fine-scale gene mapping by linkage disequilibrium STATISTICAL METHODS IN MEDICAL RESEARCH Lazzeroni, L. C. 2001; 10 (1): 57-76

    Abstract

    The past decade produced several proposals for fine-scale gene mapping using linkage disequilibrium data. The suggested methods fall into two main groups, those that rely on pairwise statistics and those that rely on haplotypes. This paper reviews each strategy's development from a chronological perspective.

    View details for Web of Science ID 000168123300004

    View details for PubMedID 11329692

  • Plaid models for gene expression data Stanford University Division of Biostatistics Technical Report Series Lazzeroni, L., Owen, A. 2000; 211
  • Statistical refinement of primer design parameters. PCR Applications: Protocols for Functional Genomics Beasley, E. M., Myers, R. M., Cox, D. R., Lazzeroni, L. C. 1999: 55-71
  • The global pairwise approach to radiation hybrid mapping Stanford University Division of Biostatistics Technical Report Series Tibshirani, R., Lazzeroni, L., Hastie, T., Olshen, A., Cox, D. 1999; 201
  • A conditional inference framework for extending the transmission/disequilibrium test HUMAN HEREDITY Lazzeroni, L. C., Lange, K. 1998; 48 (2): 67-81

    Abstract

    The transmission/disequilibrium test (TDT) of Terwilliger and Ott [Hum Hered 1992;42:337-346] and Spielman et al. [Am J Hum Genet 1993;52:506-516] is widely used to detect linkage and/or association between a genetically influenced disease and the alleles of a codominant marker locus. The TDT was specifically designed to avoid the spurious population associations produced by ethnic stratification of a sample of affected people. In this paper, we describe permutation extensions of the TDT that share this advantage. Our conditional inference framework permits extensions to multiple alleles, multiple loci, unaffected siblings, and genotypic rather than allelic associations. In the case of multiple loci, the conditional perspective provides a straightforward correction for multiple tests that can be substantially more powerful than the standard Bonferroni correction.

    View details for Web of Science ID 000072240900002

    View details for PubMedID 9526165

  • Random-effects models for smoothing post-stratification weights Journal of Official Statistics Lazzeroni LC, Little RJA 1998; 14: 61-78
  • Linkage disequilibrium and gene mapping: An empirical least-squares approach AMERICAN JOURNAL OF HUMAN GENETICS Lazzeroni, L. C. 1998; 62 (1): 159-170

    Abstract

    This paper proposes a novel approach for fine-scale mapping of disease genes that is based on the well-known linkage-disequilibrium parameter delta. Using a very simple, very general model, I show how delta can be interpreted in terms of identity-by-descent probabilities. The value of delta follows a piecewise curve along the chromosome, with the maximum occurring at the disease locus where the two pieces intersect. A semiparametric, multilocus approach is used to fit this nonlinear regression curve in order to estimate the gene location. Using the bootstrap to empirically estimate much of the probability model from the data avoids the need for many detailed population assumptions. One advantage of the approach is its use of the observed covariance structure of the data, which can be highly informative as to the gene location. I illustrate the method on the cystic fibrosis data of Kerem et al.

    View details for Web of Science ID 000072127900021

    View details for PubMedID 9490574

  • Markov chains for Monte Carlo tests of genetic equilibrium in multidimensional contingency tables ANNALS OF STATISTICS Lazzeroni, L. C., Lange, K. 1997; 25 (1): 138-168
  • Individual variation in recombination among human males AMERICAN JOURNAL OF HUMAN GENETICS Yu, J., Lazzeroni, L., Qin, J., Huang, M. M., Navidi, W., Erlich, H., Arnheim, N. 1996; 59 (6): 1186-1192

    Abstract

    Studies of recombination between the markers D6S291 and D6S109 in individuals by sperm typing provide direct evidence for significant variation in recombination among humans. A statistically significant difference in the recombination fraction (range 5.1%-11.2%) was detected among five donors. This variation could reflect polymorphisms in genes affecting recombination or in chromosome structure. Ignoring this variability in studies designed to examine the relationship between physical and genetic distances could lead to incorrect inferences. Individual variation in recombination makes it difficult to predict the recombination fraction for an interval in any particular individual. This could be important in certain genetic counseling situations.

