Academic Appointments

Administrative Appointments

  • Director, US VA Cooperative Studies Program Palo Alto Coordinating Center (2009 - 2016)
  • Co-Director, Center for Innovative Study Design (2015 - Present)
  • Co-Director, Biostatistics Core, Stanford Cancer Institute (2016 - Present)

Honors & Awards

  • The Evelyn Fix Memorial Award, Department of Statistics, University of California, Berkeley (May, 1990)
  • Healthstar Osteoporosis Medical Research Award (HOMA) for Achievements in Osteoporosis Research, The Chinese Development Foundation for Science and Technology (Ocotber, 2003)
  • Advisory Committee Service Award, U.S. Food and Drug Administation (2010)
  • Elected Fellow, American Statistical Association (2011)
  • ICSA Outstanding Service Award, International Chinese Statistical Association (June 2016)
  • Elected Fellow, American Association for the Advancement of Science (2020)

Boards, Advisory Committees, Professional Organizations

  • President Elect (2019), President (2020), Past President (2021), WNAR (2019 - 2021)
  • Associate Editor, JCO Precision Oncology ( (2016 - Present)
  • President, The International Chinese Statistical Association (President-Elect, 2013 and Past-President, 2015) (2014 - 2014)

Professional Education

  • BS, Fudan University, Mathematics (1982)
  • MS, Shanghai Jiaotong University, Applied Mathematics (1984)
  • Ph.D., UC, Berkeley, Biostatistics (1990)

Current Research and Scholarly Interests

Biostatistics, clinical trials, statistical evaluation of medical diagnostic tests, radiology, osteoporosis, meta-analysis, medical decision making

Clinical Trials

  • Limiting AAA With Metformin (LIMIT) Trial Recruiting

    In this research, the investigators are looking at the effects of a drug called metformin may have on the growth of abdominal aortic aneurysm (AAA)s. AAA is an abnormal enlargement of the aorta, which is the large artery in the abdomen (stomach area). The enlargement of the aorta carries a risk that it will rupture and cause life-threatening bleeding in the abdomen (belly). In this study the investigators hope to learn how metformin is associated with the enlargement or change in size of the AAA in study participants. Smaller studies have suggested that metformin may reduce the rate at which aortic aneurysms enlarge. This study will test this question: does metformin prevent AAAs from growing larger?

    View full details

2023-24 Courses

Stanford Advisees

  • Doctoral Dissertation Reader (AC)
    Kristy Carpenter
  • Postdoctoral Research Mentor
    Dehua Bi
  • Doctoral (Program)
    Kevin Wu

Graduate and Fellowship Programs

All Publications

  • Cultivating Patient Preferences in ALS Clinical Trials: Reliability and Prognostic Value of the Patient-Ranked Order of Function. Neurology van Eijk, R. P., van den Berg, L. H., Lu, Y. 2024; 103 (2): e209502


    The Patient-Ranked Order of Function (PROOF) is a novel approach to account for patient-reported preferences in the evaluation of treatments of amyotrophic lateral sclerosis (ALS). In this study, we assess the reliability and prognostic value of different sets of patient-reported preferences that can be used for the PROOF end point.Data were obtained through online surveys over the course of 12 months using the population-based registry of the Netherlands. Patients were asked to score functional domains of the ALS Functional Rating Scale (ALSFRS-R) and rank the order of importance of each domain. Two weeks after the initial invite, the questionnaire was repeated to evaluate test-retest reliability. Vital status was extracted from the municipal population register.In total, 611 patients with ALS were followed up for survival and 382 patients were included in the test-retest reliability study. All versions of PROOF, using different sets of preferences, resulted in excellent reliability (intraclass correlation coefficients ranged from 0.89 [95% CI 0.87-0.91] to 0.97 [95% CI 0.97-0.98], all p < 0.001), without systematic differences between baseline and week 2 (mean rank difference range -1 to -3 [95% CI range -8 to 2], all p > 0.20). Preferences about future events were more variable than preferences about current symptoms. All versions of PROOF strongly predicted overall survival (hazard ratios per 10th rank percentile ranged from 0.80 to 0.83 [95% CI range 0.76-0.87], all p < 0.001) and had a more even separation of survival curves between rank-stratified subgroups compared with the ALSFRS-R total score.In a large cohort of patients, we show how patient-reported preferences can be measured and integrated reliably with the ALSFRS-R without leading to systematic bias. Patient preferences may provide unique prognostic information in addition to what is already measured conventionally. This could provide a more comprehensive understanding of how medical interventions effectively address the patient's concerns and improve what matters most to them.

    View details for DOI 10.1212/WNL.0000000000209502

    View details for PubMedID 38875513

  • Efficacy of Chinese Medicine Treatment Based on Syndrome Differentiation for Primary Insomnia: A Randomized Placebo Controlled Triple-Blinded Trial. Chinese journal of integrative medicine Xiong, Z. Y., Lu, Y., He, L. Y., Zhang, R. S., Zhou, X. Z., Li, P., Liu, Y. J., Zhu, J. G., Yan, S. Y., Liu, B. Y. 2024


    To assess efficacy of Chinese medicine (CM) on insomnia considering characteristics of treatment based on syndrome differentiation.A total of 116 participants aged 18 to 65 years with moderate and severe primary insomnia were randomized to the placebo (n=20) or the CM group (n=96) for a 4-week treatment and a 4-week follow-up. Three CM clinicians independently prescribed treatments for each patient based on syndromes differentiation. The primary outcome was change in total sleep time (TST) from baseline. Secondary endpoints included sleep onset latency (SOL), wake time after sleep onset (WASO), sleep efficiency, Pittsburgh Sleep Quality Index (PSQI) and CM symptoms.The CM group had an average 0.6 h more (95% confidence interval (CI): 0.3-0.9, P<0.001) TST and 34.1% (10.3%-58.0%, P=0.005) more patients beyond 0.5 h TST increment than that of the placebo group. PSQI was changed -3.3 (-3.8 to -2.7) in the CM group, a -2.0 (-3.2 to -0.8, P<0.001) difference from the placebo group. The CM symptom score in the CM group decreased -2.0 (-3.3 to -0.7, P=0.003) more than the placebo group. SOL and WASO changes were not significantly different between groups. The analysis of prescriptions by these clinicians revealed blood deficiency and Liver stagnation as the most common syndromes. Prescriptions for these clinicians displayed relative stability, while the herbs varied. All adverse events were mild and were not related to study treatment.CM treatment based on syndrome differentiation can increase TST and improve sleep quality of primary insomnia. It is effective and safe for primary insomnia. In future studies, the long-term efficacy validation and the exploratory of eutherapeutic clinicians' fixed herb formulas should be addressed (Registration No. NCT01613183).

    View details for DOI 10.1007/s11655-024-3661-4

    View details for PubMedID 38753273

    View details for PubMedCentralID 8116439

  • Suggestions on Using Machine Learning Models and Cautions for Analyzing Censored Time-To-Event Outcomes. JCO precision oncology Shi, Y., Horiguchi, M., Lu, Y. 2024; 8: e2400220

    View details for DOI 10.1200/PO.24.00220

    View details for PubMedID 38781547

  • Collaborative Modeling to Compare Different Breast Cancer Screening Strategies: A Decision Analysis for the US Preventive Services Task Force. JAMA Trentham-Dietz, A., Chapman, C. H., Jayasekera, J., Lowry, K. P., Heckman-Stoddard, B. M., Hampton, J. M., Caswell-Jin, J. L., Gangnon, R. E., Lu, Y., Huang, H., Stein, S., Sun, L., Gil Quessep, E. J., Yang, Y., Lu, Y., Song, J., Muñoz, D. F., Li, Y., Kurian, A. W., Kerlikowske, K., O'Meara, E. S., Sprague, B. L., Tosteson, A. N., Feuer, E. J., Berry, D., Plevritis, S. K., Huang, X., de Koning, H. J., van Ravesteyn, N. T., Lee, S. J., Alagoz, O., Schechter, C. B., Stout, N. K., Miglioretti, D. L., Mandelblatt, J. S. 2024


    The effects of breast cancer incidence changes and advances in screening and treatment on outcomes of different screening strategies are not well known.To estimate outcomes of various mammography screening strategies.Comparison of outcomes using 6 Cancer Intervention and Surveillance Modeling Network (CISNET) models and national data on breast cancer incidence, mammography performance, treatment effects, and other-cause mortality in US women without previous cancer diagnoses.Thirty-six screening strategies with varying start ages (40, 45, 50 years) and stop ages (74, 79 years) with digital mammography or digital breast tomosynthesis (DBT) annually, biennially, or a combination of intervals. Strategies were evaluated for all women and for Black women, assuming 100% screening adherence and "real-world" treatment.Estimated lifetime benefits (breast cancer deaths averted, percent reduction in breast cancer mortality, life-years gained), harms (false-positive recalls, benign biopsies, overdiagnosis), and number of mammograms per 1000 women.Biennial screening with DBT starting at age 40, 45, or 50 years until age 74 years averted a median of 8.2, 7.5, or 6.7 breast cancer deaths per 1000 women screened, respectively, vs no screening. Biennial DBT screening at age 40 to 74 years (vs no screening) was associated with a 30.0% breast cancer mortality reduction, 1376 false-positive recalls, and 14 overdiagnosed cases per 1000 women screened. Digital mammography screening benefits were similar to those for DBT but had more false-positive recalls. Annual screening increased benefits but resulted in more false-positive recalls and overdiagnosed cases. Benefit-to-harm ratios of continuing screening until age 79 years were similar or superior to stopping at age 74. In all strategies, women with higher-than-average breast cancer risk, higher breast density, and lower comorbidity level experienced greater screening benefits than other groups. Annual screening of Black women from age 40 to 49 years with biennial screening thereafter reduced breast cancer mortality disparities while maintaining similar benefit-to-harm trade-offs as for all women.This modeling analysis suggests that biennial mammography screening starting at age 40 years reduces breast cancer mortality and increases life-years gained per mammogram. More intensive screening for women with greater risk of breast cancer diagnosis or death can maintain similar benefit-to-harm trade-offs and reduce mortality disparities.

    View details for DOI 10.1001/jama.2023.24766

    View details for PubMedID 38687505

  • CAR19 monitoring by peripheral blood immunophenotyping reveals histology-specific expansion and toxicity. Blood advances Hamilton, M. P., Craig, E., Gentille Sanchez, C., Mina, A., Tamaresis, J., Kirmani, N., Ehlinger, Z., Syal, S., Good, Z., Sworder, B., Schroers-Martin, J., Lu, Y., Muffly, L., Negrin, R. S., Arai, S., Lowsky, R., Meyer, E., Rezvani, A. R., Shizuru, J. A., Weng, W. K., Shiraz, P., Sidana, S., Bharadwaj, S., Smith, M., Dahiya, S., Sahaf, B., Kurtz, D. M., Mackall, C. L., Tibshirani, R., Alizadeh, A. A., Frank, M. J., Miklos, D. B. 2024


    Chimeric antigen receptor (CAR) T cells directed against CD19 (CAR19) are a revolutionary treatment for B-cell lymphomas. CAR19 cell expansion is necessary for CAR19 function but is also associated with toxicity. To define the impact of CAR19 expansion on patient outcomes, we prospectively followed a cohort of 236 patients treated with CAR19 (brexucabtagene autoleucel or axicabtagene ciloleucel) for mantle cell (MCL), follicular (FL), and large B-cell lymphoma (LBCL) over the course of five years and obtained CAR19 expansion data using peripheral blood immunophenotyping for 188 of these patients. CAR19 expansion was higher in patients with MCL compared to other lymphoma histologic subtypes. Notably, patients with MCL had increased toxicity and required four-fold higher cumulative steroid doses than patients with LBCL. CAR19 expansion was associated with the development of cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), and the requirement for granulocyte colony stimulating factor (GCSF) after day 14 post-infusion. Younger patients and those with elevated lactate dehydrogenase (LDH) had significantly higher CAR19 expansion. In general, no association between CAR19 expansion and LBCL treatment response was observed. However, when controlling for tumor burden, we found that lower CAR19 expansion in conjunction with low LDH was associated with improved outcomes in LBCL. In sum, this study finds CAR19 expansion principally associates with CAR-related toxicity. Additionally, CAR19 expansion as measured by peripheral blood immunophenotyping may be dispensable to favorable outcomes in LBCL.

    View details for DOI 10.1182/bloodadvances.2024012637

    View details for PubMedID 38498731

  • Analysis of Breast Cancer Mortality in the US-1975 to 2019. JAMA Caswell-Jin, J. L., Sun, L. P., Munoz, D., Lu, Y., Li, Y., Huang, H., Hampton, J. M., Song, J., Jayasekera, J., Schechter, C., Alagoz, O., Stout, N. K., Trentham-Dietz, A., Lee, S. J., Huang, X., Mandelblatt, J. S., Berry, D. A., Kurian, A. W., Plevritis, S. K. 2024; 331 (3): 233-241


    Breast cancer mortality in the US declined between 1975 and 2019. The association of changes in metastatic breast cancer treatment with improved breast cancer mortality is unclear.To simulate the relative associations of breast cancer screening, treatment of stage I to III breast cancer, and treatment of metastatic breast cancer with improved breast cancer mortality.Using aggregated observational and clinical trial data on the dissemination and effects of screening and treatment, 4 Cancer Intervention and Surveillance Modeling Network (CISNET) models simulated US breast cancer mortality rates. Death due to breast cancer, overall and by estrogen receptor and ERBB2 (formerly HER2) status, among women aged 30 to 79 years in the US from 1975 to 2019 was simulated.Screening mammography, treatment of stage I to III breast cancer, and treatment of metastatic breast cancer.Model-estimated age-adjusted breast cancer mortality rate associated with screening, stage I to III treatment, and metastatic treatment relative to the absence of these exposures was assessed, as was model-estimated median survival after breast cancer metastatic recurrence.The breast cancer mortality rate in the US (age adjusted) was 48/100 000 women in 1975 and 27/100 000 women in 2019. In 2019, the combination of screening, stage I to III treatment, and metastatic treatment was associated with a 58% reduction (model range, 55%-61%) in breast cancer mortality. Of this reduction, 29% (model range, 19%-33%) was associated with treatment of metastatic breast cancer, 47% (model range, 35%-60%) with treatment of stage I to III breast cancer, and 25% (model range, 21%-33%) with mammography screening. Based on simulations, the greatest change in survival after metastatic recurrence occurred between 2000 and 2019, from 1.9 years (model range, 1.0-2.7 years) to 3.2 years (model range, 2.0-4.9 years). Median survival for estrogen receptor (ER)-positive/ERBB2-positive breast cancer improved by 2.5 years (model range, 2.0-3.4 years), whereas median survival for ER-/ERBB2- breast cancer improved by 0.5 years (model range, 0.3-0.8 years).According to 4 simulation models, breast cancer screening and treatment in 2019 were associated with a 58% reduction in US breast cancer mortality compared with interventions in 1975. Simulations suggested that treatment for stage I to III breast cancer was associated with approximately 47% of the mortality reduction, whereas treatment for metastatic breast cancer was associated with 29% of the reduction and screening with 25% of the reduction.

    View details for DOI 10.1001/jama.2023.25881

    View details for PubMedID 38227031

  • Design and Implementation of an Electronic Health Record-Integrated Hypertension Management Application. Journal of the American Heart Association Funes Hernandez, M., Babakhanian, M., Chen, T. P., Sarraju, A., Seninger, C., Ravi, V., Azizi, Z., Tooley, J., Chang, T. I., Lu, Y., Downing, N. L., Rodriguez, F., Li, R. C., Sandhu, A. T., Turakhia, M., Bhalla, V., Wang, P. J. 2024; 13 (2): e030884


    High blood pressure affects approximately 116 million adults in the United States. It is the leading risk factor for death and disability across the world. Unfortunately, over the past decade, hypertension control rates have decreased across the United States. Prediction models and clinical studies have shown that reducing clinician inertia alone is sufficient to reach the target of ≥80% blood pressure control. Digital health tools containing evidence-based algorithms that are able to reduce clinician inertia are a good fit for turning the tide in blood pressure control, but careful consideration should be taken in the design process to integrate digital health interventions into the clinical workflow.We describe the development of a provider-facing hypertension management platform. We enumerate key steps of the development process, including needs finding, clinical workflow analysis, treatment algorithm creation, platform design and electronic health record integration. We interviewed and surveyed 5 Stanford clinicians from primary care, cardiology, and their clinical care team members (including nurses, advanced practice providers, medical assistants) to identify needs and break down the steps of clinician workflow analysis. The application design and development stage were aided by a team of approximately 15 specialists in the fields of primary care, hypertension, bioinformatics, and software development.Digital monitoring holds immense potential for revolutionizing chronic disease management. Our team developed a hypertension management platform at an academic medical center to address some of the top barriers to adoption and achieving clinical outcomes. The frameworks and processes described in this article may be used for the development of a diverse range of digital health tools in the cardiovascular space.

    View details for DOI 10.1161/JAHA.123.030884

    View details for PubMedID 38226516

  • Personalized Accelerated ChEmoRadiation (PACER) for Lung Cancer: Protocol for a Bayesian Optimal Phase I/II Trial. Clinical lung cancer Hui, C., Brown, E., Wong, S., Das, M., Wakelee, H., Neal, J., Ramchandran, K., Myall, N. J., Pham, D., Xing, L., Yang, Y., Kovalchuk, N., Yuan, Y., Lu, Y., Xiang, M., Chin, A., Diehn, M., Loo, B. W., Vitzthum, L. K. 2023


    Prior attempts to escalate radiation dose for non-small cell lung cancer (NSCLC) have not improved survival. Given the high risk for cardiopulmonary toxicity with treatment and heterogenous presentation of locally advanced NSCLC, it is unlikely that a single dose regimen is optimal for all patients. This phase I/II trial aims to evaluate a novel treatment approach where the level of accelerated hypofractionation is determined by the predicted toxicity from dose to organs at risk (OARs).Patients ≥ 18 years old with lung cancer planned for fractionated radiotherapy to the lung with concurrent chemotherapy will be eligible. Radiation therapy (RT) will be delivered to a total dose of 60 to 66 Gy in 30, 25, or 20 fractions depending on the ability to meet constraints to key organs at risk including the lungs, heart, and esophagus. The primary endpoint is high grade pulmonary, esophageal, or cardiac toxicity. A Bayesian optimized design is used to determine stopping boundaries and evaluate the primary endpoint.PACER will evaluate the safety and feasibility of personalized accelerated chemoradiotherapy for lung cancer.

    View details for DOI 10.1016/j.cllc.2023.11.004

    View details for PubMedID 38040540

  • Standardization of dual-energy x-ray visceral adipose tissue measures for comparison across clinical imaging systems. Obesity (Silver Spring, Md.) Bennett, J. P., Fan, B., Liu, E., Kazemi, L., Wu, X. P., Zhou, H. D., Lu, Y., Shepherd, J. A. 2023


    Excess visceral adipose tissue (VAT) is a major risk factor for metabolic syndrome (MetS) and clinical guidelines have been proposed to define VAT levels associated with increased risk. The aim was to standardize VAT measures between two dual-energy x-ray absorptiometry (DXA) manufacturers who provide different VAT estimates to support standardization of measures across imaging modalities.Scans from 114 individuals (ages 18-81 years) on GE HealthCare (GEHC) and Hologic DXA systems were compared via Deming regression to standardize VAT between the two systems, validated in a separate sample (n = 15), with κ statistics to assess agreement of VAT measurements for classifying patients into risk categories.The GEHC and Hologic VAT measures were highly correlated and validated in the separate data set (r2  = 0.97). VAT area measures substantially agreed for metabolic risk classification (weighted κ = 0.76) with no significant differences in the population mean values.VAT measures can be estimated from GEHC and Hologic scans that classify individuals in a substantially similar way into metabolic risk categories, and systematic bias between the measures can be removed using simple regression equations. These findings allow for DXA VAT measures to be used in complement to other imaging modalities, regardless of whether scans used GEHC or Hologic systems.

    View details for DOI 10.1002/oby.23885

    View details for PubMedID 37789584

  • Hybrid controlled clinical trials using concurrent registries in Amyotrophic Lateral Sclerosis: A feasibility study. Clinical pharmacology and therapeutics van Eijk, R. P., van den Berg, L. H., Roes, K. C., Tian, L., Lai, T. L., Nelson, L. M., Li, C., Scowcroft, A., Garcia-Segovia, J., Lu, Y. 2023


    Hybrid designs with both randomised arms and an external control cohort preserve key features of randomisation and utilise external information to augment clinical trials. In this study, we propose to leverage high-quality, patient-level concurrent registries to enhance clinical trials and illustrate the impact on trial design for amyotrophic lateral sclerosis (ALS). The proposed methodology was evaluated in a randomised, placebo-controlled clinical trial. We used patient-level information from a well-defined, population-based registry, that was running parallel to the randomised clinical trial, to identify concurrently non-participating, eligible patients who could be matched with trial participants, and integrate them into the statistical analysis. We assessed the impact of the addition of the external controls on the treatment effect estimate, precision, and time to reach a conclusion. During the runtime of the trial, a total of 1,141 registry patients were alive; 473 (41.5%) of them fulfilled the eligibility criteria and 133 (11.7%) were enrolled in the study. A matched control population could be identified among the non-participating patients. Augmenting the randomised controls with matched external controls could have avoided unnecessary randomisation of 17 patients (-12.8%) as well as reducing the study duration from 30.1 months to 22.6 months (-25.0%). Matching eligible external controls from a different calendar period led to bias in the treatment effect estimate. Hybrid trial designs utilising a concurrent registry with rigorous matching can minimise bias due to a mismatch in calendar time and differences in standard of care, and may accelerate the development of new treatments.

    View details for DOI 10.1002/cpt.2994

    View details for PubMedID 37422655

  • Improved outcomes for relapsed/refractory Hodgkin lymphoma after autologous transplantation in the era of novel agents. Blood Spinner, M. A., Sica, R. A., Tamaresis, J. S., Lu, Y., Chang, C., Lowsky, R., Frank, M. J., Johnston, L. J., Miklos, D. B., Muffly, L., Negrin, R. S., Rezvani, A. R., Shiraz, P., Shizuru, J. A., Weng, W. K., Binkley, M. S., Hoppe, R. T., Advani, R. H., Arai, S. 2023


    The treatment landscape of relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL) has evolved significantly over the past decade following the approval of brentuximab vedotin (BV) and the programmed death-1 (PD-1) inhibitors. We evaluated how outcomes and practice patterns have changed for R/R cHL patients who underwent autologous hematopoietic cell transplantation (AHCT) at our institution from 2011-2020 (N=183) compared to 2001-2010 (N=159) and evaluated prognostic factors for progression-free survival (PFS) and overall survival (OS) in both eras. OS was superior in the modern era (4-year estimates 89.1% vs 79.0%, HR 0.53, 95% CI 0.33-0.85, p=0.011) with a trend towards lower non-relapse mortality beyond 2 years post-transplant. Among patients who progressed after AHCT, 4-year post-progression survival increased from 43.3% to 71.4% in the modern era, reflecting increasing use of BV and the PD-1 inhibitors. In multivariable analysis for patients transplanted in the modern era, age ³45 years, primary refractory disease, and lack of complete remission pre-AHCT were associated with inferior PFS, while receipt of a PD-1 inhibitor-based regimen pre-AHCT was associated with superior PFS (HR 0.21, 95% CI 0.05-0.80, p=0.030). Extranodal disease at relapse was associated with inferior OS (HR 3.12, 95% CI 1.25-7.77, p=0.014). Our study demonstrates improved survival for R/R cHL after AHCT in the modern era attributed to more effective salvage regimens allowing for better disease control pre-AHCT and improved outcomes for patients who progressed after AHCT. Excellent outcomes were observed with PD-1 inhibitor-based salvage regimens pre-AHCT and support a randomized trial evaluating immunotherapy in the second line setting.

    View details for DOI 10.1182/blood.2022018827

    View details for PubMedID 36857637

  • REDACS: Regional emergency-driven adaptive cluster sampling for effective COVID-19 management. Stochastic analysis and applications Stehlík, M., Kisel'ák, J., Dinamarca, A., Alvarado, E., Plaza, F., Medina, F. A., Stehlíková, S., Marek, J., Venegas, B., Gajdoš, A., Li, Y., Katuščák, S., Bražinová, A., Zeintl, E., Lu, Y. 2023; 41 (3): 474-508


    As COVID-19 is spreading, national agencies need to monitor and track several metrics. Since we do not have perfect testing programs on the hand, one needs to develop an advanced sampling strategies for prevalence study, control and management. Here we introduce REDACS: Regional emergency-driven adaptive cluster sampling for effective COVID-19 management and control and justify its usage for COVID-19. We show its advantages over classical massive individual testing sampling plans. We also point out how regional and spatial heterogeneity underlines proper sampling. Fundamental importance of adaptive control parameters from emergency health stations and medical frontline is outlined. Since the Northern hemisphere entered Autumn and Winter season (this paper was originally submitted in November 2020), practical illustration from spatial heterogeneity of Chile (Southern hemisphere, which already experienced COVID-19 winter outbreak peak) is underlying the importance of proper regional heterogeneity of sampling plan. We explain the regional heterogeneity by microbiological backgrounds and link it to behavior of Lyapunov exponents. We also discuss screening by antigen tests from the perspective of "on the fly" biomarker validation, i.e., during the screening.

    View details for DOI 10.1080/07362994.2022.2033126

    View details for PubMedID 37982071

    View details for PubMedCentralID PMC10655945

  • A Seasonality-Adjusted Sequential Test for Vaccine Safety Surveillance. Biometrics Shen, R., Moll, K., Lu, Y., Tian, L. 2023


    Post-market active safety monitoring is important for the timely capture of safety signals associated with exposure to a new vaccine or drug. The group sequential analysis is a common method employed in safety surveillance. Specifically, it compares the post-vaccination incidence of adverse event (AE) in a vaccinated population with a pre-specified reference level by sequentially conducting hypothesis testing during the surveillance. When the number of AEs is "too high", a safety signal is identified. If the null hypothesis is never rejected, the vaccine is considered safe. Such an approach doesn't account for either the variation in determining the reference risk from a control population or the seasonality effect. Furthermore, not rejecting the null could be due to a lack of power and cannot always be interpreted as proof of safety. In this paper, we proposed a new group sequential test procedure fully accounting for both seasonality and variation from the historical controls. More importantly, we proposed to construct a confidence interval for the relative AE risk between the exposed and control groups at the end of the study, which can be used to quantify the safety of the vaccine. The proposed method is illustrated via real data examples on anaphylaxis and examined by extensive simulationstudies. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/biom.13829

    View details for PubMedID 36645553

  • A Randomized Clinical Trial to Evaluate an Atrial Fibrillation Stroke Prevention Shared Decision-Making Pathway. Journal of the American Heart Association Wang, P. J., Lu, Y., Mahaffey, K. W., Lin, A., Morin, D. P., Sears, S. F., Chung, M. K., Russo, A. M., Lin, B., Piccini, J., Hills, M. T., Berube, C., Pundi, K., Baykaner, T., Garay, G., Lhamo, K., Rice, E., Pourshams, I. A., Shah, R., Newswanger, P., DeSutter, K., Nunes, J. C., Albert, M. A., Schulman, K. A., Heidenreich, P. A., Bunch, T. J., Sanders, L. M., Turakhia, M., Verghese, A., Stafford, R. S. 2022: e8009


    Background Oral anticoagulation (OAC) reduces stroke and disability in atrial fibrillation (AF) but is underutilized. We evaluated the effects of a novel patient-clinician shared decision-making (SDM) tool in reducing OAC patient's decisional conflict as compared to usual care. Methods and Results We designed and evaluated a new digital decision aid in a multicenter, randomized, comparative effectiveness trial, ENHANCE-AF (Engaging Patients to Help Achieve Increased Patient Choice and Engagement for AF Stroke Prevention). The digital AF SDM Toolkit was developed using patient-centered design with clear health communication principles (e.g. meaningful images, limited text). Available in English and Spanish, the toolkit included the following: 1) a brief animated video; 2) interactive questions with answers; 3) a quiz to check on understanding; 4) a worksheet to be used by the patient during the encounter; and 5) an online guide for clinicians. The study population included English or Spanish speakers with non-valvular AF and a CHA2DS2-VASc stroke score ≥1 for men or ≥2 for women. Participants were randomized in a 1:1 ratio to either Usual Care (UC) or the SDM Toolkit. The primary endpoint was the validated 16-item Decisional Conflict Scale (DCS) at 1 month. Secondary outcomes included DCS at 6 months and the 10-item Decision Regret Scale (DRS) at 1 and 6 months as well as a weighted average of Mann-Whitney U-statistics for both DCS and DRS. A total of 1001 participants were enrolled and followed at 5 different sites in the United States between 12/18/19 and 8/17/22. The mean patient age was 69 ±10years (40% females, 16.9% Black, 4.5% Hispanic, 3.6% Asian), and 50% of participants had CHA2DS2-VASc scores ≥3 (M) or ≥4 (F). The primary endpoint at 1 month showed a clinically meaningful reduction in decisional conflict: a 7-point difference in median scores between the two arms (16.4 v 9.4; Mann-Whitney U-statistics=0.550; p-value=0.007). For the secondary endpoint of 1-month DRS, the difference in median scores between arms was 5 points in the direction of less decisional regret (p-value of 0.078). The treatment effects lessened over time: at 6 months the difference in medians was 4.7 points for DCS (p-value=0.060) and 0 points for DRS (p-value=0.35). Conclusions Implementation of a novel, Shared Decision-Making Toolkit (; achieved significantly lower decisional conflict compared to usual care in patients with AF.

    View details for DOI 10.1161/JAHA.122.028562

    View details for PubMedID 36342828

  • Increasing patient participation in oncology clinical trials. Cancer medicine Chen, J., Lu, Y., Kummar, S. 2022


    Timely recruitment of eligible participants is essential for the success of clinical trials, with insufficient accrual being the leading cause for premature termination of both oncology and non-oncology trials.In this paper we further elaborate on the challenges for patient participation in oncology trials from physician, patient, healthcare system, and some trial-related perspectives.We present strategies such as use of digital healthcare technologies, real-world data and real-world evidence, decentralized clinical trials, pragmatic trial designs, and supportive services to increase patient participation.Multifaceted measures are necessary to increase patient participation, especially for those who are under-represented in cancer trials.

    View details for DOI 10.1002/cam4.5150

    View details for PubMedID 36043431

  • Extensions of empirical likelihood and chi-squared-based tests for ordered alternatives. Journal of applied statistics Carmen Pardo, M., Lu, Y., Franco-Pereira, A. M. 2022; 49 (1): 24-43


    Several methods for comparing k populations have been proposed in the literature. These methods assess the same null hypothesis of equal distributions but differ in the alternative hypothesis they consider. We focus on two important alternative hypotheses: monotone and umbrella ordering. Two new families of test statistics are proposed, including two known tests, as well as two new powerful tests under monotone ordering. Furthermore, these families are adapted for testing umbrella ordering. We compare some members of the families with respect to power and Type I errors under different simulation scenarios. Finally, the methods are illustrated in several applications to real data.

    View details for DOI 10.1080/02664763.2020.1796944

    View details for PubMedID 35707803

    View details for PubMedCentralID PMC9041694

  • A Composite Endpoint for Treatment Benefit According to Patient Preference STATISTICS IN BIOPHARMACEUTICAL RESEARCH Lu, Y., Zhao, Q., Zou, J., Yan, S., Tamaresis, J. S., Nelson, L., Tu, X. M., Chen, J., Tian, L. 2022
  • A Composite Endpoint for Treatment Benefit According to Patient Preference. Statistics in biopharmaceutical research Lu, Y., Zhao, Q., Zou, J., Yan, S., Tamaresis, J. S., Nelson, L., Tu, X. M., Chen, J., Tian, L. 2022; 14 (4): 408-422


    Complex disorders usually affect multiple symptom domains measured by several outcomes. The importance of these outcomes is often different among patients. Current approaches integrate multiple outcomes without considering patient preferences at the individual level. In this paper, we propose a new composite Desirability of Outcome Ranking (DOOR) that integrates individual level ranking of outcome importance and define a winning probability measuring the overall treatment effect. Stratified randomization can be performed based on the participants' baseline outcome rankings. A Wilcoxon-Mann-Whitney U-statistic is used to average the pairwise DOOR between one treated and one control patient, considering the difference in these patients' ranking of outcome importance. We use both theoretical and empirical methods to examine the statistical properties of our method and to compare with conventional approaches. We conclude that the proposed composite DOOR properly reflects patient-level preferences and can be used in pivotal trials or comparative effectiveness trials for a patient-centered evaluation of overall treatment benefits.

    View details for DOI 10.1080/19466315.2022.2085783

    View details for PubMedID 37981982

    View details for PubMedCentralID PMC10655937

  • Nervous system drugs taken by future fathers and birth defects in offspring: a prospective registry-based cohort study. BMJ open Wensink, M., Lu, Y., Tian, L., Jensen, T. K., Skakkebak, N. E., Lindahl-Jacobsen, R., Eisenberg, M. 2022; 12 (3): e053946


    OBJECTIVES: To evaluate the association of paternal intake of antipsychotics, anxiolytics, hypnotics and sedatives, antidepressants, selective serotonin reuptake inhibitors (SSRIs) and (benzo)diazepines during the development of fertilising sperm with birth defects in offspring.DESIGN: Prospective registry-based cohort study.SETTING: Total Danish birth cohort 1997-2016 using Danish national registries.PARTICIPANTS: All 1201119 Danish liveborn singletons born 1997-2016 were eligible, 39803 (3.3%) of whom had at least one major birth defect.EXPOSURE: Offspring were considered exposed if their father had filled at least one prescription in the relevant drug category during development of fertilising sperm (the 3months prior to conception).PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was the diagnosis, in the first year of life, of at least one major birth defect as categorised in the EUROCAT guidelines. Secondary outcome was the diagnosis, in the first year of life, of at least one major birth defect in any of the EUROCAT subcategories. Adjusted ORs (AORs) were calculated, along with their 95% CIs, adjusted for year, education, smoking status and age of the mother, and education, disposable income and age of the father.RESULTS: This study found weak or null associations between birth defects and selected drugs. Specifically, antidepressants (17827 exposed births) gave 3.5% birth defects (AOR 0.97 (0.89 to 1.05)). Diazepines, oxazepines, thiazepines and oxepines (as antipsychotics, 1633 offspring) gave 4.7% birth defects (AOR 1.22 (0.97 to 1.54)), attenuated to 1.13 when excluding by mothers' prescriptions. The study was well powered assuming 100% therapy adherence, while assuming 50% therapy adherence, the study remained well powered for the largest groups (SSRIs and antidepressants overall).CONCLUSIONS: Antipsychotics, anxiolytics, hypnotics and sedatives, antidepressants, SSRIs and benzodiazepine-derived anxiolytics, when taken by the father during development of fertilising sperm, are generally safe with regard to birth defects.

    View details for DOI 10.1136/bmjopen-2021-053946

    View details for PubMedID 35354621

  • Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring : A Nationwide Cohort Study. Annals of internal medicine Wensink, M. J., Lu, Y., Tian, L., Shaw, G. M., Rizzi, S., Jensen, T. K., Mathiesen, E. R., Skakkebæk, N. E., Lindahl-Jacobsen, R., Eisenberg, M. L. 2022


    Diabetes reduces semen quality and increasingly occurs during reproductive years. Diabetes medications, such as metformin, have glucose-independent effects on the male reproductive system. Associations with birth defects in offspring are unknown.To evaluate whether the risk for birth defects in offspring varies with preconceptional pharmacologic treatment of fathers with diabetes.Nationwide prospective registry-based cohort study.Denmark from 1997 to 2016.All liveborn singletons from mothers without histories of diabetes or essential hypertension.Offspring were considered exposed if their father filled 1 or more prescriptions for a diabetes drug during the development of fertilizing sperm. Sex and frequencies of major birth defects were compared across drugs, times of exposure, and siblings.Of 1 116 779 offspring included, 3.3% had 1 or more major birth defects (reference). Insulin-exposed offspring (n = 5298) had the reference birth defect frequency (adjusted odds ratio [aOR], 0.98 [95% CI, 0.85 to 1.14]). Metformin-exposed offspring (n = 1451) had an elevated birth defect frequency (aOR, 1.40 [CI, 1.08 to 1.82]). For sulfonylurea-exposed offspring (n = 647), the aOR was 1.34 (CI, 0.94 to 1.92). Offspring whose fathers filled a metformin prescription in the year before (n = 1751) or after (n = 2484) sperm development had reference birth defect frequencies (aORs, 0.88 [CI, 0.59 to 1.31] and 0.92 [CI, 0.68 to 1.26], respectively), as did unexposed siblings of exposed offspring (3.2%; exposed vs. unexposed OR, 1.54 [CI, 0.94 to 2.53]). Among metformin-exposed offspring, genital birth defects, all in boys, were more common (aOR, 3.39 [CI, 1.82 to 6.30]), while the proportion of male offspring was lower (49.4% vs. 51.4%, P = 0.073).Information on underlying disease status was limited.Preconception paternal metformin treatment is associated with major birth defects, particularly genital birth defects in boys. Further research should replicate these findings and clarify the causation.National Institutes of Health.

    View details for DOI 10.7326/M21-4389

    View details for PubMedID 35344380

  • Joint modelling of endpoints can be used to answer various research questions in randomized clinical trials. Journal of clinical epidemiology van Eijk, R. P., Roes, K. C., van den Berg, L. H., Lu, Y. 2022


    OBJECTIVE: Correlated longitudinal and time-to-event outcomes, such as the rate of cognitive decline and the onset of Alzheimer's disease, are frequent (co-)primary and key secondary endpoints in randomized clinical trials (RCTs). Despite their biological associations, these types of data are often analyzed separately leading to loss of information and increases in bias. In this paper, we set out how joint modelling of longitudinal and time-to-event endpoints can be used in RCTs to answer various research questions.STUDY DESIGN AND SETTING: The key concepts of joint models are introduced and illustrated for a completed trial in amyotrophic lateral sclerosis.RESULTS: The output of a joint model can be used to answer different clinically relevant research questions, where the interpretation of effect estimates and those obtained from conventional methods are similar. Albeit joint models have the potential to overcome the limitations of commonly used alternatives, they require additional assumptions regarding the distributions as well as the associations between two endpoints.CONCLUSION: Improving the uptake of joint models in RCTs may start by outlining the exact research question one seeks to answer, thereby determining how best to prespecify the model and defining which parameter should be of primary interest.

    View details for DOI 10.1016/j.jclinepi.2022.03.009

    View details for PubMedID 35346783

  • REDACS: Regional emergency-driven adaptive cluster sampling for effective COVID-19 management STOCHASTIC ANALYSIS AND APPLICATIONS Stehlik, M., Dinamarca, A., Alvarado, E., Plaza, F., Medina, F. A., Stehlikova, S., Marek, J., Venegas, B., Gajdos, A., Li, Y., Katuscak, S., Brazinova, A., Zeintl, E., Lu, Y., Kiselak, J. 2022
  • Functional loss and mortality in randomized clinical trials for amyotrophic lateral sclerosis: to combine, or not to combine - that is the estimand. Clinical pharmacology and therapeutics van Eijk, R. P., Roes, K. C., de Greef-van der Sandt, I., van den Berg, L. H., Lu, Y. 1800


    Amyotrophic lateral sclerosis (ALS) is a rapidly progressive disease leading to death in, on average, three to five years after first symptom onset. Consequently, there is frequently a non-negligible number of patients who die during the course of a clinical trial. This introduces bias in endpoints such as daily functioning, muscle strength and quality of life. In this paper, we outline how the choice of strategy to handle death affects the interpretation of the trial results. We provide a general overview of the considerations, positioned in the estimand framework, and discuss the possibility that not every strategy provides a clinically relevant answer in each setting. The relevance of a strategy changes as function of the intended trial duration, hypothesized treatment effect and population included. It is important to consider this trade-off at the design stage of a clinical trial, as this will clarify the exact research question that is being answered, and better guide the planning, design and analysis of the study.

    View details for DOI 10.1002/cpt.2533

    View details for PubMedID 35076930

  • Evaluation of Surrogate Endpoints Using Information-Theoretic Measure of Association Based on Havrda and Charvat Entropy Mathematics Pardo, M. d., Zhao, Q., Jin, H., Lu, Y. 2022; 10 (3): 465

    View details for DOI 10.3390/math10030465

  • The ENHANCE-AF Clinical Trial to Evaluate an Atrial Fibrillation Shared Decision-Making Pathway: Rationale and Study Design. American heart journal Baykaner, T., Pundi, K., Lin, B., Lu, Y., DeSutter, K., Lhamo, K., Garay, G., Nunes, J. C., Morin, D. P., Sears, S. F., Chung, M. K., Paasche-Orlow, M. K., Sanders, L. M., Bunch, T. J., Hills, M. T., Mahaffey, K. W., Stafford, R. S., Wang, P. J. 2022


    Shared decision making (SDM) may result in treatment plans that best reflect the goals and wishes of patients, increasing patient satisfaction with the decision-making process.  There is a knowledge gap to support the use of decision aids in SDM for anticoagulation therapy in patients with atrial fibrillation (AF). We describe the development and testing of a new decision aid, including a multicenter, randomized, controlled, 2-arm, open-label ENHANCE-AF clinical trial (Engaging Patients to Help Achieve Increased Patient Choice and Engagement for AF Stroke Prevention) to evaluate its effectiveness in 1,200 participants.Participants will be randomized to either usual care or to a shared decision-making pathway incorporating a digital tool designed to simplify the complex concepts surrounding AF in conjunction with a clinician tool and a non-clinician navigator to guide the participants through each step of the tool. The participant-determined primary outcome for this study is the Decisional Conflict Scale, measured at 1 month after the index visit during which a decision was made regarding anticoagulation use. Secondary outcomes at both 1 and 6 months will include other decision making related scales as well as participant and clinician satisfaction, oral anticoagulation adherence, and a composite rate of major bleeding, death, stroke, or transient ischemic attack. The study will be conducted at four sites selected for their ability to enroll participants of varying racial and ethnic backgrounds, health literacy, and language skills. Participants will be followed in the study for 6 months.The results of the ENHANCE-AF trial will determine whether a decision aid facilitates high quality shared decision making in anticoagulation discussions for stroke reduction in AF. An improved shared decision-making experience may allow patients to make decisions better aligned with their personal values and preferences, while improving overall AF care.

    View details for DOI 10.1016/j.ahj.2022.01.013

    View details for PubMedID 35092723

  • Composite endpoint for ALS clinical trials based on patient preference: Patient-Ranked Order of Function (PROOF). Journal of neurology, neurosurgery, and psychiatry van Eijk, R. P., van den Berg, L. H., Lu, Y. 1800


    BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) show considerable variation in symptoms. Treatments targeting an overall improvement in symptomatology may not address what the majority of patients consider to be most important. Here, we propose a composite endpoint for ALS clinical trials that weighs the improvement in symptoms compared with what the patient population actually wants.METHODS: An online questionnaire was sent out to a population-based registry in The Netherlands. Patients with ALS were asked to score functional domains with a validated self-reported questionnaire, and rank the order of importance of each domain. This information was used to estimate variability in patient preferences and to develop the Patient-Ranked Order of Function (PROOF) endpoint.RESULTS: There was extensive variability in patient preferences among the 433 responders. The majority of the patients (62.1%) preferred to prioritise certain symptoms over others when evaluating treatments. The PROOF endpoint was established by comparing each patient in the treatment arm to each patient in the placebo arm, based on their preferred order of functional domains. PROOF averages all pairwise comparisons, and reflects the probability that a patient receiving treatment has a better outcome on domains that are most important to them, compared with a patient receiving placebo. By means of simulation we illustrate how incorporating patient preference may upgrade or downgrade trial results.CONCLUSIONS: The PROOF endpoint provides a balanced patient-focused analysis of the improvement in function and may help to refine the risk-benefit assessment of new treatments for ALS.

    View details for DOI 10.1136/jnnp-2021-328194

    View details for PubMedID 34921121

  • N-Terminal Pro-B-Type Natriuretic Peptide as a Biomarker for the Severity and Outcomes With COVID-19 in a Nationwide Hospitalized Cohort. Journal of the American Heart Association O'Donnell, C., Ashland, M. D., Vasti, E. C., Lu, Y., Chang, A. Y., Wang, P., Daniels, L. B., de Lemos, J. A., Morrow, D. A., Rodriguez, F., O'Brien, C. G. 2021: e022913


    Background Currently, there is limited research on the prognostic value of NT-proBNP (N-terminal pro-B-type natriuretic peptide) as a biomarker in COVID-19. We proposed the a priori hypothesis that an elevated NT-proBNP concentration at admission is associated with increased in-hospital mortality. Methods and Results In this prospective, observational cohort study of the American Heart Association's COVID-19 Cardiovascular Disease Registry, 4675 patients hospitalized with COVID-19 were divided into normal and elevated NT-proBNP cohorts by standard age-adjusted heart failure thresholds, as well as separated by quintiles. Patients with elevated NT-proBNP (n=1344; 28.7%) were older, with more cardiovascular risk factors, and had a significantly higher rate of in-hospital mortality (37% versus 16%; P<0.001) and shorter median time to death (7 versus 9days; P<0.001) than those with normal values. Analysis by quintile of NT-proBNP revealed a steep graded relationship with mortality (7.1%-40.2%; P<0.001). NT-proBNP was also associated with major adverse cardiac events, intensive care unit admission, intubation, shock, and cardiac arrest (P<0.001 for each). In subgroup analyses, NT-proBNP, but not prior heart failure, was associated with increased risk of in-hospital mortality. Adjusting for cardiovascular risk factors with presenting vital signs, an elevated NT-proBNP was associated with 2-fold higher adjusted odds of death (adjusted odds ratio [OR], 2.23; 95% CI, 1.80-2.76), and the log-transformed NT-proBNP with other biomarkers projected a 21% increased risk of death for each 2-fold increase (adjusted OR, 1.21; 95% CI, 1.08-1.34). Conclusions Elevated NT-proBNP levels on admission for COVID-19 are associated with an increased risk of in-hospital mortality and other complications in patients with and without heart failure.

    View details for DOI 10.1161/JAHA.121.022913

    View details for PubMedID 34889112

  • Prevalence of Multimorbidity of Chronic Noncommunicable Diseases in Brazil: Population-Based Study. JMIR public health and surveillance Shi, X., Lima, S. M., Mota, C. M., Lu, Y., Stafford, R. S., Pereira, C. V. 2021; 7 (11): e29693


    BACKGROUND: Multimorbidity is the co-occurrence of two or more chronic diseases.OBJECTIVE: This study, based on self-reported medical diagnosis, aims to investigate the dynamic distribution of multimorbidity across sociodemographic levels and its impacts on health-related issues over 15 years in Brazil using national data.METHODS: Data were analyzed using descriptive statistics, hypothesis tests, and logistic regression. The study sample comprised 679,572 adults (18-59 years of age) and 115,699 elderly people (≥60 years of age) from the two latest cross-sectional, multiple-cohort, national-based studies: the National Sample Household Survey (PNAD) of 1998, 2003, and 2008, and the Brazilian National Health Survey (PNS) of 2013.RESULTS: Overall, the risk of multimorbidity in adults was 1.7 times higher in women (odds ratio [OR] 1.73, 95% CI 1.67-1.79) and 1.3 times higher among people without education (OR 1.34, 95% CI 1.28-1.41). Multiple chronic diseases considerably increased with age in Brazil, and people between 50 and 59 years old were about 12 times more likely to have multimorbidity than adults between 18 and 29 years of age (OR 11.89, 95% CI 11.27-12.55). Seniors with multimorbidity had more than twice the likelihood of receiving health assistance in community services or clinics (OR 2.16, 95% CI 2.02-2.31) and of being hospitalized (OR 2.37, 95% CI 2.21-2.56). The subjective well-being of adults with multimorbidity was often worse than people without multiple chronic diseases (OR=12.85, 95% CI: 12.07-13.68). These patterns were similar across all 4 cohorts analyzed and were relatively stable over 15 years.CONCLUSIONS: Our study shows little variation in the prevalence of the multimorbidity of chronic diseases in Brazil over time, but there are differences in the prevalence of multimorbidity across different social groups. It is hoped that the analysis of multimorbidity from the two latest Brazil national surveys will support policy making on epidemic prevention and management.

    View details for DOI 10.2196/29693

    View details for PubMedID 34842558

  • Validation of Deep Learning-based Augmentation for Reduced 18F-FDG Dose for PET/MRI in Children and Young Adults with Lymphoma. Radiology. Artificial intelligence Theruvath, A. J., Siedek, F., Yerneni, K., Muehe, A. M., Spunt, S. L., Pribnow, A., Moseley, M., Lu, Y., Zhao, Q., Gulaka, P., Chaudhari, A., Daldrup-Link, H. E. 2021; 3 (6): e200232


    Purpose: To investigate if a deep learning convolutional neural network (CNN) could enable low-dose fluorine 18 (18F) fluorodeoxyglucose (FDG) PET/MRI for correct treatment response assessment of children and young adults with lymphoma.Materials and Methods: In this secondary analysis of prospectively collected data ( identifier: NCT01542879), 20 patients with lymphoma (mean age, 16.4 years ± 6.4 [standard deviation]) underwent 18F-FDG PET/MRI between July 2015 and August 2019 at baseline and after induction chemotherapy. Full-dose 18F-FDG PET data (3 MBq/kg) were simulated to lower 18F-FDG doses based on the percentage of coincidence events (representing simulated 75%, 50%, 25%, 12.5%, and 6.25% 18F-FDG dose [hereafter referred to as 75%Sim, 50%Sim, 25%Sim, 12.5%Sim, and 6.25%Sim, respectively]). A U.S. Food and Drug Administration-approved CNN was used to augment input simulated low-dose scans to full-dose scans. For each follow-up scan after induction chemotherapy, the standardized uptake value (SUV) response score was calculated as the maximum SUV (SUVmax) of the tumor normalized to the mean liver SUV; tumor response was classified as adequate or inadequate. Sensitivity and specificity in the detection of correct response status were computed using full-dose PET as the reference standard.Results: With decreasing simulated radiotracer doses, tumor SUVmax increased. A dose below 75%Sim of the full dose led to erroneous upstaging of adequate responders to inadequate responders (43% [six of 14 patients] for 75%Sim; 93% [13 of 14 patients] for 50%Sim; and 100% [14 of 14 patients] below 50%Sim; P < .05 for all). CNN-enhanced low-dose PET/MRI scans at 75%Sim and 50%Sim enabled correct response assessments for all patients. Use of the CNN augmentation for assessing adequate and inadequate responses resulted in identical sensitivities (100%) and specificities (100%) between the assessment of 100% full-dose PET, augmented 75%Sim, and augmented 50%Sim images.Conclusion: CNN enhancement of PET/MRI scans may enable 50% 18F-FDG dose reduction with correct treatment response assessment of children and young adults with lymphoma.Keywords: Pediatrics, PET/MRI, Computer Applications Detection/Diagnosis, Lymphoma, Tumor Response, Whole-Body Imaging, Technology AssessmentClinical trial registration no: NCT01542879 Supplemental material is available for this article. ©RSNA, 2021.

    View details for DOI 10.1148/ryai.2021200232

    View details for PubMedID 34870211

  • In-Stent Restenosis in Saphenous Vein Grafts (from the DIVA Trial). The American journal of cardiology Xenogiannis, I., Rangan, B. V., Uyeda, L., Banerjee, S., Edson, R., Bhatt, D. L., Goldman, S., Holmes, D. R., Rao, S. V., Shunk, K., Mavromatis, K., Ramanathan, K., Bavry, A. A., McFalls, E. O., Garcia, S., Thai, H., Uretsky, B. F., Latif, F., Armstrong, E., Ortiz, J., Jneid, H., Liu, J., Aggrawal, K., Conner, T. A., Wagner, T., Karacsonyi, J., Ventura, B., Alsleben, A., Lu, Y., Shih, M., Brilakis, E. S. 2021


    Saphenous vein grafts (SVGs) have high rates of in-stent restenosis (ISR). We compared the baseline clinical and angiographic characteristics of patients and lesions that did develop ISR with those who did not develop ISR during a median follow-up of 2.7 years in the DIVA study (NCT01121224). We also examined the ISR types using the Mehran classification. ISR developed in 119 out of the 575 DIVA patients (21%), with similar incidence among patients with drug-eluting stents and bare-metal stents (BMS) (21% vs 21%, p=0.957). Patients in the ISR group were younger (67 ± 7 vs 69 ± 8 years, p=0.04) and less likely to have heart failure (27% vs 38%, p=0.03) and SVG lesions with Thrombolysis In Myocardial Infarction 3 flow before the intervention (77% vs 83%, p <0.01), but had a higher number of target SVG lesions (1.33 ± 0.64 vs 1.16 ± 0.42, p <0.01), more stents implanted in the target SVG lesions (1.52 ± 0.80 vs 1.31 ± 0.66, p <0.01), and longer total stent length (31.37 ± 22.11 vs 25.64 ± 17.42 mm, p=0.01). The incidence of diffuse ISR was similar in patients who received drug-eluting-stents and BMS (57% vs 54%, p=0.94), but BMS patients were more likely to develop occlusive restenosis (17% vs 33%, p=0.05).

    View details for DOI 10.1016/j.amjcard.2021.09.024

    View details for PubMedID 34736721

  • Statistical Considerations for Sequential Analysis of the Restricted Mean Survival Time for Randomized Clinical Trials. Statistics in biopharmaceutical research Lu, Y., Tian, L. 2021; 13 (2): 210-218


    In this paper, we illustrate the method of designing a group-sequential randomized clinical trial based on the difference in restricted mean survival time (RMST). The procedure is based on theoretical formulations of Murray and Tsiatis (1999). We also present a numerical example in designing a cardiology surgical trial. Various practical considerations are discussed. R codes are provided in the Supplementary Materials. We conclude that the group-sequential design for RMST is a viable option in practice. A simulation study is performed to compare the proposed method to the Max-Combo and conventional log-rank tests. The simulation result shows that when there is a delayed treatment benefit and the proportional hazards assumption is untrue, the sequential design based on the RMST can be more efficient than that based on the log-rank test but less efficient than that based on the Max-Combo test. Compared with Max-Combo test, the RMST-based study design yield coherent estimand, statistical inference and result interpretation.

    View details for DOI 10.1080/19466315.2020.1816491

    View details for PubMedID 33927801

    View details for PubMedCentralID PMC8078843

  • The sunscreen for kindergarteners (SKIN) study trial protocol. Contemporary clinical trials Lee, G. H., Bae, G. H., Barnes, L. A., Pol-Rodriguez, M. M., Ransohoff, K. J., Nord, K. M., Lu, Y., Cannell, B., Weitlauf, J. C. 2021: 106480


    BACKGROUND: Exposure to ultraviolet radiation (UVR) is the major modifiable risk factor for skin cancers. The majority of lifetime UVR exposure occurs before age 20, underscoring an important window for risk reduction. Incorporation of skills-based sunscreen education into school health curricula may foster the development of consistent and effective use of sunscreen among children and youth. We describe the study protocol for a first-of-its-kind study that examined the feasibility of bringing skills-based sunscreen education into kindergarten classrooms.METHODS: Participants were 96 kindergarten students across four classrooms in a single elementary school. A single-blind open-label trial design was used to evaluate the feasibility of incorporating a song-based, video-guided intervention for independent application of sunscreen into the kindergarten curriculum. Students first completed a 10-day no-intervention baseline period, followed by a 10-day intervention period, and then a 10-day randomized follow-up period where students were randomly assigned to continue with the intervention or to revert to the no-intervention condition.OUTCOMES: Feasibility metrics associated with study process, resources, management, scientific outcomes and safety were gathered. The primary outcome was pre-to-post intervention changes in student engagement in the sunscreen task. The secondary outcome was pre-to-post intervention changes in the proportion of exposed skin to which a student applies sunscreen. Teacher and student perceptions of intervention value and utility were also evaluated.DISCUSSION: This is the study protocol for a clinical trial designed to determine the feasibility of implementing a skills-based sunscreen curriculum in kindergarten classrooms. Next steps include evaluation of the intervention for efficacy and effectiveness.CLINICAL TRIAL REGISTRATION: NCT03752736.

    View details for DOI 10.1016/j.cct.2021.106480

    View details for PubMedID 34126263

  • A systematic literature review of the disease burden in patients with recessive dystrophic epidermolysis bullosa. Orphanet journal of rare diseases Tang, J. Y., Marinkovich, M. P., Lucas, E., Gorell, E., Chiou, A., Lu, Y., Gillon, J., Patel, D., Rudin, D. 2021; 16 (1): 175


    BACKGROUND/OBJECTIVE: Recessive dystrophic epidermolysis bullosa (RDEB) is a genetic collagen disorder characterized by skin fragility leading to blistering, wounds, and scarring. There are currently no approved curative therapies. The objective of this manuscript is to provide a comprehensive literature review of the disease burden caused by RDEB.METHODS: A systematic literature review was conducted in MEDLINE and Embase in accordance with PRISMA guidelines. Observational and interventional studies on the economic, clinical, or humanistic burden of RDEB were included.RESULTS: Sixty-five studies were included in the review. Patients had considerable wound burden, with 60% reporting wounds covering more than 30% of their body. Increases in pain and itch were seen with larger wound size. Chronic wounds were larger and more painful than recurrent wounds. Commonly reported symptoms and complications included lesions and blistering, anemia, nail dystrophy and loss, milia, infections, musculoskeletal contractures, strictures or stenoses, constipation, malnutrition/nutritional problems, pseudosyndactyly, ocular manifestations, and dental caries. Many patients underwent esophageal dilation (29-74%; median dilations, 2-6) and gastrostomy tube placement (8-58%). In the severely affected population, risk of squamous cell carcinoma (SCC) was 76% and mortality from SCC reached 84% by age 40. Patients with RDEB experienced worsened quality of life (QOL), decreased functioning and social activities, and increased pain and itch when compared to other EB subtypes, other skin diseases, and the general population. Families of patients reported experiencing high rates of burden including financial burden (50-54%) and negative impact on private life (79%). Direct medical costs were high, though reported in few studies; annual payer-borne total medical costs in Ireland were $84,534 and annual patient-borne medical costs in Korea were $7392. Estimated annual US costs for wound dressings ranged from $4000 to $245,000. Patients spent considerable time changing dressings: often daily (13-54% of patients) with up to three hours per change (15-40%).CONCLUSION: Patients with RDEB and their families/caregivers experience significant economic, humanistic, and clinical burden. Further research is needed to better understand the costs of disease, how the burden of disease changes over the patient lifetime and to better characterize QOL impact, and how RDEB compares with other chronic, debilitating disorders.

    View details for DOI 10.1186/s13023-021-01811-7

    View details for PubMedID 33849616

  • Evaluating eligibility criteria of oncology trials using real-world data and AI. Nature Liu, R., Rizzo, S., Whipple, S., Pal, N., Pineda, A. L., Lu, M., Arnieri, B., Lu, Y., Capra, W., Copping, R., Zou, J. 2021


    There is a growing focus on making clinical trials more inclusive but the design of trial eligibility criteria remains challenging1-3. Here we systematically evaluate the effect of different eligibility criteria on cancer trial populations and outcomes with real-world data using the computational framework of Trial Pathfinder. We apply Trial Pathfinder to emulate completed trials of advanced non-small-cell lung cancer using data from a nationwide database of electronic health records comprising 61,094 patients with advanced non-small-cell lung cancer. Our analyses reveal that many common criteria, including exclusions based on several laboratory values, had a minimal effect on the trial hazard ratios. When we used a data-driven approach to broaden restrictive criteria, the pool of eligible patients more than doubled on average and the hazard ratio of the overall survival decreased by an average of 0.05. This suggests that many patients who were not eligible under the original trial criteria could potentially benefit from the treatments. We further support our findings through analyses of other types of cancer and patient-safety data from diverse clinical trials. Our data-driven methodology for evaluating eligibility criteria can facilitate the design of more-inclusive trials while maintaining safeguards for patient safety.

    View details for DOI 10.1038/s41586-021-03430-5

    View details for PubMedID 33828294

  • Bladder cancer risk stratification using a urinary mRNA biomarker panel - A path towards cystoscopy triaging. Urologic oncology Shkolyar, E., Zhao, Q., Mach, K. E., Teslovich, N. C., Lee, T. J., Cox, S., Skinner, E. C., Lu, Y., Liao, J. C. 2021


    OBJECTIVES: The risk of bladder cancer (BCa) diagnosis and recurrence necessitates cystoscopy. Improved risk stratification may inform personalized triage and surveillance strategies. We aim to develop a urinary mRNA biomarker panel for risk stratification in patients undergoing BCa screening and surveillance.METHODS AND MATERIALS: Urine samples were collected from patients undergoing cystoscopy for BCa screening or surveillance. In patients who underwent transurethral resection of bladder tumor, urine samples were categorized based on tumor histopathology, size, and focality. Subjects with intermediate and high-risk BCa based on American Urological Association (AUA) guideline for non-muscle invasive bladder cancer were classified as "increased-risk"; those with no cancer and AUA low-risk BCa were classified as "low-risk". Urine was evaluated for ROBO1, WNT5A, CDC42BPB, ABL1, CRH, IGF2, ANXA10, and UPK1B expression. A diagnostic model to detect "increased-risk" BCa was created using forward logistic regression analysis of cycle threshold values. Model validation was performed with ten-fold cross-validation. Sensitivity and specificity for detection of "increased-risk" BCa was determined and net benefit analysis performed.RESULTS: Urine samples (n = 257) were collected from 177 patients (95 screening, 76 surveillance, 6 both). There were 65 diagnoses of BCa (12 low, 22 intermediate, 31 high risk). ROBO1, CRH, and IGF2 expression correlated with "increased-risk" disease yielding sensitivity of 92.5% (95% CI, 84.9%-98.1%) and specificity of 73.5% (95% CI, 67.7-79.9%). The overall calculated standardized net benefit of the model was 0.81 (95%CI, 0.71-0.90).CONCLUSIONS: A 3-marker urinary mRNA panel allows for non-invasive identification of "increased-risk" BCa and with further validation may prove to be a tool to reduce the need for cystoscopies in low-risk patients.

    View details for DOI 10.1016/j.urolonc.2021.02.011

    View details for PubMedID 33766467

  • A Conversation with Tze Leung Lai STATISTICAL SCIENCE Lu, Y., Small, D. S., Ying, Z. 2021; 36 (1): 158–67

    View details for DOI 10.1214/20-STS775

    View details for Web of Science ID 000600652900011

  • A statistical quality assessment method for longitudinal observations in electronic health record data with an application to the VA million veteran program. BMC medical informatics and decision making Wang, H., Belitskaya-Levy, I., Wu, F., Lee, J. S., Shih, M. C., Tsao, P. S., Lu, Y. 2021; 21 (1): 289


    To describe an automated method for assessment of the plausibility of continuous variables collected in the electronic health record (EHR) data for real world evidence research use.The most widely used approach in quality assessment (QA) for continuous variables is to detect the implausible numbers using prespecified thresholds. In augmentation to the thresholding method, we developed a score-based method that leverages the longitudinal characteristics of EHR data for detection of the observations inconsistent with the history of a patient. The method was applied to the height and weight data in the EHR from the Million Veteran Program Data from the Veteran's Healthcare Administration (VHA). A validation study was also conducted.The receiver operating characteristic (ROC) metrics of the developed method outperforms the widely used thresholding method. It is also demonstrated that different quality assessment methods have a non-ignorable impact on the body mass index (BMI) classification calculated from height and weight data in the VHA's database.The score-based method enables automated and scaled detection of the problematic data points in health care big data while allowing the investigators to select the high-quality data based on their need. Leveraging the longitudinal characteristics in EHR will significantly improve the QA performance.

    View details for DOI 10.1186/s12911-021-01643-2

    View details for PubMedID 34670548

  • Parental age and preterm birth: a population-based cohort of nearly 3 million California livebirths from 2007 to 2012. Journal of perinatology : official journal of the California Perinatal Association Mayo, J. A., Lu, Y., Stevenson, D. K., Shaw, G. M., Eisenberg, M. L. 2020


    PURPOSE: To assess the relationships between parental ages and preterm birth subtypes.METHODS: A population-based cohort analysis of California livebirths 2007-2012. Associations between maternal and paternal age with spontaneous and medically indicated preterm birth were estimated from Cox proportional hazard models. Parental age was modeled with restricted cubic splines to account for nonlinear relationships.RESULTS: Young paternal age was associated with increased hazard ratios for spontaneous and medically indicated preterm birth. Older fathers showed elevated hazards for preterm birth in crude analysis but after adjustment the relationship was generally not observed. Aging mothers showed increased hazard ratios for both preterm birth phenotypes.CONCLUSIONS: After adjusting for parental demographics, births to younger fathers and older mothers had the highest risks for spontaneous preterm birth. The paternal influence on preterm birth was observed to be independent of maternal factors.

    View details for DOI 10.1038/s41372-020-00894-7

    View details for PubMedID 33293667

  • "SPOCU": scaled polynomial constant unit activation function (November, 10.1007/s00521-020-05182-1, 2020) NEURAL COMPUTING & APPLICATIONS Kiselak, J., Lu, Y., Svihra, J., Szepe, P., Stehlik, M. 2020
  • Statistical Considerations for Sequential Analysis of the Restricted Mean Survival Time for Randomized Clinical Trials STATISTICS IN BIOPHARMACEUTICAL RESEARCH Lu, Y., Tian, L. 2020
  • Classification of Two Distinct Wound Types in Recessive Dystrophic Epidermolysis Bullosa: A Retrospective and Cohort Natural History Study. Journal of the American Academy of Dermatology Solis, D. C., Teng, C., Gorell, E. S., Barriga, M., Nazaroff, J., Li, S., Lu, Y., Bruckner, A., Marinkovich, M. P., Tang, J. Y. 2020

    View details for DOI 10.1016/j.jaad.2020.08.118

    View details for PubMedID 32896597

  • "SPOCU": scaled polynomial constant unit activation function NEURAL COMPUTING & APPLICATIONS Kisel'ak, J., Lu, Y., Svihra, J., Szepe, P., Stehlik, M. 2020
  • Extensions of empirical likelihood and chi-squared-based tests for ordered alternatives JOURNAL OF APPLIED STATISTICS Carmen Pardo, M., Lu, Y., Franco-Pereira, A. M. 2020
  • A curve free Bayesian decision-theoretic design for phase Ia/Ib trials considering both safety and efficacy outcomes. Statistics in biosciences Fan, S., Lee, B. L., Lu, Y. 2020; 12 (2): 146-166


    A curve-free, Bayesian decision-theoretic two-stage design is proposed to select biological efficacious doses (BEDs) for phase Ia/Ib trials in which both toxicity and efficacy signals are observed. No parametric models are assumed to govern the dose-toxicity, dose-efficacy, and toxicity-efficacy relationships. We assume that the dose-toxicity curve is monotonic non-decreasing and the dose-efficacy curve is unimodal. In the phase Ia stage, a Bayesian model on the toxicity rates is used to locate the maximum tolerated dose. In the phase Ib stage, we model the dose-efficacy curve using a step function while continuing to monitor the toxicity rates. Furthermore, a measure of the goodness of fit of a candidate step function is proposed, and the interval of BEDs associated with the best fitting step function is recommended. At the end of phase Ib, if some doses are recommended as BEDs, a cohort of confirmation is recruited and assigned at these doses to improve the precision of estimates at these doses. Extensive simulation studies show that the proposed design has desirable operating characteristics across different shapes of the underlying true toxicity and efficacy curves.

    View details for DOI 10.1007/s12561-020-09272-5

    View details for PubMedID 33815623

    View details for PubMedCentralID PMC8014959

  • A Curve-Free Bayesian Decision-Theoretic Design for Phase Ia/Ib Trials Considering Both Safety and Efficacy Outcomes STATISTICS IN BIOSCIENCES Fan, S., Lee, B., Lu, Y. 2020
  • A Qualitative Study on the Differences Between Trial Populations and the Approved Therapeutic Indications of Antineoplastic Agents by 3 Regulatory Agencies From 2010 to 2018. Clinical therapeutics Sumi, E., Asada, R., Lu, Y., Ito-Ihara, T., Grimes, K. V. 2020


    PURPOSE: The present study aimed to examine the differences between enrolled subject populations and use of combination therapies as defined by the pivotal clinical trial protocols and the approved indications of anticancer drugs as determined by 3 major regulatory agencies.METHODS: Thirty-eight approvals were collected that received market authorization from the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Pharmaceuticals and Medical Devices Agency (PMDA) between January 2010 and September 2018 for initial approval of an anticancer drug or for an expanded therapeutic indication for a previously approved anticancer drug, based on the same pivotal clinical trial(s). The subject eligibility criteria of the pivotal clinical trials and the approved indications as established by these agencies were compared, and the differences were categorized according to patient biomarkers status, prior treatment status, and the use of combination therapies.FINDINGS: In 20 (53%) approvals, there was a discrepancy between biomarker status of enrolled subjects in the pivotal trial and the therapeutic indication. In 7 of these cases, the biomarkers were used to diagnose the target cancer or to stratify the study subjects in the pivotal trial. In 9 cases, the biomarker discrepancies were related to minor histologic subtypes of the target cancer. Regarding prior treatment status, the FDA and the EMA generally approved indications for the same treatment line as the pivotal trials, whereas the PMDA did not restrict approval to untreated patients when the pivotal trial included only treatment-naive subjects. In 14 approvals, the FDA and the EMA designated the same co-administered drugs as part of the approved indications in line with the pivotal trials. However, the PMDA did not specify the co-administered drugs in 2 approvals and did not require combination therapy in 1 case.IMPLICATIONS: In principle, the approved therapeutic indications should be determined by the characteristics of the pivotal trial subjects and combination therapies. The use of biomarkers can be essential for identifying those patients who are most likely to benefit from a drug. Unfortunately, biomarker-defined subgroups are often insufficient in size to allow meaningful interpretation of results. Consequently, regulatory agencies may deviate from one another and from the pivotal trial protocol when interpreting study results and attempting to define the optimal treatment population. The PMDA-approved indications deviated more liberally from the pivotal trial protocols regarding specification of prior treatment status and the use of co-administered drugs.

    View details for DOI 10.1016/j.clinthera.2020.01.002

    View details for PubMedID 32008723

  • Statistical Methods in Precision Oncology. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Lu, Y. n., Lee, J. J., Ford, J. M. 2020: JCO1903173

    View details for DOI 10.1200/JCO.19.03173

    View details for PubMedID 31895607

  • Background and Proposed Design for a Metformin Abdominal Aortic Aneurysm Suppression Trial Vascular & Endovascular Review Dalman, R. L., Lu, Y., Mahaffey, K. W., Chase, A. J., Stern, J. R., Chang, R. W. 2020; 3: e08

    View details for DOI 10.15420/ver.2020.03

  • Veterans Affairs Cooperative Studies Program Study #553: Chemotherapy After Prostatectomy for High-risk Prostate Carcinoma: A Phase III Randomized Study. European urology Lin, D. W., Shih, M. C., Aronson, W. n., Basler, J. n., Beer, T. M., Brophy, M. n., Cooperberg, M. n., Garzotto, M. n., Kelly, W. K., Lee, K. n., McGuire, V. n., Wang, Y. n., Lu, Y. n., Markle, V. n., Nseyo, U. n., Ringer, R. n., Savage, S. J., Sinnott, P. n., Uchio, E. n., Yang, C. C., Montgomery, R. B. 2020


    The Veterans Affairs Cooperative Studies Program study #553 was designed to evaluate the efficacy of adjuvant chemotherapy added to the standard of care (SOC) for patients who are at high risk for relapse after prostatectomy.To test whether addition of chemotherapy to surgery for high-risk prostate cancer improves progression-free survival (PFS).Eligible patients after prostatectomy were randomized to the SOC group with observation or to the chemotherapy group with docetaxel and prednisone administered every 3 wk for six cycles. Randomization was stratified for prostate-specific antigen, Gleason, tumor stage, and surgical margin status.The primary endpoint was PFS. Secondary endpoints included overall, prostate cancer-specific, and metastasis-free survival, and time to androgen deprivation therapy.A total of 298 of the planned 636 patients were randomized. The median follow-up was 59.1 mo (0.2-103.7 mo). For the primary endpoint, the two groups did not statistically differ in PFS (median 55.5 mo in the chemotherapy group and 42.2 mo in the SOC group; test adjusted for site via gamma frailty p=0.21; adjusted hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.58-1.11; p=0.18). Prespecified subgroup analyses showed benefit in PFS for patients with tumor stage ≥T3b (HR 0.54, 95% CI 0.32-0.92; p=0.022) and patients with Gleason score ≤7 (HR 0.65, 95% CI 0.43-0.99; p=0.046). Secondary endpoint analyses are hampered by low event rates. The most common adverse events (≥grade 3 related or possibly related to chemotherapy) included neutropenia (43%), hyperglycemia (20%), and fatigue (5%), with febrile neutropenia in 2%.Adjuvant chemotherapy in high-risk prostate cancer using docetaxel and prednisone did not lead to statistically significant improvement in PFS for the intention-to-treat population as a whole. The analysis was challenged by lower power due to accrual limitation. Subgroup analyses suggest potential benefit for patients with Gleason grade ≤7 and stage≥pT3b ( number NCT00132301).In this randomized trial, we tested whether addition of chemotherapy to surgery for high-risk prostate cancer decreased the risk of prostate-specific antigen rise after surgery. We found no benefit from docetaxel given after radical prostatectomy, although some subgroups of patients may benefit.

    View details for DOI 10.1016/j.eururo.2019.12.020

    View details for PubMedID 31924316

  • Association between preconception paternal health and pregnancy loss in the USA: an analysis of US claims data. Human reproduction (Oxford, England) Kasman, A. M., Zhang, C. A., Li, S. n., Lu, Y. n., Lathi, R. B., Stevenson, D. K., Shaw, G. M., Eisenberg, M. L. 2020


    Is preconception paternal health associated with pregnancy loss?Poor preconception paternal health is associated with a higher risk of pregnancy loss as confirmed in sensitivity analyses accounting for maternal age and health.Preconception paternal health can negatively impact perinatal outcomes.Retrospective cohort study of US insurance claims database from 2009 to 2016 covering 958 804 pregnancies.US insurance claims database including women, men and pregnancies within the USA between 2007 and 2016. Paternal preconception health status (e.g. metabolic syndrome diagnoses (MetS), Charlson comorbidity index (CCI) and individual chronic disease diagnoses) was examined in relation to pregnancy loss (e.g. ectopic pregnancy, miscarriage and stillbirth).In all, 958 804 pregnancies were analyzed. The average paternal age was 35.3 years (SD 5.3) and maternal age was 33.1 years (SD 4.4). Twenty-two percent of all pregnancies ended in a loss. After adjusting for maternal factors, the risk of pregnancy loss increased with increasing paternal comorbidity. For example, compared to men with no components of MetS, the risk of pregnancy loss increased for men with one (relative risk (RR) 1.10, 95% CI 1.09-1.12), two (RR 1.15, 95% CI 1.13-1.17) or three or more (RR 1.19, 95% CI 1.14-1.24) components. Specifically, less healthy men had a higher risk of siring a pregnancy ending in spontaneous abortion, stillbirth and ectopic pregnancies. Similar patterns remained with other measures of paternal health (e.g. CCI, chronic diseases, etc.). When stratifying by maternal age as well as maternal health, a similar pattern of increasing pregnancy loss risk for men with 1, 2 or 3+ MetS was observed. A statistically significant but weak association between timing of pregnancy loss and paternal health was found.Retrospective study design covering only employer insured individuals may limit generalizability.Optimization of a father's health may improve pregnancy outcomes.National Institutes of Health National Center for Advancing Translational Science Clinical and Translational Science Award (UL1 TR001085). M.L.E. is an advisor for Sandstone Diagnostics, Dadi, Hannah and Underdog. No other competing interests were declared.N/A.

    View details for DOI 10.1093/humrep/deaa332

    View details for PubMedID 33336240

  • On the empirical choice of the time window for restricted mean survival time. Biometrics Tian, L. n., Jin, H. n., Uno, H. n., Lu, Y. n., Huang, B. n., Anderson, K. M., Wei, L. J. 2020


    The t-year mean survival or restricted mean survival time (RMST) has been used as an appealing summary of the survival distribution within a time window [0, t]. RMST is the patient's life expectancy until time t and can be estimated nonparametrically by the area under the Kaplan-Meier curve up to t. In a comparative study, the difference or ratio of two RMSTs has been utilized to quantify the between-group-difference as a clinically interpretable alternative summary to the hazard ratio. The choice of the time window [0, t] may be pre-specified at the design stage of the study based on clinical considerations. On the other hand, after the survival data have been collected, the choice of time point t could be data-dependent. The standard inferential procedures for the corresponding RMST, which is also data-dependent, ignore this subtle yet important issue. In this paper, we clarify how to make inference about a random "parameter." Moreover, we demonstrate that under a rather mild condition on the censoring distribution, one can make inference about the RMST up to t, where t is less than or even equal to the largest follow-up time (either observed or censored) in the study. This finding reduces the subjectivity of the choice of t empirically. The proposal is illustrated with the survival data from a primary biliary cirrhosis study, and its finite sample properties are investigated via an extensive simulation study. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/biom.13237

    View details for PubMedID 32061098

  • Exact inference for the random-effect model for meta-analyses with rare events. Statistics in medicine Gronsbell, J., Hong, C., Nie, L., Lu, Y., Tian, L. 2019


    Meta-analysis allows for the aggregation of results from multiple studies to improve statistical inference for the parameter of interest. In recent years, random-effect meta-analysis has been employed to synthesize estimates of incidence rates of adverse events across heterogeneous clinical trials to evaluate treatment safety. However, the validity of existing approaches relies on asymptotic approximation as the number of studies becomes large. In practice, a limited number of trials are typically available for analysis. Moreover, adverse events are typically rare; thus, study-specific incidence rate estimates may be unstable or undefined. In this paper, we present a method for construction of an exact confidence interval for the location parameter of the beta-binomial model through inversion of exact tests. The coverage level of the proposed confidence interval is guaranteed to achieve at least the nominal level, regardless of the number of studies or the with-in study sample size, making it particularly applicable to the study of rare-event data.

    View details for DOI 10.1002/sim.8396

    View details for PubMedID 31820458

  • Fredholm integral relation between compound estimation and prediction (FIRCEP) STOCHASTIC ANALYSIS AND APPLICATIONS Stehlik, M., Kisel'ak, J., Bukina, E., Lu, Y., Baran, S. 2019
  • A Collection of Statistical Methods for Precision Oncology. JCO precision oncology Lu, Y., Lee, J. J. 2019; 3: 1-3

    View details for DOI 10.1200/PO.19.00308

    View details for PubMedID 35100724

  • Disease burden in offspring is associated with changing paternal demographics in the United States. Andrology Greenberg, D. R., Khandwala, Y. S., Lu, Y., Stevenson, D. K., Shaw, G. M., Eisenberg, M. L. 2019


    BACKGROUND: Average paternal age in the United States has increased substantially in the last few decades. Children of advanced age fathers have a higher incidence of early onset cancer and neuropsychiatric disease.OBJECTIVES: To quantify the number of population adjusted cases of early-onset cancer and neuropsychiatric disease in children attributable to increasing paternal age in the United States.METHODS: Paternal age in the United States from 1972 to 2015 was collected using the National Vital Statistics System (NVSS). Population attributable fraction and paternal age-specific cumulative incidence rates of several cancers and neuropsychiatric disorders were obtained from peer-reviewed publications. Paternal age-specific birth rates were correlated with paternal age-specific cumulative incidence rates to determine the number of attributable cases of disease caused by advancing age of fathers in the United States.RESULTS: The 2015 birth cohort in the United States is estimated to expect 9.2% more cases of acute lymphoblastic leukemia (ALL) diagnosed before 16years of age (157 additional cases), 13.2% more cases of embryonal tumors in children <5years of age (209 additional cases), and 13.0% more cases of breast cancer in females younger than 40years old (424 additional cases) compared to the 1972 birth cohort. We can estimate to expect 10.5% more cases of schizophrenia diagnosed before 21years of age (2864 additional cases), 6.3% more cases of autism spectrum disorder (ASD) in adolescents <17years of age (2934 additional cases), 4.5% more cases of anorexia nervosa (AN) in females 8-30years old (620 additional cases), and 9.2% more cases of bipolar disorder in young patients 16-25years old (252 additional cases) in the 2015 birth cohort compared to the 1972 birth cohort.CONCLUSION: Increasing paternal age in the United States is associated with a substantial increase in the number of cases of early-onset cancer and neuropsychiatric disease in offspring.

    View details for DOI 10.1111/andr.12700

    View details for PubMedID 31478609

  • How to Prevent a Leaky Pipeline in Academic Radiology: Insights From a Faculty Survey JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY Daldrup-Link, H., Villavasso, K., Zhao, Q., Lu, Y., Ranieri, A., Simard, C., Gambhir, S. 2019; 16 (9): 1220–24
  • Design of randomized controlled confirmatory trials using historical control data to augment sample size for concurrent controls JOURNAL OF BIOPHARMACEUTICAL STATISTICS Yuan, J., Liu, J., Zhu, R., Lu, Y., Palm, U. 2019; 29 (3): 558–73
  • Corrigendum to "Design of VA Cooperative Study #591: CERV-PTSD, Comparative Effectiveness Research in Veterans with PTSD" [Contemp. Clin. Trials 41 (2015) 75-84]. Contemporary clinical trials Schnurr, P. P., Chard, K. M., Ruzek, J. I., Chow, B. K., Shih, M., Resick, P. A., Foa, E. B., Marx, B. P., Huang, G. D., Lu, Y. 2019

    View details for PubMedID 30962124

  • Parental age and stillbirth: a population-based cohort of nearly 10 million California deliveries from 1991 to 2011 ANNALS OF EPIDEMIOLOGY Mayo, J. A., Lu, Y., Stevenson, D. K., Shaw, G. M., Eisenberg, M. L. 2019; 31: 32–37
  • Optimizing Clinical Use of Biologics in Orthopaedic Surgery: Consensus Recommendations From the 2018 AAOS/NIH U-13 Conference JOURNAL OF THE AMERICAN ACADEMY OF ORTHOPAEDIC SURGEONS Chu, C. R., Rodeo, S., Bhutani, N., Goodrich, L. R., Huard, J., Irrgang, J., LaPrade, R. F., Lattermann, C., Lu, Y., Mandelbaum, B., Mao, J., McIntyre, L., Mishra, A., Muschler, G. F., Piuzzi, N. S., Potter, H., Spindler, K., Tokish, J. M., Tuan, R., Zaslav, K., Maloney, W. 2019; 27 (2): E50–E63


    Concern that misinformation from direct-to-consumer marketing of largely unproven "biologic" treatments such as platelet-rich plasma and cell-based therapies may erode the public trust and the responsible investment needed to bring legitimate biological therapies to patients have resulted in calls to action from professional organizations and governing bodies. In response to substantial patient demand for biologic treatment of orthopaedic conditions, the American Academy of Orthopaedic Surgeons convened a collaborative symposium and established a consensus framework for improving and accelerating the clinical evaluation, use, and optimization of biologic therapies for musculoskeletal diseases. The economic and disease burden of musculoskeletal conditions is high. Of the various conditions discussed, knee osteoarthritis was identified as a "serious condition" associated with substantial and progressive morbidity and emerged as the condition with the most urgent need for clinical trial development. It was also recognized that stem cells have unique characteristics that are not met by minimally manipulated mixed cell preparations. The work group recommended that minimally manipulated cell products be referred to as cell therapy and that the untested and uncharacterized nature of these treatments be clearly communicated within the profession, to patients, and to the public. Minimum standards for product characterization and clinical research should also be followed. A framework for developing clinical trials related to knee OA was agreed upon. In addition to recommendations for development of high-quality multicenter clinical trials, another important recommendation was that physicians and institutions offering biologic therapies commit to establishing high-quality patient registries and biorepository-linked registries that can be used for postmarket surveillance and quality assessments.

    View details for DOI 10.5435/JAAOS-D-18-00305

    View details for Web of Science ID 000462411800001

    View details for PubMedID 30300216

    View details for PubMedCentralID PMC6314629

  • Differences in Cataract Surgery Rates Based on Dementia Status JOURNAL OF ALZHEIMERS DISEASE Pershing, S., Henderson, V. W., Bundorf, M., Lu, Y., Rahman, M., Andrews, C. A., Goldstein, M., Stein, J. D. 2019; 69 (2): 423–32

    View details for DOI 10.3233/JAD-181292

    View details for Web of Science ID 000470879800009

  • The Official Positions of the International Society for Clinical Densitometry: Cross Calibration, Least Significant Change, and Quality Assurance in Multiple Dual-Energy X-Ray Absorptiometry Scanner Environments. Journal of clinical densitometry : the official journal of the International Society for Clinical Densitometry Jankowski, L. G., Warner, S. n., Gaither, K. n., Lenchik, L. n., Fan, B. n., Lu, Y. n., Shepherd, J. n. 2019


    In preparation for the International Society for Clinical Densitometry Position Development Conference (PDC) 2019 in Kuala Lumpur, Malaysia, a cross-calibration and precision task force was assembled and tasked to review the literature, summarize the findings, and generate positions to answer 4 related questions provided by the PDC Steering Committee, which expand upon the current ISCD official positions on these subjects. (1) How should a provider with multiple dual-energy X-ray absorptiometry (DXA) scanners of the same make and model calculate least significant change (LSC)? (2) How should a provider with multiple DXA systems with the same manufacturer but different models calculate LSC? (3) How should a provider with multiple DXA systems from different manufacturers and models calculate LSC? (4) Are there specific phantom procedures that one can use to provide trustworthy in vitro cross calibration for same models, different models, and different makes? Based on task force deliberations and the resulting systematic literature reviews, 3 new positions were developed to address these more complex scenarios not addressed by current official positions on single scanner cross calibration and LSC. These new positions provide appropriate guidance to large multiple DXA scanner providers wishing to offer patients flexibility and convenience, and clearly define good clinical practice requirements to that end.

    View details for DOI 10.1016/j.jocd.2019.09.001

    View details for PubMedID 31558404

  • How to Prevent a Leaky Pipeline in Academic Radiology: Insights From a Faculty Survey. Journal of the American College of Radiology : JACR Daldrup-Link, H. n., Villavasso, K. n., Zhao, Q. n., Lu, Y. n., Ranieri, A. n., Simard, C. n., Gambhir, S. S. 2019

    View details for PubMedID 31092345

  • Association of paternal age with perinatal outcomes between 2007 and 2016 in the United States: population based cohort study BMJ-BRITISH MEDICAL JOURNAL Khandwala, Y. S., Baker, V. L., Shaw, G. M., Stevenson, D. K., Lu, Y., Eisenberg, M. L. 2018; 363

    View details for DOI 10.1136/bmj.k4372

    View details for Web of Science ID 000449564200004

  • Drug-eluting stents versus bare-metal stents in saphenous vein grafts: a double-blind, randomised trial LANCET Brilakis, E. S., Edson, R., Bhatt, D. L., Goldman, S., Holmes, D. R., Rao, S. V., Shunk, K., Rangan, B. V., Mavromatis, K., Ramanathan, K., Bavry, A. A., Garcia, S., Latif, F., Armstrong, E., Jneid, H., Conner, T. A., Wagner, T., Karacsonyi, J., Uyeda, L., Ventura, B., Alsleben, A., Lu, Y., Shih, M., Banerjee, S., DIVA Trial Investigators 2018; 391 (10134): 1997–2007


    Few studies have examined the efficacy of drug-eluting stents (DES) for reducing aortocoronary saphenous vein bypass graft (SVG) failure compared with bare-metal stents (BMS) in patients undergoing stenting of de-novo SVG lesions. We assessed the risks and benefits of the use of DES versus BMS in de-novo SVG lesions.Patients were recruited to our double-blind, randomised controlled trial from 25 US Department of Veterans Affairs centres. Eligible participants were aged at least 18 years and had at least one significant de-novo SVG lesion (50-99% stenosis of a 2·25-4·5 mm diameter SVG) requiring percutaneous coronary intervention with intent to use embolic protection devices. Enrolled patients were randomly assigned, in a 1:1 ratio, by phone randomisation system to receive a DES or BMS. Randomisation was stratified by presence or absence of diabetes and number of target SVG lesions requiring percutaneous coronary intervention (one or two or more) within each participating site by use of an adaptive scheme intended to balance the two stent type groups on marginal totals for the stratification factors. Patients, referring physicians, study coordinators, and outcome assessors were masked to group allocation. The primary endpoint was the 12-month incidence of target vessel failure, defined as the composite of cardiac death, target vessel myocardial infarction, or target vessel revascularisation. The DIVA trial is registered with, number NCT01121224.Between Jan 1, 2012, and Dec 31, 2015, 599 patients were randomly assigned to the stent groups, and the data for 597 patients were used. The patients' mean age was 68·6 (SD 7·6) years, and 595 (>99%) patients were men. The two stent groups were similar for most baseline characteristics. At 12 months, the incidence of target vessel failure was 17% (51 of 292) in the DES group versus 19% (58 of 305) in the BMS group (adjusted hazard ratio 0·92, 95% CI 0·63-1·34, p=0·70). Between-group differences in the components of the primary endpoint, serious adverse events, or stent thrombosis were not significant. Enrolment was stopped before the revised target sample size of 762 patients was reached.In patients undergoing stenting of de-novo SVG lesions, no significant differences in outcomes between those receiving DES and BMS during 12 months of follow-up were found. The study results have important economic implications in countries with high DES prices such as the USA, because they suggest that the lower-cost BMS can be used in SVG lesions without compromising either safety or efficacy.US Department of Veterans Affairs Cooperative Studies Program.

    View details for PubMedID 29759512

  • Trial of Prazosin for Post-Traumatic Stress Disorder in Military Veterans. The New England journal of medicine Raskind, M. A., Peskind, E. R., Chow, B. n., Harris, C. n., Davis-Karim, A. n., Holmes, H. A., Hart, K. L., McFall, M. n., Mellman, T. A., Reist, C. n., Romesser, J. n., Rosenheck, R. n., Shih, M. C., Stein, M. B., Swift, R. n., Gleason, T. n., Lu, Y. n., Huang, G. D. 2018; 378 (6): 507–17


    In randomized trials, prazosin, an α1-adrenoreceptor antagonist, has been effective in alleviating nightmares associated with post-traumatic stress disorder (PTSD) in military veterans.We recruited veterans from 13 Department of Veterans Affairs medical centers who had chronic PTSD and reported frequent nightmares. Participants were randomly assigned to receive prazosin or placebo for 26 weeks; the drug or placebo was administered in escalating divided doses over the course of 5 weeks to a daily maximum of 20 mg in men and 12 mg in women. After week 10, participants continued to receive prazosin or placebo in a double-blind fashion for an additional 16 weeks. The three primary outcome measures were the change in score from baseline to 10 weeks on the Clinician-Administered PTSD Scale (CAPS) item B2 ("recurrent distressing dreams"; scores range from 0 to 8, with higher scores indicating more frequent and more distressing dreams); the change in score from baseline to 10 weeks on the Pittsburgh Sleep Quality Index (PSQI; scores range from 0 to 21, with higher scores indicating worse sleep quality); and the Clinical Global Impression of Change (CGIC) score at 10 weeks (scores range from 1 to 7, with lower scores indicating greater improvement and a score of 4 indicating no change).A total of 304 participants underwent randomization; 152 were assigned to prazosin, and 152 to placebo. At 10 weeks, there were no significant differences between the prazosin group and the placebo group in the mean change from baseline in the CAPS item B2 score (between-group difference, 0.2; 95% confidence interval [CI], -0.3 to 0.8; P=0.38), in the mean change in PSQI score (between-group difference, 0.1; 95% CI, -0.9 to 1.1; P=0.80), or in the CGIC score (between-group difference, 0; 95% CI, -0.3 to 0.3; P=0.96). There were no significant differences in these measures at 26 weeks (a secondary outcome) or in other secondary outcomes. At 10 weeks, the mean difference between the prazosin group and the placebo group in the change from baseline in supine systolic blood pressure was a decrease of 6.7 mm Hg. The adverse event of new or worsening suicidal ideation occurred in 8% of the participants assigned to prazosin versus 15% of those assigned to placebo.In this trial involving military veterans who had chronic PTSD, prazosin did not alleviate distressing dreams or improve sleep quality. (Funded by the Department of Veterans Affairs Cooperative Studies Program; PACT number, NCT00532493 .).

    View details for PubMedID 29414272

  • Adaptive Designs ONCOLOGY CLINICAL TRIALS: SUCCESSFUL DESIGN, CONDUCT, AND ANALYSIS, 2ND EDITION Lai, T. L., Lu, Y., Tsang, K., Kelly, W. K., Halabi, S. 2018: 176–85
  • Prior-free probabilistic interval estimation for binomial proportion Test Lu, H., Jin, H., Wang, Z., Chen, C., Lu, Y. 2018
  • Short-term changes on MRI predict long-term changes on radiography in rheumatoid arthritis: an analysis by an OMERACT Task Force of pooled data from four randomised controlled trials ANNALS OF THE RHEUMATIC DISEASES Peterfy, C., Strand, V., Tian, L., Ostergaard, M., Lu, Y., DiCarlo, J., Countryman, P., Deodhar, A., Landewe, R., Ranganath, V. K., Troum, O., Conaghan, P. G. 2017; 76 (6): 992-997


    In rheumatoid arthritis (RA), MRI provides earlier detection of structural damage than radiography (X-ray) and more sensitive detection of intra-articular inflammation than clinical examination. This analysis was designed to evaluate the ability of early MRI findings to predict subsequent structural damage by X-ray.Pooled data from four randomised controlled trials (RCTs) involving 1022 RA hands and wrists in early and established RA were analysed. X-rays were scored using van der Heijde-modified or Genant-modified Sharp methods. MRIs were scored using Outcome Measures in Rheumatology (OMERACT) RA MRI Score (RAMRIS). Data were analysed at the patient level using multivariable logistic regression and receiver operating characteristic curve analyses.Progression of MRI erosion scores at Weeks 12 and 24 predicted progression of X-ray erosions at Weeks 24 and 52, with areas under the curve (AUCs) of 0.64 and 0.74, respectively. 12-week and 24-week changes in MRI osteitis scores were similarly predictive of 24-week and 52-week X-ray erosion progressions; pooled AUCs were 0.78 and 0.77, respectively. MRI changes in synovitis at Weeks 12 and 24 also predicted progression of X-ray joint damage (erosion and joint-space narrowing) at Weeks 24 and 52 (AUCs=0.72 and 0.65, respectively).Early changes in joint damage and inflammation detected with MRI predict changes in joint damage evident on subsequent X-rays. These findings support the use of MRI as a valid method for monitoring structural damage in short-duration RCTs.

    View details for DOI 10.1136/annrheumdis-2016-210311

    View details for Web of Science ID 000401138800011

  • Deep Sequencing of Urinary RNAs for Bladder Cancer Molecular Diagnostics. Clinical cancer research : an official journal of the American Association for Cancer Research Sin, M. L., Mach, K. E., Sinha, R., Wu, F., Trivedi, D., Altobelli, E., Jensen, K. C., Sahoo, D., Lu, Y., Liao, J. C. 2017


    The majority of bladder cancer patients present with localized disease and are managed by transurethral resection. However, the high rate of recurrence necessitates lifetime cystoscopic surveillance. Developing a sensitive and specific urine-based test would significantly improve bladder cancer screening, detection, and surveillance.RNA-seq was used for biomarker discovery to directly assess the gene expression profile of exfoliated urothelial cells in urine derived from bladder cancer patients (n=13) and controls (n=10). Eight bladder cancer specific and 3 reference genes identified by RNA-seq were quantitated by qPCR in a training cohort of 102 urine samples. A diagnostic model based on the training cohort was constructed using multiple logistic regression. The model was further validated in an independent cohort of 101 urines.418 genes were found to be differentially expressed between bladder cancer and controls. Validation of a subset of these genes was used to construct an equation for computing a probability of bladder cancer score (PBC) based on expression of 3-markers (ROBO1, WNT5A, and CDC42BPB). Setting PBC=0.45 as the cutoff for a positive test, urine testing using the 3-marker panel had overall 88% sensitivity and 92% specificity in the training cohort. The accuracy of the 3-marker panel in the independent validation cohort yielded an area under the curve of 0.87 and overall 83% sensitivity and 89% specificity.Urine-based molecular diagnostics using this 3-marker signature could provide a valuable adjunct to cystoscopy and may lead to a reduction of unnecessary procedures for bladder cancer diagnosis.

    View details for DOI 10.1158/1078-0432.CCR-16-2610

    View details for PubMedID 28193625

  • Cross-sectional design with a short-term follow up for prognostic imaging biomarkers Computational Statistics & Data Analysis Won, J., Wu, X., Li, S. H., Lu, Y. 2017
  • Is the non-sentinel lymph node compartment the next site for melanoma progression from the sentinel lymph node compartment in the regional nodal basin? Clinical & experimental metastasis Rios-Cantu, A. n., Lu, Y. n., Melendez-Elizondo, V. n., Chen, M. n., Gutierrez-Range, A. n., Fadaki, N. n., Thummala, S. n., West-Coffee, C. n., Cleaver, J. n., Kashani-Sabet, M. n., Leong, S. P. 2017; 34 (5): 345–50


    Melanoma patients with additional positive lymph nodes in the completion lymph node dissection (CLND) following a positive sentinel lymph node (SLN) biopsy would have a poorer prognosis than patients with no additional positive lymph nodes. We hypothesize that the progression of disease from the SLN to the non-SLN compartment is orderly and is associated with the worsening of the disease status. Thus, the SLN and non-SLN compartments are biologically different in that cancer cells, in general, arrive in the SLN compartment before spreading to the non-SLN compartment. To validate this concept, we used a large cohort of melanoma patients from our prospective SLN database in an academic tertiary medical center. Adult cutaneous melanoma patients (n = 291) undergoing CLND after a positive SLN biopsy from 1994 to 2009 were analyzed. Comparison of 5-year disease-free survival and 5-year overall survival between positive (n = 66) and negative (n = 225) CLND groups was made. The 5-year disease-free survival rates were 55% (95% CI 49-62%) for patients with no additional LN on CLND versus 14% (95% CI 8-26%) in patients with positive LN on CLND (p < 0.0001, log-rank test). The median disease-free survival time was 7.4 years with negative CLND (95% CI 4.4-15+ years) and 1.2 years with positive CLND (95% CI 1.0-1.8 years). The 5-year overall survival rates were 67% (95% CI 61-74%) for negative CLND versus 38% (95% CI 28-52%) for positive CLND (p < 0.0001, log-rank test). The median overall survival time was 12.1 years for negative CLND (95% CI 9.3-15+ years) and 2.5 years for positive CLND (95% CI 2.2-5.7 years). This study shows that CLND status is a significant prognostic factor for patients with positive SLNs undergoing CLND. Also, it suggests an orderly progression of metastasis from the SLN to the non-SLN compartment. Thus, the SLN in the regional nodal basin draining the primary melanoma may serve as an important gateway for metastasis to the non-SLN compartment and beyond to the systemic sites.

    View details for PubMedID 28699042

  • Rationale and design of the Drug-Eluting Stents vs Bare-Metal Stents in Saphenous Vein Graft Angioplasty (DIVA) Trial. Clinical cardiology Brilakis, E. S., Banerjee, S. n., Edson, R. n., Shunk, K. n., Goldman, S. n., Holmes, D. R., Bhatt, D. L., Rao, S. V., Smith, M. W., Sather, M. n., Colling, C. n., Kar, B. n., Nielsen, L. n., Conner, T. n., Wagner, T. n., Rangan, B. V., Ventura, B. n., Lu, Y. n., Holodniy, M. n., Shih, M. C. 2017


    VA Cooperative Studies Program #571 (DIVA) was designed to evaluate the efficacy of drug-eluting stents (DES) for reducing aortocoronary saphenous vein bypass graft (SVG) failure when compared with bare-metal stents (BMS) in participants undergoing stenting of de novo SVG lesions. Participants undergoing clinically indicated stenting of de novo SVG lesions were randomized in a 1:1 ratio to DES or BMS. Randomization was stratified by presence/absence of diabetes mellitus and the number of target SVG lesions (1 vs ≥2) within each participating site. At sites that did not routinely administer 12-months of dual antiplatelet therapy after SVG stenting participants without acute coronary syndromes received 1 month of open-label clopidogrel, followed by 11 months of clopidogrel for those assigned to DES and 11 months of placebo for those assigned to BMS. The primary endpoint was the 12-month incidence of target-vessel failure (defined as the composite of cardiac death, target-vessel myocardial infarction, or target-vessel revascularization). Secondary endpoints included the incidence of other clinical endpoints and the incremental cost-effectiveness of DES relative to BMS. Due to lower-than-anticipated target-vessel failure rates, target enrollment was increased from 519 to 762. The study had randomized 599 participants when recruitment ended in December 2015. The DIVA trial will provide clarity on the appropriate stent type for de novo SVG lesions.

    View details for PubMedID 28841230

  • The age of fathers in the USA is rising: an analysis of 168 867 480 births from 1972 to 2015. Human reproduction (Oxford, England) Khandwala, Y. S., Zhang, C. A., Lu, Y. n., Eisenberg, M. L. 2017; 32 (10): 2110–16


    How has the mean paternal age in the USA changed over the past 4 decades?The age at which men are fathering children in the USA has been increasing over time, although it varies by race, geographic region and paternal education level.While the rise in mean maternal age and its implications for fertility, birth outcomes and public health have been well documented, little is known about paternal characteristics of births within the USA.A retrospective data analysis of paternal age and reporting patterns for 168 867 480 live births within the USA since 1972 was conducted.All live births within the USA collected through the National Vital Statistics System (NVSS) of the Centers for Disease Control and Prevention (CDC) were evaluated. Inverse probability weighting (IPW) was used to reduce bias due to missing paternal records.Mean paternal age has increased over the past 44 years from 27.4 to 30.9 years. College education and Northeastern birth states were associated with higher paternal age. Racial/ethnic differences were also identified, whereby Asian fathers were the oldest and Black fathers were the youngest. The parental age difference (paternal age minus maternal age) has decreased over the past 44 years. Births to Black and Native American mothers were most often lacking paternal data, implying low paternal reporting. Paternal reporting was higher for older and more educated women.Although we utilized IPW to reduce the impact of paternal reporting bias, our estimates may still be influenced by the missing data in the NVSS.Paternal age is rising within the USA among all regions, races and education levels. Given the implications for offspring health and demographic patterns, further research on this trend is warranted.No funding was received for this study and there are no competing interests.N/A.

    View details for PubMedID 28938735

  • New tree structured survival analysis for hip fracture of SOF data STATISTICS AND ITS INTERFACE Jin, H., Lu, Y. 2017; 10 (2): 199-205
  • A New Overall-Subgroup Simultaneous Test for Optimal Inference in Biomarker-Targeted Confirmatory Trials Statistics in Biosciences Belitskaya, I., Wang, H., Shih, M., Tian, L., Doros, G., Lew, R. A., Lu, Y. 2017
  • Short-term changes on MRI predict long-term changes on radiography in rheumatoid arthritis: an analysis by an OMERACT Task Force of pooled data from four randomised controlled trials. Annals of the rheumatic diseases Peterfy, C., Strand, V., Tian, L., Østergaard, M., Lu, Y., DiCarlo, J., Countryman, P., Deodhar, A., Landewé, R., Ranganath, V. K., Troum, O., Conaghan, P. G. 2016


    In rheumatoid arthritis (RA), MRI provides earlier detection of structural damage than radiography (X-ray) and more sensitive detection of intra-articular inflammation than clinical examination. This analysis was designed to evaluate the ability of early MRI findings to predict subsequent structural damage by X-ray.Pooled data from four randomised controlled trials (RCTs) involving 1022 RA hands and wrists in early and established RA were analysed. X-rays were scored using van der Heijde-modified or Genant-modified Sharp methods. MRIs were scored using Outcome Measures in Rheumatology (OMERACT) RA MRI Score (RAMRIS). Data were analysed at the patient level using multivariable logistic regression and receiver operating characteristic curve analyses.Progression of MRI erosion scores at Weeks 12 and 24 predicted progression of X-ray erosions at Weeks 24 and 52, with areas under the curve (AUCs) of 0.64 and 0.74, respectively. 12-week and 24-week changes in MRI osteitis scores were similarly predictive of 24-week and 52-week X-ray erosion progressions; pooled AUCs were 0.78 and 0.77, respectively. MRI changes in synovitis at Weeks 12 and 24 also predicted progression of X-ray joint damage (erosion and joint-space narrowing) at Weeks 24 and 52 (AUCs=0.72 and 0.65, respectively).Early changes in joint damage and inflammation detected with MRI predict changes in joint damage evident on subsequent X-rays. These findings support the use of MRI as a valid method for monitoring structural damage in short-duration RCTs.