    View details for Web of Science ID A1996VV31500004

    View details for PubMedID 8940263

  • In vivo sequence diversity of the protease of human immunodeficiency virus type 1: Presence of protease inhibitor-resistant variants in untreated subjects JOURNAL OF VIROLOGY Lech, W. J., Wang, G., Yang, Y. L., Chee, Y., Dorman, K., McCrae, D., Lazzeroni, L. C., Erickson, J. W., Sinsheimer, J. S., Kaplan, A. H. 1996; 70 (3): 2038-2043

    Abstract

    We have evaluated the sequence diversity of the protease human immunodeficiency virus type 1 in vivo. Our analysis of 246 protease coding domain sequences obtained from 12 subjects indicates that amino acid substitutions predicted to give rise to protease inhibitor resistance may be present in patients who have not received protease inhibitors. In addition, we demonstrated that amino acid residues directly involved in enzyme-substrate interactions may be varied in infected individuals. Several of these substitutions occurred in combination either more or less frequently than would be expected if their appearance was independent, suggesting that one substitution may compensate for the effects of another. Taken together, our analysis indicates that the human immunodeficiency virus type 1 protease has flexibility sufficient to vary critical subsites in vivo, thereby retaining enzyme function and viral pathogenicity.

    View details for Web of Science ID A1996TV69600086

    View details for PubMedID 8627733

  • Markov chain Monte Carlo tests of genetic equilibrium in multidimensional contingency tables Stanford University Division of Biostatistics Technical Report Series Lazzeroni, L. C., Lange, K. 1995; 178
  • MULTIPOINT LINKAGE MAP OF THE HUMAN PSEUDOAUTOSOMAL REGION, BASED ON SINGLE-SPERM TYPING - DO DOUBLE CROSSOVERS OCCUR DURING MALE MEIOSIS AMERICAN JOURNAL OF HUMAN GENETICS Schmitt, K., Lazzeroni, L. C., Foote, S., Vollrath, D., Fisher, E. M., Goradia, T. M., Lange, K., Page, D. C., Arnheim, N. 1994; 55 (3): 423-430

    Abstract

    Sperm typing was used to measure recombination fractions among pseudoautosomal markers and the beginning of the X/Y-specific sequences located at the pseudoautosomal boundary. These experiments included primer-extension preamplification and PCR followed by allele typing using gel electrophoresis. A newly developed data-analysis program allowed the construction of the first multipoint-linkage sperm-typing map, using results obtained on seven loci from three individuals. The large sample size not only confirmed the increased recombination activity of the pseudoautosomal region but allowed an estimate of interference of recombination to be made. The coefficient of coincidence was calculated to be .26 over a physical distance of only approximately 1,800 kb. The observation of a few sperm presumably resulting from double recombination argues that more than one crossover event can occur in this region during male meiosis.

    View details for Web of Science ID A1994PF50900002

    View details for PubMedID 8079986

  • MULTIPOINT MAPPING CALCULATIONS FOR SPERM-TYPING DATA AMERICAN JOURNAL OF HUMAN GENETICS Lazzeroni, L. C., Arnheim, N., Schmitt, K., Lange, K. 1994; 55 (3): 431-436

    Abstract

    This paper explains how multipoint likelihoods can be computed for sperm-typing data. Experimental errors such as multiple sperm per tube, inadequate amplification, and contamination by exogenous DNA are explicitly taken into account. By limiting the number of sperm theoretically possible per tube to a predetermined maximum and by assuming no chiasma interference, maximum-likelihood estimation can be carried out rapidly using the theory of hidden Markov chains.

    View details for Web of Science ID A1994PF50900003

    View details for PubMedID 8079987

  • Models for smoothing post-stratification weights Proceedings of the Survey Research Methods Section, ASA Lazzeroni LC, Little RJA 1993: 764-769
  • Robustness of multiple-imputation techniques to model misspecification Proceedings of the Survey Research Methods Section, ASA Lazzeroni, L. C., Schenker, N., Taylor, J. M. 1990: 260-265
  • A comparison of multiple-imputation procedures under model misspecification UCLA Department of Biostatistics Technical Report Series Lazzeroni, L. C., Schenker, N., Taylor, J. . 1990