    View details for DOI 10.1136/annrheumdis-2016-210311

    View details for PubMedID 27974302

  • American Joint Committee on Cancer acceptance criteria for inclusion of risk models for individualized prognosis in the practice of precision medicine. CA: a cancer journal for clinicians Kattan, M. W., Hess, K. R., Amin, M. B., Lu, Y., Moons, K. G., Gershenwald, J. E., Gimotty, P. A., Guinney, J. H., Halabi, S., Lazar, A. J., Mahar, A. L., Patel, T., Sargent, D. J., Weiser, M. R., Compton, C. 2016; 66 (5): 370-374


    The American Joint Committee on Cancer (AJCC) has increasingly recognized the need for more personalized probabilistic predictions than those delivered by ordinal staging systems, particularly through the use of accurate risk models or calculators. However, judging the quality and acceptability of a risk model is complex. The AJCC Precision Medicine Core conducted a 2-day meeting to discuss characteristics necessary for a quality risk model in cancer patients. More specifically, the committee established inclusion and exclusion criteria necessary for a risk model to potentially be endorsed by the AJCC. This committee reviewed and discussed relevant literature before creating a checklist unique to this need of AJCC risk model endorsement. The committee identified 13 inclusion and 3 exclusion criteria for AJCC risk model endorsement in cancer. The emphasis centered on performance metrics, implementation clarity, and clinical relevance. The facilitation of personalized probabilistic predictions for cancer patients holds tremendous promise, and these criteria will hopefully greatly accelerate this process. Moreover, these criteria might be useful for a general audience when trying to judge the potential applicability of a published risk model in any clinical domain. CA Cancer J Clin 2016. © 2016 American Cancer Society.

    View details for DOI 10.3322/caac.21339

    View details for PubMedID 26784705

  • 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

  • Acupuncture for chronic knee pain: a protocol for an updated systematic review BMJ OPEN Zhang, Q., Yue, J., Sun, Z., Lu, Y. 2016; 6 (2)


    The aim of this study is to evaluate the efficacy and safety of acupuncture for patients with chronic knee pain.MEDLINE, EMBASE, CENTERAL, CINAHL and four Chinese medical databases will be searched from their inception to present. We will also manually retrieve eligible studies. Randomised controlled trials (RCTs) in which acupuncture is assessed as the sole treatment or as an adjunct treatment for chronic knee pain will be included. The primary outcome of our analysis is pain measured by the visual analogue scale (VAS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale or the 11-point numeric rating scale (NRS). The secondary outcomes will include the quality of life, measured by the 36-item Short-Form Health Survey (SF-36) and adverse events. Two researchers will conduct the study selection, data extraction and quality assessment independently. Any disagreement will be resolved through discussion with a third reviewer. The Cochrane risk-of-bias criteria and the Standards for Reporting Interventions in Controlled Trials of Acupuncture (STRICTA) checklist will be used to assess the methodological quality of the trials.This systematic review will assess the current evidence on acupuncture therapy for chronic knee pain. It uses aggregated published data instead of individual patient data and does not require an ethical board review and approval. The findings will be published in a peer-reviewed journal and disseminated in conference presentations. It will provide the latest analysis of the currently available evidence for acupuncture treating chronic knee pain.CRD42014015514.

    View details for DOI 10.1136/bmjopen-2015-008027

    View details for Web of Science ID 000381514500006

    View details for PubMedID 26911581

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

    View details for PubMedID 27017133

  • A curve-free Bayesian decision-theoretic design for two-agent phase I trials. Journal of biopharmaceutical statistics Lee, B. L., Fan, S. K., Lu, Y. n. 2016


    Although Bayesian statistical methods are gaining attention in the medical community, as they provide a natural framework for incorporating prior information, the complexity of these methods limited their adoptions in clinical trials. This article proposes a Bayesian design for two-agent phase I trials that is relatively easy for clinicians to understand and implement, yet performs comparably to more complex designs, so that it is more likely to be adopted in actual trials. In order to reduce model complexity and computational burden, we choose a working model with conjugate priors so that the posterior distributions have analytical expressions. Furthermore, we provide a simple strategy to facilitate the specification of priors based on the toxicity information accrued from single-agent phase I trials. The proposed method should be useful in terms of the ease of implementation and the savings in sample size without sacrificing performance. Moreover, the conservativeness of the dose-finding algorithm renders it a relatively safe method.

    View details for PubMedID 26882373

  • Decision tree methods: applications for classification and prediction. Shanghai archives of psychiatry Song, Y., Lu, Y. 2015; 27 (2): 130–35


    Decision tree methodology is a commonly used data mining method for establishing classification systems based on multiple covariates or for developing prediction algorithms for a target variable. This method classifies a population into branch-like segments that construct an inverted tree with a root node, internal nodes, and leaf nodes. The algorithm is non-parametric and can efficiently deal with large, complicated datasets without imposing a complicated parametric structure. When the sample size is large enough, study data can be divided into training and validation datasets. Using the training dataset to build a decision tree model and a validation dataset to decide on the appropriate tree size needed to achieve the optimal final model. This paper introduces frequently used algorithms used to develop decision trees (including CART, C4.5, CHAID, and QUEST) and describes the SPSS and SAS programs that can be used to visualize tree structure.

    View details for DOI 10.11919/j.issn.1002-0829.215044

    View details for PubMedID 26120265

  • Design of VA Cooperative Study #591: CERV-PTSD, Comparative Effectiveness Research in Veterans with PTSD CONTEMPORARY CLINICAL TRIALS Schnurr, P. P., Chard, K. M., Ruzek, J., Chow, B. K., Shih, M., Resick, P. A., Foa, E. B., Marx, B. P., Huang, G. D., Lu, Y. 2015; 41: 75-84


    CERV-PTSD is a randomized controlled trial of two of the most effective treatments for PTSD, Prolonged Exposure (PE) and Cognitive Processing Therapy (CPT). Despite solid evidence that both treatments are effective, there is limited evidence about their effectiveness relative to one another. The primary objective is to compare the effectiveness of PE and CPT for reducing PTSD symptom severity in a healthcare system that offers both treatments. The secondary objective is to compare the effectiveness of PE and CPT for reducing the severity of comorbid mental health problems and service utilization as well as improving functioning and quality of life. The tertiary objective is to examine whether discrepancy between patient preferences and treatment assignment reduces the effectiveness of each treatment. Exploratory analyses will examine whether demographic and clinical characteristics predict differential response to PE and CPT. The study is designed to randomize 900 male and female veterans with PTSD due to any traumatic military event to receive PE or CPT. The standard dose of treatment is 12 weekly sessions but veterans who improve more rapidly may finish in fewer sessions and veterans who improve more slowly may have additional sessions. The primary outcome is improvement in PTSD symptoms, measured during and after treatment and then 3 and 6 months later. As a large multi-site trial with men and women, CERV-PTSD is designed to advance the delivery of care for PTSD by providing conclusive information about whether one treatment is better than the other, overall, and for different types of patients.

    View details for DOI 10.1016/j.cct.2014.11.017

    View details for Web of Science ID 000353000500010

    View details for PubMedID 25457792

  • Development and application of a diagnostic algorithm for posttraumatic stress disorder. Psychiatry research James, L. M., Belitskaya-Lévy, I., Lu, Y., Wang, H., Engdahl, B. E., Leuthold, A. C., Georgopoulos, A. P. 2015; 231 (1): 1-7


    Intact cognitive functions rely on synchronous neural activity; conversely, alterations in synchrony are thought to underlie psychopathology. We recently demonstrated that anomalies in synchronous neural interactions (SNI) determined by magnetoencephalography represent a putative PTSD biomarker. Here we develop and apply a regression-based diagnostic algorithm to further validate SNI as a PTSD biomarker in 432 veterans (235 controls; 138 pure PTSD; 59 PTSD plus comorbid disorders). Correlation coefficients served as proximities in multidimensional scaling (MDS) to obtain a two-dimensional representation of the data. In addition, least absolute shrinkage and selection operator (LASSO) regression was used to derive a diagnostic algorithm for PTSD. Performance of this algorithm was assessed by the area under the receiver operating characteristic (ROC) curves, sensitivity, and specificity in 1000 randomly divided testing and validation datasets and in independent samples. MDS revealed that individuals with PTSD, regardless of comorbid psychiatric conditions, are highly distinct from controls. Similarly, application of the LASSO regression-derived prediction model demonstrated remarkable classification accuracy (AUCs≥0.93 for men, AUC=0.82 for women). Neural functioning in individuals with PTSD, regardless of comorbid psychiatric diagnoses, can be used as a diagnostic test to determine patient disease status, further validating SNI as a PTSD biomarker.

    View details for DOI 10.1016/j.pscychresns.2014.11.007

    View details for PubMedID 25433425

  • The debate about p-values. Shanghai archives of psychiatry Lu, Y. n., Belitskaya-Levy, I. n. 2015; 27 (6): 381–85


    The p-value is the most widely used statistical concept in biomedical research. Recently, there are controversies over its utility and over the possible relationship between p-value misuse and the relatively high proportion of published medical research that cannot be replicated. In this paper, we introduce the p-value in layman's terms and explain its randomness and limitations. However, we also point out that the available alternatives to p-value suffer similar limitations. We conclude that using p values is a valid way to test the null and alternative hypotheses in clinical trials. However, using the p-value from a single statistical test to judge the scientific merit of a research project is a misuse of the p-value; the results of inference tests using p-values need to be integrated with secondary results and other data to arrive at clinically valid conclusions. Understanding the variability and limitations of the p-value is important for the interpretation of statistical results in research studies.

    View details for PubMedID 27199532

    View details for PubMedCentralID PMC4858512

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


    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

  • Rank regression: an alternative regression approach for data with outliers. Shanghai archives of psychiatry Chen, T., Tang, W., Lu, Y., Tu, X. 2014; 26 (5): 310-315


    Linear regression models are widely used in mental health and related health services research. However, the classic linear regression analysis assumes that the data are normally distributed, an assumption that is not met by the data obtained in many studies. One method of dealing with this problem is to use semi-parametric models, which do not require that the data be normally distributed. But semi-parametric models are quite sensitive to outlying observations, so the generated estimates are unreliable when study data includes outliers. In this situation, some researchers trim the extreme values prior to conducting the analysis, but the ad-hoc rules used for data trimming are based on subjective criteria so different methods of adjustment can yield different results. Rank regression provides a more objective approach to dealing with non-normal data that includes outliers. This paper uses simulated and real data to illustrate this useful regression approach for dealing with outliers and compares it to the results generated using classical regression models and semi-parametric regression models.

    View details for DOI 10.11919/j.issn.1002-0829.214148

    View details for PubMedID 25903082

    View details for PubMedCentralID PMC4248265

  • Log-transformation and its implications for data analysis. Shanghai archives of psychiatry Feng, C., Wang, H., Lu, N., Chen, T., He, H., Lu, Y., Tu, X. M. 2014; 26 (2): 105-109


    The log-transformation is widely used in biomedical and psychosocial research to deal with skewed data. This paper highlights serious problems in this classic approach for dealing with skewed data. Despite the common belief that the log transformation can decrease the variability of data and make data conform more closely to the normal distribution, this is usually not the case. Moreover, the results of standard statistical tests performed on log-transformed data are often not relevant for the original, non-transformed data.We demonstrate these problems by presenting examples that use simulated data. We conclude that if used at all, data transformations must be applied very cautiously. We recommend that in most circumstances researchers abandon these traditional methods of dealing with skewed data and, instead, use newer analytic methods that are not dependent on the distribution the data, such as generalized estimating equations (GEE).

    View details for DOI 10.3969/j.issn.1002-0829.2014.02.009

    View details for PubMedID 25092958

  • A simple Bayesian decision-theoretic design for dose-finding trials STATISTICS IN MEDICINE Fan, S. K., Lu, Y., Wang, Y. 2012; 31 (28): 3719-3730


    A flexible and simple Bayesian decision-theoretic design for dose-finding trials is proposed in this paper. In order to reduce the computational burden, we adopt a working model with conjugate priors, which is flexible to fit all monotonic dose-toxicity curves and produces analytic posterior distributions. We also discuss how to use a proper utility function to reflect the interest of the trial. Patients are allocated based on not only the utility function but also the chosen dose selection rule. The most popular dose selection rule is the one-step-look-ahead (OSLA), which selects the best-so-far dose. A more complicated rule, such as the two-step-look-ahead, is theoretically more efficient than the OSLA only when the required distributional assumptions are met, which is, however, often not the case in practice. We carried out extensive simulation studies to evaluate these two dose selection rules and found that OSLA was often more efficient than two-step-look-ahead under the proposed Bayesian structure. Moreover, our simulation results show that the proposed Bayesian method's performance is superior to several popular Bayesian methods and that the negative impact of prior misspecification can be managed in the design stage.

    View details for DOI 10.1002/sim.5438

    View details for Web of Science ID 000311402300021

    View details for PubMedID 22763943

  • Tree-structured Subgroup Analysis of Receiver Operating Characteristic Curves for Diagnostic Tests ACADEMIC RADIOLOGY Li, C., Glueer, C., Eastell, R., Felsenberg, D., Reid, D. M., Roux, C., Lu, Y. 2012; 19 (12): 1529-1536


    Multiple diagnostic tests are often available for a disease. Their diagnostic accuracy may depend on the characteristics of testing subjects. The investigators propose a new tree-structured data-mining method that identifies subgroups and their corresponding diagnostic tests to achieve the maximum area under the receiver-operating characteristic curve.The Osteoporosis and Ultrasound Study is a prospectively designed, population-based European multicenter observational study to evaluate state-of-the-art diagnostic methods for assessing osteoporosis. A total 2837 women underwent dual x-ray absorptiometry (DXA) and quantitative ultrasound (QUS). Prevalent vertebral fractures were determined by a centralized radiology laboratory on the basis of radiographs. The data-mining algorithm includes three steps: defining the criteria for node splitting and selection of the best diagnostic test on the basis of the area under the curve, using a random forest to estimate the probability of DXA being the preferred diagnostic method for each participant, and building a single regression tree to describe subgroups for which either DXA or QUS is the more accurate test or for which the two tests are equivalent.For participants with weights ≤54.5 kg, QUS had a higher area under the curve in identifying prevalent vertebral fracture. For participants whose weights were >58.5 kg and whose heights were ≤167.5 cm, DXA was better, and for the remaining participants, DXA and QUS had comparable accuracy and could be used interchangeably.The proposed tree-structured subgroup analysis successfully defines subgroups and their best diagnostic tests. The method can be used to develop optimal diagnostic strategies in personalized medicine.

    View details for DOI 10.1016/j.acra.2012.09.007

    View details for Web of Science ID 000311654800012

    View details for PubMedID 23122572

  • On the Time to Conclusion of Phase II Cancer Clinical Trials and Its Application in Trial Designs STATISTICS IN BIOPHARMACEUTICAL RESEARCH 2012; 4 (4): 324-335
  • A multinational study to develop universal standardization of whole-body bone density and composition using GE Healthcare Lunar and Hologic DXA systems JOURNAL OF BONE AND MINERAL RESEARCH Shepherd, J. A., Fan, B., Lu, Y., Wu, X. P., Wacker, W. K., Ergun, D. L., Levine, M. A. 2012; 27 (10): 2208-2216


    Dual-energy x-ray absorptiometry (DXA) is used to assess bone mineral density (BMD) and body composition, but measurements vary among instruments from different manufacturers. We sought to develop cross-calibration equations for whole-body bone density and composition derived using GE Healthcare Lunar and Hologic DXA systems. This multinational study recruited 199 adult and pediatric participants from a site in the US (n = 40, ages 6 through 16 years) and one in China (n = 159, ages 5 through 81 years). The mean age of the participants was 44.2 years. Each participant was scanned on both GE Healthcare Lunar and Hologic Discovery or Delphi DXA systems on the same day (US) or within 1 week (China) and all scans were centrally analyzed by a single technologist using GE Healthcare Lunar Encore version 14.0 and Hologic Apex version 3.0. Paired t-tests were used to test the results differences between the systems. Multiple regression and Deming regressions were used to derive the cross-conversion equations between the GE Healthcare Lunar and Hologic whole-body scans. Bone and soft tissue measures were highly correlated between the GE Healthcare Lunar and Hologic and systems, with r ranging from 0.96 percent fat [PFAT] to 0.98 (BMC). Significant differences were found between the two systems, with average absolute differences for PFAT, BMC, and BMD of 1.4%, 176.8 g and 0.013 g/cm(2) , respectively. After cross-calibration, no significant differences remained between GE Healthcare Lunar measured results and the results converted from Hologic. The equations we derived reduce differences between BMD and body composition as determined by GE Healthcare Lunar and Hologic systems and will facilitate combining study results in clinical or epidemiological studies.

    View details for DOI 10.1002/jbmr.1654

    View details for Web of Science ID 000308925800018

    View details for PubMedID 22623101

  • How to avoid missing data and the problems they pose: design considerations. Shanghai archives of psychiatry Lin, J. Y., Lu, Y., Tu, X. 2012; 24 (3): 181-184
  • The first multicenter and randomized clinical trial of herbal Fufang for treatment of postmenopausal osteoporosis OSTEOPOROSIS INTERNATIONAL Zhu, H. M., Qin, L., Garnero, P., Genant, H. K., Zhang, G., Dai, K., Yao, X., Gu, G., Hao, Y., Li, Z., Zhao, Y., Li, W., Yang, J., Zhao, X., Shi, D., Fuerst, T., Lu, Y., Li, H., Zhang, X., Li, C., Zhao, J., Wu, Q., Zhao, S. J. 2012; 23 (4): 1317-1327


    This multicenter and randomized clinical trial showed that daily oral herbal formula Xian Ling Gu Bao (XLGB) was safe in postmenopausal women over a 1-year treatment. Those patients (n ∼ 50) treated with XLGB at the conventional dose demonstrated a statistically significant increase in dual-energy X-ray absorptiometry (DXA) bone mineral density (BMD) at lumbar spine at 6 months and a numerically increased BMD at 12 months.The aim of this study was to examine the safety and efficacy of a herbal formula XLGB in postmenopausal women (ChiCTR-TRC-00000347).One hundred eighty healthy postmenopausal women (≥60 years old) with BMD T-score ≤ -2.0 (lumbar spine or femoral neck) were recruited from four clinical centers to receive low-dose (conventional dose) XLGB (L-XLGB group, 3 g/day, n = 61) or high-dose XLGB (H-XLGB group, 6 g/day, n = 58) or placebo (CON group, n = 61). Women received daily calcium (500 mg) and vitamin D (200 IU) supplementation. Primary endpoints were lumbar spine BMD and safety; secondary endpoints were femoral neck BMD and bone turnover markers measured at baseline and at 6 and 12 months.Of 180 women recruited, 148 completed the study. The compliance in each group was comparable. Prominent adverse events were not observed in either group. In the L-XLGB group at 6 months, lumbar spine BMD by DXA increased significantly from baseline (+2.11% versus CON +0.58%, p < 0.05), but femoral neck BMD did not; at 12 months, BMD in the L-XLGB group decreased from 6-month levels yet remained higher than baseline, but without difference from the CON group. There was no dose-dependent response. Bone turnover marker levels declined during the first 6 months after XLGB treatment. There was no significant difference in the overall incidence of side effects among treatment and control groups.XLGB over 1-year treatment at the conventional dose demonstrated safe and only a statistically significant increase in BMD at lumbar spine at 6 months in postmenopausal women.

    View details for DOI 10.1007/s00198-011-1577-2

    View details for Web of Science ID 000301790500013

    View details for PubMedID 21505910

  • On the Time to Conclusion of Phase II Cancer Clinical Trials and Its Application in Trial Designs Statistics in Biopharmaceutical Research Ying Lu, Sheng-Hui Kelly Fan 2012; 4 (4): 324-335
  • Optimal Monitoring Time Interval Between DXA Measures in Children JOURNAL OF BONE AND MINERAL RESEARCH Shepherd, J. A., Wang, L., Fan, B., Gilsanz, V., Kalkwarf, H. J., Lappe, J., Lu, Y., Hangartner, T., Zemel, B. S., Fredrick, M., Oberfield, S., Winer, K. K. 2011; 26 (11): 2745-2752


    The monitoring time interval (MTI) is the expected time in years necessary to identify a change between two measures that exceeds the measurement error. Our purpose was to determine MTI values for dual-energy X-ray absorptiometry (DXA) scans in normal healthy children, according to age, sex, and skeletal site. 2014 children were enrolled in the Bone Mineral Density in Childhood Study and had DXA scans of the lumbar spine, total hip, nondominant forearm, and whole body. Measurements were obtained annually for seven visits from 2002 to 2010. Annualized rates of change were calculated by age and sex for all bone regions. A subgroup of 155 children ages 6 to 16 years (85 boys) had duplicate scans for calculation of scan precision. The bone mineral density (BMD) regions of interest included the spine, total body less head (TBLH), total hip, femoral neck, and one-third radius. Bone mineral content (BMC) was also evaluated for the spine and TBLH. The percent coefficient of variation (%CV) and MTI were calculated for each measure as a function of age and sex. The MTI values were substantially less than 1 year for the TBLH and spine BMD and BMC for boys ≤ 17 years and girls ≤ 15 years. The hip and one-third radius MTIs were generally 1 year in the same group. MTI values as low as 3 months were found during the peak growth years. However, the MTI values in late adolescence for all regions were substantially longer and became nonsensical as each region neared the age for peak bone density. All four DXA measurement sites had reasonable (< 1 year) MTI values for boys ≤ 17 years and girls ≤ 15 years. MTI was neither useful nor stable in late adolescence and young adulthood. Alternative criteria to determine scan intervals must be used in this age range.

    View details for DOI 10.1002/jbmr.473

    View details for Web of Science ID 000296391600019

    View details for PubMedID 21773995

    View details for PubMedCentralID PMC3200454

  • Cost-Saving Tree-Structured Survival Analysis for Hip Fracture of Study of Osteoporotic Fractures Data MEDICAL DECISION MAKING Jin, H., Lu, Y. 2011; 31 (2): 299-307


    It is important to predict osteoporotic fracture risk accurately in order to select high-risk patients for treatment. Previous tree-structured survival analysis (TSSA) methods focused on optimization in statistical performance in construction of survival trees. However, they did not take into account the cost of the predictive variables. Because of the high cost of some predictors, the derived algorithm may have only limited application in practice. In this article, the authors consider the cost-effectiveness in TSSA and propose a cost-saving TSSA (denoted as CSTSSA) to construct the survival tree for identifying subjects at high risk of hip fracture based on the data from Study of Osteoporotic Fractures. The new rule is compared with the optimum classification based on log-rank test statistics using the noninferiority test by Lu and others. The comparison results suggest that, for identifying patients at high risk of hip fracture, the CSTSSA is a good alternative to the optimum classification.

    View details for DOI 10.1177/0272989X10377117

    View details for Web of Science ID 000288204500012

    View details for PubMedID 20811072

  • Bayesian Decision Analysis for Choosing Between Diagnostic/Prognostic Prediction Procedures Statistics and Its Interface Kornak J, Lu Y 2011; 4 (1): 27-36
  • Bayesian decision analysis for choosing between diagnostic/prognostic prediction procedures. Statistics and its interface Kornak, J., Lu, Y. 2011; 4 (1): 27-36


    New diagnostic procedures and prognostic markers are continually being developed for a wide range of medical complaints. Medical institutions are therefore regularly faced with the decision as to whether to replace an existing procedure with a new one. The decision to adopt a new method is primarily based on diagnostic/predictive accuracy and cost-effectiveness, but this trade-off is not usually considered in a formal decision-theoretic way. The decision process for diagnostic procedures is complicated by the fact that diagnostic decisions are typically based on thresholding one or more continuous variables. Therefore, a formal decision process should account for uncertainty in the optimal threshold value for each diagnostic procedure. We here propose a Bayesian decision approach based on maximizing expected utility (incorporating accuracy and costs) with respect to diagnostic procedure and threshold level simultaneously. The Bayesian decision approach is illustrated via an application comparing the utility of different bone mineral density (BMD) measurements for determining the need for preventative treatment of osteoporotic hip fracture in elderly patients.

    View details for PubMedID 23243483

    View details for PubMedCentralID PMC3520495

  • Bayesian decision analysis for choosing between diagnostic/prognostic prediction procedures STATISTICS AND ITS INTERFACE Kornak, J., Lu, Y. 2011; 4 (1): 27-36


    New diagnostic procedures and prognostic markers are continually being developed for a wide range of medical complaints. Medical institutions are therefore regularly faced with the decision as to whether to replace an existing procedure with a new one. The decision to adopt a new method is primarily based on diagnostic/predictive accuracy and cost-effectiveness, but this trade-off is not usually considered in a formal decision-theoretic way. The decision process for diagnostic procedures is complicated by the fact that diagnostic decisions are typically based on thresholding one or more continuous variables. Therefore, a formal decision process should account for uncertainty in the optimal threshold value for each diagnostic procedure. We here propose a Bayesian decision approach based on maximizing expected utility (incorporating accuracy and costs) with respect to diagnostic procedure and threshold level simultaneously. The Bayesian decision approach is illustrated via an application comparing the utility of different bone mineral density (BMD) measurements for determining the need for preventative treatment of osteoporotic hip fracture in elderly patients.

    View details for Web of Science ID 000288681800004

    View details for PubMedCentralID PMC3520495

  • Topographic enhancement mapping of the cancer-associated breast stroma using breast MRI INTEGRATIVE BIOLOGY Nabavizadeh, N., Klifa, C., Newitt, D., Lu, Y., Chen, Y., Hsu, H., Fisher, C., Tokayasu, T., Olshen, A. B., Spellman, P., Gray, J. W., Hylton, N., Park, C. C. 2011; 3 (4): 490-496


    In animal and laboratory models, cancer-associated stroma, or elements of the supporting tissue surrounding a primary tumor, has been shown to be necessary for tumor evolution and progression. However, little is understood or studied regarding the properties of intact stroma in human cancer in vivo. In addition, for breast cancer patients, the optimal volume of local tissue to treat surrounding a primary tumor is not clear. Here, we performed an interdisciplinary study of normal-appearing breast tissue using breast magnetic resonance imaging (MRI), correlative histology and array comparative genomic hybridization to identify a cancer-associated stroma in humans. Using a novel technique for segmenting breast fibroglandular tissue, quantifiable topographic percent enhancement mapping of the stroma surrounding invasive breast cancer was found to be significantly elevated within 2 cm of the tumor edge. This region was also found to harbor increased microvessel density, and genomic changes that were closely associated with host normal breast tissue. These findings indicate that a cancer-associated stroma may be identified and characterized in human breast cancer using non-invasive imaging techniques. Identification of a cancer-associated stroma may be further developed to help guide local therapy to reduce recurrence and morbidity in breast cancer patients.

    View details for DOI 10.1039/c0ib00089b

    View details for Web of Science ID 000289154600021

    View details for PubMedID 21416100

    View details for PubMedCentralID PMC3698966

  • Does standardized BMD still remove differences between Hologic and GE-Lunar state-of-the-art DXA systems? OSTEOPOROSIS INTERNATIONAL Fan, B., Lu, Y., Genant, H., Fuerst, T., Shepherd, J. 2010; 21 (7): 1227-1236


    The standardized bone mineral density (sBMD) values, derived using universal standardized equations, were shown to be equivalent within 1.0% for hip but significantly different for spine for state-of-art fan-beam dual X-ray absorptiometry (DXA) Hologic and GE-Lunar systems. Spine L1-L4 and L2-L4 sBMD mean differences between the two systems were 0.042 g/cm(2) (4.1%) and 0.035 g/cm(2) (3.2%), respectively.The objective of this study is to validate the 1994 pencil-beam DXA "universal standardization equations" for state-of-the-art fan-beam DXA systems.The spine and bilateral femurs of 87 postmenopausal women were scanned on both Hologic Delphi and GE-Lunar Prodigy DXA systems at three different clinical centers. The scans were analyzed using Hologic Apex and GE-Lunar EnCore software. The BMD results were converted to sBMD using the equations previously developed. Linear regression analysis was used to describe the relationship of the two systems' BMD results. Bland-Altman analysis was used to assess the differences in measures.The Apex and Prodigy sBMD values were highly correlated (r ranged from 0.92 to 0.98). Spine L1-L4 and L2-L4 sBMD values had significant intercepts and slopes for Bland-Altman regression, with mean differences of 0.042 g/cm(2) (4.1%) and 0.035 g/cm(2) (3.2%), respectively. The total hip and neck sBMD showed no significant intercept and slope, except left total sBMD had a significant difference between the two systems of 0.009 g/cm(2) (1.0%).The sBMD values were shown to be equivalent within 1.0% for hip but were significantly different for spine on the two systems. Biases may persist in pooled sBMD data from different manufacturers, and further study is necessary to determine the cause.

    View details for DOI 10.1007/s00198-009-1062-3

    View details for Web of Science ID 000280137000013

    View details for PubMedID 19859644

    View details for PubMedCentralID PMC2906746

  • A statistical method (cross-validation) for bone loss region detection after spaceflight AUSTRALASIAN PHYSICAL & ENGINEERING SCIENCES IN MEDICINE Zhao, Q., Li, W., Li, C., Chu, P. W., Kornak, J., Lang, T. F., Fang, J., Lu, Y. 2010; 33 (2): 163-169


    Astronauts experience bone loss after the long spaceflight missions. Identifying specific regions that undergo the greatest losses (e.g. the proximal femur) could reveal information about the processes of bone loss in disuse and disease. Methods for detecting such regions, however, remains an open problem. This paper focuses on statistical methods to detect such regions. We perform statistical parametric mapping to get t-maps of changes in images, and propose a new cross-validation method to select an optimum suprathreshold for forming clusters of pixels. Once these candidate clusters are formed, we use permutation testing of longitudinal labels to derive significant changes.

    View details for DOI 10.1007/s13246-010-0024-6

    View details for Web of Science ID 000280699100006

    View details for PubMedID 20632144

    View details for PubMedCentralID PMC2917547

  • Evaluating the improvement in diagnostic utility from adding new predictors BIOMETRICAL JOURNAL Li, C., Lu, Y. 2010; 52 (3): 417-435


    Multiple diagnostic tests and risk factors are commonly available for many diseases. This information can be either redundant or complimentary. Combining them may improve the diagnostic/predictive accuracy, but also unnecessarily increase complexity, risks, and/or costs. The improved accuracy gained by including additional variables can be evaluated by the increment of the area under (AUC) the receiver-operating characteristic curves with and without the new variable(s). In this study, we derive a new test statistic to accurately and efficiently determine the statistical significance of this incremental AUC under a multivariate normality assumption. Our test links AUC difference to a quadratic form of a standardized mean shift in a unit of the inverse covariance matrix through a properly linear transformation of all diagnostic variables. The distribution of the quadratic estimator is related to the multivariate Behrens-Fisher problem. We provide explicit mathematical solutions of the estimator and its approximate non-central F-distribution, type I error rate, and sample size formula. We use simulation studies to prove that our new test maintains prespecified type I error rates as well as reasonable statistical power under practical sample sizes. We use data from the Study of Osteoporotic Fractures as an application example to illustrate our method.

    View details for DOI 10.1002/bimj.200900228

    View details for Web of Science ID 000279972000008

    View details for PubMedID 20496347

    View details for PubMedCentralID PMC3517010

  • A survey of bone mineral density of healthy Han adults in China OSTEOPOROSIS INTERNATIONAL Zhu, H., Fang, J., Luo, X., Yu, W., Zhao, Y., Li, X., Du, J., Lu, Y. 2010; 21 (5): 765-772


    A recent survey of bone mineral density (BMD) in China recruited 7,042 healthy Han Chinese aged 20 years and older. The mean BMDs were different in gender, age, and region; the proportions of men and women older than 50 years with a high risk of osteoporosis were estimated as 10.4% and 31.2%, respectivelyA survey of BMD was completed during 2002-2006 in China. By three-stage sampling, a total of 7,042 healthy Han Chinese aged 20 years and older were recruited in ten cities: 2,694 subjects from Beijing, Tianjin, Haerbin, Lanzhou, and Yantai of northern China and 4,348 from Shanghai, Changsha, Chengdu, Haikou, and Foshan of southern China.Two dual X-ray absorptiometry (DXA) systems (Hologic and Lunar) were used with parallel measurements of the European spine phantoms in each center. The mean BMDs in age groups older than 50 and the peak bone mineral density (pBMD) at femoral neck and that at greater trochanter were higher for men than women, and the pBMDs for northern China were higher than those for southern China, ranging from 1% to 4%.This work has provided two useful references for the first time: one is the estimation of the proportion and number of individuals older than 50 years with a high risk of osteoporosis, 10.4% and 12.5 million men, 31.2% and 37.2 million women, which is important for health care planning and marketing projections, and another is the conversion equations for cross-calibration among different types of DXA instruments frequently used in China.

    View details for DOI 10.1007/s00198-009-1010-2

    View details for Web of Science ID 000276075600008

    View details for PubMedID 19597908

  • Basal Cell Carcinoma Chemoprevention with Nonsteroidal Anti-inflammatory Drugs in Genetically Predisposed PTCH1(+/-) Humans and Mice CANCER PREVENTION RESEARCH Tang, J. Y., Aszterbaum, M., Athar, M., Barsanti, F., Cappola, C., Estevez, N., Hebert, J., Hwang, J., Khaimskiy, Y., Kim, A., Lu, Y., So, P., Tang, X., Kohn, M. A., McCulloch, C. E., Kopelovich, L., Bickers, D. R., Epstein, E. H. 2010; 3 (1): 25-34


    In vitro and epidemiologic studies favor the efficacy of nonsteroidal anti-inflammatory drugs (NSAID) in preventing skin squamous photocarcinogenesis, but there has been relatively little study of their efficacy in preventing the more common skin basal cell carcinoma (BCC) carcinogenesis. We first compared the relative anti-BCC effects of genetic deletion and NSAID pharmacologic inhibition of cyclooxygenase (COX) enzymes in the skin of Ptch1(+/-) mice. We then assessed the effects of celecoxib on the development of BCCs in a 3-year, double-blinded, randomized clinical trial in 60 (PTCH1(+/-)) patients with the basal cell nevus syndrome. In Ptch1(+/-) mice, genetic deletion of COX1 or COX2 robustly decreased (75%; P < 0.05) microscopic BCC tumor burden, but pharmacologic inhibition with celecoxib reduced microscopic BCCs less efficaciously (35%; P < 0.05). In the human trial, we detected a trend for oral celecoxib reducing BCC burden in all subjects (P = 0.069). Considering only the 60% of patients with less severe disease (<15 BCCs at study entry), celecoxib significantly reduced BCC number and burden: subjects receiving placebo had a 50% increase in BCC burden per year, whereas subjects in the celecoxib group had a 20% increase (P(difference) = 0.024). Oral celecoxib treatment inhibited BCC carcinogenesis in PTCH1(+/-) mice and had a significant anti-BCC effect in humans with less severe disease.

    View details for DOI 10.1158/1940-6207.CAPR-09-0200

    View details for Web of Science ID 000273295500006

    View details for PubMedID 20051370

    View details for PubMedCentralID PMC2894531

  • Integrating tobacco cessation into mental health care for posttraumatic stress disorder: a randomized controlled trial JAMA McFall M, Saxon AJ; Malte CA; Chow B; Bailey S; Baker DG; Beckham JC; Boardman KD; Carmod TP; Joseph AM; Smith MW; Shih MC; Lu Y; Holodniy M; Lavori PW 2010; 304 (22): 2485-93
  • An optical imaging method to monitor stem cell migration in a model of immune-mediated arthritis OPTICS EXPRESS Sutton, E. J., Boddington, S. E., Nedopil, A. J., Henning, T. D., Demos, S. G., Baehner, R., Sennino, B., Lu, Y., Daldrup-Link, H. E. 2009; 17 (26): 24403-24413


    The objective of this work is to establish an optical imaging technique that would enable monitoring of the integration of mesenchymal stem cells (MSC) in arthritic joints. Our approach is based on first developing a labeling technique of MSC with the fluorescent dye DiD followed by tracking the cell migration kinetics from the spatial distribution of the DiD fluorescence in optical images (OI). The experimental approach involves first the in vitro OI of MSC labeled with DiD accompanied by fluorescence microscopy measurements to establish localization of the signal within the cells. Thereafter, DiD-labeled MSC were injected into polyarthritic, athymic rats and the signal localization within the experimental animals was monitored over several days. The experimental results indicate that DiD integrated into the cell membrane. DiD-labeled MSC localization in the arthritic ankle joints was observed with OI indicating that this method can be applied to monitor MSC in arthritic joints.

    View details for Web of Science ID 000273156200107

    View details for PubMedID 20052149

  • Comparison of correlated proportions based on paired binary data from clustered samples JOURNAL OF STATISTICAL PLANNING AND INFERENCE Jin, H., Lu, Y. 2009; 139 (12): 4206–12
  • Bone fracture risk estimation based on image similarity BONE Li, W., Kornak, J., Harris, T. B., Keyak, J., Li, C., Lu, Y., Cheng, X., Lang, T. 2009; 45 (3): 560-567


    We propose a fracture risk estimation technique based on image similarity. We employ image similarity indices to determine how images are similar to each other in their 3D bone mineral density distributions. Our premise for fracture risk estimation is that if a given scan is more similar to scans of subjects known to have fractures than to scans of control subjects, this subject is likely to have a higher degree of fracture risk. To test this hypothesis, we analyzed hip QCT scans of 37 patients with hip fractures and 38 age-matched controls. We divided the scans randomly into two groups: the Model Group and the Test Group. For each scan in the Test Group, the difference between the mean value of its image similarities to the Model fracture group and the mean value of its image similarities to the Model control group was used as index of fracture risk. We then used the estimated fracture risk indices to discriminate the fractured patients and controls in the Test Group. A test scan with a larger mean value of image similarities with respect to the Model fracture group was classified as a scan from a fractured patient, otherwise it was classified as a scan from a control subject. Based on ROC analysis, we compared the discrimination performances using image similarity measures with that obtained by using bone mineral density (BMD). When using BMD measured in the femoral neck, with the optimal BMD cutoff, the sensitivity and specificity were 86.5% and 73.7%. For the image similarity measures, the sensitivity ranged between 86.5% and 100%, and specificity ranged between 63.2% and 76.3%. By combining BMD with image similarity measures, the sensitivity and specificity reached 94.6% and 76.3% using linear discriminant analysis (LDA) algorithm, or 91.9% and 81.6% using recursive partitioning and regression trees (RPART) algorithm. In the RPART approach, the AUC value of the ROC curve was 0.923, higher than the AUC value of 0.835 when using BMD alone (p-value: 0.0046). Our results showed that combining BMD with image similarity measures resulted in improved hip fracture risk estimation.

    View details for DOI 10.1016/j.bone.2009.04.250

    View details for Web of Science ID 000269378200023

    View details for PubMedID 19414074

    View details for PubMedCentralID PMC2896043

  • Prognostic Implications of Positive Nonsentinel Lymph Nodes Removed During Selective Sentinel Lymphadenectomy for Breast Cancer BREAST JOURNAL Lang, J. E., Liu, L., Lu, Y., Jenkins, T., Hwang, S. E., Esserman, L. J., Ewing, C. A., Alvarado, M., Morita, E., Treseler, P., Leong, S. P. 2009; 15 (3): 242-246


    Nonsentinel lymph nodes (SLNs) are commonly removed at the time of selective sentinel lymphadenectomy (SSL). Their predictive value for the rest of the nodal basin is unknown. A retrospective review of 436 breast cancer patients who underwent SSL between 12/97 and 04/03 at a single institution. One-hundred nineteen patients had non-SLNs removed at SSL; eight were positive (6.7%). Positive non-SLNs predicted that SLNs would also be positive (p = 0.008). There was no difference in rates of additional positive nodes found on completion axillary node dissection between the non-SLN and SLN positive patients (p = 0.62). After adjustment for covariates, the presence of positive non-SLNs was not associated with poorer disease free survival (p = 0.24), time to systemic recurrence (p = 0.57), or overall survival (p = 0.70). Positive non-SLNs removed during SSL are not a significant risk factor for additional positive nodes on completion axillary nodal dissection (CALND) or for worse survival than positive SLNs.

    View details for DOI 10.1111/j.1524-4741.2009.00712.x

    View details for Web of Science ID 000265899300005

    View details for PubMedID 19645778

  • Identify fracture-critical regions inside the proximal femur using statistical parametric mapping BONE Li, W., Kornak, J., Harris, T., Keyak, J., Li, C., Lu, Y., Cheng, X., Lang, T. 2009; 44 (4): 596-602


    We identified regions inside the proximal femur that are most strongly associated with hip fracture. Bone densitometry based on such fracture-critical regions showed improved power in discriminating fracture patients from controls.Hip fractures typically occur in lateral falls, with focal mechanical failure of the sub-volumes of tissue in which the applied stress exceeds the strength. In this study, we describe a new methodology to identify proximal femoral tissue elements with highest association with hip fracture. We hypothesize that bone mineral density (BMD) measured in such sub-volumes discriminates hip fracture risk better than BMD in standard anatomic regions such as the femoral neck and trochanter.We employed inter-subject registration to transform hip QCT images of 37 patients with hip fractures and 38 age-matched controls into a voxel-based statistical atlas. Within voxels, we performed t-tests between the two groups to identify the regions which differed most. We then randomly divided the 75 scans into a training set and a test set. From the training set, we derived a fracture-driven region of interest (ROI) based on association with fracture. In the test set, we measured BMD in this ROI to determine fracture discrimination efficacy using ROC analysis. Additionally, we compared the BMD distribution differences between the 29 patients with neck fractures and the 8 patients with trochanteric fractures.By evaluating fracture discrimination power based on ROC analysis, the fracture-driven ROI had an AUC (area under curve) of 0.92, while anatomic ROIs (including the entire proximal femur, the femoral neck, trochanter and their cortical and trabecular compartments) had AUC values between 0.78 and 0.87. We also observed that the neck fracture patients had lower BMD (p=0.014) in a small region near the femoral neck and the femoral head, and patients with trochanteric fractures had lower BMD in trochanteric regions such as in the internal calcar septum (p=0.006).We have identified the sub-volumes of proximal femoral tissue which have the strongest association with hip fracture. The power to predict fracture can be improved, by focusing on BMD measurements in the fracture-critical regions, rather than in standard ROIs.

    View details for DOI 10.1016/j.bone.2008.12.008

    View details for Web of Science ID 000264614400012

    View details for PubMedID 19130910

    View details for PubMedCentralID PMC2656587

  • Reduction in proximal femoral strength due to long-duration spaceflight BONE Keyak, J. H., Koyama, A. K., Leblanc, A., Lu, Y., Lang, T. F. 2009; 44 (3): 449-453


    Loss of bone mass is a well-known medical complication of long-duration spaceflight. However, we do not know how changes in bone density and geometry ultimately combine to affect the strength of the proximal femur as a whole. The goal of this study was to quantify the changes in proximal femoral strength that result from long-duration spaceflight. Pre-and post-flight CT scan-based patient-specific finite element models of the left proximal femur of 13 astronauts who spent 4.3 to 6.5 months on the International Space Station were generated. Loading conditions representing single-limb stance and a fall onto the posterolateral aspect of the greater trochanter were modeled, and proximal femoral strength (F(FE)) was computed. Mean F(FE) decreased from 18.2 times body weight (BW) pre-flight to 15.6 BW post-flight for stance loading and from 3.5 BW pre-flight to 3.1 BW post-flight for fall loading. When normalized for flight duration, F(FE) under stance and fall loading decreased at mean rates of 2.6% (0.6% to 5.0%) per month and 2.0% (0.6% to 3.9%) per month, respectively. These values are notably greater than previously reported reductions in DXA total femoral bone mineral density (0.4 to 1.8% per month). In some subjects, the magnitudes of the reductions in proximal femoral strength were comparable to estimated lifetime losses associated with aging. Although average post-flight proximal femoral strength is greater than forces expected to occur due to falls or normal activities, some subjects have small margins of safety. If proximal femoral strength is not recovered, some crew members may be at increased risk for age-related hip fractures decades after their missions.

    View details for DOI 10.1016/j.bone.2008.11.014

    View details for Web of Science ID 000263895500010

    View details for PubMedID 19100348

  • Comparison of correlated proportions based on paired binary data from clustered samples Journal of Statistical Planning and Inference Jin H, Lu Y 2009; 139 (12): 4217-4223
  • The ROC region of a regression tree Statistics and Probability Letters Jin H, Lu Y 2009; 79 (7): 936-942
  • Permutation test for non-inferiority of the linear to the optimal combination of multiple tests Statistics and Probability Letters Jin H, Lu Y 2009; 79 (5): 664-669
  • Design Issues in Dose-Finding Phase I Trials for Combinations of Two Agents JOURNAL OF BIOPHARMACEUTICAL STATISTICS Fan, S. K., Venook, A. P., Lu, Y. 2009; 19 (3): 509-523


    Combination therapy of two antitumor agents may provide treatment additivity or synergy. Phase I trials for combination therapy search for the maximum tolerated dose (MTD) for combined agents. The conventional approach is to preselect an escalation path, usually increasing the dose of one agent and then another, and to use the standard 3 + 3 design. However, this procedure may miss the optimum dose combination, prolong the time it takes, and increase the number of patients necessary to reach the MTD. In this study, we present strategies for a comprehensive search for MTD for a two-agent combination therapy. We evaluate algorithms based on two-stage and three-stage design as well as variations in cohort size. A two-dimensional isotonic estimation method for toxicity rate is provided. We use simulation methods to compare 2 + 1 + 3 vs. 3 + 3 cohort sizes. We conclude that the comprehensive search proposed in our study can be more practical and efficient in identifying the MTD in combination-therapy of two agents.

    View details for DOI 10.1080/10543400902802433

    View details for Web of Science ID 000265414100009

    View details for PubMedID 19384692

  • A non-inferiority test of areas under two parametric ROC curves Contemp Clin Trials Jin H, Lu Y 2009; 30 (4): 375-379
  • The optimal linear combination of multiple predictors under the generalized linear models Statistics and Probability Letters Jin H, Lu Y 2009; 79 (22): 2321-2327
  • An update survey of academic radiologists' clinical productivity. Journal of the American College of Radiology Lu, Y., Zhao, S., Chu, P. W., Arenson, R. L. 2008; 5 (7): 817-826


    The total number of procedures and their relative value units (RVUs) were used to measure the productivity of radiologists. Besides variations in productivity due to differences in the percentage of clinical effort, baseline productivity also varies among clinical subspecialty sections. The authors' previous research used the full-time equivalent (FTE) as the unit to adjust for differences in the percentage of clinical effort and a set of adjustment factors (or calibration constants) to modify the default work RVUs according to types of procedures. These adjustments led to comparable average productivity measurements across subspecialty sections. Since 2003, radiology practice has continued to change, including the introduction of positron emission tomography/computed tomography into clinical practice, suggesting a need to update the understanding of clinical productivity and refine the authors' adjustment procedure. In this study, the authors analyzed the most recent survey of academic departments and derived updated adjustment factors for differences in workload among subspecialty sections. The results can be used to determine faculty staffing requirements and evaluate radiologists' performance.A survey performed by the Society of Chairmen of Academic Radiology Departments collected data in 2006 for 1,134 radiologists in 24 departments, including 10 departments that also reported productivity in an earlier 2003 survey. These data included the numbers of procedures (represented by Current Procedural Terminology [CPT] codes) performed by radiologists, percentage clinical effort, subspecialty sections, and the number of clinical days. The numbers of CPT codes were converted into total work RVUs per FTE faculty member. By grouping the CPT codes into 6 prespecified examination categories, adjustment factors were created to adjust the RVUs for CPT categories to ensure that the median total adjusted work RVUs from different subspecialty sections were comparable.Overall, the mean clinical workload in 2006 was 9,671 examinations, a statistically significant 15% increase from 2003. The mean number of work RVUs per FTE was 7,136, a 22% increase from 2003. The adjustment factors have been modified from those presented in the authors' earlier paper, including reductions for interventional radiology, computed tomography, magnetic resonance imaging, nuclear medicine, and a new adjustment factor for "special procedures." These adjustments reduced differences in adjusted RVUs per FTE between subspecialty sections.Clinical workload, as measured by RVUs per FTE and adjusted RVUs per FTE, is very useful for determining optimal staffing in subspecialty sections and in radiology departments in general. Workload continues to increase, both in examination complexity and in numbers of overall procedures. Adjustment factors make workload comparisons between subspecialty sections more valid and meaningful.

    View details for DOI 10.1016/j.jacr.2008.02.018

    View details for PubMedID 18585659

  • Invasive breast cancer: Predicting disease recurrence by using high-spatial-resolution signal enhancement ratio imaging RADIOLOGY Li, K., Partridge, S. C., Joe, B. N., Gibbs, J. E., Lu, Y., Esserman, L. J., Hylton, N. M. 2008; 248 (1): 79-87


    To retrospectively evaluate high-spatial-resolution signal enhancement ratio (SER) imaging for the prediction of disease recurrence in patients with breast cancer who underwent preoperative magnetic resonance (MR) imaging.This retrospective study was approved by the institutional review board and was HIPAA compliant; informed consent was waived. From 1995 to 2002, gadolinium-enhanced MR imaging data were acquired with a three time point high-resolution method in women undergoing neoadjuvant therapy for invasive breast cancers. Forty-eight women (mean age, 49.1 years; range, 29.7-72.4 years) were divided into recurrence-free or recurrence groups. Volume measurements were tabulated for SER values between set ranges; cutoff criteria were defined to predict disease recurrence after surgery. Wilcoxon rank sum tests and the multivariate Cox proportional hazards regression model were used for evaluation.Breast tumor volume calculated from the number of voxels with SER values above a threshold corresponding to the upper limit of mean redistribution rate constant in benign tumors (0.88 minutes(-1)) and the volume of cancerous breast tissue infiltrating into the parenchyma were important predictors of disease recurrence. Seventy-five percent of patients with recurrence and 100% of deceased patients were identified as being at high risk for recurrence. Thirty percent of patients with recurrence and 67% of deceased patients were identified as having high risk before chemotherapy. No patients in the recurrence-free group were misidentified as likely to have recurrence. All three prechemotherapy parameters (total tumor volume, tumor volumes with high and low SER) and the postchemotherapy tumor volume with high SER were significantly different between the two groups. The multivariate Cox proportional hazards regression showed that, of the three prechemotherapy covariates, only the low SER and high SER tumor volumes (P = .017 and .049, respectively) were significant and independent predictors of tumor recurrence. Tumor volume with high SER was the only significant postchemotherapy covariate predictor (P = .038).High-spatial-resolution SER imaging may improve prediction for patients at high risk for disease recurrence and death.

    View details for Web of Science ID 000256978900009

    View details for PubMedID 18566170

  • Comparing BMD results between two similar DXA systems using the generalized least significant change JOURNAL OF CLINICAL DENSITOMETRY Shepherd, J. A., Morgan, S. L., Lu, Y. 2008; 11 (2): 237-242


    One of the long-standing frustrations of clinical densitometry practice is not being able to compare bone mineral density (BMD) measures taken on different densitometers and know if the difference represents a true change. Recently, a method for comparing measures on different systems was published. This method, called the generalized least significant change (GLSC) requires after a procedure to quantify the precision of both systems as well as the in vivo cross-calibration relationship when there is a difference in the technology of the systems. We followed this procedure when a Hologic QDR-4500A was replaced with a Hologic Discovery/W even though these systems would be similar if not identical for hip and spine measures. Thirty participants were scanned twice on each system at the hip and spine. We found that the precisions of each system were similar and the differences in the average BMD values from the spine phantom and in vivo measures for the total spine, total hip, and neck regions were less than 1%. However, the correlation coefficients ranged from 0.96 to 0.98. The magnitude of change needed for significance was typically twice as large for intersystem scan (6-10%) comparisons than intrasystem (3-6%). In summary, we have presented an example of how the GLSC is calculated and used in a clinical practice. The results show that there is a substantial loss in sensitivity to change when comparing scans taken on different systems even in this case of similar technology. A revision of the International Society for Clinical Densitometry's policies for comparing scans from systems of the same technology may be appropriate.

    View details for DOI 10.1016/j.jocd.2008.02.001

    View details for Web of Science ID 000256640900004

    View details for PubMedID 18455677

  • Whole brain voxel-wise analysis of single-subject serial DTI by permutation testing NEUROIMAGE Chung, S., Pelletier, D., Sdika, M., Lu, Y., Berman, J. L., Henry, R. G. 2008; 39 (4): 1693-1705


    Diffusion tensor MRI (DTI) has been widely used to investigate brain microstructural changes in pathological conditions as well as for normal development and aging. In particular, longitudinal changes are vital to the understanding of progression but these studies are typically designed for specific regions of interest. To analyze changes in these regions traditional statistical methods are often employed to elucidate group differences which are measured against the variability found in a control cohort. However, in some cases, rather than collecting multiple subjects into two groups, it is necessary and more informative to analyze the data for individual subjects. There is also a need for understanding changes in a single subject without prior information regarding the spatial distribution of the pathology, but no formal statistical framework exists for these voxel-wise analyses of DTI. In this study, we present PERVADE (permutation voxel-wise analysis of diffusion estimates), a whole brain analysis method for detecting localized FA changes between two separate points in time of any given subject, without any prior hypothesis about where changes might occur. Exploiting the nature of DTI that it is calculated from multiple diffusion-weighted images of each region, permutation testing, a non-parametric hypothesis testing technique, was modified for the analysis of serial DTI data and implemented for voxel-wise hypothesis tests of diffusion metric changes, as well as for suprathreshold cluster analysis to correct for multiple comparisons. We describe PERVADE in detail and present results from Monte Carlo simulation supporting the validity of the technique as well as illustrative examples from a healthy subject and patients in the early stages of multiple sclerosis.

    View details for DOI 10.1016/j.neuroimage.2007.10.039

    View details for Web of Science ID 000253241800019

    View details for PubMedID 18082426

  • A procedure for determining whether a simple combination of diagnostic tests may be non-inferior to the theoretical optimum combination Medical Decision Making Jin H, Lu Y 2008; 28 (6): 909-916
  • A generalized least significant change for individuals measured on different DXA systems JOURNAL OF CLINICAL DENSITOMETRY Shepherd, J. A., Lu, Y. 2007; 10 (3): 249-258


    In this article, we derive a generalized expression for the least significant change (LSC), which we call the generalized LSC (GLSC), to be used when an individual is measured on 2 different systems. The commonly used LSC is defined as the least amount of change between 2 measurements over time that must be exceeded before a change can be considered true (with 95% confidence). The LSC has clinical applications in monitoring disease progression or treatment effects in bone mineral density (BMD) and bone mineral content. Mathematically, the "ideal" LSC (ILSC) is 2.77 times the precision errors for measures on a single system. When BMD values of an individual are measured by 2 different systems, the LSC will depend not only on the precision errors of both systems but also on the calibration relationship between the systems. Like the ILSC, the GLSC is a simple equation applicable for inter machine comparisons. The GLSC can be defined for any 2 systems with measures obtained from cross-calibration and precision studies using the protocols recommended by the International Society for Clinical Densitometry. We validated the GLSC using 10,000 simulated measurements taken between 2 systems and offer several common uses of the GLSC such as system upgrades within a single manufacturer and replacement of 1 manufacturer by another. We found that when upgrading a Hologic QDR-2000 to a QDR-4500, GLSC was twice as large as the QDR-2000 LSC (0.0432 and 0.0215 g/cm2, respectively). The GLSC was 2.6 (spine) to 3.6 (total hip) times larger than the LSC when comparing scans between the Hologic Delphi and the GE Lunar Prodigy. We also explore how the magnitude of the correlation coefficient and sample size change the GLSC and show that a correlation coefficient less than 0.95 increases the %GLSC to above 10%, and that increasing study sample sizes beyond 30 in the cross-calibration studies can only decrease the magnitude of the GLSC accuracy by 4%. We conclude that the GLSC, defined using commonly used clinical cross-calibration and precision assessments, is the most accurate method to compare scans between dual-energy X-ray absorptiometry systems.

    View details for DOI 10.1016/j.jocd.2007.05.002

    View details for Web of Science ID 000249053900004

    View details for PubMedID 17616413

  • Comparison of bootstrap approaches for estimation of uncertainties of DTI parameters NEUROIMAGE Chung, S., Lu, Y., Henry, R. G. 2006; 33 (2): 531-541


    Bootstrap is an empirical non-parametric statistical technique based on data resampling that has been used to quantify uncertainties of diffusion tensor MRI (DTI) parameters, useful in tractography and in assessing DTI methods. The current bootstrap method (repetition bootstrap) used for DTI analysis performs resampling within the data sharing common diffusion gradients, requiring multiple acquisitions for each diffusion gradient. Recently, wild bootstrap was proposed that can be applied without multiple acquisitions. In this paper, two new approaches are introduced called residual bootstrap and repetition bootknife. We show that repetition bootknife corrects for the large bias present in the repetition bootstrap method and, therefore, better estimates the standard errors. Like wild bootstrap, residual bootstrap is applicable to single acquisition scheme, and both are based on regression residuals (called model-based resampling). Residual bootstrap is based on the assumption that non-constant variance of measured diffusion-attenuated signals can be modeled, which is actually the assumption behind the widely used weighted least squares solution of diffusion tensor. The performances of these bootstrap approaches were compared in terms of bias, variance, and overall error of bootstrap-estimated standard error by Monte Carlo simulation. We demonstrate that residual bootstrap has smaller biases and overall errors, which enables estimation of uncertainties with higher accuracy. Understanding the properties of these bootstrap procedures will help us to choose the optimal approach for estimating uncertainties that can benefit hypothesis testing based on DTI parameters, probabilistic fiber tracking, and optimizing DTI methods.

    View details for DOI 10.1016/j.neuroimage.2006.07.001

    View details for Web of Science ID 000241406800011

    View details for PubMedID 16938472

  • Quality and performance measures in bone densitometry - Part 2: Fracture risk OSTEOPOROSIS INTERNATIONAL Glueer, C. C., Lu, Y., Engelke, K. 2006; 17 (10): 1449-1458


    This is part 2 of a core chapter of the forthcoming Report on Bone Densitometry commissioned by the International Commission on Radiation Units (ICRU). It is written with the aim to review definitions of quantities and units used in bone densitometry research and to describe parameters and methods that can be used to compare and standardize densitometric equipment and measurements. Part 2 of this chapter contains the section on fracture risk.Building on concepts of risk assessment, including risk ratios and odds ratios, we review statistical concepts commonly used in cross-sectional and prospective fracture studies. Performance measures are defined that allow a comparison of the ability of densitometry techniques to assess fracture risk.The methods of discriminant analysis, logistic regression, Poisson regression models, and the Cox proportional hazard model are presented and compared. In addition, statistical concepts to characterize risk for the individual patient are reviewed.

    View details for DOI 10.1007/s00198-005-0038-1

    View details for Web of Science ID 000240531900002

    View details for PubMedID 16821004

  • Adaptation of the proximal femur to skeletal reloading after long-duration spaceflight JOURNAL OF BONE AND MINERAL RESEARCH Lang, T. F., Leblanc, A. D., Evans, H. J., Lu, Y. 2006; 21 (8): 1224-1230


    We studied the effect of re-exposure to Earth's gravity on the proximal femoral BMD and structure of astronauts 1 year after missions lasting 4-6 months. We observed that the readaptation of the proximal femur to Earth's gravity entailed an increase in bone size and an incomplete recovery of volumetric BMD.Bone loss is a well-known result of skeletal unloading in long-duration spaceflight, with the most severe losses occurring in the proximal femur. However, there is little information about the recovery of bone loss after mission completion and no information about effect of reloading on the structure of load-bearing bone. To address these questions, we carried out a study of the effect of re-exposure to Earth's gravity on the BMD and structure of the proximal femur 1 year after missions lasting 4-6 months.In 16 crew members of the International Space Station (ISS) making flights of 4.5-6 months, we used QCT imaging to measure the total, trabecular, and cortical volumetric BMD (vBMD) of the proximal femur. In addition to vBMD, we also quantified BMC, bone volume, femoral neck cross-sectional area (CSA), and femoral neck indices of compressive and bending strength at three time-points: preflight, postflight, and 1 year after mission.Proximal femoral bone mass was substantially recovered in the year after spaceflight, but measures of vBMD and estimated bone strength showed only partial recovery. The recovery of BMC, in the absence of a comparable increase in vBMD, was explained by increases in bone volume and CSA during the year after spaceflight.Adaptation of the proximal femur to reloading entailed an increase in bone size and an incomplete recovery of vBMD. The data indicate that recovery of skeletal density after long-duration space missions may exceed 1 year and supports the evidence in the aging literature for periosteal apposition as a compensatory response for bone loss. The extent to which this compensatory effect protects against fracture remains to be seen.

    View details for DOI 10.1359/JBMR.060509

    View details for Web of Science ID 000239299400006

    View details for PubMedID 16869720

  • Reduction of sampling bias of odds ratios for vertebral fractures using propensity scores OSTEOPOROSIS INTERNATIONAL Lu, Y., Jin, H., Chen, M. H., Gluer, C. C. 2006; 17 (4): 507-520


    Assessment of the predictive power of a newly introduced diagnostic technique with regard to fracture risk is frequently limited by the enormous costs and long time periods required for prospective studies. A preliminary estimate of predictive power usually relies on cross-sectional case-control studies in which bone measurements of normal and fractured subjects are compared. The measured discriminatory power is taken as an estimate of predictive power. Because of possible sample selection bias, study participants may have different bone mineral density (BMD) values, and fractured patients may have fractures of different severity levels. The same diagnostic techniques for the measured discriminatory power, expressed as odds ratios, will differ among studies with different patient and control populations.In this paper, we propose a weighted logistic regression approach to adjust the odds ratio in order to reduce the effect of sampling bias. The weight is derived from age, deformity severity, BMD, and the interactions of these, using the propensity score theory and reference population data.Simulation examples using data from the Osteoporosis and Ultrasound Study (OPUS) demonstrate that such a procedure can effectively reduce the estimation bias of odds ratios introduced by sampling differences, such as for dual x-ray absorptiometry (DXA) scans of the spine and hip as well as various quantitative ultrasound techniques. The derived estimated odds ratios are substantially less biased, and the corresponding 95% confidence intervals contain the true odds ratios from the population data.We conclude that a statistical correction procedure based on propensity scores and weighted logistic regression can effectively reduce the effect of sampling bias on the odds ratios calculated from cross-sectional case-control studies. For a new diagnostic technique, hip BMD and deformity severity information are necessary and likely sufficient to derive the propensity scores required to adjust the measured standardized odds ratios.

    View details for DOI 10.1007/s00198-005-0021-x

    View details for Web of Science ID 000236356100003

    View details for PubMedID 16369725

  • Cross-calibration and minimum precision standards for dual-energy x-ray absorptiometry: The 2005 ISCD official positions JOURNAL OF CLINICAL DENSITOMETRY Shepherd, J. A., Lu, Y., Wilson, K., Fuerst, T., Genant, H., Hangartner, T. N., Wilson, C., Hans, D., Leib, E. S. 2006; 9 (1): 31-36


    The International Society for Clinical Densitometry (ISCD) Committee on Standards of Bone Measurement (CSBM) consists of experts in technical aspects of bone densitometry. The CSBM recently reviewed the scientific literature on cross-calibration and precision assessment. A report with recommendations was presented at the 2005 ISCD Position Development Conference (PDC). Based on a thorough review of the data by the ISCD Expert Panel during the conference, the ISCD adopted Official Positions with respect to (1) cross-calibration when changing or replacing hardware; (2) the approach to cross-calibration when an entire system is changed to one made by either the same or a different manufacturer; (3) when no cross-calibration study or bone mineral density (BMD) comparison is done between facilities; and (4) the minimum acceptable precision for an individual technologist. We present here the ISCD Official Positions on these topics that were established as a result of the 2005 PDC, together with the associated rationales and supportive evidence.

    View details for DOI 10.1016/j.jocd.2006.05.005

    View details for Web of Science ID 000238525000005

    View details for PubMedID 16731429

  • Prostate cancer: Endorectal MR imaging and MR spectroscopic imaging - Distinction of true-positive results from chance-detected lesions RADIOLOGY Hom, J. J., Coakley, F. V., Simko, J. P., Qayyum, A., Lu, Y., Schmitt, L., Carroll, P. R., Kurhanewicz, J. 2006; 238 (1): 192-199


    To retrospectively investigate size criteria for the identification of chance-detected lesions at endorectal magnetic resonance (MR) imaging and MR spectroscopic imaging of prostate cancer.Approval of the committee on human research and written informed consent were obtained. This study was HIPAA compliant. Endorectal MR imaging and MR spectroscopic imaging were performed with a 1.5-T MR imager in 48 men with a mean age of 59 years (age range, 47-75 years) prior to radical prostatectomy. Two independent readers recorded the size and location of all suspected peripheral zone tumor nodules on MR images alone and on images obtained with combined MR imaging and MR spectroscopic imaging. Nodules detected at MR imaging were classified as matched lesions if tumor was present in the same location at step-section histopathologic review. For all matched lesions, kappa values were calculated to examine agreement between measured and actual tumor size. Lesions that were overmeasured at MR imaging with a kappa value of less than 0.2 were considered chance-detected lesions.At MR imaging, two of 27 and four of 35 matched lesions for readers 1 and 2, respectively, were chance-detected lesions. The corresponding numbers of lesions at combined MR imaging and MR spectroscopic imaging were one of 21 and one of 31, respectively. In all but two cases, the measured diameter of chance-detected lesions was more than twice that of the diameter at histopathologic analysis. By using this diameter threshold to distinguish true-positive results, the mean diameter of detected tumors at histopathologic analysis was 15 mm compared with 4 mm for both undetected and chance-detected tumors (P < .05).To ensure uniformity in the comparison of scientific studies, peripheral zone tumors detected at MR imaging and MR spectroscopic imaging of the prostate that are in the same location as tumors detected at histopathologic review should be considered chance-detected lesions if the MR transverse diameter is more than twice the histopathologic transverse diameter.

    View details for DOI 10.1148/radiol.2381041675

    View details for Web of Science ID 000234271600024

    View details for PubMedID 16373767

  • Detection of hepatocellular carcinoma by ferumoxides-enhanced MR imaging in cirrhosis: Incremental value of dynamic gadolinium-enhancement JOURNAL OF MAGNETIC RESONANCE IMAGING Qayyum, A., Thoeni, R. F., Coakley, F. V., Lu, Y., Guay, J. P., Ferrell, L. D. 2006; 23 (1): 17-22


    To investigate the incremental value of dynamic gadolinium-enhancement performed immediately after ferumoxides-enhanced magnetic resonance (MR) imaging on the detection of hepatocellular carcinoma in patients with cirrhosis.We retrospectively reviewed MR scans of 62 cirrhotic patients over a two-year period. Sequences included ferumoxides-enhanced T2-weighted fast spin echo followed by dynamic gadolinium-enhanced T1-weighted spoiled gradient echo. Two readers independently documented the presence of hepatocellular carcinoma on a three-point confidence scale, without and with gadolinium-enhanced images. The presence or absence of hepatocellular carcinoma was established by histopathology (58 patients) or follow-up imaging (four patients) over a mean period of nine months.A total of 71 hepatocellular carcinomas were found in 42 patients. There was no statistically significant difference in sensitivity for the diagnosis of hepatocellular carcinoma without vs. with gadolinium-enhanced images (68% vs. 74% for reader 1 and 62% vs. 73% for reader 2, respectively, P > 1.3). However, both readers showed a lower mean confidence for tumor detection without vs. with gadolinium-enhanced images (2.3 vs. 2.7 for reader 1, 2.3 vs. 2.9 for reader 2, P < 0.01).In our study, the addition of dynamic gadolinium-enhancement to ferumoxides-enhanced MR imaging did not improve hepatocellular carcinoma detection, but the addition of gadolinium-enhancement is recommended if ferumoxides-enhanced imaging is used because it increased reader confidence.

    View details for DOI 10.1002/jmri.20449

    View details for Web of Science ID 000234488500003

    View details for PubMedID 16315209

  • The academic radiologist's clinical productivity: An update ACADEMIC RADIOLOGY Lu, Y., Arenson, R. L. 2005; 12 (9): 1211-1223


    The purpose of this project was to further understand the academic radiologist's clinical workload with comparison to the prior studies in the past decade. This updated data is very important in determining faculty staffing requirements.A survey performed by the Society of Chairmen of Academic Radiology Departments (SCARD) collected data in 2003 for radiologists in 23 departments. This data included Current Procedure Terminology (CPT) codes by radiologist. The CPT codes were converted into relative value units (RVUs) per full-time equivalent (FTE) faculty. By grouping the CPT codes into similar examination categories, adjustment factors were created for the RVU values for each CPT in order to compensate for workload variations. These adjustment factors are identical to the adjustments made in 2001 except for a new factor for nuclear medicine.Overall, the average clinical workload in 2003 was 5,872 RVU/FTE, a 32% increase compared to 4,458 RVU/FTE in 1998 and 55% increase compared to 3,790 RVU/FTE in 1996. The average number of examinations per FTE had a smaller (17%) increase since 1998. The adjustment factors remain very similar to those presented in 2001. The only change was a new adjustment factor of 1.3 for nuclear medicine.Clinical workload as measured by RVU/FTE and adjusted RVU/FTE are very useful for determining optimal staffing in subspecialty sections and in the department as a whole. The workload continues to increase, but more in examination complexity than in numbers of procedures overall.

    View details for DOI 10.1016/j.acra.2005.05.015

    View details for Web of Science ID 000231463500019

    View details for PubMedID 16112517

  • Indeterminate ovarian mass at US: Incremental value of second imaging test for characterization-meta-analysis and Bayesian analysis RADIOLOGY Kinkel, K., Lu, Y., Mehdizade, A., Pelte, M. F., Hricak, H. 2005; 236 (1): 85-94


    To compare value of current diagnostic strategies in assessment of changes in posttest probability of ovarian cancer when menopausal status and combination and sequence of diagnostic imaging tests are considered.Prevalence of ovarian cancer according to menopausal status in women with an ovarian mass and performance of combined gray-scale and Doppler ultrasonography (US), computed tomography (CT), and non-enhanced magnetic resonance (MR) imaging and contrast material-enhanced MR imaging after indeterminate results at gray-scale US were derived from meta-analysis by using MEDLINE database and institutional data. Study was approved by the institutional review board of University Hospital Geneva, Geneva, Switzerland; informed consent was waived. Posttest probability values were computed through Bayesian analysis and Monte Carlo simulation after initial gray-scale US and secondary combined gray-scale and Doppler US, CT, or MR imaging, while dependence of test results among imaging modalities was considered. Changes in posttest probability were compared among imaging modalities with summary receiver operating characteristic curves.Prevalence of ovarian cancer was 8.75% in premenopausal women and 32.40% in postmenopausal women with an ovarian mass. After characterization with initial gray-scale US, posttest probability in pre- and postmenopausal women changed, respectively, to 25% and 63% for indeterminate results and to 2% and 7% for benign results. Subsequent use of combined gray-scale and Doppler US, CT, or MR imaging had significant higher positive and lower negative posttest probability than did use of gray-scale US alone. In women with an indeterminate initial US result, posttest probability decreased after secondary testing with benign results for all imaging modalities to 2% in premenopausal women and to 8%-10% in postmenopausal women. After secondary testing for suspicious lesions, posttest probability increased more after non-enhanced (premenopausal women, 70%; postmenopausal women, 92%) or contrast-enhanced MR imaging (premenopausal women, 80%; postmenopausal women, 95%) than it did after combined gray-scale and Doppler US (premenopausal women, 30%; postmenopausal women, 69%) or CT (premenopausal women, 38%; postmenopausal women, 76%) (P < .001).In women with an indeterminate ovarian mass at gray-scale US, MR imaging results contributed to change in probability of ovarian cancer in both pre- and postmenopausal women more than did CT or combined gray-scale and Doppler US results.

    View details for DOI 10.1148/radiol.2361041618

    View details for Web of Science ID 000229905300011

    View details for PubMedID 15955864

  • Towards standardization of dual X-ray absorptiometry (DXA) at the forearm - A common region of interest (ROI) improves the comparability among DXA devices CALCIFIED TISSUE INTERNATIONAL Prevrhal, S., Lu, Y., Genant, H. K., Toschke, J. O., Shepherd, J. A. 2005; 76 (5): 348-354


    Manufacturer-implemented regions of interest (ROIs) to determine the bone mineral density (BMD) at the forearm are currently not standardized across dual X-ray absorptiometry (DXA) devices. We hypothesized that their differences introduce considerable variation in measurement results for forearm BMD when taken on different devices, and that a ROIs common to all devices with standardized placement and size significantly improve device comparability. The common ROI was defined to have a fixed length of 2 cm and to extend proximally from the location where the ulna and radius bones superimpose on the DXA image. The effects of universal standardization of forearm BMD were combined with and compared to those of the common ROI. They were drawn on 91 female study participants (ages 20-80 years, 10 per decade) who were scanned on Hologic QDR-4500, Aloka DCS-600EX, GE Lunar PIXI and Norland pDEXA DXA scanners. For all device combinations, manufacturer-implemented ROI root mean-square errors were significantly higher than for the common ROI, suggesting that implementing an ROI with common design on all scanners is a good way to reduce interdevice variability. When manufacturer-implemented ROIs were universally standardized root mean-square error (RMSE) values were less different from that of the nonstandardized Common ROI, suggesting that universal standardization can further improve interdevice comparability even when a common ROI such as the one implemented here is used. ROI standardization dramatically improves interdevice comparability.

    View details for DOI 10.1007/s00223-004-0050-z

    View details for Web of Science ID 000230091700005

    View details for PubMedID 15868279

  • Design of phase II cancer trials with both total and complete responses. Statistics in Medicine Lu Y, Jin H; Lamborn K 2005; 24 (20): 3155-70
  • Alternative tree-structured survival analysis based on variance of survival time MEDICAL DECISION MAKING Jin, H., Lu, Y., Stone, K., Black, D. M. 2004; 24 (6): 670-680


    Tree-structured survival analysis (TSSA) is a popular alternative to the Cox proportional hazards regression in medical research of survival data. Several methods for constructing a tree of different survival profiles have been developed, including TSSA based on log-rank statistics, martingale residuals, Lp Wasserstein metrics between Kaplan-Meier survival curves, and a method based on a weighted average of the within-node impurity of the death indicator and the within-node loss function of follow-up times. Lu and others used variance of restricted mean lifetimes as an index of degree of separation (DOS) to measure the efficiency in separations of survival profiles by a classification method. Like tree-based regression analysis that uses variance as a criterion for node partition and pruning, the variance of restricted mean lifetimes between different groups can be an alternative index to log-rank test statistics in construction of survival trees. In this article, the authors explore the use of DOS in TSSA. They propose an algorithm similar to the least square regression tree for survival analysis based on the variance of the restricted mean lifetimes. They apply the proposed method to prospective cohort data from the Study of Osteoporotic Fracture that motivated the research and then compare their classification rule to those rules based on the conventional TSSA mentioned above. A limited simulation study suggests that the proposed algorithm is a competitive alternative to the log-rank or martingale residual-based TSSA approaches.

    View details for Web of Science ID 000225206600010

    View details for PubMedID 15534347

  • Classification algorithms for hip fracture prediction based on recursive partitioning methods MEDICAL DECISION MAKING Jin, H., Lu, Y., Harris, S. T., Black, D. M., Stone, K., Hochberg, M. C., Genant, H. 2004; 24 (4): 386-398


    This article presents 2 modifications to the classification and regression tree. The authors improved the robustness of a split in the test sample approach and developed a cost-saving classification algorithm by selecting noninferior to the optimum splits from variables with lower cost or being used in parent splits. The new algorithm was illustrated by 43 predictive variables for 5-year hip fracture previously documented in the Study of Osteoporotic Fractures. The authors generated the robust optimum classification rule without consideration of classification variable costs and then generated an alternative cost-saving rule with equivalent diagnostic utility. A 6-fold cross-validation study proved that the cost-saving alternative classification is statistically noninferior to the optimal one. Their modified classification and regression tree algorithm can be useful in clinical applications. A dual X-ray absorptiometry hip scan and information from clinical examinations can identify subjects with elevated 5-year hip fracture risk without loss of efficiency to more costly and complicated algorithms.

    View details for Web of Science ID 000222813900006

    View details for PubMedID 15271277

  • Whole-organ magnetic resonance imaging score (WORMS) of the knee in osteoarthritis OSTEOARTHRITIS AND CARTILAGE Peterfy, C. G., Guermazi, A., Zaim, S., Tirman, P. F., Miaux, Y., White, D., Kothari, M., Lu, Y., Fye, K., Zhao, S., Genant, H. K. 2004; 12 (3): 177-190


    To describe a semi-quantitative scoring method for multi-feature, whole-organ evaluation of the knee in osteoarthritis (OA) based on magnetic resonance imaging (MRI) findings. To determine the inter-observer agreement of this scoring method. To examine associations among the features included in the scoring method.Nineteen knees of 19 patients with knee OA were imaged with MRI using conventional pulse sequences and a clinical 1.5 T MRI system. Images were independently analyzed by two musculoskeletal radiologists using a whole-organ MRI scoring method (WORMS) that incorporated 14 features: articular cartilage integrity, subarticular bone marrow abnormality, subarticular cysts, subarticular bone attrition, marginal osteophytes, medial and lateral meniscal integrity, anterior and posterior cruciate ligament integrity, medial and lateral collateral ligament integrity, synovitis/effusion, intraarticular loose bodies, and periarticular cysts/bursitis. Intraclass correlation coefficients (ICC) were determined for each feature as a measure of inter-observer agreement. Associations among the scores for different features were expressed as Spearman Rho.All knees showed structural abnormalities with MRI. Cartilage loss and osteophytes were the most prevalent features (98% and 92%, respectively). One of the least common features was ligament abnormality (8%). Inter-observer agreement for WORMS scores was high (most ICC values were >0.80). The individual features showed strong inter-associations.The WORMS method described in this report provides multi-feature, whole-organ assessment of the knee in OA using conventional MR images, and shows high inter-observer agreement among trained readers. This method may be useful in epidemiological studies and clinical trials of OA.

    View details for DOI 10.1016/j.joca.2003.11.003

    View details for Web of Science ID 000189282600001

    View details for PubMedID 14972335

  • On comparison of two classification methods with survival endpoints Handbook of Statistics: Advances in Survival Analysis Lu Y, Jin H; Mi J 2004; 23: 43-59
  • On the non-inferiority of a, diagnostic test based on paired observations STATISTICS IN MEDICINE Lu, Y., Jin, H., Genant, H. K. 2003; 22 (19): 3029-3044


    Non-inferiority of a diagnostic test to the standard or the optimum test is a common issue in medical research. Often we want to determine if a new diagnostic test is as good as the standard reference test. Sometimes we are interested in an inexpensive test that may have an acceptably inferior sensitivity or specificity. While hypothesis testing procedures and sample size formulae for the equivalence of sensitivity or specificity alone have been proposed, very few studies have discussed simultaneous comparisons of both parameters. In this paper, we present three different testing procedures and sample size formulae for simultaneous comparison of sensitivity and specificity based on paired observations and with known disease status. These statistical procedures are then used to compare two classification rules that identify women for future osteoporotic fracture. Simulation experiments demonstrate that the new tests and sample size formulae give the appropriate type I and II error rates. Differences between our approach and the approach of Lui and Cumberland are discussed.

    View details for DOI 10.1002/sim.1569

    View details for Web of Science ID 000185451700004

    View details for PubMedID 12973785

  • Measuring stem cell frequency in epidermis: A quantitative in vivo functional assay for long-term repopulating cells PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Schneider, T. E., Barland, C., Alex, A. M., Mancianti, M. L., Lu, Y., Cleaver, J. E., Lawrence, H. J., Ghadially, R. 2003; 100 (20): 11412-11417


    Epidermal stem cells play a central role in tissue homeostasis, wound repair, tumor initiation, and gene therapy. A major impediment to the purification and molecular characterization of epidermal stem cells is the lack of a quantitative assay for cells capable of long-term repopulation in vivo, such as exists for hematopoietic cells. The tremendous strides made in the characterization and purification of hematopoietic stem cells have been critically dependent on the availability of competitive transplantation assays, because these assays permit the accurate quantitation of long-term repopulating cells in vivo. We have developed an analogous functional assay for epidermal stem cells, and have measured the frequency of functional epidermal stem cells in interfollicular epidermis. These studies indicate that cells capable of long-term reconstitution of a squamous epithelium reside in the interfollicular epidermis. We find that the frequency of these long-term repopulating cells is 1 in 35,000 total epidermal cells, or in the order of 1 in 104 basal epidermal cells, similar to that of hematopoietic stem cells in the bone marrow, and much lower than previously estimated in epidermis. Furthermore, these studies establish a novel functional assay that can be used to validate immunophenotypic markers and enrichment strategies for epidermal stem cells, and to quantify epidermal stem cells in various keratinocyte populations. Thus further studies using this type of assay for epidermis should aid in the progress of cutaneous stem cell-targeted gene therapy, and in more basic studies of epidermal stem cell regulation and differentiation.

    View details for DOI 10.1073/pnas.2034935100

    View details for Web of Science ID 000185685700044

    View details for PubMedID 13679571

    View details for PubMedCentralID PMC208771

  • Study of hip fracture risk using tree structured survival analysis J. Miner. Stoffwechs Lu, Y., Black, D., Mathur, A. K., Genant, H. K. 2003; 10 (1): 11-16
  • Detection of hepatic metastases from cancers of the gastrointestinal tract by using noninvasive imaging methods (US, CT, MR imaging, PET): A meta-analysis RADIOLOGY Kinkel, K., Lu, Y., Both, M., Warren, R. S., Thoeni, R. F. 2002; 224 (3): 748-756


    To perform a meta-analysis to compare current noninvasive imaging methods (ultrasonography [US], computed tomography [CT], magnetic resonance [MR] imaging, and (18)F fluorodeoxyglucose [FDG] positron emission tomography [PET]) in the detection of hepatic metastases from colorectal, gastric, and esophageal cancers.A MEDLINE literature search and review of article bibliographies and our institutional charts of patients with colorectal cancer identified data with histopathologic correlation or at least 6 months of patient follow-up. Two authors independently abstracted data sets and excluded data without contingency tables or data published more than once. Summary-weighted estimates of sensitivity were obtained and stratified according to specificity of less than 85% or 85% and higher. A covariate analysis was used to evaluate the influence of patient- or study-related factors on sensitivity.Among 111 data sets, nine US (509 patients), 25 CT (1,747 patients), 11 MR imaging (401 patients), and nine PET (423 patients) data sets met the inclusion criteria. In studies with a specificity higher than 85%, the mean weighted sensitivity was 55% (95% CI: 41, 68) for US, 72% (95% CI: 63, 80) for CT, 76% (95% CI: 57, 91) for MR imaging, and 90% (95% CI: 80, 97) for FDG PET. Results of pairwise comparison between imaging modalities demonstrated a greater sensitivity of FDG PET than US (P =.001), CT (P =.017), and MR imaging (P =.055).At equivalent specificity, FDG PET is the most sensitive noninvasive imaging modality for the diagnosis of hepatic metastases from colorectal, gastric, and esophageal cancers.

    View details for DOI 10.1148/radiol.2243011362

    View details for Web of Science ID 000177621700019

    View details for PubMedID 12202709

  • Receiver operating characteristic (ROC) analysis for diagnostic examinations with uninterpretable cases STATISTICS IN MEDICINE Lu, Y., Heller, D. N., Zhao, S. J. 2002; 21 (13): 1849-1865


    Receiver operating characteristic (ROC) analysis plots true positive rates over false positive rates to describe the discriminatory power of a test to differentiate between two specifiable populations (that is 'normal' from 'abnormal') using a continuous dichotomous threshold. This assumes that the test separates cases into observed 'normal' or 'abnormal'. However, in practice many tests have some uninterpretable results as an inherent feature of the test itself, whether independent or dependent on the sample populations. This paper defines a method to describe the ability of tests to discriminate between specifiable populations when uninterpretable results occur non-informatively about disease status. A mixed model modified ROC curve is developed. Formulae to estimate the area under the modified ROC curve are given. Comparisons of conventional with the mixed model ROC analysis are shown in mathematical formulae as well as simulated experiments. An example of diagnosis of spinal fracture in renal transplant patients is presented.

    View details for DOI 10.1002/sim.1143

    View details for Web of Science ID 000176642000003

    View details for PubMedID 12111893

  • Statistical issues in classification and diagnosis of osteoporosis Chinese Journal of Bone Tumor and Bone Disease Lu, Y., Zhao, Y. 2002; 1 (5): 289-293
  • Classification of osteoporosis based on bone mineral densities JOURNAL OF BONE AND MINERAL RESEARCH Lu, Y., Genant, H. K., Shepherd, J., Zhao, S. J., Mathur, A., Fuerst, T. P., Cummings, S. R. 2001; 16 (5): 901-910


    In this article we examine the role of bone mineral density (BMD) in the diagnosis of osteoporosis. Using information from 7671 women in the Study of Osteoporotic Fractures (SOF) with BMD measurements at the proximal femur, lumbar spine, forearm, and calcaneus, we examine three models with differing criteria for the diagnosis of osteoporosis. Model 1 is based on the World Health Organization (WHO) criteria using a T score of -2.5 relative to the manufacturers' young normative data aged 20-29 years, with modifications using information from the Third National Health and Nutrition Examination Survey (NHANES). Model 2 uses a T score of -1 relative to women aged 65 years at the baseline of the SOF population. Model 3 classifies women as osteoporotic if their estimated osteoporotic fracture risk (spine and/or hip) based on age and BMD is above 14.6%. We compare the agreement in osteoporosis classification according to the different BMD measurements for the three models. We also consider whether reporting additional BMD parameters at the femur or forearm improves risk assessment for osteoporotic fractures. We observe that using the WHO criteria with the manufacturers' normative data results in very inconsistent diagnoses. Only 25% of subjects are consistently diagnosed by all of the eight BMD variables. Such inconsistency is reduced by using a common elderly normative population as in model 2, in which case 50% of the subjects are consistently diagnosed as osteoporotic by all of the eight diagnostic methods. Risk-based diagnostic criteria as in model 3 improve consistency substantially to 68%. Combining the results of BMD assessments at more than one region of interest (ROI) from a single scan significantly increases prediction of hip and/or spine fracture risk and elevates the relative risk with increasing number of low BMD subregions. We conclude that standardization of normative data, perhaps referenced to an older population, may be necessary when applying T scores as diagnostic criteria in patient management. A risk-based osteoporosis classification does not depend on the manufacturers' reference data and may be more consistent and efficient for patient diagnosis.

    View details for Web of Science ID 000168201500012

    View details for PubMedID 11341335

  • Standardization of bone mineral density at femoral neck, trochanter and Ward's triangle OSTEOPOROSIS INTERNATIONAL Lu, Y., Fuerst, T., Hui, S., Genant, H. K. 2001; 12 (6): 438-444


    The International Committee for Standards in Bone Measurement (ICSBM) has published standardization formulas for total hip bone mineral density (BMD). In many applications, however, BMD of hip subregions, such as femoral neck (FN), trochanter (TR), and Ward's triangle (WT), are commonly measured. This paper addresses whether the standardization formulas for total hip BMD can be adequately used for hip subregions. We used data from 100 healthy women, from 20 to 80 years old, who had hip BMD measured in both the total hip and hip subregions by a Hologic QDR 2000, a Lunar DPX, and a Norland XR26 Mark II. The same women were used by ICSBM for the standardization of total hip BMD. In addition, we used data of 3139 patients from a clinical trial to validate our results. We derived standardization formulas for FN, TR, and WT using the same statistical method as that used for total hip BMD. We applied both total hip calibration formulas and subregion-specific formulas to the data and compared the corresponding effect. We found that the total hip calibration formulas can partially reduce BMD differences between the Hologic and Lunar as well as the Lunar and Norland scanners in hip subregions, but increase differences between the Hologic and Norland scanners. The subregion calibration formulas are most appropriate for calibrating subregion BMD values and their absolute changes, and should be adopted. Standardization is unnecessary for BMD percentage changes in our clinical trial data.

    View details for Web of Science ID 000169773700002

    View details for PubMedID 11446558

  • Long-term effectiveness evaluation and prediction of hepatitis B vaccination with a mathematical model in Shanghai International Journal of Epidemiology Zhao S, Xu Z; Lu Y 2000; 29: 744-52
  • Comparative calibration without a gold standard STATISTICS IN MEDICINE Lu, Y., Ye, K. Y., Mathur, A. K., Hui, S., Fuerst, T. P., Genant, H. K. 1997; 16 (16): 1889-1905


    Comparative calibration is the broad statistical methodology used to assess the calibration of a set of p instruments, each designed to measure the same characteristic, on a common group of individuals. Different from the usual calibration problem, the true underlying quantity measured is unobservable. Many authors have shown that this problem, in general, does not have a unique solution. Most commonly used assumptions to obtain a unique solution are (i) one instrument is the gold standard (that is, unbiased) and (ii) the measurement errors of the p instruments are independent. Such constraints, however, may not be valid for many clinical applications, for example, the universal standardization project for dual X-ray absorptiometry (DXA) scanners. In this paper, we propose a new approach to resolve the comparative calibration problem when a gold standard is unavailable. Instead of the usual assumptions, we use external information in addition to data from the p instruments, to solve the problem. We address statistical estimation, hypothesis testing and missing data problems. We apply the new method specifically to the universal standardization project data where a group of individuals have been measured for bone mineral density (BMD) by three DXA scanners. We compare the results of the new method to currently used methods and show that they have better statistical properties.

    View details for Web of Science ID A1997XR01700008

    View details for PubMedID 9280040

  • Noninvasive assessment of bone mineral and structure: State of the art JOURNAL OF BONE AND MINERAL RESEARCH Genant, H. K., Engelke, K., Fuerst, T., Gluer, C. C., Grampp, S., Harris, S. T., Jergas, M., Lang, T., Lu, Y., Majumdar, S., Mathur, A., Takada, M. 1996; 11 (6): 707-730

    View details for Web of Science ID A1996UN81500001

    View details for PubMedID 8725168

  • Dual X-ray absorptiometry quality control: Comparison of visual examination and process-control charts JOURNAL OF BONE AND MINERAL RESEARCH Lu, Y., Mathur, A. K., Blunt, B. A., Gluer, C. C., Will, A. S., Fuerst, T. P., Jergas, M. D., ANDRIANO, K. N., Cummings, S. R., Genant, H. K. 1996; 11 (5): 626-637


    Dual X-ray absorptiometry (DXA) is widely used to monitor treatment efficacy in reducing the rate of bone mineral loss. In order to assure the validity of these measurements, instrument quality control of the DXA scanners becomes very important. This paper compares five quality control procedures (visual inspection, Shewhart chart with sensitizing rules, Shewhart chart with sensitizing rules and a filter for clinically insignificant mean changes, moving average chart and standard deviation, and cumulative sum chart [CUSUM]) in their ability to identify scanner malfunction by means of (1) an analysis of five longitudinal phantom data sets that had been collected during a clinical trial and (2) an analysis of simulated data sets. The visual inspection method is relatively subjective and depends on the operator's experience and attention. The regular Shewhart chart with sensitizing rules has a high false alarm rate. The Shewhart chart with sensitizing rules and an additional filter for clinically insignificant mean changes has the lowest false alarm rate but a relatively low sensitivity. The CUSUM method has good sensitivity and a low false alarm rate. In addition, this method provides an estimate of the date a change in the DXA scanner performance might have occurred. The method combining a moving average chart and a moving standard deviation chart came closest to the performance of the CUSUM method. Comparing the advantages and disadvantages of all methods, we propose the use of the CUSUM method as a quality control procedure for monitoring DXA scanner performance. For clinical trials use of the more intuitive Shewhart charts may be acceptable at the individual sites provided their scanner performance is followed up by CUSUM analysis at a central quality assurance center.

    View details for Web of Science ID A1996UG29000009

    View details for PubMedID 9157777



    In this paper we formalize the problem of testing the one-sided equivalence in the sensitivities of two medical diagnostic tests under a matched-pair study design. We derive conditional and unconditional sample size formulae which are decreasing functions of the probability of being diagnosed by both tests. We calculate upper boundary and midpoint sample sizes. Results of a Monte Carlo simulation study that compares the proposed sample size formulae with that of Lachenbruch suggest that our midpoint conditional sample size is the best choice to obtain the desired power for the type of equivalence studies discussed in the paper.

    View details for Web of Science ID A1995RQ64200010

    View details for PubMedID 7481214



    Because of the occult nature of tumors, the time-to-tumor is usually unobservable in animal studies of chemical carcinogenicity. In this paper, we propose new test approaches for simultaneous comparison of the marginal tumor incidence rates with several tumor types. We first set forth a model for tumor development and discuss the identifiability of parameters in this model. We then combine the results of tests for each marginal tumor incidence rate to develop simultaneous tests of all marginal tumor incidences. We apply the proposed methods to data from the ED01 study. This study, which used about 24,000 mice, was designed to determine the carcinogenic effect of the compound 2-acetylaminofluorene (2-AAF) at low dosages. We also present some simulation results to illustrate the application of simultaneous test methods to small experiments using 100 mice per dose group.

    View details for Web of Science ID A1995QX73300008

    View details for PubMedID 7766797



    Assessment of precision errors in bone mineral densitometry is important for characterization of a technique's ability to detect longitudinal skeletal changes. Short-term and long-term precision errors should be calculated as root-mean-square (RMS) averages of standard deviations of repeated measurements (SD) and standard errors of the estimate of changes in bone density with time (SEE), respectively. Inadequate adjustment for degrees of freedom and use of arithmetic means instead of RMS averages may cause underestimation of true imprecision by up to 41% and 25% (for duplicate measurements), respectively. Calculation of confidence intervals of precision errors based on the number of repeated measurements and the number of subjects assessed serves to characterize limitations of precision error assessments. Provided that precision error are comparable across subjects, examinations with a total of 27 degrees of freedom result in an upper 90% confidence limit of +30% of the mean precision error, a level considered sufficient for characterizing technique imprecision. We recommend three (or four) repeated measurements per individual in a subject group of at least 14 individuals to characterize short-term (or long-term) precision of a technique.

    View details for Web of Science ID A1995RQ04400008

    View details for PubMedID 7492865



    In 1989, Turner and colleagues proposed a new method for automated classification and prediction of outcomes for hospitalized patients with AIDS, based on severity of illness. The authors have confirmed this system, which includes three main stages and 20 substages, in a cohort of HIV-1-infected symptomatic patients admitted to the Miami Veteran's Affairs Medical Center (VAMC) since 1988. They propose a new model of Markov illness-and-death processes and use it to describe the disease progression of the patient cohort. The new Markov model also measures transitions between stages, including risk factors associated with the speed of transitions. Significant differences in survival experiences were found from the different disease stages. The estimated mean (median) survival times were: from stage 1, 21.0 (17.8) months; from stage 2, 10.5 (8.4) months; and from stage 3, 6.7 (4.7) months. In addition, age at HIV-1 diagnosis and homosexual behavior were significant prognostic factors for disease progression and survival. The results indicate that the combination of a severity-of-illness clinical staging system with Markov illness-and-death process modeling is particularly useful for the evaluation of prognostic factors influencing the course of HIV-1 disease progression.

    View details for Web of Science ID A1994NV49500008

    View details for PubMedID 7934714



    The development of two types of tumors in an animal survival-sacrifice experiment can be described by a Markov illness-and-death process with four unknown tumor transition rates and four unknown death rates. Due to the occult nature of tumors, these transition rates cannot be identified through the use of a completely nonparametric model. We propose a semiparametric model that assumes that the four tumor transition rates are proportional to each other and can be described by a known parametric function. We show that these tumor transition rates can be estimated using an ECM algorithm and that inferences about these parameters can be drawn using the likelihood ratio test. We illustrate this model and the algorithm with data from the ED01 study.

    View details for Web of Science ID A1994NV69300005

    View details for PubMedID 8081051

  • Evaluation of antipruritic effects of serlopitant, a neurokinin 1 receptor antagonist, in patients with epidermolysis bullosa: A phase 2 randomized controlled trial. Journal of the European Academy of Dermatology and Venereology : JEADV Okata-Karigane, U., Pathmarajah, P., Gorell, E. S., Sum, K., Yekrang, K., Phung, M., Barriga, M., Udrizar, P., Bailey, I., Li, S., Lu, Y., Tang, J. Y., Chiou, A. S. 2024

    View details for DOI 10.1111/jdv.20189

    View details for PubMedID 38949042

  • Editorial. Novel Statistical Methods and Designs for Clinical Trials N Engl J STAT DATA SCI Ji, Y., Lu, Y., Wang, H. 2024; 2 (1): 1-3
  • The SHARE: SHam Acupuncture REporting guidelines and a checklist in clinical trials. Journal of evidence-based medicine Ma, P., Liu, X., Liu, Z., Guo, Y., Zhou, K., Bian, Z., Sun, C., Liu, T., Xiong, Z., Xie, Y., Lu, Y., Lao, L., He, L., Liu, B., Liu, C., Yan, S. 2023

    View details for DOI 10.1111/jebm.12560

    View details for PubMedID 37906211

  • Visceral adipose tissue reference data computed for GE HealthCare DXA from the National Health and Nutrition Examination Survey data set. Obesity (Silver Spring, Md.) Bennett, J. P., Quon, B. K., Fan, B., Liu, E., Kazemi, L., Villegas-Valle, R. C., Ahgun, R., Wu, X. P., Zhou, H. D., Lu, Y., Shepherd, J. A. 2023


    The National Health and Nutrition Examination Survey (NHANES) characterizes body composition representative of the US population using dual-energy x-ray absorptiometry (DXA) scans. These population-level trends of abdominal subcutaneous and visceral adipose tissue (SAT and VAT) are useful for identifying measures associated with increased disease risk. Recently, VAT and SAT data collected by Hologic DXA in NHANES were published online; however, there are known differences in the absolute calibration of DXA systems by make. The purpose of this study was to create reference tables suitable for calculating z scores and percentile values for GE HealthCare (GEHC) DXA systems.DXA scans were acquired on participants aged 8 to 59 years using Hologic systems. DXA measures were converted to GEHC and described using the least median squares curve fitting method in pediatrics (aged <20 years) and adults (aged 20-59 years).A total of 11,972 adults and 7298 pediatrics were included for this analysis. Adult and pediatric curves were generated by sex and by ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic, Asian, Other) and were derived as a function of age.These results show the ability to generate VAT and SAT reference data for GEHC systems using Hologic DXA data representative of the US youth and adult population.

    View details for DOI 10.1002/oby.23888

    View details for PubMedID 37795576

  • Prediction of Multimorbidity in Brazil: Latest Fifth of a Century Population Study. JMIR public health and surveillance Li, X., Huang, H., Lu, Y., Stafford, R. S., Lima, S. M., Mota, C., Shi, X. 2023; 9: e44647


    BACKGROUND: Multimorbidity is characterized by the co-occurrence of 2 or more chronic diseases and has been a focus of the health care sector and health policy makers due to its severe adverse effects.OBJECTIVE: This paper aims to use the latest 2 decades of national health data in Brazil to analyze the effects of demographic factors and predict the impact of various risk factors on multimorbidity.METHODS: Data analysis methods include descriptive analysis, logistic regression, and nomogram prediction. The study makes use of a set of national cross-sectional data with a sample size of 877,032. The study used data from 1998, 2003, and 2008 from the Brazilian National Household Sample Survey, and from 2013 and 2019 from the Brazilian National Health Survey. We developed a logistic regression model to assess the influence of risk factors on multimorbidity and predict the influence of the key risk factors in the future, based on the prevalence of multimorbidity in Brazil.RESULTS: Overall, females were 1.7 times more likely to experience multimorbidity than males (odds ratio [OR] 1.72, 95% CI 1.69-1.74). The prevalence of multimorbidity among unemployed individuals was 1.5 times that of employed individuals (OR 1.51, 95% CI 1.49-1.53). Multimorbidity prevalence increased significantly with age. People over 60 years of age were about 20 times more likely to have multiple chronic diseases than those between 18 and 29 years of age (OR 19.6, 95% CI 19.15-20.07). The prevalence of multimorbidity in illiterate individuals was 1.2 times that in literate ones (OR 1.26, 95% CI 1.24-1.28). The subjective well-being of seniors without multimorbidity was 15 times that among people with multimorbidity (OR 15.29, 95% CI 14.97-15.63). Adults with multimorbidity were more than 1.5 times more likely to be hospitalized than those without (OR 1.53, 95% CI 1.50-1.56) and 1.9 times more likely need medical care (OR 1.94, 95% CI 1.91-1.97). These patterns were similar in all 5 cohort studies and remained stable for over 21 years. A nomogram model was used to predict multimorbidity prevalence under the influence of various risk factors. The prediction results were consistent with the effects of logistic regression; older age and poorer participant well-being had the strongest correlation with multimorbidity.CONCLUSIONS: Our study shows that multimorbidity prevalence varied little in the past 2 decades but varies widely across social groups. Identifying populations with higher rates of multimorbidity prevalence may improve policy making around multimorbidity prevention and management. The Brazilian government can create public health policies targeting these groups, and provide more medical treatment and health services to support and protect the multimorbidity population.

    View details for DOI 10.2196/44647

    View details for PubMedID 37252771

  • Patient-reported outcome measures for chronic itch in epidermolysis bullosa: An exploratory analysis of a randomized controlled trial Okata-Karigane, U., Pathmarajah, P., Li, S., Lu, Y., Tang, J. Y., Chiou, A. S. ELSEVIER SCIENCE INC. 2023: S101
  • Nonalcoholic fatty liver disease (NAFLD) detection and deep learning in a Chinese community-based population. European radiology Yang, Y., Liu, J., Sun, C., Shi, Y., Hsing, J. C., Kamya, A., Keller, C. A., Antil, N., Rubin, D., Wang, H., Ying, H., Zhao, X., Wu, Y. H., Nguyen, M., Lu, Y., Yang, F., Huang, P., Hsing, A. W., Wu, J., Zhu, S. 2023


    We aimed to develop and validate a deep learning system (DLS) by using an auxiliary section that extracts and outputs specific ultrasound diagnostic features to improve the explainable, clinical relevant utility of using DLS for detecting NAFLD.In a community-based study of 4144 participants with abdominal ultrasound scan in Hangzhou, China, we sampled 928 (617 [66.5%] females, mean age: 56 years ± 13 [standard deviation]) participants (2 images per participant) to develop and validate DLS, a two-section neural network (2S-NNet). Radiologists' consensus diagnosis classified hepatic steatosis as none steatosis, mild, moderate, and severe. We also explored the NAFLD detection performance of six one-section neural network models and five fatty liver indices on our data set. We further evaluated the influence of participants' characteristics on the correctness of 2S-NNet by logistic regression.Area under the curve (AUROC) of 2S-NNet for hepatic steatosis was 0.90 for ≥ mild, 0.85 for ≥ moderate, and 0.93 for severe steatosis, and was 0.90 for NAFLD presence, 0.84 for moderate to severe NAFLD, and 0.93 for severe NAFLD. The AUROC of NAFLD severity was 0.88 for 2S-NNet, and 0.79-0.86 for one-section models. The AUROC of NAFLD presence was 0.90 for 2S-NNet, and 0.54-0.82 for fatty liver indices. Age, sex, body mass index, diabetes, fibrosis-4 index, android fat ratio, and skeletal muscle via dual-energy X-ray absorptiometry had no significant impact on the correctness of 2S-NNet (p > 0.05).By using two-section design, 2S-NNet had improved the performance for detecting NAFLD with more explainable, clinical relevant utility than using one-section design.• Based on the consensus review derived from radiologists, our DLS (2S-NNet) had an AUROC of 0.88 by using two-section design and yielded better performance for detecting NAFLD than using one-section design with more explainable, clinical relevant utility. • The 2S-NNet outperformed five fatty liver indices with the highest AUROCs (0.84-0.93 vs. 0.54-0.82) for different NAFLD severity screening, indicating screening utility of deep learning-based radiology may perform better than blood biomarker panels in epidemiology. • The correctness of 2S-NNet was not significantly influenced by individual's characteristics, including age, sex, body mass index, diabetes, fibrosis-4 index, android fat ratio, and skeletal muscle via dual-energy X-ray absorptiometry.

    View details for DOI 10.1007/s00330-023-09515-1

    View details for PubMedID 36892645

    View details for PubMedCentralID 6770992

  • Cross-sectional and longitudinal associations between body flexibility and sarcopenia. Journal of cachexia, sarcopenia and muscle Gao, P., Gan, D., Li, S., Kang, Q., Wang, X., Zheng, W., Xu, X., Zhao, X., He, W., Wu, J., Lu, Y., Hsing, A. W., Zhu, S. 2022


    BACKGROUND: The associations between body flexibility and sarcopenia were not well understood. This study aimed to explore the cross-sectional and longitudinal associations of flexibility with sarcopenia.METHODS: Our study selected participants aged 50-80 from the WELL-China cohort and the Lanxi cohort. Participants from the urban area of the Lanxi cohort were followed up 4years later. Body flexibility was measured by the sit-and-reach test. Muscle mass was evaluated by dual-energy X-ray absorptiometry. Muscle strength was evaluated using handgrip strength. Sarcopenia was defined as having both low muscle mass and low muscle strength. We used multivariable logistic regressions to assess the cross-sectional associations of body flexibility with low muscle mass, low muscle strength and sarcopenia. We also used multivariable logistic regressions to explore the associations of baseline flexibility and 4-year changes in flexibility with incident low muscle mass, low muscle strength and sarcopenia.RESULTS: A total of 9453 participants were enrolled in the cross-sectional study, and 1233 participants were included in the longitudinal analyses. In the cross-sectional analyses, compared with low body flexibility, high body flexibility was inversely associated with low muscle mass (odds ratio [OR], 0.58; 95% confidence interval [CI], 0.50-0.68; P<0.001), low muscle strength (OR, 0.62; 95% CI, 0.55-0.69; P<0.001) and sarcopenia (OR, 0.52; 95% CI, 0.41-0.65; P<0.001), and these associations did not differ in different age groups, sex or physical activity levels. In the longitudinal analyses, compared with participants with low body flexibility, participants with high body flexibility had lower risk of the incident low muscle strength (OR, 0.53; 95% CI, 0.38-0.74; P<0.001) and sarcopenia (OR, 0.36; 95% CI, 0.21-0.61; P<0.001), but not incident low muscle mass (OR, 0.59; 95% CI, 0.33-1.06; P=0.076). Every 1-cm increase in flexibility during 4years was associated with reduced risk of incident low muscle mass (OR, 0.96; 95% CI, 0.93-1.00; P=0.025), low muscle strength (OR, 0.96; 95% CI, 0.94-0.98; P=0.002) and sarcopenia (OR, 0.96; 95% CI, 0.93-0.99; P=0.007).CONCLUSIONS: High flexibility was associated with reduced risk of incident low muscle strength and sarcopenia. Increases in flexibility were associated with reduced risk of incident low muscle mass, low muscle strength and sarcopenia. Flexibility exercises and monitoring the dynamic change of flexibility might be helpful in preventing sarcopenia among adults aged 50years or over.

    View details for DOI 10.1002/jcsm.13157

    View details for PubMedID 36564014

  • Changes in lifestyles and depressive symptom among patients with chronic diseases during COVID-19 lockdown. Scientific reports He, W., Zhao, X., Yang, Z., Min, Y., Wu, Y. H., Kang, Q., Frost, E., Gao, P., Yang, Y., Chen, X., Chen, L., Lu, Y., Hsing, A. W., Zhu, S. 2022; 12 (1): 11407


    This study aims to investigate the impact of COVID-19 lockdown on lifestyle behaviors and depressive symptom among patients with NCDs (noncommunicable diseases). We incorporated a COVID-19 survey to the WELL China cohort, a prospective cohort study with the baseline survey conducted 8-16 months before the COVID-19 outbreak in Hangzhou, China. The COVID-19 survey was carried out to collect information on lifestyle and depressive symptom during lockdown. A total of 3327 participants were included in the COVID-19 survey, including 2098 (63.1%) reported having NCDs at baseline and 1457 (44%) without NCDs. The prevalence of current drinkers decreased from 42.9% before COVID-19 lockdown to 23.7% during lockdown, current smokers from 15.9 to 13.5%, and poor sleepers from 23.9 to 15.3%, while low physical activity increased from 13.4 to 25.2%, among participants with NCDs (P < 0.05 for all comparisons using McNemar's test). Participants with NCDs were more likely than those without to have depressive symptom (OR, 1.30; 95% CI 1.05-1.61), especially among those who need to refill their medication during the COVID-19 lockdown (OR, 1.52; 95% CI 1.15-2.02). Our findings provide insight into the development of targeted interventions to better prepare patients with NCDs and healthcare system to meet the challenge of future pandemic and lockdown.

    View details for DOI 10.1038/s41598-022-15333-0

    View details for PubMedID 35794125

  • Association between napping status and depressive symptoms in urban residents during the COVID-19 epidemic. Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences Lin, W., Bai, G., He, W., Yang, F., Li, W., Min, Y., Lu, Y., Hsing, A., Zhu, S. 2021; 50 (6): 741-747


    : To explore the association between napping status and depressive symptoms in urban residents during the coronavirus disease 2019 (COVID-19) epidemic. : The survey was embedded in the Wellness Living Laboratory-China (WELL China) cohort study. Health and lifestyle information during the COVID-19 epidemic were obtained via the telephone interview from April 8, 2020 to May 29, 2020. A total of 3075 residents aged 18 to from Gongshu district of Hangzhou city with complete data were included in the analyses. The World Health Organization-Five Well-being Index (WHO-5) was used to measure depressive symptoms. Multiple logistic regression model was used to assess the association between napping status and depressive symptoms in the participants. : The prevalence of depressive symptoms was 20.6% in the participants during the epidemic. Daytime napping behavior, especially napping time ≤30 min, was associated with a lower risk of prevalent depressive symptoms (=0.61, 95%: 0.47-0.79, <0.01) and incident depressive symptoms in the population (=0.66, 95%: 0.50-0.88, <0.01). Among those with depressive symptoms at baseline, napping time ≤ was beneficial for the outcome of depressive symptoms (=0.42, 95%: 0.21-0.82, <0.05). : One in five urban residents have depressive symptoms during the COVID-19 epidemic, and a short nap during the day may be a protective factor against depressive symptoms.

    View details for DOI 10.3724/zdxbyxb-2021-0296

    View details for PubMedID 35347909

  • Shared Decision-Making in Cardiac Electrophysiology Procedures and Arrhythmia Management. Circulation. Arrhythmia and electrophysiology Chung, M. K., Fagerlin, A., Wang, P. J., Ajayi, T. B., Allen, L. A., Baykaner, T., Benjamin, E. J., Branda, M., Cavanaugh, K. L., Chen, L. Y., Crossley, G. H., Delaney, R. K., Eckhardt, L. L., Grady, K. L., Hargraves, I. G., True Hills, M., Kalscheur, M. M., Kramer, D. B., Kunneman, M., Lampert, R., Langford, A. T., Lewis, K. B., Lu, Y., Mandrola, J. M., Martinez, K., Matlock, D. D., McCarthy, S. R., Montori, V. M., Noseworthy, P. A., Orland, K. M., Ozanne, E., Passman, R., Pundi, K., Roden, D. M., Saarel, E. V., Schmidt, M. M., Sears, S. F., Stacey, D., Stafford, R. S., Steinberg, B. A., Youn Wass, S., Wright, J. M. 2021: CIRCEP121007958


    Shared decision-making (SDM) has been advocated to improve patient care, patient decision acceptance, patient-provider communication, patient motivation, adherence, and patient reported outcomes. Documentation of SDM is endorsed in several society guidelines and is a condition of reimbursement for selected cardiovascular and cardiac arrhythmia procedures. However, many clinicians argue that SDM already occurs with clinical encounter discussions or the process of obtaining informed consent and note the additional imposed workload of using and documenting decision aids without validated tools or evidence that they improve clinical outcomes. In reality, SDM is a process and can be done without decision tools, although the process may be variable. Also, SDM advocates counter that the low-risk process of SDM need not be held to the high bar of demonstrating clinical benefit and that increasing the quality of decision-making should be sufficient. Our review leverages a multidisciplinary group of experts in cardiology, cardiac electrophysiology, epidemiology, and SDM, as well as a patient advocate. Our goal is to examine and assess SDM methodology, tools, and available evidence on outcomes in patients with heart rhythm disorders to help determine the value of SDM, assess its possible impact on electrophysiological procedures and cardiac arrhythmia management, better inform regulatory requirements, and identify gaps in knowledge and future needs.

    View details for DOI 10.1161/CIRCEP.121.007958

    View details for PubMedID 34865518

  • Mgta-145+Plerixafor Provides GCSFFree Rapid and Reliable Hematopoietic Stem Cell Mobilization for Autologous Stem Cell Transplant in Patients with Multiple Myeloma: A Phase 2 Study Sidana, S., Bankova, A. K., Hosoya, H., Kumar, S., Tamaresis, J., Le, A., Muffly, L., Johnston, L. J., Arai, S., Lowsky, R., Meyer, E. H., Rezvani, A. R., Weng, W., Frank, M. J., Shiraz, P., Girgenti, D., Goncalves, K. A., Schmelmer, V., Davis, J. C., Lu, Y., Shizuru, J. A., Miklos, D. B. AMER SOC HEMATOLOGY. 2021
  • Daytime napping is associated with retinal microcirculation: a large population-based study in China. Sleep Liu, X., Wang, G., Wang, X., Wang, Y., Min, Y., Zhang, J., Chang, R. T., Zhao, X., He, W., Moshfeghi, D. M., Lu, Y., Hsing, A. W., Yao, K., Zhu, S. 2021


    STUDY OBJECTIVES: To investigate the association between daytime napping and retinal microcirculation.METHODS: This is a cross-sectional study from a prospective population-based cohort. 2,662 participants were recruited after quota sampling. Information on napping was collected through face-to-face interviews. Retinal vascular calibers (RVCs), including central retinal arteriolar equivalent (CRAE), central retinal venular equivalent (CRVE), and arterio-to-venous ratio (AVR), were obtained from fundus photography. Multivariate regression and restricted cubic spline curve were performed to determine the association between RVCs and daytime napping duration.RESULTS: 56.4% participants reported daytime napping regularly. Compared to no nap, daytime nap was related to higher CRAE, with nap duration of 0.5-1 h showing the most significant association. 0.5-1 h daytime nappers displayed an average of 4.18 m (95% confidence interval [CI] 2.45-5.91, p < 0.001) wider CRAE than non-nappers after adjustment. No significant association was found between CRVE and daytime napping. Moreover, individuals with 0.5-1 h daytime napping had a lower risk for AVR reduction (odds ratio [OR] 0.70, 95% confidence interval [CI] 0.56-0.86, p = 0.001) than non-nappers. Similar association persisted in non-hypertensive population. Restricted cubic spline indicated a J-shaped relationship between AVR reduction and nap duration.CONCLUSION: Retinal microcirculation was positively associated with self-reported 0.5-1 h daytime napping. Better indicators of retinal microcirculation were probably related to nap duration in a J-shaped manner. Also, the possibly beneficial role of 0.5-1 h daytime napping on retinal microcirculation might be independent of clinically diagnosed vascular diseases.

    View details for DOI 10.1093/sleep/zsab277

    View details for PubMedID 34875091

  • Coping with the COVID-19 pandemic: Contemplative practice behaviors are associated with better mental health outcomes and compliance with shelter-in-place orders in a prospective cohort study. Preventive medicine reports Chrisinger, B. W., Rich, T., Lounsbury, D., Peng, K., Zhang, J., Heaney, C. A., Lu, Y., Hsing, A. W. 2021; 23: 101451


    Psychosocial health can influence the development and experience of several chronic diseases, and has been negatively affected for many individuals amid the COVID-19 global pandemic. To understand the impact of contemplative practices on emotional and mental health during COVID-19, the Stanford WELL for Life Study (US component), incorporated a series of additional surveys into its ongoing study. A total of 1,097 participants residing in California who responded to at least one of three COVID-19 surveys were included in this analysis. Linear and generalized mixed-effects regression models were used to investigate relationships between individual contemplative practice behaviors (CPB) (embodied observing meditation, non-reactive mindfulness meditation, self-compassion cultivation, cultivation of compassion for others) and four psychosocial outcomes measured in the original WELL questionnaire (resilience, dealing with stress, positive emotions, and negative emotions). In addition, the associations between CPB and depression, distress, and compliance with local Shelter-In-Place orders were also investigated. Participants who engaged in any contemplative practice reported significantly more resilience and positive emotions, dealing better with stress, lower distress, and were less likely to report an experience with depression in the last week. Similar findings held when CPB was modeled as a continuous variable. Significant interactions between the duration of the SIP and CPB were also observed for resilience and SIP compliance outcomes, indicating that steeper declines were observed among participants with little or no CPB across the study period. Further investigation into the potential protective benefits of CPB during times of major disruption and uncertainty is warranted.

    View details for DOI 10.1016/j.pmedr.2021.101451

    View details for PubMedID 34189024

  • Associations of park access, park use and physical activity in parks with wellbeing in an Asian urban environment: a cross-sectional study. The international journal of behavioral nutrition and physical activity Petrunoff, N. A., Yi, N. X., Dickens, B., Sia, A., Koo, J., Cook, A. R., Lin, W. H., Ying, L., Hsing, A. W., van Dam, R. M., Muller-Riemenschneider, F. 2021; 18 (1): 87


    BACKGROUND: Relationships between park access, park use, and wellbeing remain poorly understood. The objectives of this study were to investigate: (1) perceived and objective park access in relation to park use and physical activity in parks; and; (2) perceived and objective park access, park use and physical activity in parks and their associations with wellbeing.METHODS: An interviewer-assisted survey collected data on perceived time to walk to parks, park use time, park physical activity time and wellbeing (using a scale containing nine domains) amongst adult participants of the Singapore Multi-Ethnic Cohort. Geospatial maps of parks and the "walkable" street networks were created for the city-state of Singapore to objectively determine distances to accessible points on park boundaries. Multiple linear regression models estimated the importance of park access to park use and associations of park access and park use with wellbeing, adjusting for potential confounders.RESULTS: Participants' (n=3435) average age was 48.8years (SD, 12.8), 44.8% were male and 72.6% were of Chinese ethnicity. Better perceived but not true park access was significantly associated with greater park use. Park access (perceived or true) was not associated with physical activity time in parks. Greater participant park time and physical activity time in parks were associated with higher wellbeing scores (p<0.001). The differences in wellbeing scores between the reference groups, who spent negligible time in parks, and the highest quartiles of time in parks (10.8h/month) and physical activity in parks (8.3h/month) were 3.2 (95% CI 2.1-4.4) and 4.2 (95% CI 4.1-6.3) points out of 100 respectively. These associations were similar for most domains of wellbeing, with clear dose-response relationships.CONCLUSIONS: While perceived park access was strongly associated with park use and well-being, true park access was not, and neither park access measure was associated with park physical activity. Future studies could investigate the influence of park attributes on park use, physical activity in parks and wellbeing. The consistent associations of park use and particularly physical activity in parks with wellbeing suggest that promoting park use, and especially physical activity in parks, is a promising strategy for improving wellbeing in urban settings.

    View details for DOI 10.1186/s12966-021-01147-2

    View details for PubMedID 34215259

  • PHYSICAL ACTIVITY AS STRESS MANAGEMENT DURING COVID-19 Vogel, E. A., Zhang, J., Peng, K., Heaney, C. A., Lu, Y., Lounsbury, D. W., Hsing, A. W., Prochaska, J. J. OXFORD UNIV PRESS INC. 2021: S357
  • Clinical characteristics associated with increased wound size in patients with recessive dystrophic epidermolysis bullosa. Pediatric dermatology Solis, D. C., Gorell, E. S., Teng, C., Barriga, M., Nazaroff, J., Li, S., Subica, A., Lu, Y., Marinkovich, M. P., Tang, J. Y. 2021


    As more therapeutic clinical trials focus on treatment of individual wounds in patients with recessive dystrophic epidermolysis bullosa, it has become crucial to understand the baseline clinical characteristics of these wounds. To investigate these features, we administered an RDEB-specific wound survey. Forty participants reported on location, size, pain, infection frequency, wound type, and duration of 189 wounds; a subset of 22 participants reported on pruritus in 63 wounds. Increased wound size was significantly associated with increased pain, increased pruritus, longer wound duration, increased infection frequency, and patients with mutations resulting in truncated type VII collagen.

    View details for DOI 10.1111/pde.14576

    View details for PubMedID 33749033

  • Paternal prescription medication before conception: A retrospective cohort study of all births in Denmark 1997-2017. Scandinavian journal of public health Wensink, M. J., Rizzi, S., Jensen, T. K., Skakkebaek, N. E., Lu, Y., Lindahl-Jacobsen, R., Eisenberg, M. L. 2021: 1403494820987468


    AIM: To study what medication fathers are being prescribed in the months preceding conception.METHODS: A retrospective cohort study of Danish national registries, comprising all births in Denmark 1997-2017 (1.3 million births). Time trends and absolute levels of paternal prescription medication in the 6 months prior to conception were assessed. While all medications were examined (N = 1335), we focused on the main medication groups, medications that have increased in use over time, and medications for which previous evidence exists of an effect on sperm quality.RESULTS: The average number of prescriptions increased over the study period (from 0.75 prescriptions to 0.82 per birth). Polypharmacy (three or more prescriptions) increased from less than 8% to 10% of fathers. The use of pain medication, proton-pump inhibitors, selective serotonin reuptake inhibitors and some inhalants have all increased markedly over the last 20 years.CONCLUSIONS: Potential harm to the offspring done by paternal medication may present an increasing problem. As paternal medication exposure is increasing, examination of generational effects, such as major birth defects, is necessary.

    View details for DOI 10.1177/1403494820987468

    View details for PubMedID 33615897

  • Physical activity and stress management during COVID-19: a longitudinal survey study. Psychology & health Vogel, E. A., Zhang, J. S., Peng, K., Heaney, C. A., Lu, Y., Lounsbury, D., Hsing, A. W., Prochaska, J. J. 2021: 1–11


    OBJECTIVE: Physical activity (PA) during COVID-19 shelter-in-place (SIP) may offset stress. This study examined associations between PA, stress and stress management strategies during SIP.DESIGN AND MAIN OUTCOME MEASURES: Participants (N=990) from a cohort of Northern California adults completed surveys during early SIP (3/23/20-4/2/20) and mid-SIP (4/24/20-5/8/20). Participants self-reported past-month PA (meeting vs. not meeting guidelines), changes in stress (decreased/unchanged vs. increased) and use (yes/no) of 10 stress management strategies. We tested differences in mid-SIP stress and stress management strategies by PA, and differences in mid-SIP stress by stress management strategies.RESULTS: Compared to participants inactive at mid-SIP, active participants reported less stress (AOR = 0.60 [0.45, 0.81]). Active participants were more likely to manage stress using outdoor PA, indoor PA, yoga/meditation/prayer, gardening, and reading (AORs > 1.42), and less likely to sleep (AOR = 0.65 [0.48, 0.89]) or eat ([AOR = 0.48 [0.35, 0.66]) more. Managing stress using outdoor PA, indoor PA or reading was associated with lower stress; managing stress using TV/movies, sleeping or eating was associated with increased stress (ps < 0.05).CONCLUSIONS: Meeting PA guidelines during SIP was associated with less stress. Inactive participants reported greater sleeping and eating to cope; active participants used active stress management strategies. Engagement in physically active stress management was associated with lower stress.

    View details for DOI 10.1080/08870446.2020.1869740

    View details for PubMedID 33405969

  • Physical performance and risk of hip fracture in community-dwelling elderly people in China: A 4-year longitudinal cohort study. Maturitas Zhong, B. X., Zhong, H. L., Zhou, G. Q., Xu, W. Q., Lu, Y. n., Zhao, Q. n. 2021; 146: 26–33


    This study aims to evaluate the association between the risk of hip fracture and score on the Short Physical Performance Battery (SPPB) and handgrip strength in community-dwelling elderly people in China.A total of 5,958 community-dwelling Chinese people aged 60 years or more from the China Health and Retirement Longitudinal Study (CHARLS) were surveyed in 2011 (baseline) and followed through to 2016. Score on the SPPB (which comprises tests of balance, walking speed, and repeated chair stands) and handgrip strength were determined at baseline. Binary logistic regression models were used to estimate the risk ratio (RR) and 95 % CI.During an average of approximately 4 years of follow-up, 180 (3.0 %) participants experienced incident hip fracture. After multivariate adjustment, the overall SPPB score and repeated chair stands alone distinguished a gradient of hip fracture risks. The risk of hip fracture was 1.65-fold higher in poor SPPB performers (score 0-6) than in good SPPB performers (score 10-12). Participants unable to complete repeated chair stands, and those who took ≥16.7 s or 13.7-16.6 s to complete them, had a higher risk than those who took ≤ 11.1 s to complete them, with RRs of 2.45, 2.12, and 1.93, respectively. Participants unable to complete the balance tests had a higher hip fracture risk than those with scores of 4, with an RR of 2.16. Walking speed and handgrip strength were not associated with increased hip fracture risk.Among community-dwelling elderly Chinese people, overall SPPB score, as well as performance on repeated chair stands and balance tests within the SPPB, were significantly and independently associated with increased hip fracture risk. These indicators could be used to predict hip fracture in clinical settings.

    View details for DOI 10.1016/j.maturitas.2021.01.003

    View details for PubMedID 33722361

  • Modeling the contribution of the obesity epidemic to the temporal decline in sperm counts. Archivio italiano di urologia, andrologia : organo ufficiale [di] Societa italiana di ecografia urologica e nefrologica Kasman, A., Del Giudice, F., Shkolyar, E., Porreca, A., Busetto, G. M., Lu, Y., Eisenberg, M. L. 2020; 92 (4)


    OBJECTIVE: Total sperm count (TSC) has been declining worldwide over the last several decades due to unknown etiologies. Our aim was to model the contribution that the obesity epidemic may have on declining TSC.MATERIALS AND METHODS: Obesity rates were determined since 1973 using the WHO's Global Health Observatory data. A literature review was performed to determine the association between TSC and obesity. Using the measured obesity rates and published TSC since 1973, a model was created to evaluate the association between temporal trends in obesity/temperature and sperm count.RESULTS: Since 1973, obesity prevalence in the United States was increased from 41% to 67.9%. A review of the literature showed that body mass index (BMI) categories 2, 3, and 4 were associated with TSC (millions) of 164.27, 155.71, and 142.29, respectively. The contribution to change over time for obesity from 1974 to 2011 was modeled at 1.8%. When the model was changed to represent the most extreme possible contribution to obesity reported, the modeled change over time rose to 7.2%. When stratified according to fertility status, the contribution that BMI had to falling sperm counts for all comers was 1.7%, while those presenting for fertility evaluation was 2.1%.CONCLUSIONS: While the decline in TSC may be partially due to rising obesity rates, these contributions are minimal which highlights the complexity of this problem.

    View details for DOI 10.4081/aiua.2020.4.357

    View details for PubMedID 33348967

  • Characterization of dietary patterns and assessment of their relationships with metabolomic profiles: A community-based study. Clinical nutrition (Edinburgh, Scotland) Ru, Y., Wang, N., Min, Y., Wang, X., McGurie, V., Duan, M., Xu, X., Zhao, X., Wu, Y., Lu, Y., Hsing, A. W., Zhu, S. 2020


    BACKGROUND & AIMS: Determining dietary patterns in China is challenging due to lack of external validation and objective measurements. We aimed to characterize dietary patterns in a community-based population and to validate these patterns using external validation cohort and metabolomic profiles.DESIGN: We studied 5145 participants, aged 18-80 years, from two districts of Hangzhou, China. We used one district as the discovery cohort (N=2521) and the other as the external validation cohort (N=2624). We identified dietary patterns using a k-means clustering. Associations between dietary patterns and metabolic conditions were analyzed using adjusted logistic models. We assessed relationships between metabolomic profile and dietary patterns in 214 participants with metabolomics data.RESULTS: We identified three dietary patterns: the traditional (rice-based), the mixed (rich in dairy products, eggs, nuts, etc.), and the high-alcohol diets. Relative to the traditional diet, the mixed (ORadj=1.7, CI 1.3-2.4) and the high-alcohol diets (ORadj=1.9, CI 1.3-2.7) were associated with type 2 diabetes and hypertension, respectively. Similar results were confirmed in the external validation cohort. In addition, we also identified 18 and 22 metabolites that could distinguish the mixed (error rate=12%; AUC=96%) and traditional diets (error rate=19%; AUC=88%) from the high-alcohol diet.CONCLUSIONS: Despite the complexity of Chinese diet, identifying dietary patterns helps distinguish groups of individuals with high risk of metabolic diseases, which can also be validated by external population and metabolomic profiles.

    View details for DOI 10.1016/j.clnu.2020.12.006

    View details for PubMedID 33349486

  • Risk of pre-term births and major birth defects resulting from paternal intake of COVID-19 medications prior to conception. BMC research notes Rizzi, S., Wensink, M. J., Lindahl-Jacobsen, R., Tian, L., Lu, Y., Eisenberg, M. L. 2020; 13 (1): 509


    OBJECTIVE: With the ongoing COVID-19 pandemic, large numbers of people will receive one of the several medications proposed to treat COVID-19, including patients of reproductive age. Given that some medications have shown adverse effects on sperm quality, there might be a transgenerational concern. We aim at examining the association between drugs proposed to treat COVID-19 when taken by the father around conception and any pre-term birth or major birth defects in offspring in a nation-wide cohort study using Danish registry data. Offspring whose father filled at least one prescription of the following medications in the 3months preceding conception were considered exposed: chloroquine, hydroxychloroquine, losartan, azithromycin, naproxen, dexamethasone and prednisone.RESULTS: For azithromycin and naproxen, large numbers of offspring were exposed (>1800 offspring), and we found no association with adverse birth outcomes. For chloroquine, losartan and dexamethasone, exposure was intermediate (~900 offspring), and there was no statistically significant association with birth defects. For hydroxychloroquine and prednisone, exposure was limited (<300 offspring). Our evidence suggests that azithromycin and naproxen are safe with respect to pre-term birth and birth defects. For the other drugs investigated larger exposures are needed for conclusive statements.

    View details for DOI 10.1186/s13104-020-05358-x

    View details for PubMedID 33160408

  • Effect of heat-clearing and detoxifying Chinese medicines combined with conventional therapy on mild hand, foot, and mouth disease with fever: An individual patient data meta-analysis. Medicine Yan, S., Lu, Y., Zhang, G., Li, X., Wang, Z., Yao, C., Wu, G., Luo, L., Ai, Y., Guo, Z., Li, H., Li, T., Jia, Z., Wang, J., He, L., Liu, B. 2020; 99 (23): e20473


    BACKGROUND: In China, heat-clearing and detoxifying Chinese medicines combined with conventional therapy are commonly applied to treat the mild hand, foot, and mouth disease (HFMD). However, there is lack of solid evidence on the efficacy and safety of such therapies.METHODS: We conducted a pooled analysis with individual patient data from 5 strictly randomized controlled clinical trials to assess the efficacy and safety of this combination therapy for mild HFMD. An intention-to-treat analysis was performed. A 2-stage meta-analysis method was adopted to analyze the pooled effect size.RESULTS: In total, 947 patients were included. Compared with conventional therapy, the combination therapy significantly reduced the progression rate of HFMD from mild to severe (odds ratio [OR] 0.43, 95% confidence interval [CI]: 0.22 to 0.83, P = .01). Meanwhile, the healing time of skin rash and oral ulcer in the combination therapy group was significantly shorter than that of conventional therapy. The overall hazard ratio (HR) of healing time of the skin rash or oral ulcer was 1.22 (95%CI: 1.04 to 1.43; P = .02). However, except Jinlianqingre effervescent tablets, the combination therapy cannot shorten the time to fever resolution (HR 1.12, 95%CI: 0.97 to 1.29, P = .14). Because of the heterogeneity, Jinlianqingre effervescent tablets were analyzed separately and the HRs of the time to fever resolution and the healing time of skin rash or oral ulcer were 3.88 (95%CI: 3.19 to 4.72; P < .0001) and 3.79 (95%CI: 2.81 to 5.11; P < .0001), respectively. There were 30 adverse events reported in total; 2 cases were related to Chinese medicines.CONCLUSION: In conclusion, the heat-clearing and detoxifying Chinese medicines on top of conventional therapy can effectively reduce the progressive rate of mild HFMD and improve healing of skin and oral mucosal lesions. More studies are needed for the time to fever resolution.

    View details for DOI 10.1097/MD.0000000000020473

    View details for PubMedID 32501994

  • Receipt of Eye Care Services among Medicare Beneficiaries with and without Dementia. Ophthalmology Pershing, S., Goldstein, M. K., Henderson, V. W., Bundorf, M. K., Lu, Y., Rahman, M., Stein, J. D. 2020


    PURPOSE: To examine the relationship between dementia status and receipt of eye care among US Medicare beneficiaries.DESIGN: Retrospective, claims-based analysis.PARTICIPANTS: A 20% representative sample of Medicare beneficiaries who received care between January 1, 2006, and December 31,2015.METHODS: Dementia was identified from diagnosis codes documented in a beneficiary's first 3 years of observed Medicare enrollment. Eye care visits were identified from provider specialty codes on each encounter claim. We used multivariable Cox proportional hazards regression models with time-varying covariates to compare the likelihood of receiving eye care between beneficiaries with and without dementia. All models were adjusted for potential confounders, including demographics, urban/rural residence, systemic health (Charlson Index), and ocular comorbidities.MAIN OUTCOME MEASURES: Hazard ratio (HR) and 95% confidence interval (CI) for (1) being seen by any eye care provider (ophthalmologist or optometrist); (2) being seen by an ophthalmologist specifically; and (3) receiving cataract surgery (among beneficiaries with ophthalmologist encounters).RESULTS: A total of 4451200 beneficiaries met inclusion criteria; 3805718 (85.5%) received eye care during the study period, and 391 556 (8.8%) had diagnosed dementia. Some 73.4% of beneficiaries diagnosed with dementia saw an eye care provider during the study period and 55.4% saw an ophthalmologist versus 86.7% and 74.0% of beneficiaries, respectively, without dementia diagnoses. Compared with those without dementia diagnoses, beneficiaries with diagnosed dementia had lower likelihood of seeing any eye care provider (adjusted HR, 0.69; 95% CI, 0.69-0.70) and were less likely to see an ophthalmologist (adjusted HR, 0.55; 95% CI, 0.55-0.55). Among the subset of beneficiaries who did see ophthalmologists, those with diagnosed dementia were also less likely to receive cataract surgery than beneficiaries without diagnosed dementia (HR, 0.62; 95% CI, 0.62-0.63) and less likely to receive a cataract diagnosis (18% vs. 82%).CONCLUSIONS: US Medicare beneficiaries diagnosed with dementia are less likely to receive eye care thanthose without diagnosed dementia. Depending on visual acuity and functional status, this may have implications for injury prevention, physical and cognitive function, and quality of life. Further work is needed to identify barriers to receiving eye care, determine eye care services and settings that provide greatest value topatients with dementia, and implement measures to improve access to appropriate eye care.

    View details for DOI 10.1016/j.ophtha.2020.02.022

    View details for PubMedID 32317179

  • Risk of pre-term births and major birth defects resulting from paternal intake of COVID-19 medications prior to conception. Research square Rizzi, S. n., Wensink, M. J., Lindahl-Jacobsen, R. n., Tian, L. n., Lu, Y. n., Eisenberg, M. n. 2020


    With the ongoing COVID-19 pandemic, large numbers of people will receive one of the several medications proposed to treat COVID-19, including patients of reproductive age. Given that some medications have shown adverse effects on sperm quality, there might be a transgenerational concern. We aim at examining the association between drugs proposed to treat COVID-19 when taken by the father around conception and any pre-term birth or major birth defects in offspring in a nation-wide cohort study using Danish registry data. Offspring whose father filled at least one prescription of the following medications in the three months preceding conception were considered exposed: chloroquine, hydroxychloroquine, losartan, azithromycin, naproxen, dexamethasone and prednisone.For azithromycin and naproxen, large numbers of offspring were exposed (> 1800 offspring), and we found no association with adverse birth outcomes. For chloroquine, losartan and dexamethasone, exposure was intermediate (~ 900 offspring), and there was no statistically significant association with birth defects. For hydroxychloroquine and prednisone, exposure was limited (< 300 offspring). There is strong evidence that azithromycin and naproxen are safe with respect to pre-term birth and birth defects. With some caution, the other drugs investigated can be considered safe.

    View details for DOI 10.21203/

    View details for PubMedID 32869015

    View details for PubMedCentralID PMC7457584

  • A data capture model and its associate study on the public web published COVID-19 data Liang, Z., Zhang, P., Liu, B., Xu, N., Tian, L., Lu, Y., Park, T., Cho, Y. R., Hu, Yoo, Woo, H. G., Wang, J., Facelli, J., Nam, S., Kang, M. IEEE COMPUTER SOC. 2020: 2005-2008
  • Cataract Surgery Complexity and Surgical Complication Rates among Medicare Beneficiaries with and without Dementia. American journal of ophthalmology Pershing, S. n., Henderson, V. W., Goldstein, M. K., Lu, Y. n., Bundorf, M. K., Rahman, M. n., Stein, J. D. 2020


    To evaluate cataract surgery complexity and complications among US Medicare beneficiaries with and without dementia.Retrospective claims-based cohort study PARTICIPANTS: A 20% representative sample of Medicare beneficiaries, 2006-2015.Dementia was identified from diagnosis codes on or prior to each beneficiary's first-eye cataract surgery. For each surgery, we identified setting, routine versus complex coding, anesthesia provider type, duration, and any postoperative hospitalization. We evaluated 30- and 90-day complication rates-return to operating room, endophthalmitis, suprachoroidal hemorrhage, retinal detachment, retinal tear, macular edema, glaucoma, or choroidal detachment-and used adjusted regression models to evaluate likelihood of surgical characteristics and complications. Complications analyses were stratified by second-eye cataract surgery within 90 days postoperatively.We identified 457,128 beneficiaries undergoing first-eye cataract surgery, 23,332 (5.1%) with dementia. None of the evaluated surgical complications were more likely in dementia-diagnosed beneficiaries. There was also no difference in likelihood of non-ambulatory surgery center setting, anesthesiologist provider, or postoperative hospitalization. Dementia-diagnosed beneficiaries were more likely to have surgeries coded as complex (15.6% of cases versus 8.8%, p<0.0001), and surgeries exceeding 30 minutes (OR=1.21, 95%CI=1.17-1.25).Among US Medicare beneficiaries undergoing cataract surgery, those with dementia are more likely to have "complex" surgery" lasting over 30 minutes. However, they do not have greater likelihood of surgical complications, higher-acuity setting, advanced anesthesia care, or postoperative hospitalization. This may be influenced by case selection and may suggest missed opportunities to improve vision. Future research is needed to identify dementia patients likely to benefit from cataract surgery.

    View details for DOI 10.1016/j.ajo.2020.08.025

    View details for PubMedID 32828874

  • Kinetics of SARS-CoV-2 positivity of infected and recovered patients from a single center. Scientific reports Huang, J. n., Zheng, L. n., Li, Z. n., Hao, S. n., Ye, F. n., Chen, J. n., Gans, H. A., Yao, X. n., Liao, J. n., Wang, S. n., Zeng, M. n., Qiu, L. n., Li, C. n., Whitin, J. C., Tian, L. n., Chubb, H. n., Hwa, K. Y., Ceresnak, S. R., Zhang, W. n., Lu, Y. n., Maldonado, Y. A., McElhinney, D. B., Sylvester, K. G., Cohen, H. J., Liu, L. n., Ling, X. B. 2020; 10 (1): 18629


    Recurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive detection in infected but recovered individuals has been reported. Patients who have recovered from coronavirus disease 2019 (COVID-19) could profoundly impact the health care system. We sought to define the kinetics and relevance of PCR-positive recurrence during recovery from acute COVID-19 to better understand risks for prolonged infectivity and reinfection. A series of 414 patients with confirmed SARS-Cov-2 infection, at The Second Affiliated Hospital of Southern University of Science and Technology in Shenzhen, China from January 11 to April 23, 2020. Statistical analyses were performed of the clinical, laboratory, radiologic image, medical treatment, and clinical course of admission/quarantine/readmission data, and a recurrence predictive algorithm was developed. 16.7% recovered patients with PCR positive recurring one to three times, despite being in strict quarantine. Younger patients with mild pulmonary respiratory syndrome had higher risk of PCR positivity recurrence. The recurrence prediction model had an area under the ROC curve of 0.786. This case series provides characteristics of patients with recurrent SARS-CoV-2 positivity. Use of a prediction algorithm may identify patients at high risk of recurrent SARS-CoV-2 positivity and help to establish protocols for health policy.

    View details for DOI 10.1038/s41598-020-75629-x

    View details for PubMedID 33122706

  • Intraoperative Imaging with a Portable Gamma Camera May Reduce the False-Negative Rate for Melanoma Sentinel Lymph Node Surgery (vol 25, pg 3326, 2018) ANNALS OF SURGICAL ONCOLOGY Leong, S. P., Wu, M., Lu, Y., Torre, D. M., von Bakonyi, A., Ospina, A. M., Newsom, J. D., Luckett, W. S., Soon, C. W., Kim, K. B., Kashani-Sabet, M. 2019; 26: S883
  • Accelerated Cord Atrophy Precedes Conversion to Secondary Progressive Disease in Relapsing Multiple Sclerosis Bischof, A., Papinutto, N., Keshavan, A., Zhang, X., Rajesh, A., Sacco, S., Kirkish, G., Gundel, T., Stern, W., Caverzasi, E., Zhao, C., Zhou, Y., Lu, Y., Gomez, R., Ragan, N., Santaniello, A., Zhu, A., Juwono, J., Bevan, C., Bove, R., Crabtree-Hartman, E., Gelfand, J., Goodin, D., Graves, J., Oksenberg, J., Waubant, E., Wilson, M., Zamvil, S., Green, A., Cree, B., Hauser, S., Henry, R. LIPPINCOTT WILLIAMS & WILKINS. 2019
  • Correction to: Intraoperative Imaging with a Portable Gamma Camera May Reduce the False-Negative Rate for Melanoma Sentinel Lymph Node Surgery. Annals of surgical oncology Leong, S. P., Wu, M., Lu, Y., Torre, D. M., von Bakonyi, A., Ospina, A. M., Newsom, J. D., Luckett, W. S., Soon, C. W., Kim, K. B., Kashani-Sabet, M. 2019


    The article "Intraoperative Imaging with a Portable Gamma Camera May Reduce the False-Negative Rate for Melanoma Sentinel Lymph Node Surgery," written by Stanley P. Leong et al., was originally published electronically on the publisher's internet portal (currently SpringerLink) on August 13, 2018, without open access.

    View details for PubMedID 30805804

  • An XHTML Solution for a Secure EDC System for Traditional Chinese Medicine Clinics Based on ICD-11 MMS Database and E-Signature Liang, Z., Kong, J., Xu, N., Liu, B., Lu, Y., Yoo, I. H., Bi, J. B., Hu IEEE. 2019: 2634–41
  • Accelerated cord atrophy precedes conversion to secondary progressive disease in relapsing multiple sclerosis Bischof, A., Papinutto, N., Keshavan, A., Zhang, X., Rajesh, A., Sacco, S., Kirkish, G., Gundel, T., Stern, W., Caverzasi, E., Zhao, C., Zhou, Y., Lu, Y., Gomez, R., Ragan, N., Santaniello, A., Zhu, A., Juwono, J., Bevan, C., Bove, R., Crabtree, E., Gelfand, J., Goodin, D., Graves, J., Oksenberg, J., Waubant, E., Wilson, M., Zamvil, S., Green, A., Cree, B., Hauser, S., Henry, R. SAGE PUBLICATIONS LTD. 2018: 992–93
  • Intraoperative Imaging with a Portable Gamma Camera Reduces the False-negative Rate for Melanoma Sentinel Lymph Node Surgery Leong, S. P., Max, W., Lu, Y., Torre, D. M., von Bakonyi, A., Wight, A., Newson, J., Luckett, W., Kashani-Sabet, M. SPRINGER. 2018: S66
  • Local warming therapy for treating chronic wounds: A systematic review. Medicine Yue, J. H., Zhang, S. J., Sun, Q. n., Sun, Z. R., Wang, X. X., Golianu, B. n., Lu, Y. n., Zhang, Q. n. 2018; 97 (12): e9931


    Several studies suggest that local warming therapy (LWT) may help to treat chronic wounds, such as pressure ulcers, venous ulcers, arterial ulcers, and diabetic foot ulcers. However, evidence supporting the efficacy of this treatment is still incomplete. This study aimed to assess the effects of LWT in treating chronic wounds.For this review, we searched the Cochrane Wounds Specialized Register (March 6, 2017); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2017 issue 3); Ovid MEDLINE (1946 to March 6, 2017); Ovid Embase (1974 to March 6, 2017); EBSCO CINAHL (1982 to March 6, 2017); Chinese Biomedical Literature Database (1980 to March 20, 2017); China National Knowledge Infrastructure (1980 to March 20, 2017); VIP Information (1980 to March 20, 2017) (Chinese Database); and Wanfang Data (1980 to March 20, 2017). We did not apply date or language restrictions. Published or unpublished randomized controlled trials (RCTs) analyzing the effects of LWT in the treatment of chronic wounds (pressure ulcers, venous ulcers, arterial ulcers, and diabetic foot ulcers) were screened and selected. Two review authors independently conducted study selection, we planned that 2 review authors would also assess risk of bias and extract study data.No studies (RCTs) met the inclusion criteria for this review. Thus, it was impossible to undertake a meta-analysis or a narrative description of studies.The effects of LWT for treating chronic wounds are unclear because we did not identify any studies that met the inclusion criteria for this review. Quality improvement for LWT trials is urgently needed.

    View details for PubMedID 29561463

  • Updated systematic review and meta-analysis of acupuncture for chronic knee pain. Acupuncture in medicine : journal of the British Medical Acupuncture Society Zhang, Q. n., Yue, J. n., Golianu, B. n., Sun, Z. n., Lu, Y. n. 2017; 35 (6): 392–403


    To assess the effectiveness and safety of acupuncture for the treatment of chronic knee pain (CKP).We searched the MEDLINE, EMBASE, Cochrane CENTERAL, CINAHL and four Chinese medical databases from their inception to June 2017. We included randomised controlled trials of acupuncture as the sole treatment or as an adjunctive treatment for CKP. The primary outcome was pain intensity measured by visual analogue scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale and 11-point numeric rating scale. Secondary outcome measurements included the 36-Item Short Form Health Survey and adverse events. The quality of all included studies was evaluated using the Cochrane risk-of-bias criteria and the STRICTA (Standards for Reporting Interventions in Controlled Trials of Acupuncture) checklist.Nineteen trials were included in this systematic review. Of these, data from 17 studies were available for analysis. Regarding the effectiveness of acupuncture alone or combined with other treatment, the results of the meta-analysis showed that acupuncture was associated with significantly reduced CKP at 12 weeks on WOMAC pain subscale (mean difference (MD) -1.12, 95% confidence interval (CI) -1.98 to -0.26, I2=62%, 3 trials, 608 participants) and VAS (MD -10.56, 95% CI -17.69 to -3.44, I2=0%, 2 trials, 145 patients). As for safety, no difference was found between the acupuncture and control groups (risk ratio 1.08, 95% CI 0.54 to 2.17, I2=29%).From this systematic review, we conclude that acupuncture may be effective at relieving CKP 12 weeks after acupuncture administration, based on the current evidence and our protocol. However, given the heterogeneity and methodological limitations of the included trials, we are currently unable to draw any strong conclusions regarding the effectiveness of acupuncture for chronic knee pain. In addition, we found that acupuncture appears to have a satisfactory safety profile, although further studies with larger numbers of participants are needed to confirm the safety of this technique.Systematic review without language restrictions.Only a few high-quality and consistent trials could be included in this review.

    View details for PubMedID 29117967

  • Extended report: Short-term changes on MRI predict long-term changes on radiography in rheumatoid arthritis: an analysis by an OMERACT Task Force of pooled data from four randomised controlled trials Ann Rheum Dis Peterfy, C. G., Strand, V., Tian, L., Ostergaard, M., Lu, Y., et al 2016
  • Acupuncture treatment for chronic knee pain: study by Hinman et al underestimates acupuncture efficacy. Acupuncture in medicine Zhang, Q., Yue, J., Lu, Y. 2015; 33 (2): 170-?

    View details for DOI 10.1136/acupmed-2015-010776

    View details for PubMedID 25742694

  • Establishing a data monitoring committee for clinical trials. Shanghai archives of psychiatry Lin, J. Y., Lu, Y. 2014; 26 (1): 54-56


    A data monitoring committee (DMC) is a group of clinicians and biostatisticians appointed by study sponsors who provide independent assessment of the safety, scientific validity and integrity of clinical trials. In the United States, the Food and Drug Administration requires the formation of DMC in all trials that assess new interventions. DMC are also strongly recommended in other clinical studies that have substantial safety issues, that have double-blind treatment assignment or that are expected to have a major impact on clinical practice. They are important in clinical research in psychiatry because they provide an added layer of protection for the vulnerable populations that are often enrolled in such studies. This report describes the role, formation and operation of DMC.

    View details for DOI 10.3969/j.issn.1002-0829.2014.01.009

    View details for PubMedID 25114483

    View details for PubMedCentralID PMC4118004

  • CT of acute appendicitis: can diagnostic accuracy serve as a practical performance metric for readers specialized in abdominal imaging? CLINICAL IMAGING Chu, L. L., Webb, E. M., Stengel, J. W., Yeh, B. M., Lu, Y., Coakley, F. V. 2014; 38 (1): 56-59


    To investigate diagnostic accuracy for acute appendicitis at computed tomography (CT) as a performance metric for radiologists specialized in abdominal imaging.We retrospectively identified six attending abdominal imagers who each independently interpreted over 100 CT studies for suspected acute appendicitis.The mean number of studies per reader was 311 (range, 129-386). Mean reader diagnostic accuracy was 95.0% (range, 91.4-97.1%). Only one had a diagnostic accuracy (91.4%) that was significantly lower than all others.Diagnostic accuracy for acute appendicitis at CT may be an impractical performance metric for radiologists specialized in abdominal imaging.

    View details for DOI 10.1016/j.clinimag.2013.08.014

    View details for Web of Science ID 000328314100010

    View details for PubMedID 24080371

  • Features of Occult Invasion in Biopsy-Proven DCIS at Breast MRI BREAST JOURNAL Wisner, D. J., Hwang, E. S., Chang, C. B., Tso, H. H., Joe, B. N., Lessing, J. N., Lu, Y., Hylton, N. M. 2013; 19 (6): 650-658


    The purpose of this study is to determine if MRI BI-RADS criteria or radiologist perception correlate with presence of invasive cancer after initial core biopsy of ductal carcinoma in situ (DCIS). Retrospective search spanning 2000-2007 identified all core-biopsy diagnoses of pure DCIS that coincided with preoperative MRI. Two radiologists fellowship-trained in breast imaging categorized lesions according to ACR MRI BI-RADS lexicon and estimated likelihood of occult invasion. Semiquantitative signal enhancement ratio (SER) kinetic analysis was also performed. Results were compared with histopathology. 51 consecutive patients with primary core biopsy-proven DCIS and concurrent MRI were identified. Of these, 13 patients (25%) had invasion at excision. Invasion correlated significantly with presence of a mass for both readers (p = 0.012 and 0.001), rapid initial enhancement for Reader 1 (p = 0.001), and washout kinetics for Reader 2 (p = 0.012). Significant correlation between washout and invasion was confirmed by SER (p = 0.006) when threshold percent enhancement was sufficiently high (130%), corresponding to rapidly enhancing portions of the lesion. Radiologist perception of occult invasion was strongly correlated with true presence of invasion. These results provide evidence that certain BI-RADS MRI criteria, as well as radiologist perception, correlate with occult invasion after an initial core biopsy of DCIS.

    View details for DOI 10.1111/tbj.12201

    View details for Web of Science ID 000326029000012

    View details for PubMedID 24165314

  • Effects of age and sex on the strength and cortical thickness of the femoral neck BONE Carpenter, R. D., Sigurdsson, S., Zhao, S., Lu, Y., Eiriksdottir, G., Sigurdsson, G., Jonsson, B. Y., Prevrhal, S., Harris, T. B., Siggeirsdottir, K., Guonason, V., Lang, T. F. 2011; 48 (4): 741-747


    A group of 48 men (22 aged 65-75 years, 26 aged 80-90 years) and 59 women (32 aged 65-75 years, 27 aged 80-90 years) were enrolled in the Age, Gene/Environment Susceptibility-Reykjavik study and imaged with in vivo volumetric Quantitative Computed Tomography (QCT) to investigate the effects of age and sex on femoral neck structure and strength. Femoral neck cross-sectional moment of inertia for bending directions near those of standing and walking (I(AP)), bending strength (M(y)), and axial compressive strength (F(y)) were computed at the location of minimum cross-sectional area (minCSA). Local cortical thickness was computed in the inferior femoral neck based on density profiles extending through the cortex of the minCSA femoral neck section. Multivariate models accounting for height, weight, and age group (younger or older) showed that men had a 46% higher M(y) and a 23% higher F(y) than women, while women had a 13% thicker inferior cortex than men. Cortical thickness in the inferoposterior region of the femoral neck was significantly related to bending and axial strength after adjusting for overall volumetric bone mineral density. Both minCSA and I(AP) were higher in the older, gender-pooled age group, but F(y) and M(y) did not differ between the two age groups. The results suggest that age-related expansion of the femoral neck primarily occurs in the superior and inferior directions and helps maintain homeostasis of femoral neck stiffness and strength. The higher bending strength of the male femoral neck may partly explain why elderly men have a lower risk of hip fracture than elderly women.

    View details for DOI 10.1016/j.bone.2010.12.004

    View details for Web of Science ID 000288920900008

    View details for PubMedID 21168538

    View details for PubMedCentralID PMC3075958

  • MR Spectroscopy of Normative Premature Newborns JOURNAL OF MAGNETIC RESONANCE IMAGING Xu, D., Bonifacio, S. L., Charlton, N. N., Vaughan, C. P., Lu, Y., Ferriero, D. M., Vigneron, D. B., Barkovich, A. J. 2011; 33 (2): 306-311


    To establish normative metabolite ratios throughout the newborn brain using three-dimensional (3D) MR spectroscopic imaging (MRSI).MRI and MRSI have been valuable tools for assessing normal and abnormal neuronal maturation for newborns. In this study, we performed whole brain 3D MRSI in addition to comprehensive anatomic and other functional imaging methods to examine maturation. Fifty-five newborn subjects (28.4 ± 2.6 weeks postconception age at birth, 34.1 ± 3.1 weeks postconception age at scan, 32 males and 23 females) had high quality MRSI studies (104 exams) and normal neurodevelopmental outcome (neuromotor score = 0, mental development index score > 85) at age 12 months.The NAA to Cho ratio increased significantly with age for all regions. Lac to NAA ratio decreased significantly with age in the regions of thalamus, basal ganglia, cortical spinal tract, and parietal white matter, and showed a decreasing trend in the other regions.Brain metabolites can be obtained through in vivo 3D MRSI and used to monitor newborn brain maturation.

    View details for DOI 10.1002/jmri.22460

    View details for Web of Science ID 000286953300005

    View details for PubMedID 21274971

    View details for PubMedCentralID PMC3391540

  • Intraoperative Frozen Section Analysis of Sentinel Lymph Nodes in Breast Cancer Patients CANCER Liu, L., Lang, J. E., Lu, Y., Roe, D., Hwang, S. E., Ewing, C. A., Esserman, L. J., Morita, E., Treseler, P., Leong, S. P. 2011; 117 (2): 250-258


    Accurate intraoperative pathologic examination of sentinel lymph nodes (SLNs) has been an important tool that can reduce the need for reoperations in patients with SLN-positive breast cancer. The objective of the current study was to determine the accuracy of intraoperative frozen section (IFS) of SLNs during breast cancer surgery.The authors retrospectively reviewed the records of 326 patients with breast cancer who underwent IF analysis of SLNs at a single institution. Then, they conducted a meta-analysis that included 47 published studies of IFS of SLNs in patients with breast cancer.Hematoxylin and eosin (H&E) staining revealed metastasis in SLNs in 99 patients (30.4%), including 61 patients with macrometastasis (MAM) (>2 mm) (the MAM group) and 38 patients with micrometastasis (Mi) or isolated tumor cell (ITC) deposits (the Mi/ITC group). The overall sensitivity of the institutional series was 60.6% (60 of 99 patients), and overall specificity was 100% (227 of 227 true negatives). The sensitivity of IFS was significantly lower in the Mi/ITC group (28.9%) than in the MAM group (80.3%; P < .0001). According to the meta-analysis of published studies and data from the author's institution (47 studies, for a total of 13,062 patients who underwent SLN dissection with IFS of SLNs), the mean sensitivity was 73%, and the mean specificity was 100%. The mean sensitivity was 94% for the MAM group and 40% for the Mi/ITC group.IFS of SLNs was more reliable for detecting MAM than for detecting Mi/ITC deposits. It lacked sufficient accuracy to rule out Mi/ITC deposits.

    View details for DOI 10.1002/cncr.25606

    View details for Web of Science ID 000285976100003

    View details for PubMedID 20818649

  • Comparison of the Geneat-modified Sharp and van der Heijde-modified Sharp scoring methods for radiographic assessment in rheumatoid arthritis International Journal of Clinical Rheumatology Peterfy CG, Wu C; Szechinski J; DiCarlo J; Lu Y; Genovese M; Strand V; Genant HK 2011; 6 (1): 15-24
  • Selection of Tumorigenic Melanoma Cells Using ALDH JOURNAL OF INVESTIGATIVE DERMATOLOGY Boonyaratanakornkit, J. B., Yue, L., Strachan, L. R., Scalapino, K. J., LeBoit, P. E., Lu, Y., Leong, S. P., Smith, J. E., Ghadially, R. 2010; 130 (12): 2799-2808


    Despite increasing knowledge regarding melanoma-initiating cells (MICs), questions persist regarding the number and phenotypic nature of cells with tumor-generating capability. Evidence for a phenotypically distinct human MIC has been found in NOD/SCID (non-obese diabetic/severe combined immunodeficiency) mice. However, a phenotypically distinct human MIC was not found in the NOD/SCIDIl2rg(-)/(-) (NSG) mouse model. The demonstration of a distinct population of human melanoma cells responsible for tumorigenesis and tumor cell self-renewal would provide an important target for new melanoma therapies. In this study, we show a 100-fold range in MIC frequency in human melanoma (1 in 18,000 to 1 in 1,851,000 cells) in the NOD/SCID mouse. In this model, human melanoma cells with high aldehyde dehydrogenase (ALDH) activity were enriched 16.8-fold in tumorigenic cells over unfractionated (UNF) cells, such that 1 in 21,000 cells was a MIC. In the NSG mouse, the ALDH expressing cell population was enriched 100-fold in tumorigenic cells over UNF cells, such that one in four cells was a MIC. Xenograft melanomas that developed from ALDH(+) cells displayed robust self-renewal, whereas those from ALDH(-) cells showed minimal self-renewal in vitro. Thus, ALDH(+) melanoma cells have enhanced tumorigenicity over ALDH(-) cells and superior self-renewal ability.

    View details for DOI 10.1038/jid.2010.237

    View details for Web of Science ID 000284151000018

    View details for PubMedID 20739950

  • Dual-Energy X-ray Absorptiometry With Serum Ferritin Predicts Liver Iron Concentration and Changes in Concentration Better Than Ferritin Alone JOURNAL OF CLINICAL DENSITOMETRY Shepherd, J. A., Fan, B., Lu, Y., Marquez, L., Salama, K., Hwang, J., Fung, E. B. 2010; 13 (4): 399-406


    Accurate assessment of liver iron concentration (LIC) is critical for optimal monitoring of iron toxicity in multitransfused patients. Serum ferritin is the most widely used although its association to LIC is only modest. We studied if a liver-specific measure using dual-energy X-ray absorptiometry (DXA) systems could improve LIC estimates over ferritin alone in Thalassemia (Thal) patients. Thirty-seven patients with Thal (19.2 ± 9.0 yr, 20 male) were studied and 10 had multiple visits. Height, weight, ferritin, whole-body DXA, and hepatic superconducting quantum interference device (SQUID) were measured within 5 wk. DXA hepatic density was measured using right rib, whole liver, and multiple subliver regions. The best agreement to SQUID LIC was found using a combination of ferritin, weight, DXA subliver region 3 bone mineral content (BMC), and right rib BMC. DXA with ferritin improved the ferritin alone correlation from R(2)=0.35 to R(2)=0.62. Serial LIC changes using DXA were associated with serial SQUID changes (r=0.73, p=0.02). Changes in ferritin alone were not significant (p=0.06). We conclude that the addition of whole-body DXA measures and body weight substantially increased the accuracy of LIC and change in LIC estimates over the use of ferritin alone and could be useful when magnetic resonance imaging or SQUID is not available.

    View details for DOI 10.1016/j.jocd.2010.05.003

    View details for Web of Science ID 000283892400011

    View details for PubMedID 20663700

  • Diagnostic accuracy of dual-source CT coronary angiography: The effect of average heart rate, heart rate variability, and calcium score in a clinical perspective ACTA RADIOLOGICA Zhang, L., Wu, S., Wang, J., Lu, Y., Zhang, Z., Jiang, S., Zhou, C., Lu, G. 2010; 51 (7): 727-740


    Dual-source CT coronary angiography (CTCA) has been used to detect coronary artery disease; however, the factors with potential to affect its diagnostic accuracy remain to be defined.To prospectively evaluate the accuracy of dual-source CTCA in diagnosing coronary artery stenosis according to conventional coronary angiography (CAG), and the effect of average heart rate, heart rate variability, and calcium score on the accuracy of CTCA.A total of 113 patients underwent both dual-source CTCA and CAG. The results were used to evaluate the findings in dual-source CTCA to assess the accuracy in the diagnosis of > or =50% (significant stenosis) and >75% (severe stenosis) of coronary artery according to those by CAG. Patients were divided into subgroups according to their heart rate (HR), HR variability (HRV), and calcium score, and the accuracy of CTCA was further evaluated. The chi-square test was used to analyze the difference in sensitivity and specificity for the detection of > or =50% and >75% coronary stenosis among subgroups. The generalized estimation equation method was used in per-vessel analysis to adjust for within-patient correlation.In all, 113 patients had 338 vessels and 1661 segments evaluated by CAG. Dual-source CTCA displayed 1527 segments (91.9%). Among them, 1468 segments (calcium score by CAG score 1, n=1018; score 2, n=270; score 3, n=180) were assessable in CTCA. On a per-patient analysis, the sensitivity and specificity of CTCA were 93.9% and 93.5% for significant stenosis and 86.9% and 98.1% for severe stenosis. On a per-vessel basis, the sensitivity and specificity were 90.2% and 97.1% for significant and 83.3% and 98.1% for severe stenosis. On a per-segment analysis, the sensitivity and specificity were 90.2% and 97.1% for significant and 83.3% and 98.1% for severe stenosis. Average HR had no effect on the sensitivity and specificity of CTCA (P>0.05); whereas HRV and calcium score had some effect on the sensitivity and specificity of CTCA (P<0.05).On a per-patient, per-vessel, and per-segment basis, dual-source CTCA has a high sensitivity and specificity for the diagnosis of coronary artery stenosis. Average HR has no effect on the diagnostic accuracy of CTCA, while HRV and calcium score have a statistically significant effect on the sensitivity and specificity of CTCA.

    View details for DOI 10.3109/02841851.2010.492792

    View details for Web of Science ID 000281771500003

    View details for PubMedID 20707657

  • Densitometric and geometric measurement of the proximal femur in elderly women with and without osteoporotic vertebral fractures by volumetric quantitative multi-slice CT JOURNAL OF BONE AND MINERAL METABOLISM Wu, S., Qi, J., Lu, Y., Lan, J., Yu, J., Wen, L., Zhang, Z. 2010; 28 (6): 682-689


    There is a lack of research on volumetric multi-slice CT (MSCT) application in hip densitometric assessment and geometric measures in elderly women with osteoporotic vertebral fractures. A total of 237 elderly women were divided into three groups based on BMD values of the lumbar spine (AP-SPINE) and/or the femoral neck (NECK) by dual energy X-ray absorptiometry (DXA): osteoporosis with (OP_FX, 53 cases) or without vertebral fracture (OP_NONFX, 94 cases), or normal BMD (CONTROL, 90 cases). Volumetric BMD of trabecular bone (TRAB), integral bone (INTGL) and cortical bone (CORT) with neck axis length (NAL) and minimum cross-section area (mCSA) measures of the left femoral neck were calculated, respectively, by using OsteoCAD software based on MSCT scans of the abdominal-pelvic region of all participants, then the index of femoral neck strength (FNSI) was estimated. The values of TRAB, CORT and INTGL of OP_FX were significantly lower than those of OP_NONFX, with the decrease in 6.8-21.8%, as well as being lower than those in CONTROL, whereas no significant differences in the values of AP-SPINE and NECK were found between OP_FX and OP_NONFX. No significant difference of the value of mCSA was found among these three groups. The NAL value of OP_NONFX was larger than that of CONTROL. FNSI of femoral neck in OP_FX (0.42 ± 0.15 g(2)/cm(4)) was significantly lower than OP_NONFX (0.50 ± 0.14 g(2)/cm(4)) (p < 0.05). vQCT measurement seemed to be more effective than DXA in evaluating hip densitometric changes and discriminating osteoporotic elderly subjects with fractured vertebrae from the non-fractured in a group of Chinese women.

    View details for DOI 10.1007/s00774-010-0174-3

    View details for Web of Science ID 000285859400010

    View details for PubMedID 20369370

  • Labeling Human Embryonic Stem Cell-Derived Cardiomyocytes With Indocyanine Green for Noninvasive Tracking With Optical Imaging: An FDA-Compatible Alternative to Firefly Luciferase CELL TRANSPLANTATION Boddington, S. E., Henning, T. D., Jha, P., Schlieve, C. R., Mandrussow, L., DeNardo, D., Bernstein, H. S., Ritner, C., Golovko, D., Lu, Y., Zhao, S., Daldrup-Link, H. E. 2010; 19 (1): 55-65


    Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) have demonstrated the ability to improve myocardial function following transplantation into an ischemic heart; however, the functional benefits are transient possibly due to poor cell retention. A diagnostic technique that could visualize transplanted hESC-CMs could help to optimize stem cell delivery techniques. Thus, the purpose of this study was to develop a labeling technique for hESCs and hESC-CMs with the FDA-approved contrast agent indocyanine green (ICG) for optical imaging (OI). hESCs were labeled with 0.5, 1.0, 2.0, and 2.5 mg/ml of ICG for 30, 45, and 60 min at 37 degrees C. Longitudinal OI studies were performed with both hESCs and hESC-CMs. The expression of surface proteins was assessed with immunofluorescent staining. hESCs labeled with 2 mg ICG/ml for 60 min achieved maximum fluorescence. Longitudinal studies revealed that the fluorescent signal was equivalent to controls at 120 h postlabeling. The fluorescence signal of hESCs and hESC-CMs at 1, 24, and 48 h was significantly higher compared to precontrast data (p < 0.05). Immunocytochemistry revealed retention of cell-specific surface and nuclear markers postlabeling. These data demonstrate that hESCs and hESC-CMs labeled with ICG show a significant fluorescence up to 48 h and can be visualized with OI. The labeling procedure does not impair the viability or functional integrity of the cells. The technique may be useful for assessing different delivery routes in order to improve the engraftment of transplanted hESC-CMs or other stem cell progenitors.

    View details for DOI 10.3727/096368909X

    View details for Web of Science ID 000276592500007

    View details for PubMedID 20370988

    View details for PubMedCentralID PMC2939828

  • Transit-Amplifying Cell Frequency and Cell Cycle Kinetics Are Altered in Aged Epidermis JOURNAL OF INVESTIGATIVE DERMATOLOGY Charruyer, A., Barland, C. O., Yue, L., Wessendorf, H. B., Lu, Y., Lawrence, H. J., Mancianti, M. L., Ghadially, R. 2009; 129 (11): 2574-2583


    Aged epidermis is less proliferative than young, as exemplified by slower wound healing. However, it is not known whether quantitative and/or qualitative alterations in the stem and/or transit-amplifying (TA) compartments are responsible for the decreased proliferation. Earlier studies found a normal or decreased frequency of putative epidermal stem cells (EpiSCs) with aging. We show, using long-term repopulation in vivo and colony formation in vitro, that, although no significant difference was detected in EpiSC frequency with aging, TA cell frequency is increased. Moreover, aged TA cells persist longer, whereas their younger counterparts have already differentiated. Underlying the alteration in TA cell kinetics in the aged is an increase in the proportion of cycling keratinocytes, as well as an increase in cell cycle duration. In summary, although no significant difference in EpiSC frequency was found, TA cell frequency was increased (as measured by in vivo repopulation, growth fraction, and colony formation). Furthermore, the proliferative capacity (cellular output) of individual aged EpiSCs and TA cells was decreased compared to that of young cells. Although longer cell cycle duration contributes to the decreased proliferative output from aged progenitors, the greater number of TA cells may be a compensatory mechanism tending to offset this deficit.

    View details for DOI 10.1038/jid.2009.127

    View details for Web of Science ID 000270982900010

    View details for PubMedID 19458632

  • MRI of the Spine: Image Quality and Normal-Neoplastic Bone Marrow Contrast at 3 T Versus 1.5 T AMERICAN JOURNAL OF ROENTGENOLOGY Zhao, J., Krug, R., Xu, D., Lu, Y., Link, T. M. 2009; 192 (4): 873-880


    The objectives of our study were to compare image quality of the spine and visualization of spine abnormalities at 3 T and 1.5 T as well as to evaluate differences in quantitative assessment of normal and neoplastic vertebral bone marrow.One hundred nine MR examinations of the spine were performed at 1.5 T and 3 T in the same patients within a time interval of less than 3 months. Visualization of anatomic and pathologic structures was analyzed by two radiologists. Normal and pathologic bone marrow was assessed on T1-weighted fast spin-echo (FSE) sequences. The signal intensity contrast of neoplastic bone marrow versus normal vertebral bone marrow was measured at 1.5 T versus 3 T. Sensitivity, specificity, and accuracy with 95% CIs were computed to assess the performance of muscle and disk as standards to differentiate between neoplastic and normal bone marrow on T1-weighted sequences at 1.5 T and 3 T.For all anatomic structures evaluated, image quality was rated significantly higher at 3 T than at 1.5 T, with 71.6% of the studies overall being superior at 3 T. The contrast between normal and pathologic bone marrow was significantly larger at 3 T (mean +/- SD, 0.33 +/- 0.13) than at 1.5 T (0.27 +/- 0.11). The highest accuracy was found using muscle signal at 3 T to differentiate between normal and pathologic bone marrow.The use of 3-T MRI improves visualization of anatomic structures in the spine over 1.5-T MRI. As an internal standard on T1-weighted FSE images, skeletal muscle can be used to differentiate between infiltrative and normal bone marrow with higher accuracy at 3 T than at 1.5 T.

    View details for DOI 10.2214/AJR.08.1750

    View details for Web of Science ID 000264358900008

    View details for PubMedID 19304689



    To evaluate whether pretreatment combined endorectal magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging (MRSI) findings are predictive of outcome in patients who undergo external beam radiotherapy for prostate cancer.We retrospectively identified 67 men with biopsy-proven prostate cancer who underwent combined endorectal MRI and MRSI at our institution between January 1998 and October 2003 before whole-pelvis external beam radiotherapy. A single reader recorded tumor presence, stage, and metabolic abnormality at combined MRI and MRSI. Kaplan-Meier survival and Cox univariate and multivariate analyses explored the relationship between clinical and imaging variables and outcome, using biochemical or metastatic failure as endpoints.After a mean follow-up of 44 months (range, 3-96), 6 patients developed both metastatic and biochemical failure, with an additional 13 patients developing biochemical failure alone. Multivariate Cox analysis demonstrated that the only independent predictor of biochemical failure was the volume of malignant metabolism on MRSI (hazard ratio [HR] 1.63, 95% confidence interval [CI] 1.29-2.06; p < 0.0001). The two independent predictors of metastatic failure were MRI tumor size (HR 1.34, 95% CI 1.03-1.73; p = 0.028) and the finding of seminal vesicle invasion on MRI (HR 28.05, 95% CI 3.96-198.67; p = 0.0008).In multivariate analysis, MRI and MRSI findings before EBRT in patients with prostate cancer are more accurate independent predictors of outcome than clinical variables, and in particular, the findings of seminal vesicle invasion and extensive tumor predict a worse prognosis.

    View details for DOI 10.1016/j.ijrobp.2008.04.056

    View details for Web of Science ID 000263440900006

    View details for PubMedID 18760545

    View details for PubMedCentralID PMC2737354

  • Evaluation of diffuse liver steatosis by ultrasound, computed tomography, and magnetic resonance imaging: which modality is best? CLINICAL IMAGING Qayyum, A., Chen, D. M., Breiman, R. S., Westphalen, A. C., Yeh, B. M., Jones, K. D., Lu, Y., Coakley, F. V., Callen, P. W. 2009; 33 (2): 110-115


    To compare ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) determination of diffuse liver steatosis.Quantification of liver steatosis on ultrasound, CT, and MRI was correlated with histopathology in 67 patients.Opposed-phase MRI demonstrated the highest correlation with steatosis (0.68 and 0.69, P<.01; intraclass correlation coefficient, 0.93). Spearman's correlation (and intraclass correlation) coefficients were lowest for ultrasound [0.54, 0.33 (0.40)] and enhanced CT [0.33, 0.39 (0.97)].Opposed-phase MRI demonstrated best overall performance for determining steatosis.

    View details for DOI 10.1016/j.clinimag.2008.06.036

    View details for Web of Science ID 000264016200005

    View details for PubMedID 19237053

    View details for PubMedCentralID PMC2743961

  • Diagnostic value of PET/CT for the staging and restaging of pediatric tumors EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING Kleis, M., Daldrup-Link, H., Matthay, K., Goldsby, R., Lu, Y., Schuster, T., Schreck, C., Chu, P. W., Hawkins, R. A., Franc, B. L. 2009; 36 (1): 23-36


    The objective of this retrospective study was to compare the diagnostic value of 2-[(18)F]fluoro-2-deoxy-D: -glucose positron emission tomography ((18)F-FDG PET)/CT versus (18)F-FDG PET and CT alone for staging and restaging of pediatric solid tumors.Forty-three children and adolescents (19 females and 24 males; mean age, 15.2 years; age range, 6-20 years) with osteosarcoma (n = 1), squamous cell carcinoma (n = 1), synovial sarcoma (n = 2), germ cell tumor (n = 2), neuroblastoma (n = 2), desmoid tumor (n = 2), melanoma (n = 3), rhabdomyosarcoma (n = 5), Hodgkin's lymphoma (n = 7), non-Hodgkin-lymphoma (n = 9), and Ewing's sarcoma (n = 9) who had undergone (18)F-FDG PET/CT imaging for primary staging or follow-up of metastases were included in this study. The presence, location, and size of primary tumors was determined separately for PET/CT, PET, and CT by two experienced reviewers. The diagnosis of the primary tumor was confirmed by histopathology. The presence or absence of metastases was confirmed by histopathology (n = 62) or clinical and imaging follow-up (n = 238).The sensitivities for the detection of solid primary tumors using integrated (18)F-FDG PET/CT (95%), (18)F-FDG PET alone (73%), and CT alone (93%) were not significantly different (p > 0.05). Seventeen patients showed a total of 153 distant metastases. Integrated PET/CT had a significantly higher sensitivity for the detection of these metastases (91%) than PET alone (37%; p < 0.05), but not CT alone (83%; p > 0.05). When lesions with a diameter of less than 0.5 cm were excluded, PET/CT (89%) showed a significantly higher specificity compared to PET (45%; p < 0.05) and CT (55%; p < 0.05). In a sub-analysis of pulmonary metastases, the values for sensitivity and specificity were 90%, 14%, 82% and 63%, 78%, 65%, respectively, for integrated PET/CT, stand-alone PET, and stand-alone CT. For the detection of regional lymph node metastases, (18)F-FDG PET/CT, (18)F-FDG PET alone, and CT alone were diagnostically correct in 83%, 61%, and 42%. A sub-analysis focusing on the ability of PET/CT, PET, and CT to detect osseous metastases showed no statistically significant difference between the three imaging modalities (p > 0.05).Our study showed a significantly increased sensitivity of PET/CT over that of PET for the detection of distant metastases but not over that of CT alone. However, the specificity of PET/CT for the characterization of pulmonary metastases with a diameter > 0.5 cm and lymph node metastases with a diameter of <1 cm was significantly increased over that of CT alone.

    View details for DOI 10.1007/s00259-008-0911-1

    View details for Web of Science ID 000261422600004

    View details for PubMedID 18719909

  • Is It Necessary to Harvest Additional Lymph Nodes after Resection of the Most Radioactive Sentinel Lymph Node in Breast Cancer? JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS Liu, L., Lang, J. E., Jenkins, T., Lu, Y., Ewing, C. A., Hwang, S. E., Sokol, S., Alvarado, M., Esserman, L. J., Morita, E., Treseler, P., Leong, S. P. 2008; 207 (6): 853-858


    No consensus exists about the number of sentinel lymph nodes (SLNs) that should be removed based on radioactivity counts in breast cancer, although the "10% rule" is often used. We hypothesized that the node with the highest radioactivity would have the strongest probability of being a positive SLN, and we sought to determine the lowest radioactive count of a node harboring cancer.We retrospectively studied 332 breast cancer patients who underwent lymphoscintigraphy by injection of technetium 99m-labeled thiosulfate colloid and sentinel lymphadenectomy (SL) between 1997 and 2006, with intraoperative determination of radioactive counts of nodes by a gamma probe. All SLNs were examined by permanent sections consisting of at least 3 levels of 40- to 100-mum intervals for hematoxylin and eosin evaluation, with or without immunohistochemical staining for cytokeratins.Seventy-four percent of patients had more than 1 SLN removed (mean 2.8 per patient); 23.5% had SLN metastasis. Of the node-positive patients, the hottest SLN was positive in 85.9% (67 of 78). Five of the 78 patients (6.4%) with positive nodes had counts less than 10% of those of the hottest node. The lowest radioactive count of a positive SLN was 4.2% of that of the hottest node. Lymphatic mapping based on the 10% rule could greatly improve the false-negative rates compared with removing only the hottest SLN (14.1% versus 6.4%).Most positive SLNs had the highest radioactivity. Our institutional experience indicates that to obtain an acceptable false-negative rate, nodes should be removed until the 10% rule is met.

    View details for DOI 10.1016/j.jamcollsurg.2008.08.008

    View details for Web of Science ID 000261592800008

    View details for PubMedID 19183531

  • Improved precision with Hologic Apex software OSTEOPOROSIS INTERNATIONAL Fan, B., Lewiecki, E. M., Sherman, M., Lu, Y., Miller, P. D., Genant, H. K., Shepherd, J. A. 2008; 19 (11): 1597-1602


    The precision of Hologic Apex v2.0 analysis software is significantly improved from Hologic Delphi v11.2 software and is comparable to GE Lunar Prodigy v7.5 software. Apex and Delphi precisions were, respectively, 1.0% vs. 1.2% (L1-L4 spine), 1.l % vs. 1.3% (total femur), 1.6% vs. 1.9% (femoral neck), and 0.7% vs. 0.9% (dual total femur).Precision of bone mineral density (BMD) measurements by dual-energy X-ray absorptiometry (DXA) is known to vary by manufacturer, model, and technologist. This study evaluated the precision of three analysis versions: Apex v2.0 and Delphi v11.2 (Hologic, Inc.), and Prodigy v7.5 (GE Healthcare, Inc.) independent of technologist skill.Duplicate spine and dual hip scans on 90 women were acquired on both Delphi and Prodigy DXA systems at three clinics. BMD measures were converted to standardized BMD (sBMD) units. Precision errors were described as a root-mean-square (RMS) standard deviations and RMS percent coefficients of variation across the population.Apex and Delphi values were highly correlated (r ranged from 0.90 to 0.99). Excluding the right neck, the Apex precision error was found to be 20% to 25% lower than the Delphi (spine: 1.0% versus 1.2% (p < 0.05), total hip: 1.1% versus 1.3% (p < 0.05), right neck: 2.3% versus 2.6% (p > 0.1)). No statistically significant differences were found in the precision error of the Apex and Prodigy (p > 0.05) except for the right neck (2.3% versus 1.8% respectively, p = 0.03).The Apex software has significantly lower precision error compared to Delphi software with similar mean values, and similar precision to that of the Prodigy.

    View details for DOI 10.1007/s00198-008-0594-2

    View details for Web of Science ID 000259820200011

    View details for PubMedID 18373054

  • MRI and CT of Insufficiency Fractures of the Pelvis and the Proximal Femur AMERICAN JOURNAL OF ROENTGENOLOGY Cabarrus, M. C., Ambekar, A., Lu, Y., Link, T. M. 2008; 191 (4): 995-1001


    Pelvic and proximal femur insufficiency fractures are of increasing significance in our aging population, and cross-sectional imaging is challenging. The aims of this study were to compare the sensitivity of CT and MRI in detecting insufficiency fractures; to analyze the typical location, morphology, and combinations thereof in these fractures; to analyze imaging morphology; and to analyze associated clinical findings.MRI studies obtained at 1.5 T were analyzed in 145 patients with pelvic insufficiency fractures. In 64 of 145 patients, MRI and multidetector CT (MDCT) findings were compared. Imaging studies were analyzed by two radiologists; combined clinical history, findings from all imaging studies, and follow-up imaging studies served as the standard of reference.In the subgroup undergoing both imaging techniques, MRI detected 128 of 129 (99%) fractures in 63 of 64 (98%) subjects, whereas CT detected only 89 of 129 (69%) fractures in 34 of 64 (53%) subjects. In particular, fractures at the femoral head and acetabulum were better detected with MRI. In the complete population, two or more fractures were found in 70.3% (102/145) of patients, and 89.2% (33/37) of patients with pubic insufficiency fractures had concomitant fractures at other locations. In 63 of 145 (43.4%) patients, a previous malignancy was found; in only 93 of 145 (64.1%) patients, the leading symptom responsible for the MRI examination was pain.This study showed that MRI was substantially better than CT in detecting insufficiency fractures. In addition, two or more insufficiency fractures were frequently present, typical fracture combinations were found, and insufficiency fractures were frequently associated with malignant disease.

    View details for DOI 10.2214/AJR.07.3714

    View details for Web of Science ID 000259364100008

    View details for PubMedID 18806133

  • Diagnostic performance of in vivo 3-T MRI for articular cartilage abnormalities in human osteoarthritic knees using histology as standard of reference EUROPEAN RADIOLOGY Saadat, E., Jobke, B., Chu, B., Lu, Y., Cheng, J., Li, X., Ries, M. D., Majumdar, S., Link, T. M. 2008; 18 (10): 2292-2302


    The purpose of this study was (1) to evaluate the sensitivity, specificity and accuracy of sagittal in vivo 3-T intermediate-weighted fast spin-echo (iwFSE) sequences in the assessment of knee cartilage pathologies using histology as the reference standard in patients undergoing total knee replacement, and (2) to correlate MR imaging findings typically associated with osteoarthritis such as bone marrow edema pattern (BMEP) and cartilage swelling with histological findings. Tibial plateaus and femoral condyles of eight knees of seven patients were resected during surgery, and sagittal histological sections were prepared for histology. Preoperative MRI findings were compared to the corresponding region in histological sections for thickness, surface integrity and signal pattern of cartilage, and histological findings in areas of BMEP and swelling were documented. The overall sensitivity, specificity and accuracy were 72%, 69% and 70% for thickness, 69%, 74% and 73% for surface and 36%, 62% and 45% for intracartilaginous signal pattern. For all cases of BMEP on MRI subchondral ingrowth of fibrovascular tissue and increased bone remodeling were observed. MRI using fat-saturated iwFSE sequences showed good performance in assessing cartilage thickness and surface lesions, while signal changes of cartilage were not suited to characterize the severity of cartilage degeneration as validated by histology.

    View details for DOI 10.1007/s00330-008-0989-7

    View details for Web of Science ID 000259141900032

    View details for PubMedID 18491096

    View details for PubMedCentralID PMC2838768

  • Comparison of T-1 and T-2 metabolite relaxation times in glioma and normal brain at 3T 14th Annual Meeting of the International-Society-for-Magnetic-Resonance-in-Medicine Li, Y., Srinivasan, R., Ratiney, H., Lu, Y., Chang, S. M., Nelson, S. J. JOHN WILEY & SONS INC. 2008: 342–50


    To measure T(1) and T(2) relaxation times of metabolites in glioma patients at 3T and to investigate how these values influence the observed metabolite levels.A total of 23 patients with gliomas and 10 volunteers were studied with single-voxel two-dimensional (2D) J-resolved point-resolved spectral selection (PRESS) using a 3T MR scanner. Voxels were chosen in normal appearing white matter (WM) and in regions of tumor. The T(1) and T(2) of choline containing compounds (Cho), creatine (Cr), and N-acetyl aspartate (NAA) were estimated.Metabolite T(1) relaxation values in gliomas were not significantly different from values in normal WM. The T(2) of Cho and Cr were statistically significantly longer for grade 4 gliomas than for normal WM but the T(2) of NAA was similar. These differences were large enough to impact the corrections of metabolite levels for relaxation times with tumor grade in terms of metabolite ratios (P < 0.001).The differential increase in T(2) for Cho and Cr relative to NAA means that the ratios of Cho/NAA and Cr/NAA are higher in tumor at longer echo times (TEs) relative to values in normal appearing brain. Having this information may be useful in defining the acquisition parameters for optimizing contrast between tumor and normal tissue in MR spectroscopic imaging (MRSI) data, in which limited time is available and only one TE can be used.

    View details for DOI 10.1002/jmri.21453

    View details for Web of Science ID 000258387300008

    View details for PubMedID 18666155

    View details for PubMedCentralID PMC3033227

  • Prostate cancer: Is inapparent tumor at endorectal MR and MR spectroscopic imaging a favorable prognostic finding in patients who select active surveillance? RADIOLOGY Cabrera, A. R., Coakley, F. V., Westphalen, A. C., Lu, Y., Zhao, S., Shinohara, K., Carroll, P. R., Kurhanewicz, J. 2008; 247 (2): 444-450


    To retrospectively determine whether inapparent tumor at endorectal magnetic resonance (MR) imaging and MR spectroscopic imaging is a favorable prognostic finding in prostate cancer patients who select active surveillance for management.Committee on Human Research approval was obtained and compliance with HIPAA regulations was observed, with waiver of requirement for written consent. Ninety-two men (mean age, 64 years; range, 43-85 years) were retrospectively identified who had biopsy-proved prostate cancer, who had undergone baseline endorectal MR imaging and MR spectroscopic imaging, and who had selected active surveillance for management. Their mean baseline serum prostate-specific antigen (PSA) level was 5.5 ng/mL, and the median Gleason score was 6. Two readers with 10 and 3 years of experience independently reviewed all MR images and determined whether tumor was apparent on the basis of evaluation of established morphologic and metabolic findings. Another investigator compiled data about baseline clinical stage, biopsy findings, and serum PSA measurements. Multiple logistic regression analysis was used to investigate the relationship between the clinical parameters and tumor apparency at MR imaging and the biochemical outcome.At baseline MR imaging, readers 1 and 2 considered 54 and 26 patients, respectively, to have inapparent tumor (fair interobserver agreement; kappa = 0.30). During a mean follow-up of 4.8 years, 52 patients had a stable PSA level and 40 had an increasing PSA level. In multivariate analysis, no significant association was found between the baseline clinical stage, Gleason score, serum PSA level, or the presence of apparent tumor at endorectal MR imaging and MR spectroscopic imaging for either reader and the biochemical outcome (P > .05 for all).Endorectal MR imaging and MR spectroscopic imaging findings of tumor apparency or inapparency in prostate cancer patients who select active surveillance for management do not appear to be of prognostic value.

    View details for DOI 10.1148/radiol.2472070770

    View details for Web of Science ID 000255289700017

    View details for PubMedID 18430877

  • The feasibility of characterizing the spatial distribution of cartilage T-2 using texture analysis OSTEOARTHRITIS AND CARTILAGE Blumenkrantz, G., Stahl, R., Carballido-Gamio, J., Zhao, S., Lu, Y., Munoz, T., Le Graverand-Gastineau, M. H., Jain, S. K., Link, T. M., Majumdar, S. 2008; 16 (5): 584-590


    The purpose of this study was (1) to characterize the spatial distribution of cartilage T(2) in postmenopausal osteoarthritis (OA) patients and age-matched healthy subjects using second order texture measures at baseline, and (2) to analyze changes in the texture of cartilage T(2) after 9 months.3.0T-MRI of the knee was performed in 8 mild OA patients and 10 age-matched controls at baseline and after 9 months. Cartilage T(2), volume, and average thickness were calculated in all patients. Texture analysis, based on the gray level co-occurrence matrix, was performed on the cartilage T(2) maps. Texture parameters, including entropy and angular second moment, were calculated at 0 degrees (corresponding to the anterior-posterior axis) and at 90 degrees (corresponding to the superior-inferior axis), with pixel offsets ranging from 1 to 3 pixels.Least square means analysis showed that mean T(2) values, their standard deviation (SD), and their entropy were greater (P<0.05) in OA patients than in controls. Over 9 months, the SD and entropy of cartilage T(2) significantly (P<0.05) decreased in OA patients, while no significant changes were evident in cartilage thickness or volume.The mean cartilage T(2) values, their SD, and their entropy were greater in OA patients than in controls, indicating that the T(2) values in osteoarthritic cartilage are not only elevated, but also more heterogeneous than those in healthy cartilage. The longitudinal results demonstrate that changes in texture parameters of cartilage T(2) may precede morphological changes in thickness and volume in the progression of OA.

    View details for DOI 10.1016/j.joca.2007.10.019

    View details for Web of Science ID 000255840600008

    View details for PubMedID 18337129

    View details for PubMedCentralID PMC2838772

  • Prostate cancer: Role of pretreatment MR in predicting outcome after external-beam radiation therapy - Initial experience RADIOLOGY McKenna, D. A., Coakley, F. V., Westphalen, A. C., Zhao, S., Lu, Y., Webb, E. M., Pickett, B., Roach, M., Kurhanewicz, J. 2008; 247 (1): 141-146


    To retrospectively determine if pretreatment endorectal magnetic resonance (MR) imaging findings are predictive of outcome in patients who undergo external-beam radiation therapy for prostate cancer.Committee on Human Research approval, with waiver of the requirement for informed consent, was obtained for this HIPAA-compliant study. Eighty men with biopsy-proved prostate cancer (mean age, 59 years; range, 47-75 years) who underwent endorectal MR imaging of the prostate prior to external-beam radiation therapy were retrospectively identified; details of baseline tumor characteristics, treatment, and outcome were recorded. Two experienced readers independently reviewed all MR imaging studies and recorded tumor T stage and the radial diameter of extracapsular extension (if present). Univariate and multivariate stepwise Cox regression analyses were used to investigate the relationship between baseline imaging and clinical predictive variables and the end point of metastatic failure.At MR imaging, readers 1 and 2, respectively, considered 50 and 60 patients to have T1 or T2 disease (ie, organ-confined disease) and 30 and 20 patients to have T3 disease. After a mean follow-up of 43 months, four patients developed metastases. Univariate Cox analysis revealed that baseline serum prostate-specific antigen level, presence of extracapsular extension at MR imaging (according to either reader), and degree of extracapsular extension (according to either reader) were all significantly (P < .05) related to the development of metastases. Multivariate Cox analysis revealed that the sole independent predictive variable was mean diameter of extracapsular extension (relative hazard ratio, 2.06; 95% confidence interval: 1.22, 3.48; P = .007). In particular, three of five patients with extracapsular extension of more than 5 mm at pretreatment MR imaging developed metastases 24, 43, and 63 months after therapy.The presence and degree of extracapsular extension at MR imaging prior to external-beam radiation therapy are important predictors of posttreatment metastatic recurrence.

    View details for DOI 10.1148/radiol.2471061982

    View details for Web of Science ID 000254358600017

    View details for PubMedID 18258811

  • Brain metabolite levels assessed by lactate-edited MR spectroscopy in premature neonates with and without pentobarbital sedation AMERICAN JOURNAL OF NEURORADIOLOGY Wang, Z. J., Vigneron, D. B., Miller, S. P., Mukherjee, P., Charlton, N. N., Lu, Y., Barkovich, A. J. 2008; 29 (4): 798-801


    Pentobarbital is known to affect cerebral metabolism; pentobarbital sedation is, however, frequently used for MR imaging and MR spectroscopy, especially in children. Accurate assessment of the brain metabolite levels is important, particularly in neonates with suspected brain injury. We investigated whether pentobarbital sedation has any effect on the ratios of spectral metabolites lactate, N-acetylaspartate, or choline in a group of premature neonates.MR spectroscopy was performed in 43 premature neonates, all with normal concurrent MR imaging and normal neurodevelopmental outcome at 12 months of age. Of those neonates, 14 (33%) required pentobarbital (Nembutal 1 mg/kg) sedation during MR spectroscopy; the remaining 29 neonates did not receive any sedation. Ratios of lactate, choline, and N-acetylaspartate were calculated in the basal ganglia, thalami, and corticospinal tracts and compared between those neonates with and without sedation.Small amounts of brain lactate were detected in all of the premature neonates. The basal ganglia lactate/choline and lactate/N-acetylaspartate ratios were significantly lower, by 17% and 25% respectively, in the neonates with pentobarbital sedation compared with the age-matched neonates without sedation (P < .05). Sedation did not affect the lactate level in the thalami or the corticospinal tracts. The N-acetylaspartate/choline ratios were unaffected by pentobarbital sedation.Pentobarbital sedation is associated with lower lactate/choline and lactate/N-acetylaspartate ratios in the basal ganglia of premature neonates, as determined by proton MR spectroscopy. Investigators should be aware of this phenomenon for accurate interpretation of their MR spectroscopy results.

    View details for DOI 10.3174/ajnrA0912

    View details for Web of Science ID 000255129700034

    View details for PubMedID 18184837

    View details for PubMedCentralID PMC2745552

  • Pelvic body composition measurements by quantitative computed tomography: Association with recent hip fracture BONE Lang, T., Koyarna, A., Li, C., Li, J., Lu, Y., Saeed, I., Gazze, E., Keyak, J., Harris, T., Cheng, X. 2008; 42 (4): 798-805


    Loss of subcutaneous fat, decreased muscle cross-sectional area (CSA) and increased muscle adiposity are related to declining physical function and disability in the elderly, but there is little information about the relationship of these tissue changes to hip fracture. Thus we have compared body composition measures in women with hip fractures to age-matched controls, using quantitative computed tomography (QCT) imaging of the hip to characterize total adiposity, muscle CSA and muscle attenuation coefficient, a measure of adiposity.45 Chinese women (mean age 74.71+/-5.94) with hip fractures were compared to 66 healthy control subjects (mean age 70.70+/-4.66). Hip QCT scans were analyzed to compute total adipose CSA as well as CSA and attenuation values of muscle groups in the CT scan field of view, including hip extensors, abductors, adductors and flexors. The total femur areal BMD (aBMD) was estimated from the QCT images. Logistic regression was employed to compare body composition measures between fracture subjects and controls after adjustment for age, height, BMI and aBMD. Receiver-operator curve (ROC) analyses determined whether combinations of aBMD and body composition had higher area under curve (AUC) than aBMD alone.Fracture subjects had lower fat CSA (p<0.0001) than controls but had higher muscle adiposity as indicated by lower attenuation in the adductor, abductor and flexor groups (0.00001

    View details for DOI 10.1016/j.bone.2007.12.002

    View details for Web of Science ID 000254643500022

    View details for PubMedID 18234578

  • Contrast extravasation on CT predicts mortality in primary intracerebral hemorrhage AMERICAN JOURNAL OF NEURORADIOLOGY Kim, J., Smith, A., Hemphill, J. C., Smith, W. S., Lu, Y., Dillon, W. P., Wintermark, M. 2008; 29 (3): 520-525


    Recent studies of intracerebral hemorrhage (ICH) treatments have highlighted the need to identify reliable predictors of hematoma expansion. The goal of this study was to determine whether contrast extravasation on multisection CT angiography (CTA) and/or contrast-enhanced CT (CECT) of the brain is associated with hematoma expansion and increased mortality in patients with primary ICH.All patients with primary ICH who underwent CTA and CECT, as well as follow-up noncontrast CT (NCCT) before discharge/death from January 1, 2003, to September 30, 2005, were retrospectively identified. One neuroradiologist reviewed admission and follow-up NCCT for hematoma size and growth. A second neuroradiologist independently reviewed CTA and CECT for active contrast extravasation. Univariate and multivariate logistic regression analyses were performed to evaluate the significance of clinical and radiologic variables in predicting 30-day mortality, designated as the primary outcome. Hematoma growth was considered as a secondary outcome.Of 56 patients, contrast extravasation was seen in 17.9% of patients on initial CTA and in 23.2% of patients on initial CECT following CTA. Univariate analysis showed that the presence of extravasation on CT, large initial hematoma size (>30 mL), the presence of "swirl sign" on NCCT, the Glasgow Coma Scale and ICH scores, and international normalized ratio were associated with increased mortality. On multivariate analysis, only contrast extravasation on CT (P = .017) independently predicted mortality. Contrast extravasation on CT (P < .001) was also an independent predictor of hematoma growth on multivariate analysis.Active contrast extravasation on CT in patients with primary ICH independently predicts mortality and hematoma growth.

    View details for DOI 10.3174/ajnr.A0859

    View details for Web of Science ID 000254066700021

    View details for PubMedID 18065505

  • Accuracy of plain abdominal radiographs in the detection of retained surgical needles in the peritoneal cavity ANNALS OF SURGERY Ponrartana, S., Coakley, F. V., Yeh, B. M., Breiman, R. S., Qayyum, A., Joe, B. N., Poder, L., Lu, Y., Gibbs, V. C., Roberts, J. P. 2008; 247 (1): 8-12


    To determine the accuracy of plain abdominal radiographs in the detection of retained surgical needles of varying size in the peritoneal cavity.Accidental retention of surgical foreign bodies in the peritoneal cavity is estimated to occur once in every 1000 to 1500 abdominal operations and early prevention and identification of retained foreign bodies is increasingly important because of mounting public awareness. Most of the existing literature on the imaging detection of surgical foreign bodies has focused on retained sponges, even though retained needles may account for up to 50% of such objects and the true accuracy of plain abdominal radiographs in the detection of retained needles is not well established.Eight plain radiographs were obtained of a 41 kg pig cadaver after placement of a total of 39 surgical needles of varying size (4-77 mm in length) in a randomized selection of the 9 segments of the peritoneal cavity. Five radiologists independently reviewed the radiographs and indicated the location of all suspected retained needles. Analyses were performed using the known site and size of placed needles as the standard of reference.In total for all readers, 195 needles were detectable in 360 abdominal segments. The overall mean accuracy, sensitivity, and specificity for plain radiographs in the detection of retained surgical needles were 74% (267 of 360), 69% (135 of 195), and 80% (132 of 165), respectively. Sensitivity for needles 25 mm or more in length was significantly (P < 0.0001) higher than that for needles of 11 to 24 mm or 10 mm or less, with respective values of 99% (69 of 70), 84% (46 of 55), and 29% (20 of 70). Readers demonstrated moderate interobserver agreement, with a multireader kappa value of 0.60.Abdominal radiographs have high sensitivity and interobserver agreement in the detection of retained surgical needles over 10 mm in length, but smaller needles are detected with significantly lower sensitivity and the utility of plain abdominal radiographs in this setting is more debatable.

    View details for DOI 10.1097/SLA.0b013e31812eeca5

    View details for Web of Science ID 000251982400002

    View details for PubMedID 18156915

  • Hip fracture risk estimation based on bone mineral density of a biomechanically-guided region of interest: a preliminary study Medical Imaging 2008 Conference Li, W., Kornak, J., Li, C., Koyama, A., Saeed, I., Lu, Y., Lang, T. SPIE-INT SOC OPTICAL ENGINEERING. 2008

    View details for DOI 10.1117/12.769588

    View details for Web of Science ID 000256051300039

  • Peripheral zone prostate cancer: Accuracy of different interpretative approaches with MR and MR spectroscopic imaging RADIOLOGY Westphalen, A. C., Coakley, F. V., Qayyum, A., Swanson, M., Simko, J. P., Lu, Y., Zhao, S., Carroll, P. R., Yeh, B. M., Kurhanewicz, J. 2008; 246 (1): 177-184


    To retrospectively compare relative accuracy of different interpretative approaches to magnetic resonance (MR) and MR spectroscopic imaging of peripheral zone prostate cancer, by using histologic examination results as the reference standard.This HIPAA-compliant study had institutional Committee on Human Research approval, with waiver of written consent requirement. Spectroscopic voxels of unequivocally benign (n = 66) or malignant (n = 77) peripheral zone tissue were identified by using step-section histopathologic tumor maps created for 28 men (mean age, 60 years; range, 46-71 years) who underwent endorectal MR and MR spectroscopic imaging before radical prostatectomy. Two readers (9 and 8 years of experience) independently scored the selected voxels on a scale from 1 (likely benign) to 5 (likely malignant) at randomized review of the corresponding tissue outlined on a transverse T2-weighted MR image (T2 approach), the MR spectrum from the selected voxel only (single-voxel approach), the MR spectra from all voxels at the same axial level (multivoxel approach), and both the corresponding tissue outlined on a transverse T2-weighted image and the MR spectra from all voxels at the same axial level (integrated approach). Readers were aware that spectra were derived in patients with biopsy-proved diagnoses of prostate cancer and represented either benign or malignant tissue but were unaware of which voxels had been labeled benign or malignant and of all other clinical, histopathologic, and MR imaging findings. Receiver operating characteristic (ROC) curve analysis was performed. Generalized estimating equation method was used to estimate sensitivity and specificity for specific cutoff values.Mean areas under the ROC curve (AUCs) for the T2, single-voxel, multivoxel, and integrated approaches were 0.69, 0.72, 0.72, and 0.76, respectively. AUC of the integrated approach was significantly higher than those of the other three approaches (P < .001). kappa Values for assessment of interobserver variability for the T2, single-voxel, multivoxel, and integrated approaches were 0.39, 0.39, 0.34, and 0.48, respectively.Addition of MR spectroscopic imaging to MR imaging significantly improves characterization of peripheral zone prostate tissue as benign or malignant; improved performance is obtained when both data sets are interpreted in an integrated fashion.

    View details for DOI 10.1148/radiol.2453062042

    View details for Web of Science ID 000252795300023

    View details for PubMedID 18024434

  • Voxel-based modeling and quantification of the proximal femur using inter-subject registration of quantitative CT images BONE Li, W., Kezele, I., Collins, D. L., Zijdenbos, A., Keyak, J., Kornak, J., Koyama, A., Saeed, I., LeBlanc, A., Harris, T., Lu, Y., Lang, T. 2007; 41 (5): 888-895


    We have developed a general framework which employs quantitative computed tomography (QCT) imaging and inter-subject image registration to model the three-dimensional structure of the hip, with the goal of quantifying changes in the spatial distribution of bone as it is affected by aging, drug treatment or mechanical unloading. We have adapted rigid and non-rigid inter-subject registration techniques to transform groups of hip QCT scans into a common reference space and to construct composite proximal femoral models. We have applied this technique to a longitudinal study of 16 astronauts who on average, incurred high losses of hip bone density during spaceflights of 4-6 months on the International Space Station (ISS). We compared the pre-flight and post-flight composite hip models, and observed the gradients of the bone loss distribution. We performed paired t-tests, on a voxel by voxel basis, corrected for multiple comparisons using false discovery rate (FDR), and observed regions inside the proximal femur that showed the most significant bone loss. To validate our registration algorithm, we selected the 16 pre-flight scans and manually marked 4 landmarks for each scan. After registration, the average distance between the mapped landmarks and the corresponding landmarks in the target scan was 2.56 mm. The average error due to manual landmark identification was 1.70 mm.

    View details for DOI 10.1016/j.bone.2007.07.006

    View details for Web of Science ID 000250528900018

    View details for PubMedID 17707712

    View details for PubMedCentralID PMC2080679

  • Vaccination of metastatic colorectal cancer patients with matured dendritic cells loaded with multiple major histocompatibility complex class I peptides JOURNAL OF IMMUNOTHERAPY Kavanagh, B., Ko, A., Venook, A., Margolin, K., Zeh, H., Lotze, M., Schillinger, B., Liu, W., Lu, Y., Mitsky, P., Schilling, M., Bercovici, N., Loudovaris, M., Guillermo, R., Lee, S. M., Bender, J., Mills, B., Fong, L. 2007; 30 (7): 762-772


    Developing a process to generate dendritic cells (DCs) applicable for multicenter trials would facilitate cancer vaccine development. Moreover, targeting multiple antigens with such a vaccine strategy could enhance the efficacy of such a treatment approach. We performed a phase 1/2 clinical trial administering a DC-based vaccine targeting multiple tumor-associated antigens to patients with advanced colorectal cancer (CRC). A qualified manufacturing process was used to generate DC from blood monocytes using granulocyte macrophage colony-stimulating factor and IL-13, and matured for 6 hours with Klebsiella-derived cell wall fraction and interferon-gamma (IFN-gamma). DCs were also loaded with 6 HLA-A*0201 binding peptides derived from carcinoembryonic antigen (CEA), MAGE, and HER2/neu, as well as keyhole limpet hemocyanin protein and pan-DR epitope peptide. Four planned doses of 35x10(6) cells were administered intradermally every 3 weeks. Immune response was assessed by IFN-gamma enzyme-linked immunosorbent spot (ELISPOT). Matured DC possessed an activated phenotype and could prime T cells in vitro. In the trial, 21 HLA-A2+ patients were apheresed, 13 were treated with the vaccine, and 11 patients were evaluable. No significant treatment-related toxicity was reported. T-cell responses to a CEA-derived peptide were detected by ELISPOT in 3 patients. T cells induced to CEA possessed high avidity T-cell receptors. ELISPOT after in vitro restimulation detected responses to multiple peptides in 2 patients. All patients showed progressive disease. This pilot study in advanced CRC patients demonstrates DC-generated granulocyte macrophage colony-stimulating factor and IL-13 matured with Klebsiella-derived cell wall fraction and IFN-gamma can induce immune responses to multiple tumor-associated antigens in patients with advanced CRC.

    View details for Web of Science ID 000249795500009

    View details for PubMedID 17893568

  • Diffusion tensor MR imaging tractography of the pyramidal tracts correlates with clinical motor function in children with congenital hemiparesis AMERICAN JOURNAL OF NEURORADIOLOGY Glenn, O. A., Ludeman, N. A., Berman, J. I., Wu, Y. W., Lu, Y., Bartha, A. I., Vigneron, D. B., Chung, S. W., Ferriero, D. M., Barkovich, A. J., Henry, R. G. 2007; 28 (9): 1796-1802


    Children with congenital hemiparesis have greater asymmetry in diffusion parameters of the pyramidal tracts compared with control subjects. We hypothesized that the asymmetry correlates with the severity of hemiparesis and that diffusion metrics would be abnormal in the affected tracts and normal in the unaffected tracts.Fifteen patients with congenital hemiparesis and 17 age-matched control subjects were studied with diffusion tensor MR imaging tractography. Hemipareses were scored as mild, moderate, or severe. We measured tract-specific diffusion parameters (fractional anisotropy, mean, and directional diffusion coefficients) of the pyramidal tracts. We compared tract-specific parameters and asymmetry between the right and left tracts of the differing severity groups and control subjects.We observed many different causes of congenital hemiparesis including venous infarction, arterial infarction, and polymicrogyria. Clinical severity of hemiparesis correlated with asymmetry in fractional anisotropy (P < .0001), transverse diffusivity (P < .0001), and mean diffusivity (P < .03). With increasing severity of hemiparesis, fractional anisotropy decreased (P < .0001) and transverse diffusivity (P < .0001) and mean diffusivity (P < .02) increased in the affected pyramidal tract compared with controls. Diffusion metrics in the unaffected tract were similar to those in the control subjects.Asymmetry in fractional anisotropy, transverse diffusivity, and mean diffusivity, as well as the degree of abnormality in the actual values of the affected pyramidal tracts themselves, correlates with the severity of motor dysfunction in infants and children with congenital hemiparesis from different causes. This suggests that abnormalities detected by diffusion tensor MR imaging tractography in the affected pyramidal tract are related to the functional ability of the affected pyramidal tract, regardless of the etiology of motor dysfunction.

    View details for DOI 10.3174/ajnr.A0676

    View details for Web of Science ID 000250312200038

    View details for PubMedID 17893220

  • Kinetic assessment of breast tumors using high spatial resolution signal enhancement ratio (SER) imaging MAGNETIC RESONANCE IN MEDICINE Li, K., Henry, R. G., Wilmes, L. J., Gibbs, J., Zhu, X., Lu, Y., Hylton, N. M. 2007; 58 (3): 572-581


    The goal of this study was to investigate the relationship between an empirical contrast kinetic parameter, the signal enhancement ratio (SER), for three-timepoint, high spatial resolution contrast-enhanced (CE) MRI, and a commonly analyzed pharmacokinetic parameter, kep, using dynamic high temporal resolution CE-MRI. Computer simulation was performed to investigate: 1) the relationship between the SER and the contrast agent concentration ratio (CACR) of two postcontrast timepoints (tp1 and tp2); 2) the relationship between the CACR and the redistribution rate constant (kep) based on a two-compartment pharmacokinetic model; and 3) the sensitivity of the relationship between the SER and kep to native tissue T1 relaxation time, T10, and to errors in an assumed vascular input function. The relationship between SER and kep was verified experimentally using a mouse model of breast cancer. The results showed that a monotonic mathematical relationship between SER and kep could be established if the acquisition parameters and the two postinjection timepoints of SER, tp1, tp2, were appropriately chosen. The in vivo study demonstrated a close correlation between SER and kep on a pixel-by-pixel basis (Spearman rank correlation coefficient=0.87+/-0.03). The SER is easy to calculate and may have a unique role in breast tissue characterization.

    View details for DOI 10.1002/mrm.21361

    View details for Web of Science ID 000249260200017

    View details for PubMedID 17685424

  • AG-013736, a novel inhibitor of VEGF receptor tyrosine kinases, inhibits breast cancer growth and decreases vascular permeability as detected by dynamic contrast-enhanced magnetic resonance imaging MAGNETIC RESONANCE IMAGING Wilmes, L. J., Pallavicini, M. G., Fleming, L. M., Gibbs, J., Wang, D., Li, K., Partridge, S. C., Henry, R. G., Shalinsky, D. R., Hu-Lowe, D., Park, J. W., McShane, T. M., Lu, Y., Brasch, R. C., Hylton, N. M. 2007; 25 (3): 319-327


    Dynamic contrast-enhanced MRI (DCE-MRI) was used to noninvasively evaluate the effects of AG-03736, a novel inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, on tumor microvasculature in a breast cancer model. First, a dose response study was undertaken to determine the responsiveness of the BT474 human breast cancer xenograft to AG-013736. Then, DCE-MRI was used to study the effects of a 7-day treatment regimen on tumor growth and microvasculature. Two DCE-MRI protocols were evaluated: (1) a high molecular weight (MW) contrast agent (albumin-(GdDTPA)(30)) with pharmacokinetic analysis of the contrast uptake curve and (2) a low MW contrast agent (GdDTPA) with a clinically utilized empirical parametric analysis of the contrast uptake curve, the signal enhancement ratio (SER). AG-013736 significantly inhibited growth of breast tumors in vivo at all doses studied (10-100 mg/kg) and disrupted tumor microvasculature as assessed by DCE-MRI. Tumor endothelial transfer constant (K(ps)) measured with albumin-(GdDTPA)(30) decreased from 0.034+/-0.005 to 0.003+/-0.001 ml min(-1) 100 ml(-1) tissue (P<.0022) posttreatment. No treatment-related change in tumor fractional plasma volume (fPV) was detected. Similarly, in the group of mice studied with GdDTPA DCE-MRI, AG-013736-induced decreases in tumor SER measures were observed. Additionally, our data suggest that 3D MRI-based volume measurements are more sensitive than caliper measurements for detecting small changes in tumor volume. Histological staining revealed decreases in tumor cellularity and microvessel density with treatment. These data demonstrate that both high and low MW DCE-MRI protocols can detect AG-013736-induced changes in tumor microvasculature. Furthermore, the correlative relationship between microvasculature changes and tumor growth inhibition supports DCE-MRI methods as a biomarker of VEGF receptor target inhibition with potential clinical utility.

    View details for DOI 10.1016/j.mri.2006.09.041

    View details for Web of Science ID 000245614500004

    View details for PubMedID 17371720

  • Disparity between ratios of diameters and blood flows in central pulmonary arteries in postoperative congenital heart disease using MRI JOURNAL OF MAGNETIC RESONANCE IMAGING Ordovas, K. G., Tan, C., Reddy, G. P., Weber, O. M., Lu, Y., Higgins, C. B. 2007; 25 (4): 721-726


    To compare the relative severity of stenoses of right or left pulmonary arteries with differences in flow to each lung after repair of congenital heart disease (CHD).A total of 15 patients with postoperative congenital heart disease underwent MRI to evaluate branch pulmonary artery stenoses. Spin-echo images and MR angiography were used to assess morphology, and velocity-encoded cine (VEC) MRI was used to measure flow in the right and left pulmonary arteries. The ratios of the narrowest diameters of the right to left pulmonary arteries (R/L size) and right to left pulmonary arterial flow (R/L flow) were compared using Spearman's correlation. F test was used to assess the significance of the regression coefficients.R/L size ratio varied from 0.50 to 2.66, while the R/L flow ratio varied from 0.36 to 12.02. There was an exponential relationship between R/L size and R/L flow, with r2=0.78 and P=0.001. However, severity of morphologic stenoses was not clinically useful for predicting flow reduction. Prediction residuals ranged from -136% to 54% of the true R/L flow.Anatomical evaluation of the pulmonary arteries does not predict accurately differential blood flow in patients with pulmonary stenoses. Therefore, blood flow measurements are essential when considering the need for further surgical or interventional procedures.

    View details for DOI 10.1002/jmri.20863

    View details for Web of Science ID 000245633300007

    View details for PubMedID 17335010

  • Liver fat: Effect of hepatic iron deposition on evaluation with opposed-phase MR imaging RADIOLOGY Westphalen, A. C., Qayyum, A., Yeh, B. M., Merriman, R. B., Lee, J. A., Lamba, A., Lu, Y., Coakley, F. V. 2007; 242 (2): 450-455


    To retrospectively determine the effect of liver iron deposition on the evaluation of liver fat by using opposed-phase magnetic resonance (MR) imaging.Committee on Human Research approval was obtained, and compliance with HIPAA regulations was observed. Patient consent was waived by the committee. Thirty-eight patients with cirrhosis (30 men, eight women; mean age, 58 years; range, 34-76 years) who underwent abdominal MR imaging and had contemporaneous liver biopsy were retrospectively identified. Two radiologists independently quantified liver fat according to the relative loss of signal intensity and compared this loss on opposed-phase and in-phase T1-weighted gradient-echo images. Liver fat percentage and presence of iron deposition were independently recorded by a pathologist. Generalized linear models, which included a mixed-random effects model, were used to determine the effect of iron deposition on the Spearman correlation coefficient for relative signal intensity loss versus histopathologically determined fat percentage.Liver iron deposition was found in 25 of 38 patients. Liver fat percentage (mean, 3%; range, 0%-25%) was identified histopathologically in 14 of 38 patients and in nine of 25 patients with iron deposition. For both readers, relative signal intensity loss at opposed-phase imaging was closely and significantly correlated (P < .05) with histopathologically determined liver fat percentage in patients without iron deposition (r = 0.7 for reader 1, r = 0.6 for reader 2), but no such correlation was found in patients with iron deposition (r = 0.1 for reader 1, r = -0.31 for reader 2; P > .05).Signal intensity loss on in-phase images caused by the presence of liver iron is a potential pitfall in the determination of liver fat percentage at opposed-phase MR imaging in chronic liver disease.

    View details for Web of Science ID 000244032100016

    View details for PubMedID 17255416

  • High-grade prostatic intraepithelial neoplasia in patients with prostate cancer: MR and MR spectroscopic imaging features - initial experience RADIOLOGY Hom, J. J., Coakley, F. V., Simko, J. P., Lu, Y., Qayyum, A., Westphalen, A. C., Schmitt, L. D., Carroll, P. R., Kurhanewicz, J. 2007; 242 (2): 483-489


    To retrospectively determine the magnetic resonance (MR) and MR spectroscopic imaging features of high-grade prostatic intraepithelial neoplasia (HGPIN) in patients with prostate cancer.Approval of the committee on human research was obtained, with a waiver of consent for this HIPAA-compliant study. Endorectal MR imaging and MR spectroscopic imaging were performed in 48 men (mean age, 59 years; range, 47-75 years) prior to radical prostatectomy for prostate cancer. T2-weighted signal intensity and metabolic ratios of peripheral zone HGPIN foci of 6 mm or greater in diameter were recorded by two readers with knowledge of step-section histopathologic findings using areas of confirmed normal and cancerous peripheral zone tissue for comparison. A random effects statistical model was used to compare metabolic ratios from normal, HGPIN, and cancer voxels.A total of 123 peripheral zone HGPIN foci with a mean diameter of 3 mm (range, 1-28 mm) were identified in 37 (77%) patients, but only 20 foci in 14 patients had a diameter of 6 mm or greater. Six foci were excluded, yielding 14 large HGPIN lesions from 11 patients in the final statistical analysis. The larger HGPIN foci were not associated with any focal reduction in T2-weighted signal intensity but demonstrated metabolic findings intermediate between normal and cancerous tissue; the mean ratios of choline (Cho) to creatine (Cr) for normal, HGPIN, and cancer were 0.92, 1.75, and 1.99, respectively, (P < .01), and the corresponding ratios of Cho plus Cr to citrate were 0.34, 0.50, and 0.78 (P < .01).HGPIN is metabolically intermediate between normal peripheral zone tissue and prostate cancer at MR spectroscopic imaging but does not manifest any MR imaging abnormality and is rarely of sufficient size to cause substantial error in evaluation of peripheral zone tumor extent in patients with prostate cancer.

    View details for Web of Science ID 000244032100020

    View details for PubMedID 17179396

  • Discrimination contributing factors to bone fragility using vQCT in vivo International Symposium on Advanced Biotechnologies for Assessing Quality of Bone and Scaffold Biomaterials Meta, M., Lu, Y., Keyak, J. H., Lang, T. F. SPRINGER-VERLAG BERLIN. 2007: 431–449
  • Young-elderly differences in bone density, geometry and strength indices depend on proximal femur sub-region: A cross sectional study in Caucasian-American women BONE Meta, M., Lu, Y., Keyak, J. H., Lang, T. 2006; 39 (1): 152-158


    Fragility fractures at the trochanter (TR) and the femoral neck (FN) have distinct etiologies, but the underlying age-related structural changes at these proximal femoral sub-regions are poorly understood. 28 young (41+/-3 years) and 124 elderly (74+/-3 years) healthy Caucasian women underwent volumetric quantitative computed tomography at the hip. Integral (i), cortical (c) and trabecular (t) bone mineral density and content (BMD, BMC) were measured. Geometric parameters included cross sectional area (CSA), and volumes of the integral, cortical and trabecular regions (VOL). Structural measures included indices of compressive (Compstr) and bending (BSI) strength. After adjusting for height and weight, an F-test was used to compare the TR and the FN mean values between young and elderly and to test for interaction to compare logarithmic difference of young and elderly (log(Young)-log(Elderly), Y/Ed) between the FN and the TR in an ANOCOVA model. All BMC, iBMD and tBMD values were significantly lower in elderly than in young women, with the largest Y/Ed in the FN tBMC and tBMD (P<0.0011 and P<0.0001). cBMD in young and elderly groups was not significantly different at the TR while at the FN it was greater (P=0.0075) in elderly than young women, showing significant Y/Ed (P=0.0003) dependence on skeletal site. Elderly women had significantly larger iVOL and CSA values (0.0001

    View details for DOI 10.1016/j.bone.2005.11.020

    View details for Web of Science ID 000238429300017

    View details for PubMedID 16459156

    View details for PubMedCentralID PMC1482801

  • Perfusion, diffusion and spectroscopy values in newly diagnosed cerebral gliomas NMR IN BIOMEDICINE Catalaa, I., Henry, R., Dillon, W. P., Graves, E. E., McKnight, T. R., Lu, Y., Vigneron, D. B., Nelson, S. J. 2006; 19 (4): 463-475


    To evaluate perfusion, diffusion, and spectroscopy values in enhancing and non-enhancing lesions for patients with newly diagnosed gliomas of different grades.Sixty-seven patients with newly diagnosed glioma were entered into the study 20 grade II, 26 grade III and 21 grade IV. MR data were acquired at 1.5T and included diffusion weighted images (59/67 patients), dynamic perfusion weighted images (30/67 patients) and 3D H-1 MR spectroscopy (64/67 patients). Enhancing and non-enhancing lesions were delineated by a neuroradiologist and applied to maps of relative cerebral blood volume (rCBV), apparent diffusion coefficient (ADC), relative anisotropy (RA) and metabolite intensities.The median rCBV within enhancing regions of grade IV gliomas was significantly elevated relative to enhancing regions in grade III gliomas and normal brain. ADC was elevated relative to normal brain, but was not significantly different between grades or between enhancing and non-enhancing regions. The RA was higher in the non-enhancing region of grade IV gliomas relative to grade II and grade III. Levels of lactate plus lipid were significantly elevated in grade IV relative to grade II and grade III gliomas. Both enhancing and non-enhancing regions in grade IV gliomas showed significant correlations between CBV, ADC and choline levels.The data were consistent with grade IV gliomas having higher membrane turnover, increased cell density and increased vascularity within enhancing lesions. Analysis of the correlations among parameters within grade IV gliomas suggested that high vascularity (high rCBV) was correlated with increased cellularity (low ADC) and increased membrane turnover (high choline) in these lesions. The non-enhancing region of grades II and III gliomas had MR parameters consistent with increased cellularity and/or membrane turnover.

    View details for DOI 10.1002/nbm.1059

    View details for Web of Science ID 000238883100004

    View details for PubMedID 16763973

  • Performance of an automated computer-based scoring method to assess joint space narrowing in rheumatoid arthritis - A longitudinal study ARTHRITIS AND RHEUMATISM Finckh, A., de Pablo, P., Katz, J. N., Neumann, G., Wolfe, F., Duryea, J. 2006; 54 (5): 1444-1450


    To compare the diagnostic performance of a computer-based method for measuring joint space width with the Sharp joint space narrowing (JSN) scoring method in patients with rheumatoid arthritis (RA).A random sample of patients with early RA, for whom sequential hand radiographs and Sharp scores were available, was selected from the National Data Bank for Rheumatic Diseases. Hand joint space width was measured using an automated, computer-based method in random order and with blinding for clinical information. We constructed a receiver operating characteristic curve and compared the diagnostic performance of the computer-based and Sharp methods based on the areas under the curve.One hundred twenty-nine patients with early RA who underwent serial radiography were included. Changes in the computer-based and Sharp methods were highly correlated (r = 0.75, P < 0.001). The computer-based method was significantly more discriminant than the Sharp JSN subscale. The area under the curve of the computer-based method was 0.96 (95% confidence interval [95% CI] 0.94, 0.99) compared with 0.93 (95% CI 0.89, 0.96) for the Sharp subscale (P = 0.024). At the most discriminant cutoff, specificity of the computer-based method was 88.4% compared with 81.4% for the Sharp subscale (P = 0.11); sensitivity was 87.6% for the computer-based method compared with 82.2% for Sharp subscale (P = 0.19). The signal-to-noise ratio for the computer-based method was 83% compared with 70% for the Sharp subscale (P = 0.013).The computer-based method for measuring joint space width is more discriminant than the semiquantitative Sharp JSN subscale.

    View details for DOI 10.1002/art.21802

    View details for Web of Science ID 000237533100013

    View details for PubMedID 16645974

  • Comparison of BMD precision for Prodigy and Delphi spine and femur scans. Osteoporosis international Shepherd, J. A., Fan, B., Lu, Y., Lewiecki, E. M., Miller, P., Genant, H. K. 2006; 17 (9): 1303-1308


    Precision error in bone mineral density (BMD) measurement can be affected by patient positioning, variations in scan analysis, automation of software, and both short- and long-term fluctuations of the densitometry equipment. Minimization and characterization of these errors is essential for reliable assessment of BMD change over time.We compared the short-term precision error of two dual-energy X-ray absorptiometry (DXA) devices: the Lunar Prodigy (GE Healthcare) and the Delphi (Hologic). Both are fan-beam DXA devices predominantly used to measure BMD of the spine and proximal femur. In this study, 87 women (mean age 61.6+/-8.9 years) were measured in duplicate, with repositioning, on both systems, at one of three clinical centers. The technologists were International Society for Clinical Densitometry (ISCD) certified and followed manufacturer-recommended procedures. All scans were acquired using 30-s scan modes. Precision error was calculated as the root-mean-square standard deviation (RMS-SD) and coefficient of variation (RMS-%CV) for the repeated measurements. Right and left femora were evaluated individually and as a combined dual femur precision. Precision error of Prodigy and Delphi measurements at each measurement region was compared using an F test to determine significance of any observed differences.While precision errors for both systems were low, Prodigy precision errors were significantly lower than Delphi at L1-L4 spine (1.0% vs 1.2%), total femur (0.9% vs 1.3%), femoral neck (1.5% vs 1.9%), and dual total femur (0.6% vs 0.9%). Dual femur modes decreased precision errors by approximately 25% compared with single femur results.This study suggests that short-term BMD precision errors are skeletal-site and manufacturer specific. In clinical practice, precision should be considered when determining: (a) the minimum time interval between baseline and follow-up scans and (b) whether a statistically significant change in the patient's BMD has occurred.

    View details for PubMedID 16823544

  • 3.0 vs 1.5 T MRI in the detection of focal cartilage pathology - ROC analysis in an experimental model OSTEOARTHRITIS AND CARTILAGE Link, T. M., Sell, C. A., Masi, J. N., Phan, C., Newitt, D., Steinbach, L., Majumdar, S. 2006; 14 (1): 63-70


    To use receiver operator characteristics (ROC) analysis for assessing the diagnostic performance of three cartilage-specific MR sequences at 1.5 and 3 T in detecting cartilage lesions created in porcine knees.Eighty-four cartilage lesions were created in 27 porcine knee specimens at the patella, the medial and lateral femoral and the medial and lateral tibial cartilage. MR imaging was performed using a fat saturated spoiled gradient echo (SPGR) sequence (in plane spatial resolution/slice thickness: 0.20 x 0.39 mm2/1.5 mm) and two fat saturated proton density weighted (PDw) sequences (low spatial resolution: 0.31 x 0.47 mm2/3 mm and high spatial resolution: 0.20 x 0.26 mm2/2 mm). The images were independently analyzed by three radiologists concerning the absence or presence of lesions using a five-level confidence scale. Significances of the differences for the individual sequences were calculated based on comparisons of areas under ROC curves (A(Z)).The highest A(Z)-values for all three radiologists were consistently obtained for the SPGR (A(Z) = 0.84) and the high-resolution (hr) PDw (A(Z) = 0.79) sequences at 3T. The corresponding A(Z)-values at 1.5 T were 0.77 and 0.69; the differences between 1.5 and 3 T were statistically significant (P < 0.05). A(Z)-values for the low-resolution PDw sequence were lower: 0.59 at 3 T and 0.55 at 1.5 T and the differences between 1.5 and 3T were not significant.With optimized hr MR sequences diagnostic performance in detecting cartilage lesions was improved at 3 T. For a standard, lower spatial resolution PDw sequence no significant differences, however, were found.

    View details for DOI 10.1016/j.joca.2005.08.002

    View details for Web of Science ID 000234961900008

    View details for PubMedID 16188466

  • Tractography-based quantitation of diffusion tensor imaging parameters in white matter tracts of preterm newborns JOURNAL OF MAGNETIC RESONANCE IMAGING Partridge, S. C., Mukherjee, P., Berman, J. I., Henry, R. G., Miller, S. P., Lu, Y., Glenn, O. A., Ferriero, D. M., Barkovich, A. J., Vigneron, D. B. 2005; 22 (4): 467-474


    To evaluate the feasibility of performing diffusion tensor tractography (DTT) to map and quantify the pyramidal white matter tracts of premature newborns.Fourteen diffusion tensor MRI (DTI) examinations of nine premature newborns were evaluated. DTT was performed to segment bilateral pyramidal tracts, using a fiber-tracking algorithm originating in the cerebral peduncle (CP) and filtering through the posterior limb of the internal capsule (PLIC) and precentral gyrus (PCG). Voxels containing the resulting tracts were then used for quantitation of DTI parameters along the tract. The DTT-based tract measurements were compared with standard manually placed region-of-interest (ROI) measurements at four locations along the pyramidal tract, and the reproducibility of each technique was evaluated.DTT demonstrated improved reproducibility over manual ROI measurement for pyramidal tract quantitation and was less subject to intra-operator variability (P < 0.0001, Fisher test for equal variance). In general, the anatomic locations and measurements obtained with the two techniques were in good agreement, although some systematic differences were identified in the PLIC and CP.Fiber DTT is feasible in premature newborns, provides more reproducible tract measurements than manual ROI methods, and allows quantitation along the entire tract for more detailed DTI assessment of white matter maturation.

    View details for DOI 10.1002/jmri.20410

    View details for Web of Science ID 000232317700004

    View details for PubMedID 16161075

  • Comparing microstructural and macrostructural development of the cerebral cortex in premature newborns: Diffusion tensor imaging versus cortical gyration NEUROIMAGE deIpolyi, A. R., Mukherjee, P., Gill, K., Henry, R. G., Partridge, S. C., Veeraraghavan, S., Jin, H., Lu, Y., Miller, S. P., Ferriero, D. M., Vigneron, D. B., Barkovich, A. J. 2005; 27 (3): 579-586


    This study assessed microstructural development in four regions of the human cerebral cortex during preterm maturation using diffusion tensor imaging (DTI), compared to the macrostructural development of cortical gyration evaluated using three-dimensional volumetric T1-weighted MR imaging. Thirty-seven premature infants of estimated gestational age (EGA) ranging from 25 to 38 weeks were prospectively enrolled and imaged in an MR-compatible neonatal incubator with a high-sensitivity neonatal head coil. Cortical gyration was measured quantitatively as the ratio of gyral height to width on the volumetric MR images in four regions bilaterally (superior frontal, superior occipital, precentral, and postcentral gyri). Mean diffusivity (D(av)), fractional anisotropy (FA-the fraction of D(av) that is anisotropic), and the three DTI eigenvalues (components of diffusivity radial and tangential to the pial surface of cortex) were measured in the same cortical regions. Cortical gyration scores, FA, and radial diffusivity were all significantly correlated with EGA (P < 0.0001). However, in multivariate analysis, no significant relationship (P > 0.05) was found between DTI parameters and cortical gyration beyond their common association with estimated gestational age. Pre- and postcentral gyri had significantly lower anisotropy than the superior occipital and superior frontal gyri (P < 0.05), indicating that DTI is sensitive to regional heterogeneity in cortical development. Maturational changes in the DTI eigenvalues of cortical gray matter were found to differ from those that have previously been described in developing white matter, with a significant age-related decline in the radial diffusivity (P < 0.0001) but not in the tangential diffusivities (P > 0.05).

    View details for DOI 10.1016/j.neuroimage.2005.04.027

    View details for Web of Science ID 000231543600010

    View details for PubMedID 15921934

  • The effect of sentinel node tumor burden on non-sentinel node status and recurrence rates in breast cancer ANNALS OF SURGICAL ONCOLOGY Fan, Y. G., Tan, Y. Y., Wu, C. T., Treseler, P., Lu, Y., Chan, C. W., Hwang, S., Ewing, C., Esserman, L., Morita, E., Leong, S. P. 2005; 12 (9): 705-711


    Routine axillary lymph node dissection (ALND) after selective sentinel lymphadenectomy (SSL) in the treatment of breast cancer remains controversial. We sought to determine the need for routine ALND by exploring the relationship between sentinel lymph node (SLN) and non-SLN (NSLN) status. We also report our experience with disease relapse in the era of SSL and attempt to correlate this with SLN tumor burden.This was a retrospective study of 390 patients with invasive breast cancer treated at a single institution who underwent successful SSL from November 1997 to November 2002.Of the 390 patients, 115 received both SSL and ALND. The percentage of additional positive NSLNs in the SLN-positive group (34.2%) was significantly higher than in the SLN-negative group (5.1%; P = .0004). The SLN macrometastasis group had a significantly higher rate of positive NSLNs (39.7%) compared with the SLN-negative group (5.1%; P = .0001). Sixteen patients developed recurrences during follow-up, including 6.1% of SLN-positive and 3.3% of SLN-negative patients. Among the SLN macrometastasis group, 8.7% had recurrence, compared with 2.2% of SLN micrometastases over a median follow-up period of 31.1 months. One regional failure developed out of 38 SLN-positive patients who did not undergo ALND.ALND is recommended for patients with SLN macrometastasis because of a significantly higher incidence of positive NSLNs. Higher recurrence rates are also seen in these patients. However, the role of routine ALND in patients with a low SLN tumor burden remains to be further determined by prospective randomized trials.

    View details for DOI 10.1245/ASO.2005.08.020

    View details for Web of Science ID 000231368600006

    View details for PubMedID 16079953

  • Primary tumor characteristics predict sentinel lymph node macrometastasis in breast cancer BREAST JOURNAL Tan, Y. Y., Wu, C. T., Fan, Y. G., Hwang, S., Ewing, C., Lane, K., Esserman, L., Lu, Y., Treseler, P., Morita, E., Leong, S. P. 2005; 11 (5): 338-343


    Selective sentinel lymphadenectomy (SSL) is rapidly becoming the standard of care in the surgical management of patients with early breast cancer. Sentinel lymph node macrometastasis has been well documented in the literature to have a higher risk of nonsentinel node tumor involvement when compared to micrometastasis. The aim of our study was to determine the primary tumor characteristics associated with sentinel node macrometastasis that will allow us to preoperatively determine this subgroup of patients at risk. This study was a retrospective review of 644 patients who underwent successful SSL as part of their surgical treatment of breast cancer at the University of California San Francisco Carol Franc Buck Breast Care Center from November 1997 to August 2003. All patients underwent preoperative lymphoscintigraphy followed by wide excision or mastectomy and sentinel lymphadenectomy with or without axillary lymph node dissection. One hundred twenty-two patients had positive sentinel nodes on histology. Micrometastasis was present in 43 of these patients and macrometastasis in the remaining 79. Statistical analysis showed that a tumor size greater than 15 mm, poor tubule formation by the tumor cells, and lymphovascular invasion were significantly associated with sentinel node macrometastasis. A high mitotic count showed a trend but was not significant in our study. Patients with a tumor size greater than 15 mm, poor tubule formation, and lymphovascular invasion are at risk of having sentinel node macrometastasis. These patients can be identified preoperatively based on imaging and biopsy criteria, allowing the option of selective intraoperative pathologic evaluation of the sentinel node and immediate completion axillary dissection as necessary.

    View details for Web of Science ID 000235489800008

    View details for PubMedID 16174155

  • Growth rate of hepatocellular carcinoma - Evaluation with serial computed tomography or magnetic resonance imaging JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY Taouli, B., Goh, J. S., Lu, Y., Qayyum, A., Yeh, B. M., Merriman, R. B., Coakley, F. V. 2005; 29 (4): 425-429


    To evaluate the growth rate of untreated hepatocellular carcinoma (HCC) by calculating tumor volume doubling time (TVDT) on serial computed tomography (CT) or magnetic resonance imaging (MRI) and to predict TVDT based on initial tumor size.Sixteen untreated HCCs in 11 patients with cirrhosis who underwent serial CT or MRI at our institution were retrospectively identified. Two independent readers recorded bidimensional measurements for all tumors, which were used to determine tumor volume (TV). Growth rate was expressed as TVDT. A mathematic model was used to predict TVDT based on baseline tumor size.Mean baseline and follow-up TVs were 10.5 cm3 (range: 0.7-243.6 cm3) and 22.0 cm3 (range: 2.5-870.8 cm3), respectively. Mean duration of follow-up was 176 days (range: 76-472 days). Mean TVDT was 127 days (95% confidence interval: 80, 203; range: 17.5-541.4 days). Expected TVDT could be expressed as TVDT = 114 x (baseline volume)0.14 (P < 0.002).The results of this study suggest a preferred interval follow-up of approximately 4.5 months (127 days) for HCC screening. Small HCCs show a tendency toward faster growth and may require shorter follow-up to demonstrate progression.

    View details for Web of Science ID 000230832200001

    View details for PubMedID 16012295

  • Ratio of positive to total number of sentinel nodes predicts nonsentinel node status in breast cancer patients BREAST JOURNAL Tan, Y. Y., Fan, Y. G., Lu, Y., Hwang, S., Ewing, C., Esserman, L., Morita, E., Treseler, P., Leong, S. P. 2005; 11 (4): 248-253


    Selective sentinel lymphadenectomy (SSL) has replaced axillary lymph node dissection (ALND) for many patients with early breast cancer and negative sentinel lymph nodes (SLNs). Yet many patients with a positive SLN are undergoing unnecessary ALND, as no further disease is found in the axilla. The aim of our study was to determine factors associated with additional positive lymph nodes in the axilla in patients who have a positive SLN. This was a retrospective study of patients undergoing SSL with ALND as part of their treatment for breast cancer at a single institution from November 1997 to August 2003. Only patients with one or more positive SLNs were selected for this study. There were 86 patients who fit our study criteria. Of these, 38% had further positive lymph nodes upon ALND. More than one positive SLN and a ratio of positive SLNs to total SLNs of greater than 0.5 were found to be predictors for additional axillary nodal involvement in both univariate and multivariate analyses. The number of positive SLNs and the ratio of positive SLNs to total SLNs is an indication of total tumor burden in the sentinel nodes and may be a reflection of the propensity of the tumor for further lymphatic invasion in the axillary basin.

    View details for Web of Science ID 000235489600005

    View details for PubMedID 15982390

  • MRI measurements of breast tumor volume predict response to neoadjuvant chemotherapy and recurrence-free survival AMERICAN JOURNAL OF ROENTGENOLOGY Partridge, S. C., Gibbs, J. E., Lu, Y., Esserman, L. J., Tripathy, D., Wolverton, D. S., Rugo, H. S., Hwang, G. E., Ewing, C. A., Hylton, N. M. 2005; 184 (6): 1774-1781


    The purpose of this study was to assess the value of MRI measurements of breast tumor size for predicting recurrence-free survival (RFS) in patients undergoing neoadjuvant (preoperative) chemotherapy and to compare the predictive value of MRI with that of established prognostic indicators.The study included 62 patients undergoing neoadjuvant chemotherapy. The longest diameter and volume of each tumor were measured on MRI before and after one and four cycles of treatment. Change in diameter on clinical examination, tumor size at pathology, and the number of positive nodes were determined. Each measure of tumor extent was assessed for the ability to predict RFS.Univariate Cox analysis showed initial MRI volume was the strongest predictor of RFS (p = 0.002). Final change in MRI volume (p = 0.015) was more predictive than change in diameter on MRI (p = 0.077) or clinical examination (p = 0.27). Initial diameter on MRI (p = 0.003) and clinical examination (p = 0.033), tumor size at pathology (p = 0.016), and number of positive nodes (p = 0.045) were also significantly predictive of RFS. Early change in MRI volume (p = 0.071) and diameter (p = 0.081) after one chemotherapy cycle showed trends of association with RFS. Multivariate analysis showed initial MRI volume (p = 0.005) and final change in MRI volume (p = 0.003) were significant independent predictors.MRI tumor volume was more predictive of RFS than tumor diameter, suggesting that volumetric changes measured using MRI may provide a more sensitive assessment of treatment efficacy.

    View details for Web of Science ID 000229328700011

    View details for PubMedID 15908529

  • Diffusion-weighted and fluid-attenuated inversion recovery imaging in Creutzfeldt-Jakob disease: High sensitivity and specificity for diagnosis AMERICAN JOURNAL OF NEURORADIOLOGY Young, G. S., Geschwind, M. D., Fischbein, N. J., Martindale, J. L., Henry, R. G., Liu, S. L., Lu, Y., Wong, S., Liu, H., Miller, B. L., Dillon, W. P. 2005; 26 (6): 1551-1562


    Abnormalities on diffusion-weighted images (DWIs) and fluid-attenuated inversion recovery (FLAIR) images are reported in Creutzfeldt-Jakob disease (CJD). To our knowledge, no large study has been conducted to determine the sensitivity and specificity of DWI and FLAIR imaging for diagnosing CJD.Two neuroradiologists, blinded to diagnosis, retrospectively evaluated DWI and FLAIR images from 40 patients with probable or definite CJD and 53 control subjects with other forms of dementia and rated the likelihood of CJD on the basis of the imaging findings.DWI and FLAIR imaging was 91% sensitive, 95% specific, and 94% accurate for CJD. Interrater reliability was high (kappa = 0.93). Sensitivity was higher for DWI than FLAIR imaging. Abnormalities involved cortex and deep gray matter (striatum and/or thalamus) in 68% of patients with CJD, cortex alone in 24%, and deep gray matter alone in 5%. The most typical and specific patterns were corresponding hyperintensity on both FLAIR images and DWIs confined to the gray matter in the cortex, striatum, medial and/or posterior thalamus, or a combination of these areas. Narrow-window soft-copy review of artifact-free DWIs and FLAIR images and recognition of the normal variation in cortical signal intensity proved critical for successful differentiation of CJD from other dementias.Because specific patterns of abnormality on DWI and FLAIR images are highly sensitive and specific for CJD, these sequences should be performed whenever CJD is suspected.

    View details for Web of Science ID 000229815800047

    View details for PubMedID 15956529

  • Longitudinal multivoxel MR spectroscopy study of pediatric diffuse brainstem gliomas treated with radiotherapy 46th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Laprie, A., Pirzkall, A., Haas-Kogan, D. A., Cha, S., Banerjee, A., Le, T. P., Lu, Y., Nelson, S., McKnight, T. R. ELSEVIER SCIENCE INC. 2005: 20–31


    After radiotherapy (RT), children with diffuse intrinsic pontine gliomas (DIPG) are followed with sequential magnetic resonance imaging (MRI). However, MRI changes do not necessarily reflect tumor progression, and therefore additional noninvasive tools are needed to improve the definition of progression vs. treatment-related changes. In this study, we determined the feasibility and accuracy of multivoxel proton magnetic resonance spectroscopic imaging (1H-MRSI) for monitoring pediatric patients with DIPG.Twenty-four serial examinations of MRI/MRSI (7 2D-MRSI and 17 3D-MRSI) were performed on 8 patients with DIPG who received local RT. A total of 1635 voxels were categorized as "normal" or "abnormal" based on corresponding imaging findings on contrast-enhanced T1- and T2-weighted MRI. The choline to N-acetyl-aspartate ratio (Cho:NAA) and choline to creatine ratios (Cho:Cr) within each category of MRI abnormality were compared to their counterpart in normal surrounding tissues. The changes in these ratios corresponding to each type of abnormality were evaluated before RT, at response, and at recurrence, as determined by the clinical status of the patients. The presence or absence of lactate and lipid peaks was noted for each voxel. MRI/MRSI was performed on posterior fossa and supratentorial tissue of 3 volunteer pediatric patients.The Cho:NAA and Cho:Cr values within the imaging abnormalities (3.8 +/- 0.93 and 3.55 +/- 1.37, respectively) were significantly higher than the mean values in normal-appearing regions (0.93 +/- 0.2 and 1.13 +/- 0.38, respectively) (p < 0.005). Cho:NAA values decreased from studies at diagnosis to the time of response to RT (3.12 +/- 0.5 and 2.08 +/- 0.73, respectively), followed by an increase at the time of relapse (from 1.83 +/- 0.92 to 4.29 +/- 1.08). Loss of lactate and lipid peaks correlated with response, and their presence and stability with relapse. In 3 patients, increased spectral abnormalities preceded the radiological and clinical deterioration by 2-5 months.Multivoxel MRSI is a feasible and reproducible noninvasive tool for assessing pediatric DIPG. Longitudinal multivoxel MRSI measurements have potential value in assessing response to radiation or other therapies, because they offer more coverage than single-voxel techniques and provide reliable spectral data.

    View details for DOI 10.1016/j.ijropb.2004.09.027

    View details for Web of Science ID 000228652700003

    View details for PubMedID 15850898

  • Anti-rejection drug treatment increases basal cell carcinoma burden in Ptch1+/- mice JOURNAL OF INVESTIGATIVE DERMATOLOGY Vogt, A., Hebert, J., Hwang, J., Lu, Y., Epstein, E. H. 2005; 124 (1): 263-267


    The development of extensive and severe non-melanoma skin cancer is an extremely common complication of organ transplantation and is assumed to be caused by long-term treatment with anti-rejection drugs (ARD). Despite this florid clinical problem, ARD treatments have been reported to affect experimental murine skin carcinogenesis only weakly. We report here that treatment of cesium-137-irradiated Ptch1+/- mice with immunosuppressive doses of cyclosporine A plus prednisolone for 4-1/2 mo increased basal cell carcinoma burden by 2.5-fold. Thus, these mice provide a good model for study of the effects of long-term administration of ARD on at least one type of non-melanoma skin cancer.

    View details for DOI 10.1111/j.0022-202X.2004.23573.x

    View details for Web of Science ID 000225951300041

    View details for PubMedID 15654983

  • Endorectal MR imaging MR spectroscopic imaging for locally recurrent prostate cancer after external beam radiation therapy: Preliminary experience RADIOLOGY Coakley, F. V., Teh, H. S., Qayyum, A., Swanson, M. G., Lu, Y., Roach, M., Pickett, B., Shinohara, K., Vigneron, D. B., Kurhanewicz, J. 2004; 233 (2): 441-448


    To evaluate endorectal magnetic resonance (MR) imaging and MR spectroscopic imaging for the depiction of locally recurrent prostate cancer after external beam radiation therapy.Endorectal MR imaging and MR spectroscopic imaging were performed in 21 patients with biochemical failure after external beam radiation therapy for prostate cancer. Two readers independently and retrospectively reviewed MR images and rated the likelihood of recurrent tumor on a five-point scale. Spectroscopic voxels were considered suspicious for malignancy if the choline level was elevated and citrate was absent. Receiver operating characteristic curve analysis was used to assess cancer detection in each side of the prostate with endorectal MR imaging and spectroscopic imaging at different thresholds based on the scores assigned by the two readers and on the number of suspicious voxels in each hemiprostate, respectively. The presence or absence of cancer at subsequent transrectal biopsy was used as the standard of reference.Biopsy demonstrated locally recurrent prostate cancer in nine hemiprostates in six patients. The area under the receiver operating characteristic curve for the detection of locally recurrent cancer with MR imaging was 0.49 and 0.51 for readers 1 and 2, respectively. By using the number of suspicious voxels to define different diagnostic thresholds, the area under the receiver operating characteristic curve for MR spectroscopic imaging was significantly (P < .005) higher, at 0.81. In particular, the presence of three or more suspicious voxels in a hemiprostate showed a sensitivity and specificity of 89% and 82%, respectively, for the diagnosis of local recurrence. Seven hemiprostates demonstrated complete metabolic atrophy at spectroscopic imaging and only postirradiation atrophy at biopsy.Preliminary data suggest that MR spectroscopic imaging, but not endorectal MR imaging, may be of value for the depiction of locally recurrent prostate cancer after radiation therapy.

    View details for DOI 10.1148/radiol.2332032086

    View details for Web of Science ID 000224650400019

    View details for PubMedID 15375223

  • Organ-confined prostate cancer: Effect of prior trans rectal biopsy on endorectal MRI and MR spectroscopic imaging AMERICAN JOURNAL OF ROENTGENOLOGY Qayyum, A., Coakley, F. V., Lu, Y., Olpin, J. D., Wu, L., Yeh, B. M., Carroll, P. R., Kurhanewicz, J. 2004; 183 (4): 1079-1083


    Our aim was to determine the effect of prior transrectal biopsy on endorectal MRI and MR spectroscopic imaging findings in patients with organ-confined prostate cancer.Endorectal MRI and MR spectroscopic imaging were performed in 43 patients with biopsy-proven prostate cancer before radical prostatectomy confirming organ-confined disease. For each sextant, two independent reviewers scored the degree of hemorrhage on a scale from 1 to 5 and recorded the presence or absence of capsular irregularity. A spectroscopist recorded the number of spectrally degraded voxels in the peripheral zone. The outcome variables of capsular irregularity and spectral degradation were correlated with the predictor variables of time from biopsy and degree of hemorrhage after biopsy.Capsular irregularity was unrelated to time from biopsy or to degree of hemorrhage. Spectral degradation was inversely related to time from biopsy (p < 0.01); the mean percentage of degraded peripheral zone voxels was 18.5% within 8 weeks of biopsy compared with 7% after 8 weeks. Spectral degradation was unrelated to the degree of hemorrhage.In organ-confined prostate cancer, capsular irregularity can be seen at any time after biopsy and is independent of the degree of hemorrhage, whereas spectral degradation is seen predominantly in the first 8 weeks after biopsy. MRI staging criteria and guidelines for scheduling studies after biopsy may require appropriate modification.

    View details for Web of Science ID 000224217200035

    View details for PubMedID 15385308

  • T2 relaxation time of cartilage at MR imaging: Comparison with severity of knee osteoarthritis RADIOLOGY Dunn, T. C., Lu, Y., Jin, H., Ries, M. D., Majumdar, S. 2004; 232 (2): 592-598


    To evaluate differences in T2 values in femoral and tibial cartilage at magnetic resonance (MR) imaging in patients with varying degrees of osteoarthritis (OA) compared with healthy subjects and to develop a mapping and display method based on calculation of T2 z scores for visual grading and assessment of cartilage heterogeneity in patients with OA.Knee cartilage was evaluated in 55 subjects who were categorized with radiography as healthy (n = 7) or as having mild OA (n = 20) or severe OA (n = 28). Cartilage regions were determined with manual segmentation of an MR image acquired with spoiled gradients and fat suppression. The segmentation was applied to a map of T2 relaxation time and was analyzed in four knee cartilage compartments (ie, the medial and lateral tibia and femur). Differences between cartilage compartment T2 values and subject groups were analyzed with analysis of covariance. Correlations of cartilage T2 values with clinically reported symptoms and cartilage thickness and volume were examined. Cartilage T2 values were converted to z scores per voxel on the basis of normal population values in the same cartilage compartment to better interpret cartilage heterogeneity and variation from normal.Healthy subjects had mean T2 values of 32.1-35.0 msec, while patients with mild and severe OA had mean T2 values of 34.4-41.0 msec. All cartilage compartments except the lateral tibia showed significant (P <.05) increases in T2 relaxation time between healthy and diseased knees; however, no significant difference was found between patients with mild and severe OA. Correlation of T2 values with clinical symptoms and cartilage morphology was found predominantly in medial compartments.Femoral and medial tibial cartilage T2 values increase with the severity of OA.

    View details for Web of Science ID 000222839500041

    View details for PubMedID 15215540

  • Topical tazarotene chemoprevention reduces basal cell carcinoma number and size in Ptch1 +/- mice exposed to ultraviolet or ionizing radiation CANCER RESEARCH So, P. L., Lee, K., Hebert, J., Walker, P., Lu, Y., Hwang, J., Kopeovich, L., Athar, M., Bickers, D., Aszterbaum, M., Epstein, E. H. 2004; 64 (13): 4385-4389


    Oral retinoids can reduce basal cell carcinoma (BCC) incidence in genetically susceptible patients, and one topical retinoid, tazarotene, has been reported to cure some sporadic BCCs. Therefore, we have tested whether this agent would affect BCCs in Ptch1+/- mice in a controlled chemoprevention trial. We found that topical tazarotene dramatically inhibits the formation of BCCs induced with either UV or ionizing radiation. The ability of tazarotene to inhibit BCC formation in this mouse model provides encouragement for the use of tazarotene in skin cancer chemoprevention trials in humans.

    View details for Web of Science ID 000222407300001

    View details for PubMedID 15231643

  • Diffusion tensor imaging: serial quantitation of white matter tract maturity in premature newborns NEUROIMAGE Partridge, S. C., Mukherjee, P., Henry, R. G., Miller, S. P., Berman, J. I., Jin, H., Lu, Y., Glenn, O. A., Ferriero, D. M., Barkovich, A. J., Vigneron, D. B. 2004; 22 (3): 1302-1314


    Magnetic resonance diffusion tensor imaging (DTI) enables the discrimination of white matter pathways before myelination is evident histologically or on conventional MRI. In this investigation, 14 premature neonates with no evidence of white matter abnormalities by conventional MRI were studied with DTI. A custom MR-compatible incubator with a novel high sensitivity neonatal head coil and improved acquisition and processing techniques were employed to increase image quality and spatial resolution. The technical improvements enabled tract-specific quantitative characterization of maturing white matter, including several association tracts and subcortical projection tracts not previously investigated in neonates by MR. Significant differences were identified between white matter pathways, with earlier maturing commissural tracts of the corpus callosum, and deep projection tracts of the cerebral peduncle and internal capsule exhibiting lower mean diffusivity (Dav) and higher fractional anisotropy (FA) than later maturing subcortical projection and association pathways. Maturational changes in white matter tracts included reductions in Dav and increases in FA with age due primarily to decreases in the two minor diffusion eigenvalues (lambda2 and lambda3). This work contributes to the understanding of normal white matter development in the preterm neonatal brain, an important step toward the use of DTI for the improved evaluation and treatment of white matter injury of prematurity.

    View details for DOI 10.1016/j.neuroimaging.2004.02.038

    View details for Web of Science ID 000222423200028

    View details for PubMedID 15219602

  • Regional angiographic grading system for collateral flow - Correlation with cerebral infarction in patients with middle cerebral artery occlusion STROKE Kim, J. J., Fischbein, N. J., Lu, Y., Pham, D., Dillon, W. P. 2004; 35 (6): 1340-1344


    Collateral flow plays an important role in maintaining tissue viability in proximal large vessel occlusion. We developed and tested a regional angiographic collateral grading system for patients with angiographically confirmed acute symptomatic middle cerebral artery occlusion to predict regional infarction.A subset of 42 patients was selected from 180 patients enrolled in the Prolyse in Acute Cerebral Thromboembolism II (PROACT II) trial. Readers evaluated baseline cerebral angiograms in a blinded fashion for the degree of regional collateral circulation, which was graded on a 4-point scale in each of 15 anatomic regions. Regional and total collateral flow scores were compared with the presence or absence of infarction on 7- to 10-day follow-up computed tomography (CT), as well as clinical outcome as assessed by National Institute of Health Stroke Scale (NIHSS) scores.The collateral flow score on baseline angiography accurately predicted infarction, demonstrating a receiver operating characteristic curve of 0.87 (95% CI: 0.83 to 0.91) for all regions. Collateral grades on baseline angiography correlated moderately with infarct volume on follow-up CT scan at 7 to 10 days (R=0.61; P=0.0001). Collateral grades also correlated with follow-up NIHSS scores for patients who received thrombolysis (R=0.36 to 0.49, P<0.05), but not for control patients.An angiographic grading system for regional collateral flow accurately predicts the extent and location of cerebral infarction. This study corroborates the correlation between the presence of collateral flow, infarction volume, and clinical outcome, and it reinforces the need to control for collateral flow in clinical trials.

    View details for DOI 10.1161/01.STR.0000126043.83777.3a

    View details for Web of Science ID 000221676600021

    View details for PubMedID 15087564

  • In vitro and in vivo spiral CT to determine bone mineral density: Initial experience in patients at risk for osteoporosis RADIOLOGY Link, T. M., Koppers, B. B., Licht, T., Bauer, J., Lu, Y., Rummeny, E. J. 2004; 231 (3): 805-811


    To evaluate, both experimentally and in vivo, if nondedicated standard spiral computed tomography (CT) may be used to obtain reliable bone mineral density (BMD) data.Twenty lumbar spine specimens from human cadavers were examined with standard quantitative CT and spiral CT. In addition, 50 patients with a history of lymphoma and chemotherapy were examined. These patients underwent long-term follow-up CT to rule out tumor recurrence. Quantitative CT was performed before contrast medium administration to assess potential posttherapeutic osteoporosis. In addition, fracture status of the spine was determined. Mean BMD values and SDs were calculated, and relationships between measurements obtained with quantitative CT and spiral CT were assessed with linear regression analysis and two-tailed tests of significance (t test). A linear fit was used to calculate quantitative CT data from spiral CT values.For the specimens, a coefficient of determination (r(2) = 0.99, P <.001) was found between BMD measurements obtained with quantitative CT and those obtained with spiral CT. Mean BMD in specimens was 63.6 mg/mL +/- 36.6 with quantitative CT and 74.4 mg/mL +/- 38.2 with spiral CT. Mean BMD in patients was 105.0 mg/mL +/- 34.6 with quantitative CT and 139.5 mg/mL +/- 42.7 with contrast medium-enhanced spiral CT. A coefficient of determination (r(2) = 0.91, P <.001) was obtained between these measurements. Mean BMD from L1 through L3 vertebrae was calculated, and spiral CT data were multiplied by 0.77 to yield quantitative CT data. Differences in BMD were significant (P <.05) for patients with (n = 9) and those without fractures (n = 41), as determined with spiral CT and quantitative CT.Correlations between BMD data obtained with spiral CT and standard quantitative CT were highly significant. By using a conversion factor, BMD measurements can be determined with routine abdominal spiral CT scans.

    View details for DOI 10.1148/radiol.2313030325

    View details for Web of Science ID 000221585200030

    View details for PubMedID 15105454

  • Cortical and trabecular bone mineral loss from the spine and hip in long-duration spaceflight JOURNAL OF BONE AND MINERAL RESEARCH Lang, T., Leblanc, A., Evans, H., Lu, Y., Genant, H., Yu, A. 2004; 19 (6): 1006-1012


    We measured cortical and trabecular bone loss using QCT of the spine and hip in 14 crewmembers making 4- to 6-month flights on the International Space Station. There was no compartment-specific loss of bone in the spine. Cortical bone mineral loss in the hip occurred primarily by endocortical thinning.In an earlier study, areal BMD (aBMD) measurements by DXA showed that cosmonauts making flights of 4- to 12-month duration on the Soviet/Russian MIR spacecraft lost bone at an average rate of 1%/month from the spine and 1.5%/month from the hip. However, because DXA measurements represent the sum of the cortical and trabecular compartments, there is no direct information on how these bone envelopes are affected by spaceflight.To address this, we performed a study of crewmembers (13 males and 1 female; age range, 40-55 years) on long-duration missions (4-6 months) on the International Space Station (ISS). We used DXA to obtain aBMD of the hip and spine and volumetric QCT (vQCT) to assess integral, cortical, and trabecular volumetric BMD (vBMD) in the hip and spine. In the heel, DXA was used to measure aBMD, and quantitative ultrasound (QUS) was used to measure speed of sound (SOS) and broadband ultrasound attenuation (BUA).aBMD was lost at rates of 0.9%/month at the spine (p < 0.001) and 1.4-1.5%/month at the hip (p < 0.001). Spinal integral vBMD was lost at a rate of 0.9%/month (p < 0.001), and trabecular vBMD was lost at 0.7%/month (p < 0.05). In contrast to earlier reports, these changes were generalized across the vertebrae and not focused in the posterior elements. In the hip, integral, cortical, and trabecular vBMD was lost at rates of 1.2-1.5%/month (p < 0.0001), 0.4-0.5%/month (p < 0.01), and 2.2-2.7%/month (p < 0.001), respectively. The cortical bone loss in the hip occurred primarily by cortical thinning. Calcaneal aBMD measurements by DXA showed smaller mean losses (0.4%/month) than hip or spine measurements, with SOS and BUA showing no change. In summary, our results show that ISS crewmembers, on average, experience substantial loss of both trabecular and cortical bone in the hip and somewhat smaller losses in the spine. These results do not support the use of calcaneal aBMD or QUS measurements as surrogate measures to estimate changes in the central skeleton.

    View details for DOI 10.1359/JBMR.040307

    View details for Web of Science ID 000221573400016

    View details for PubMedID 15125798

  • In vivo application of 3D-line skeleton graph analysis (LSGA) technique with high-resolution magnetic resonance imaging of trabecular bone structure OSTEOPOROSIS INTERNATIONAL Pothuaud, L., Newitt, D. C., Lu, Y., MacDonald, B., Majumdar, S. 2004; 15 (5): 411-419


    Over the last several years magnetic resonance (MR) imaging has emerged as a means of measuring in vivo 3D trabecular bone structure. In particular, MR based diagnosis could be used to complement standard bone mineral density (BMD) methods for assessing osteoporosis and evaluating longitudinal changes. The aim of this study was to demonstrate the feasibility of using the 3D-LSGA technique for the evaluation of trabecular bone structure of high-resolution MR images, particularly for assessing longitudinal changes, in vivo. First, the reproducibility of topological 3D-LSGA based measurements was evaluated in a set of seven volunteers, and coefficients of variations ranged from 3.5% to 6%. Second, high-resolution MR images of the radius in 30 postmenopausal women from a placebo controlled drug study (Idoxifene), divided into placebo ( n=9) and treated ( n=21) groups, were obtained at baseline (BL) and after 1 year of treatment (follow-up, FU). In addition, dual X-ray absorptiometry (DXA) measures of BMD were obtained in the distal radius. Standard morphological measurements based on the mean intercept length (MIL) technique as well as 3D-LSGA based measurements were applied to the 3D MR images. Significant changes from BL to FU were detected, in the treated group, using the topological 3D-LSGA based measurements, morphological measures of volume of connected trabeculae and App Tb.N from MIL analysis. The duration of the study was short, and the number of patients remaining in the study was small, hence these results cannot be interpreted with regard to a true therapeutic response. Furthermore, the site (wrist) and the drug (idoxifene) are not optimal for follow-up study. However, this paper demonstrated the feasibility of using 3D-LSGA based evaluation coupled with in vivo high-resolution MR imaging as a complementary approach for the monitoring of trabecular bone changes in individual subjects.

    View details for DOI 10.1007/s00198-003-1563-4

    View details for Web of Science ID 000220939000009

    View details for PubMedID 15022037

  • Survival analysis in patients with glioblastoma multiforme: Predictive value of choline-to-N-acetylaspartate index, apparent diffusion coefficient, and relative cerebral blood volume JOURNAL OF MAGNETIC RESONANCE IMAGING Oh, J., Henry, R. G., Pirzkall, A., Lu, Y., Li, X. J., Catalaa, I., Chang, S., Dillon, W. P., Nelson, S. J. 2004; 19 (5): 546-554


    To investigate the potential value of pre-external-beam radiation therapy (XRT) choline-to-NAA (N-acetylaspartate) index (CNI), apparent diffusion coefficient (ADC), and relative cerebral blood volume (rCBV) for predicting survival in newly diagnosed patients with glioblastoma multiforme (GBM).Twenty-eight patients with GBM were studied using in vivo proton magnetic resonance spectroscopic imaging (1H MRSI) and diffusion- and perfusion-weighted imaging after surgery but prior to XRT. Patients were categorized on the basis of their volumes of morphologic and metabolic abnormalities (volume of CNI > or = 2 and CNI values), normalized ADC (nADC), or rCBV values within the T1 contrast-enhancing and T2 regions. The median survival time was compared.A significantly shorter median survival time was observed for patients with a large volume of metabolic abnormality than for those with a small abnormality (12.0 and 17.1 months, respectively, P = 0.002). A similar pattern was observed for patients with a low mean nADC value compared to those with high mean nADC value within the T2 region (11.2 and 21.7 months, respectively, P = 0.004). A shorter median survival time was also observed for patients with contrast-enhancing residual disease than for those without the presence of contrast enhancement with marginal significance.The pre-XRT volume of the metabolic abnormality and the nADC value within the T2 region may be valuable in predicting outcome for patients with GBM.

    View details for DOI 10.1002/jmri.20039

    View details for Web of Science ID 000221254100010

    View details for PubMedID 15112303

  • Immunoprevention of basal cell carcinomas with recombinant hedgehog-interacting protein JOURNAL OF EXPERIMENTAL MEDICINE Vogt, A., Chuang, P. T., Hebert, J., Hwang, J., Lu, Y., KOPELOVICH, L., Athar, M., Bickers, D. R., Epstein, E. H. 2004; 199 (6): 753-761


    Basal cell carcinomas (BCCs) are driven by abnormal hedgehog signaling and highly overexpress several hedgehog target genes. We report here our use of one of these target genes, hedgehog-interacting protein (Hip1), as a tumor-associated antigen for immunoprevention of BCCs in Ptch1+/- mice treated with ionizing radiation. Hip1 mRNA is expressed in adult mouse tissues at levels considerably lower than those in BCCs. Immunization with either of two large recombinant Hip1 polypeptides was well tolerated in Ptch1+/- mice, induced B and T cell responses detectable by enzyme-linked immunosorbent assay, Western blot, delayed type hypersensitivity, and enzyme-linked immunospot assay, and reduced the number of BCCs by 42% (P < 0.001) and 32% (P < 0.01), respectively. We conclude that immunization with proteins specifically up-regulated by hedgehog signaling may hold promise as a preventive option for patients such as those with the basal cell nevus syndrome who are destined to develop large numbers of BCCs.

    View details for DOI 10.1084/jem.20031190

    View details for Web of Science ID 000220335000002

    View details for PubMedID 15024045

    View details for PubMedCentralID PMC2212732

  • A three-dimensional MRI analysis of knee kinematics JOURNAL OF ORTHOPAEDIC RESEARCH Patel, V. V., Hall, K., Ries, M., Lotz, J., Ozhinsky, E., Lindsey, C., Lu, Y., Majumdar, S. 2004; 22 (2): 283-292


    To quantify normal, in vivo tibio-femoral knee joint kinematics in multiple weight bearing positions using non-invasive, high-resolution MRI and discuss the potential of developing future kinematic methods to assess patients with abnormal joint pathologies.Ten volunteers with clinically normal knees pushed inferiorly on the footplate of a weight bearing apparatus inside the MR scanner. The volunteers held the weight (133 N) for five scans as the knee motion was evaluated from 0 degrees to 60 degrees of flexion. Full extension was set as the zero point for all measured parameters. Using 3D reconstructions, tibia motion relative to the femur and flexion angle was measured as varus-valgus angle, axial rotation, anterior-posterior translation, and medial-lateral translation. Medial and lateral compartment tibio-femoral contact areas were examined and centroids of the contract areas were calculated.Tibial internal rotation averaged 4.8 degrees at 40 degrees of flexion and then decreased. Tibial valgus increased by 8 degrees at 60 degrees of flexion. Femoral roll back also increased to 18.5 mm average at 60 degrees of flexion, while the tibia translated medially 2.5 mm. Medial compartment femoro-tibial contact area started at 374 mm2 and decreased to 308 mm2 with flexion of 60 degrees, while lateral compartment contact area did not change significantly from 276 mm2.Results correlate with previous studies of knee kinematics while providing greater three-dimensional detail. MR imaging allows excellent non-invasive evaluation of knee joint kinematics with weight bearing. This tool may potentially be used for assessing knee kinematics in patients with knee pathology.

    View details for DOI 10.1016/j.orthres.2003.08.015

    View details for Web of Science ID 000220027800008

    View details for PubMedID 15013086

  • Identification of MRI and H-1 MRSI parameters that may predict survival for patients with malignant gliomas NMR IN BIOMEDICINE Li, X. J., Jin, H., Lu, Y., Oh, J., Chang, S., Nelson, S. J. 2004; 17 (1): 10-20


    Although MR imaging (MRI) and MR spectroscopic imaging (MRSI) have been applied in the diagnosis and treatment planning for brain tumors, their prognostic significance has not yet been determined. The goal of this study was to identify pre-treatment MRI and MRSI parameters for patients with malignant glioma that may be useful in predicting survival. Two populations of patients with newly-diagnosed malignant glioma were examined with MRI and three-dimensional proton ((1)H) MRSI. Thirty-nine patients (22 grade 3 and 17 glioblastoma multiforme, GBM) were studied prior to surgery, and 33 GBM patients were studied after surgery but prior to treatment with radiation and chemotherapy. Signal intensities of choline (Cho), creatine (Cr), N-acetyl aspartate (NAA), and lactate/lipid (LL) were estimated from the spectra. Recursive partitioning methods were applied to parameters that included age, histological grade, MRI and MRSI variables to generate survival trees. Patients were grouped into high and low risk categories and the corresponding Kaplan-Meier curves were plotted for comparison between groups. The parameters that were selected by recursive partitioning as being predictive of poor outcome were older age, larger contrast enhancement, higher Cho-to-Cr, higher Cho-to-NAA, higher LL and lower Cr-to-NAA abnormalities. The survival functions were significantly different between the sub-groups of patients obtained from the survival tree for both pre-surgery and post-surgery data. The results of this study suggest that pre-treatment MRI and three-dimensional (1)H-MRSI provide information that predicts outcome for patients with malignant gliomas and have drawn attention to variables that should be examined prospectively in future studies using these techniques.

    View details for Web of Science ID 000220114200002

    View details for PubMedID 15011246

  • The unique impact of changes in normal appearing brain tissue on cognitive dysfunction in secondary progressive multiple sclerosis patients MULTIPLE SCLEROSIS JOURNAL Cox, D., Pelletier, D., Genain, C., Majumdar, S., Lu, Y., Nelson, S., Mohr, D. C. 2004; 10 (6): 626-629


    The purpose of this study was to examine the relationships between cognitive functioning, whole brain magnetic transfer ratio (MTR) imaging, supratentorial 1H-magnetic resonance spectroscopy imaging (1HMRSI), and conventional T1 and T2 imaging in a homogenous sample of SPMS patients.Nineteen patients underwent a single 90-min imaging session that obtained T1-and T2-weighted images and MTR. 1HMRSI was obtained on 14 of these patients. Patients underwent a neuropsychological battery, which was used to create an integrated measure of cognitive impairment. Cognitive impairment was the dependent variable in two hierarchical multiple regression analyses in which T2 lesion load, T1 lesion load, and MTR or NAA/Cr were entered sequentially.MTR was significantly related to cognitive functioning (deltaR2 = 0.22, P = 0.02) after accounting for T2 lesion load (deltaR2 = 0.33, P = 0.01) and T1 lesion load (deltaR2 = 0.00, P = 0.98). NAA/Cr was not significantly related to cognitive functioning.Cognitive dysfunction may act as a clinical marker of normal appearing brain tissue pathology in multiple sclerosis.

    View details for DOI 10.1191/1352458504ms1095oa

    View details for Web of Science ID 000225101700006

    View details for PubMedID 15584486

  • Prostate cancer localization with endorectal MR imaging and MR spectroscopic imaging: Effect of clinical data on reader accuracy RADIOLOGY Dhingsa, R., Qayyum, A., Coakley, F. V., Lu, Y., Jones, K. D., Swanson, M. G., Carroll, P. R., Hricak, H., Kurhanewicz, J. 2004; 230 (1): 215-220


    To determine the effect of digital rectal examination findings, sextant biopsy results, and prostate-specific antigen (PSA) levels on reader accuracy in the localization of prostate cancer with endorectal magnetic resonance (MR) imaging and MR spectroscopic imaging.This was a retrospective study of 37 patients (mean age, 57 years) with biopsy-proved prostate cancer. Transverse T1-weighted, transverse high-spatial-resolution, and coronal T2-weighted MR images and MR spectroscopic images were obtained. Two independent readers, unaware of clinical data, recorded the size and location of suspicious peripheral zone tumor nodules on a standardized diagram of the prostate. Readers also recorded their degree of diagnostic confidence for each nodule on a five-point scale. Both readers repeated this interpretation with knowledge of rectal examination findings, sextant biopsy results, and PSA level. Step-section histopathologic findings were the reference standard. Logistic regression analysis with generalized estimating equations was used to correlate tumor detection with clinical data, and alternative free-response receiver operating characteristic (AFROC) curve analysis was used to examine the overall effect of clinical data on all positive results.Fifty-one peripheral zone tumor nodules were identified at histopathologic evaluation. Logistic regression analysis showed awareness of clinical data significantly improved tumor detection rate (P <.02) from 15 to 19 nodules for reader 1 and from 13 to 19 nodules for reader 2 (27%-37% overall) by using both size and location criteria. AFROC analysis showed no significant change in overall reader performance because there was an associated increase in the number of false-positive findings with awareness of clinical data, from 11 to 21 for reader 1 and from 16 to 25 for reader 2.Awareness of clinical data significantly improves reader detection of prostate cancer nodules with endorectal MR imaging and MR spectroscopic imaging, but there is no overall change in reader accuracy, because of an associated increase in false-positive findings. A stricter definition of a true-positive result is associated with reduced sensitivity for prostate cancer nodule detection.

    View details for DOI 10.1148/radiol.2301021562

    View details for Web of Science ID 000187613100030

    View details for PubMedID 14695396

  • Magnetic resonance imaging of patellofemoral kinematics with weight-bearing. journal of bone and joint surgery. American volume Patel, V. V., Hall, K., Ries, M., Lindsey, C., Ozhinsky, E., Lu, Y., Majumdar, S. 2003; 85-A (12): 2419-2424


    Previous studies of the patellofemoral joint have been limited by the use of invasive techniques, measurements under non-weight-bearing conditions, cadaveric specimens, or computerized models. It has been shown that soft tissue and bone can be accurately quantified with magnetic resonance imaging. The present study was designed to define the relationship between the patellofemoral contact area and patellofemoral kinematics in vivo.Ten subjects with clinically normal knee joints were scanned with high-resolution magnetic resonance imaging while they pushed a constant weight (133 N) on the foot-plate of a custom-designed load-bearing apparatus. Images were obtained at five positions of flexion between -10 degrees and 60 degrees. Three-dimensional reconstructions were used to measure the patellofemoral cartilage contact area, patellar centroid, patellar medial and inferior translation, patellar medial and inferior tilt, and patellar varus-valgus rotation. All translation and area measurements were normalized on the basis of the interepicondylar distance. Random-effects models of quadratic regressions were used to evaluate the data.The mean contact area ranged from 126 mm(2) in extension to 560 mm(2) at 60 degrees of flexion. The patella translated inferiorly to a maximum distance of 34 mm at 60 degrees of flexion and translated medially to a maximum distance of 3.2 mm at 30 degrees of flexion before returning to nearly 0 mm at 60 degrees of flexion. The patella tilted inferiorly to a mean of nearly 35 degrees at 60 degrees of flexion and medially to a maximum of 4.2 degrees at 30 degrees of flexion. By 60 degrees of flexion, the centroid of the contact area had shifted to an inferior and posterior maximum of 20 and 10 mm, respectively.We found that lateral patellar subluxation and tilt occurred in these normal knees at full extension and the patella was reduced into the trochlear groove at 30 degrees of flexion. Therefore, we believe that lateral patellar tilt and subluxation observed during arthroscopy of the extended knee may not represent a pathological condition.

    View details for PubMedID 14668513

  • CT signs of hepatofugal portal venous flow in patients with cirrhosis AMERICAN JOURNAL OF ROENTGENOLOGY Bryce, T. J., Yeh, B. M., Qayyum, A., Pacharn, P., Bass, N. M., Lu, Y., Coakley, F. V. 2003; 181 (6): 1629-1633


    We investigated whether CT signs can be used to predict hepatofugal flow in the main portal vein in patients with cirrhosis.We retrospectively identified 36 patients with cirrhosis, 18 with hepatopetal and 18 with hepatofugal flow in the main portal vein, who underwent contemporaneous abdominal sonography and CT. Two independent observers evaluated the following features on the randomized CT studies: diameter of the portal, splenic, and superior mesenteric veins; spleen size; and the presence of ascites, varices, or arterial phase portal venous enhancement. These data were correlated with the flow direction seen on sonography.A small main portal vein was the only sign significantly (p

    View details for Web of Science ID 000186749700032

    View details for PubMedID 14627587

  • Distinction of renal cell carcinomas from high-attenuation renal cysts at portal venous phase contrast-enhanced CT RADIOLOGY Suh, M., Coakley, F. V., Qayyum, A., Yeh, B. M., Breiman, R. S., Lu, Y. 2003; 228 (2): 330-334


    To determine if renal cell carcinomas can be distinguished from high-attenuation renal cysts on portal venous phase contrast material-enhanced computed tomographic (CT) scans.Fifty-seven renal cell carcinomas and 37 high-attenuation (>20 HU) renal cysts that were at least 1 cm in diameter were retrospectively identified in 90 patients who underwent portal venous phase contrast-enhanced CT. Two independent readers recorded the CT number and degree of internal heterogeneity (uniform or mildly, moderately, or markedly heterogeneous) of all lesions. Logistic regression analysis with adjustment for the two readers was used to examine the association between clinical and CT parameters and the final diagnosis. Stepwise logistic regression analysis was used to identify independent distinguishing variables, which were then incorporated in a classification and regression tree analysis to construct the most efficient classification algorithm.Renal cell carcinomas were of significantly greater size (5.10 cm vs 2.84 cm, P <.001), mean attenuation (101.2 HU vs 55.3 HU, P <.001), and internal heterogeneity (P <.001) than high-attenuation renal cysts. Stepwise logistic regression showed attenuation and internal heterogeneity were both independent variables associated with final diagnosis, but lesion size was not an independent distinguishing variable after adjustment for internal heterogeneity. Classification and regression tree analysis demonstrated that an attenuation greater than 70 HU or the presence of moderate or marked internal heterogeneity was an accurate sign of renal cell carcinoma, with a sensitivity of 91% (52 of 57) for both readers and a specificity of 92% (34 of 37) for reader 1 and 84% (31 of 37) for reader 2.On portal venous phase contrast-enhanced CT scans, attenuation greater than 70 HU or moderate or marked internal heterogeneity favor a diagnosis of renal cell carcinoma over a diagnosis of high-attenuation renal cyst.

    View details for DOI 10.1148/radiol.2282020922

    View details for Web of Science ID 000184381100008

    View details for PubMedID 12819331

  • A micro-computed tomography study of the trabecular bone structure in the femoral head. Journal of musculoskeletal & neuronal interactions Issever, A. S., Burghardt, A., Patel, V., Laib, A., Lu, Y., Ries, M., Majumdar, S. 2003; 3 (2): 176-184


    The goal of this study was to characterize the trabecular microarchitecture of the femoral head using micro-computed tomography (ICT). Femoral head specimens were obtained from subjects following total hip replacement. Cylindrical cores from the specimens were scanned to obtain 3-D images with an isotropic resolution of 26 Im. Bone structural parameters were evaluated on a per millimeter basis: relative bone volume (BV/TV), trabecular number (Tb.N), thickness (Tb.Th) and separation (Tb.Sp), structure model index (SMI), and connectivity (Conn.D). The ICT data show that the first two millimeters, starting at the joint surface, are characterized by more plate-like trabeculae, and are significantly denser than the underlying trabecular bone. Regional differences in the trabecular architecture reveal that the superior pole has significantly higher BV/TV, Tb.N and Tb.Th values, with lower Tb.Sp compared to the inferior and side poles. Because subchondral bone is essential in the load attenuation of joints, the difference in bone structure between the subchondral and trabecular bone might arise from the different functions each have within joint-forming bones. The denser trabecular structure of the superior pole as compared to the inferior pole can be interpreted as a functional adaptation to higher loading in this area.

    View details for PubMedID 15758359

  • Magnetic resonance imaging in patients diagnosed with ductal carcinoma-in-situ: Value in the diagnosis of residual disease, occult invasion, and multicentricity ANNALS OF SURGICAL ONCOLOGY Hwang, E. W., Kinkel, K., Esserman, L. J., Lu, Y., Weidner, N., Hylton, N. M. 2003; 10 (4): 381-388


    Although magnetic resonance imaging (MRI) has been shown to be a sensitive imaging tool for invasive breast cancers, its utility in ductal carcinoma-in-situ (DCIS) of the breast remains controversial. We studied the performance of MRI in patients with known DCIS for assessment of residual disease, occult invasion, and multicentricity to determine the clinical role of MRI in this setting.Fifty-one patients with biopsy-proven DCIS underwent contrast-enhanced MRI before surgical treatment. Pre-, early post-, and late postcontrast three-dimensional gradient echo images were obtained and MRI findings were correlated with histopathology. When possible, the performance of MRI and mammography was compared.The accuracy of MRI was 88% in predicting residual disease, 82% in predicting invasive disease, and 90% in predicting multicentricity. The performance of MRI was equivalent in the core biopsy group when compared with the surgical biopsy group. For occult invasion only, MRI and mammography were equivalent. However, overall, MRI was more sensitive and had a higher negative predictive value than mammography.MRI of DCIS can serve as a useful adjunct to mammography by providing a more accurate assessment of the extent of residual or multicentric disease. The performance of MRI is not significantly affected by antecedent surgical excision. MRI may be particularly valuable if preoperatively negative.

    View details for DOI 10.1245/ASO.2003.03.085

    View details for Web of Science ID 000182754700010

    View details for PubMedID 12734086

  • Challenges in dynamic contrast-enhanced MR imaging of cervical lymph nodes to detect metastatic disease 8th Annual Meeting of the International-Society-for-Magnetic-Resonance-in-Medicine (ISMRM) Noworolski, S. M., Fischbein, N. J., Kaplan, M. J., Lu, Y., Nelson, S. J., Carvajal, L., Henry, R. G. JOHN WILEY & SONS INC. 2003: 455–62


    To identify and overcome challenges in using dynamic contrast-enhanced magnetic resonance imaging (MRI) to distinguish tumor from nontumor in the cervical lymph nodes of patients with squamous cell carcinoma of the head and neck.Signal-to-noise ratio (S/N), motion, node heterogeneity, and tissue normalizations were examined. Twenty-one patients with squamous cell carcinoma of the head and neck were scanned before a neck dissection (two-dimensional fast spoiled gradient-echo: 10 locations/13 seconds). Peak time, peak enhancement, maximum upslope, and washout slope were measured in pathologically confirmed tumor and nontumor nodes and in the submandibular gland and the sternocleidomastoid muscle.Surface coil arrays provided high coverage and high S/N. Motion averaged 1.1 pixels and was corrected. Large tumor nodes were heterogeneous in their contrast enhancement, while the nontumor nodes were homogeneous. The contrast enhancement parameters were significantly different for all regions except for the submandibular gland compared to the nontumor nodes.Challenges of dynamic imaging of cervical lymph nodes were overcome and significant differences were found between the tumor and nontumor nodes, indicating that dynamic imaging is feasible and may aid this patient population.

    View details for DOI 10.1002/jmri.10280

    View details for Web of Science ID 000182453200009

    View details for PubMedID 12655585

  • Phalangeal quantitative ultrasound, phalangeal morphometric variables, and vertebral fracture discrimination CALCIFIED TISSUE INTERNATIONAL Guglielmi, G., Njeh, C. F., de Terlizzi, F., De Serio, D. A., Scillitani, A., Cammisa, M., Fan, B., Lu, Y., Genant, H. K. 2003; 72 (4): 469-477


    The aim of this study was to evaluate the association among phalangeal morphometric parameters, amplitude-dependent speed of sound (AD-SOS), ultrasound bone profile index (UBPI), and spinal bone mineral density (BMD) and fracture status. One hundred women (controls, mean age 53 +/- 12 years) and 40 osteoporotic women (mean age 59 +/- 7 years) with atraumatic fractures, diagnosed by spinal radiographs, were investigated. Quantitative ultrasound (QUS) assessment was performed using the DBM Sonic 1200. Morphological properties of the phalanges were measured from a digitized X-ray image of the hand acquired using industrial film. Spinal BMD was assessed by dual X-ray absorptiometry (DXA) and quantitative computed tomography (QCT). An increase in medullary canal width and a decrease in cortical thickness with aging were observed from the morphometric analysis of the hand radiographs. This phenomenon can be attributed mainly to endosteal resorption. QUS measurements at the phalanges were not significantly related to finger thickness (r <0.20, n.s.). They were significantly correlated to medullary canal ratio (r = -0.57, P <0.0001, for AD-SOS and r = -0.64, P <0.0001, for UBPI) and to cortical thickness (r = +0.52, P <0.0001 for AD-SOS and r = +0.59, P <0.0001 for UBPI). In the discrimination analysis between nonfractured and atraumatic vertebral fracture subjects we found that cortical thickness at the level of the phalanges were similar to lumbar spine BMD. The age and BMI-adjusted odds ratio ranged from 2.0 to 3.1 for QUS, 4.28 for BMD by QCT, 4.1 for BMD by DXA, and 4.1 for cortical thickness. We conclude from these data that phalangeal QUS is related to cortical thickness, which in turn is influenced by endosteal bone resorption occurring in association with spinal osteoporosis.

    View details for DOI 10.1007/s00223-001-1092-0

    View details for Web of Science ID 000182518500002

    View details for PubMedID 12574870

  • Distinguishing features of self-limiting adult small-bowel intussusception identified at CT RADIOLOGY Lvoff, N., Breiman, R. S., Coakley, F. V., Lu, Y., Warren, R. S. 2003; 227 (1): 68-72


    To determine if clinical or computed tomographic (CT) findings can be used to distinguish self-limiting cases of adult small-bowel intussusception from those requiring surgery.Thirty-seven cases of adult small-bowel intussusception were identified by a retrospective computerized search of 69,040 abdominopelvic CT examinations performed over a 4-year period. Two independent readers recorded CT features. Clinical findings and outcomes were determined by review of all available medical records. Outcome was classified as either surgical or self-limiting. Association between predictive variables and outcome was assessed by the Fisher exact test and logistic regression models. A multivariate, stepwise, logistic regression model was used to determine the best predictors of outcome.Six patients (16%) underwent surgery, and all had lead-point tumors. Thirty-one patients were cared for conservatively (84%) and none required surgery at a mean follow-up of 5.2 months (range, 0-46 months). Multivariate, stepwise, logistic regression analysis showed intussusception length was the only variable that was independently predictive of outcome. All 20 patients with an intussusception length of 3.5 cm or less, as measured by either reader, had cases that were self-limiting. Seventeen patients had an intussusception length greater than 3.5 cm, as measured by either reader. Eleven patients had an intussusception that was self-limiting, and six patients had an intussusception that required surgery.Intussusception length is the main factor in distinguishing the majority of small-bowel intussusceptions detected at CT that are self-limiting from the minority that require surgery. An intussusception that is shorter than 3.5 cm is likely to be self-limiting.

    View details for DOI 10.1148/radiol.2272020455

    View details for Web of Science ID 000181901100010

    View details for PubMedID 12668740

  • Osteoarthritis: MR imaging findings in different stages of disease and correlation with clinical findings RADIOLOGY Link, T. M., Steinbach, L. S., Ghosh, S., Ries, M., Lu, Y., Lane, N., Majumdar, S. 2003; 226 (2): 373-381


    To determine whether knee pain, stiffness, and limited function in patients with different stages of osteoarthritis correlate with the degree of disease assessed on magnetic resonance (MR) images and radiographs.Radiographs in 50 patients with varying degrees of osteoarthritis of the knee were assessed by using the the Western Ontario and McMaster University (WOMAC) osteoarthritis index and the Kellgren-Lawrence (KL) scale. MR images were obtained and analyzed by two readers for cartilage lesions, bone marrow edema pattern, and ligamentous and meniscal lesions.Thirteen of 16 knees with a KL score of 4 showed full-thickness cartilage lesions and bone marrow edema pattern. Cruciate ligament tears were found in five of 12 knees with a KL score of 3 and in nine of 16 knees with a KL score of 4. While the KL score correlated significantly (P <.05) with the grade of cartilage lesions, and a substantially higher percentage of lesions with higher KL scores were found on MR images, the correlations between MR imaging findings and KL score versus clinical findings were not significant (P >.05). Significant differences between WOMAC scores were found only for the grades of cartilage lesions (P <.05).Cartilage lesions, bone marrow edema pattern, and meniscal and ligamentous lesions were frequently demonstrated on MR images in patients with advanced osteoarthritis. Clinical findings showed no significant correlations with KL score and extent of findings at MR imaging.

    View details for DOI 10.1148/radiol.2262012190

    View details for Web of Science ID 000180657000012

    View details for PubMedID 12563128

  • Micro-computed tomography evaluation of trabecular bone structure on loaded mice tail vertebrae SPINE Issever, A. S., Walsh, A., Lu, Y., Burghardt, A., Lotz, J. C., Majumdar, S. 2003; 28 (2): 123-128


    A micro-computed tomography (CT) study of the trabecular bone structure on loaded mice tail vertebral bodies was conducted.To depict and characterize changes in the trabecular bone structure of mice tail vertebral bodies after in vivo application of static compressive load.Static compressive loading leads to significant structural changes in murine tail intervertebral discs, such as disorganization of the anulus fibrosus, increase in apoptosis, and associated loss of cellularity. Wolff's Law suggests that alterations in spinal loading will also influence the architecture of the adjacent vertebral bodies. Because of biomechanical and biologic interdependencies between the disc and vertebra, these tissues should be considered simultaneously when investigating the etiology of degenerative spinal conditions.Mice tail discs between the ninth and 10th caudal vertebrae were compressed in vivo for 7 days with static axial loads using external fixators. Micro-CT scans of the vertebral bodies were performed at an isotropic resolution of 18 microm, to obtain trabecular bone structural parameters. Random effects models were used to evaluate statistical significance of these parameters in different compressed conditions.With loading, the connectivity density of the trabecular network increases significantly. After a period of in vivo recovery on load removal, the trabeculae become more rod-like; corresponding changes such as disorganization of the anulus fibrosus and loss of nuclear and inner-anular cellularity are also seen.In vivo compressive loading leads to significant architectural changes within vertebral bodies. These observations may be helpful in understanding the pathologic processes and the chronology of degenerative spinal conditions.

    View details for Web of Science ID 000180513000005

    View details for PubMedID 12544927

  • MRI measurements of tumor volume and vascularity are valuable prognostic indicators for monitoring neoadjuvant chemotherapy of breast cancer. Partridge, S. C., Gibbs, J. E., Lu, Y., Esserman, L. J., Hylton, N. M. KLUWER ACADEMIC PUBL. 2002: S150
  • Accuracy of MR imaging for revealing residual breast cancer in patients who have undergone neoadjuvant chemotherapy 10th Annual Meeting of the International-Society-for-Magnetic-Resonance-in-Medicine (ISMRM) Partridge, S. C., Gibbs, J. E., Lu, Y., Esserman, L. J., Sudilovsky, D., Hylton, N. M. AMER ROENTGEN RAY SOC. 2002: 1193–99


    Our study investigated the usefulness of contrast-enhanced MR imaging for accurately measuring the size of residual tumor after patients have undergone neoadjuvant (pre-operative) chemotherapy. The imaging analysis method was optimized for identifying residual disease in the treated breast. Tumor sizes measured on the MR images and at the clinical examination were compared with the size of residual disease measured at pathology after surgery.Before undergoing surgery, 52 patients were imaged before and after receiving neoadjuvant chemotherapy. For each patient, specific malignancy criteria were applied to MR images before chemotherapy to identify the location of tumor, and residual disease was then identified as any remaining enhancement in the same area on the MR images after chemotherapy. Residual tumor size was measured using both the MR technique and the clinical examination findings, and the degree of measurement error for each method was assessed in comparison with the pathologic findings.The correlation with pathology was an r value of 0.89 for MR measurements compared with an r value of 0.60 for clinical measurements. In addition, MR imaging revealed all cases of residual disease, whereas clinical assessment resulted in five false-negative interpretations in the 52 treated lesions.The high correlation between measurements of residual disease obtained on MR images and those obtained at pathology validates the sensitivity of MR imaging of the breast after chemotherapy.

    View details for Web of Science ID 000178725800017

    View details for PubMedID 12388497

  • Epidermal stem cell frequency: A novel in vivo functional assay Barland, C., Schneider, T. E., Alex, A. M., Mancianti, M. L., Lu, Y., Lawrence, J. H., Ghadially, R. AMER SOC CELL BIOLOGY. 2002: 122A–123A
  • Dissociating perceptual and conceptual implicit memory in multiple sclerosis patients BRAIN AND COGNITION Blum, D., Yonelinas, A. P., Luks, T., Newitt, D., Oh, J., Lu, Y., Nelson, S., Goodkin, D., Pelletier, D. 2002; 50 (1): 51-61


    Previous studies indicate that Multiple Sclerosis (MS) patients exhibit deficits in tests of explicit memory such as free recall, but show normal priming on implicit tests of memory such as word stem completion. However, the memory performance of patients with different MS disease subtypes has not been fully examined. In the current study, memory was assessed in Primary Progressive (PPMS), Relapsing Remitting (RRMS), and Secondary Progressive (SPMS) MS subgroups. Explicit memory as well as perceptual and conceptual implicit memory were examined using free recall, word fragment completion, and exemplar generation tests, respectively. All three groups of MS patients exhibited free recall deficits and normal priming on the exemplar generation test. However, the PPMS group exhibited a deficit in word fragment completion priming, whereas the RRMS and SPMS groups exhibited normal levels of priming on this task. Lesion load was assessed using magnetic resonance imaging and was negatively correlated with explicit memory performance, but it did not account for the observed deficits in perceptual implicit memory. The results indicate that PPMS patients exhibit a pattern of memory impairment that is distinct from that of the RRMS and SPMS groups. Moreover, the results indicate that perceptual implicit memory can be neurologically dissociated from conceptual implicit memory.

    View details for Web of Science ID 000178573800005

    View details for PubMedID 12372351

  • Histopathological validation of a three-dimensional magnetic resonance spectroscopy index as a predictor of tumor presence JOURNAL OF NEUROSURGERY McKnight, T. R., von dem Bussche, M. H., Vigneron, D. B., Lu, Y., Berger, M. S., McDermott, M. W., Dillon, W. P., Graves, E. E., Pirzkall, A., Nelson, S. J. 2002; 97 (4): 794-802


    Data obtained preoperatively from three-dimensional (3D)/proton magnetic resonance (MR) spectroscopy were compared with the results of histopathological assays of tissue biopsies obtained during surgery to verify the sensitivity and specificity of a choline-containing compound-N-acetylaspartate index (CNI) used to distinguish tumor from nontumorous tissue within T2-hyperintense and contrast-enhancing lesions of patients with untreated gliomas. The information gleaned from the biopsy correlation study was used to test the hypothesis that there is metabolically active tumor in nonenhancing regions of the T2-hyperintense lesion that can be detected using MR spectroscopy.Patients suspected of harboring a glioma underwent 3D MR spectroscopy during their preoperative MR imaging examination. Surgical navigation techniques were used to record the location of tissue biopsies collected during open resection of the tumor. A receiver operating curve analysis of the CNI and histological characteristics of specimens at each biopsy location was performed to determine the optimal threshold of the CNI required to separate tumor from nontumorous tissue. Histograms of the CNIs within enhancing and nonenhancing regions of lesions appearing on MR images were generated to determine the spatial distribution of CNIs consistent with tumor.Biopsy samples containing tumor were distinguished from those containing a mixture of normal, edematous, gliotic, and necrotic tissue with 90% sensitivity and 86% specificity by using a CNI threshold of 2.5. The CNIs of nontumorous specimens were significantly different from those of biopsy specimens containing Grade II (p < 0.03), Grade III (p < 0.005), and Grade IV (p < 0.01) tumors. On average, one third to one half of the T2-hyperintense lesion outside the contrast-enhancing lesion contained CNI greater than 2.5.

    View details for Web of Science ID 000178626400014

    View details for PubMedID 12405365

  • 3-D echo planar (HMRS)-H-1 imaging in MS: metabolite comparison from supratentorial vs. central brain MAGNETIC RESONANCE IMAGING Pelletier, D., Nelson, S. J., Grenier, D., Lu, Y., Genain, C., Goodkin, D. E. 2002; 20 (8): 599-606


    To determine if metabolite ratios as measured by 3-dimensional echo planar spectroscopy imaging (3D-EPSI) from central brain regions of interest (ROI) centered at the corpus callosum reflect imaging metrics of large volumes of supratentorial brain (STB) from patients with multiple sclerosis.48 MS patients with relapsing-remitting, secondary progressive, and primary progressive disease underwent a 3D-EPSI sequence covering large volumes of STB. Metabolite ratios were first estimated from all voxels within a STB mask using a linear regression of N-acetylaspartate (NAA) over Creatine (Cr), NAA over choline (Cho) and Cho over Cr. Secondly, spectroscopic voxels from a central brain (CB) ROI centered at the corpus callosum were selected within the STB. Ratios were compared using Bland-Altman regression analysis and Spearman's correlation coefficients between STB versus central brain. Ratios from studied ROIs were correlated with the EDSS and compared to normal controls.Very strong correlations ranging from 0.884 and 0.938 (p < 0.0001) were found for all metabolite ratios between STB versus central brain. NAA/Cr ratios were similarly and negatively correlated with the EDSS across all ROIs, trends ranging from -0.257 to -0.314 (p < 0.1). NAA/Cr from all MS patients was similarly decreased compared to controls across all ROIs (p < 0.01).Metabolite ratios from a central brain ROI were statistically equivalent and highly correlated with ratios from the STB. The study of NAA/Cr using (1)HMRS from a central brain ROI centered at the corpus callosum seems to be representative of brainwide axonal changes in patients with MS.

    View details for Web of Science ID 000179740500005

    View details for PubMedID 12467867

  • Analysis of the spatial characteristics of metabolic abnormalities in newly diagnosed glioma patients 9th Annual Meeting of the International-Society-for-Magnetic-Resonance-in-Medicine (ISMRM) Li, X. J., Lu, Y., Pirzkall, A., McKnight, T., Nelson, S. J. JOHN WILEY & SONS INC. 2002: 229–37


    To evaluate the role of 3D MR spectroscopic imaging (MRSI) as a tool for characterizing heterogeneity within a lesion in glioma patients.Forty-nine patients with newly diagnosed glioma were studied with 3D water-suppressed proton (1-H) MRSI. Signal intensities from choline (Cho), creatine (Cr), N-acytel aspartate (NAA), and lactate/lipid (LL) were estimated from the spectra. Regions of interest (ROIs) corresponding to the metabolic abnormalities were defined and compared with the anatomic lesions.This study showed that the tumor burden measured with either the volumes of the metabolic abnormalities or the metabolic levels in the most abnormal voxels was correlated with the degree of malignancy of the tumor. The volumes of elevated Cho and decreased NAA were useful for distinguishing low-grade from high-grade lesions. The volume of abnormal LL was correlated with the existence of necrosis and with the volume of contrast-enhancing lesions in high-grade lesions. The differences in the volume of abnormal LL were also statistically significant between patients in each grade.These 3D-MRSI data provide important additional information to conventional MRI for evaluating and characterizing gliomas.

    View details for DOI 10.1002/jmri.10147

    View details for Web of Science ID 000177650900001

    View details for PubMedID 12205577

  • Effect of long-duration Spaceflight on integral and compartmental bone density in the spine and hip. Lang, T. F., Evans, H., Rianon, N., Lu, Y., Genant, H., Leblanc, A. AMER SOC BONE & MINERAL RES. 2002: S243
  • Sonographic evaluation of liver nodularity: Inspection of deep versus superficial surfaces of the liver JOURNAL OF CLINICAL ULTRASOUND Filly, R. A., Reddy, S. G., Nalbandian, A. B., Lu, Y., Callen, P. W. 2002; 30 (7): 399-407


    We determined the diagnostic performance of assessing the nodularity of deep versus superficial surfaces of the liver as a predictor of cirrhosis.One sonologist retrospectively reviewed the sonograms of 100 patients at risk for cirrhosis based on clinical data and laboratory tests. A second sonologist reviewed the sonograms of a subset of 25 patients to assess for inter-reader variability, while the first sonologist re-reviewed the sonograms of a different subset of 25 patients for intrareader variability. Sonograms of all patients were obtained with standard sector- or curved-array transducers. Biopsy confirmation of cirrhosis was used as the standard for diagnostic accuracy.Fifty of the 100 patients had a pathologic diagnosis of cirrhosis. The sensitivity of inspection of the deep surface versus the superficial surface was 86% versus 53% (p = 0.0003), respectively. Sensitivity was not dependent on pathologic type. Intrareader agreement was better for deep than for superficial surface observations. The overall inter-reader agreement was fair and comparable for both deep and superficial surface methods.The sensitivity for detecting cirrhosis based on surface nodularity is greater for deep than for superficial surface observations. As the prevalence of disease increases, the accuracy of assessment of the deep surface in predicting cirrhosis increases.

    View details for DOI 10.1002/jcu.10095

    View details for Web of Science ID 000177685800001

    View details for PubMedID 12210457

  • Computed tomographic findings in patients undergoing intra-arterial thrombolysis for acute ischemic stroke due to middle cerebral artery occlusion - Results from the PROACT II trial STROKE Roberts, H. C., Dillon, W. P., Furlan, A. J., Wechsler, L. R., Rowley, H. A., Fischbein, N. J., Higashida, R. T., Kase, C., Schulz, G. A., Lu, Y., Firszt, C. M. 2002; 33 (6): 1557-1565


    The purpose of this study was to evaluate the role of noncontrast CT in the selection of patients to receive thrombolytic therapy for acute ischemic stroke and to predict radiological and clinical outcomes.One hundred eighty patients with stroke due to middle cerebral artery (MCA) occlusion were randomized 2:1 within 6 hours of onset to receive intra-arterial recombinant prourokinase plus intravenous heparin or intravenous heparin only. Four hundred fifty-four CT examinations were digitized to calculate early infarct changes, infarct volumes, and hemorrhagic changes among the 162 patients treated as randomized (108 recombinant prourokinase-treated patients and 54 control patients). CT changes were correlated with baseline stroke severity, angiographic clot location, collateral vessels, and outcome at 90 days.Baseline CT scans, 120 (75%) of 159, showed early infarct-related abnormalities. The baseline CT abnormality volume was not correlated with the baseline National Institutes of Health Stroke Scale (NIHSS) score (r=-0.11) but was correlated weakly with the outcome (r=0.17, P<0.05). Compared with patients with M2 occlusions, patients with M1 MCA occlusions had significantly higher baseline NIHSS scores (P<0.05), more basal ganglia involvement on CT, and larger hypodensity volumes on follow-up CTs. Compared with patients with partial or no collateral supply, patients with full collateral supply had lower baseline NIHSS scores, significantly smaller baseline CT infarct volumes, and less cortical involvement (P<0.05).Noncontrast CT is not correlated with baseline stroke severity and does not predict outcome in patients with stroke due to MCA occlusion. However, baseline CT changes, clinical presentation, and the evolution of CT changes are influenced by clot location and the presence of a collateral supply.

    View details for DOI 10.1161/01.STR.0000018011.66817.41

    View details for Web of Science ID 000176164300034

    View details for PubMedID 12052991

  • Prostate cancer tumor volume: Measurement with endorectal MR and MR spectroscopic imaging RADIOLOGY Coakley, F. V., Kurhanewicz, J., Lu, Y., Jones, K. D., Swanson, M. G., Chang, S. D., Carroll, P. R., Hricak, H. 2002; 223 (1): 91-97


    To determine accuracy of magnetic resonance (MR) and three-dimensional (3D) MR spectroscopic imaging in prostate cancer tumor volume measurement.Endorectal MR and 3D MR spectroscopic imaging were performed in 37 patients before radical prostatectomy. Two independent readers recorded peripheral zone tumor nodule location and volume. Results were analyzed with step-section histopathologic tumor localization and volume measurement as the standard. Accuracy of tumor volume measurement was assessed with the Pearson correlation coefficient. P values were calculated with a random effects model. Bland-Altman regression analysis was used to evaluate systematic bias between tumor volumes measured with MR imaging and true tumor volumes. Analyses were performed for all nodules and nodules greater than 0.50 cm(3).Mean volume of peripheral zone tumor nodules (n = 51) was 0.79 cm(3) (range, 0.02-3.70 cm(3)). Two readers detected 20 (65%) and 23 (74%) of 31 peripheral zone tumor nodules greater than 0.50 cm(3). For these nodules, measurements of tumor volume with MR imaging, 3D MR spectroscopic imaging, and a combination of both were all positively correlated with histopathologic volume (Pearson correlation coefficients of 0.49, 0.59, and 0.55, respectively); only measurements with 3D MR spectroscopic imaging and a combination of MR and 3D MR spectroscopic imaging demonstrated statistical significance (P <.05). Tumor volume estimation with all three methods was more accurate for higher tumor volumes.Addition of 3D MR spectroscopic imaging to MR imaging increases overall accuracy of prostate cancer tumor volume measurement, although measurement variability limits consistent quantitative tumor volume estimation, particularly for small tumors.

    View details for DOI 10.1148/radiol.2231010575

    View details for Web of Science ID 000174611900013

    View details for PubMedID 11930052

  • Universal standardization of forearm bone densitometry JOURNAL OF BONE AND MINERAL RESEARCH Shepherd, J. A., Cheng, X. G., Lu, Y., Njeh, C., Toschke, J., Engelke, K., Grigorian, M., Genant, H. K. 2002; 17 (4): 734-745


    As part of an effort to quantify device-dependent differences in forearm bone density, 101 women, aged 20-80 years (approximately 16 women in each age decade), were scanned on six forearm bone densitometers: the Aloka DCS-600EX, the Hologic QDR-4500A, the Lunar PIXI, the Norland pDEXA, the Osteometer DTX-200, and the Pronosco X-posure System. Regression statistics are reported for all similar regions of interest (ROIs). However, comparisons were confounded because of large differences in the ROI size and placement. The number of ROIs reported for a single scan by each device varied from 1 to 12. The correlation coefficients ranged from 0.7 < r < 0.97, with the highest correlation coefficients and lowest SEs for comparisons between the most similar ROIs. Standardized units of bone mineral density are derived for distal (sdBMD), mid-(smBMD), and proximal (spBMD) ROTs that allow for comparable mean bone densities to be derived for patient populations. Five phantoms were scanned and characterized on five of the devices and the precision and mean values were reported. These phantom values will aid in the in vitro cross-calibration between manufacturers to recreate the presented in vivo relationships. Care should be exercised when using these equations for cross-calibrating patient databases or pooling clinical data from different devices because the least significant differences detectable from measurements taken on two different machines can be increased substantially.

    View details for Web of Science ID 000174436200022

    View details for PubMedID 11918231

  • Research publications in vascular and interventional radiology: Research topics, study designs, and statistical methods JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY Huang, W., LaBerge, J. M., Lu, Y., Glidden, D. V. 2002; 13 (3): 247-255


    Statistical analysis is the universal language of medical research and is a vital tool for communicating the results of vascular and interventional radiology (VIR) procedures. Major articles in two radiology journals were surveyed to characterize the research topics, study designs, and statistical methods seen in recent VIR research publications.The authors retrospectively reviewed 130 major clinical VIR articles published from July 2000 to June 2001: 72 articles (55%) from JVIR and 58 articles (45%) from RADIOLOGY: Articles were categorized by research topic and study design. Data were collected on the statistical methodology of each article.Research topics included vascular intervention in 65 of 130 articles (50%), nonvascular intervention in 26 (20%), vascular imaging in 23 (18%), biopsy in nine (7%), and other topics in seven (5%). Study design was descriptive in 87 studies (67%), comparative in 39 studies (30%), and involved secondary data analysis in four studies (3%). Of 126 primary clinical studies, outcome was cross-sectional (assessed at a single time point) in 40 studies (32%) and longitudinal (measured over time) in 86 studies (68%). Median sample size was 61. Basic tests of association (t-test, chi(2) test, etc.) were used in 71 articles (56%) and advanced tests of association (regression analysis) were presented in 25 (20%). Survival analysis was applied in 34 articles (27%). Decision statistics such as sensitivity/specificity were not used commonly (12%). Confidence intervals and power calculations were reported infrequently (15% and 7%, respectively).VIR publications focus on time-dependent outcomes after therapeutic interventions. Readers should understand basic tests of association and survival analysis--these include only 20 named statistical tests.

    View details for Web of Science ID 000174490400004

    View details for PubMedID 11875084

  • Bone structure of the distal radius and the calcaneus vs BMD of the spine and proximal femur in the prediction of osteoporotic spine fractures EUROPEAN RADIOLOGY Link, T. M., Vieth, V., Matheis, J., Newitt, D., Lu, Y., Rummeny, E. J., Majumdar, S. 2002; 12 (2): 401-408


    The aim of this study was to compare structure measures obtained from high-resolution MR images of the calcaneus and the distal radius with bone mineral density (BMD) of the spine and hip in the prediction of osteoporotic spine fracture status. High-resolution MR images of the calcaneus and radius were obtained in 24 post-menopausal women with spine fractures and 22 age-matched controls. Imaging was performed at 1.5 T using a T1-weighted spin-echo sequence (slice thickness 1 mm, in-plane spatial resolution 195 x 195 microm(2)). Structure analysis was performed using parameters analogous to standard histomorphometry. Bone mineral density of the spine was obtained using quantitative CT and of the hip with dual-energy X-ray absorptiometry. Significant differences between both patient groups were obtained with BMD and all structure parameters ( p<0.05). Using receiver operating characteristic analysis to determine the diagnostic performance in differentiating both groups, the best results were found for BMD of the spine, one of the radial structure measures and a combination of the calcaneal structure measures. In this study BMD of the spine and structure measures of the distal radius were best suited to predict the osteoporotic fracture status of the spine. A combination of BMD and structure measures did not yield any additional information on fracture status.

    View details for DOI 10.1007/s003300101127

    View details for Web of Science ID 000174127700022

    View details for PubMedID 11870442

  • New model-independent measures of trabecular bone structure applied to in vivo high-resolution MR images OSTEOPOROSIS INTERNATIONAL Laib, A., Newitt, D. C., Lu, Y., Majumdar, S. 2002; 13 (2): 130-136


    Complementing measurements of bone mass with measurements of the architectural status of trabecular bone is expected to improve predictions of fracture risk in osteoporotic patients and improve the assessment of response to drug therapy. With high-resolution MRI the trabecular network can be imaged with 156 x 156 x 500 microm3 voxels, sufficient to depict individual trabeculae, albeit with inaccurate thickness. In this work, distance transformation techniques were applied to the three-dimensional image of the distal radius of postmenopausal patients. Structural indices such as trabecular number (app.Tb.N), thickness (app.Tb.Th) and separation (app.Tb.Sp) were determined without model assumptions. A new metric index, the apparent intra-individual distribution of separations (app.Tb.Sp.SD), is introduced. The reproducibility of the MR procedure and structure assessment was determined on volunteers, and the coefficient of variation was found to be 2.7-4.6% for the mean values of structural indices and 7.7% for app.Tb.Sp.SD. The distance transformation methods were then applied to two groups of patients: one of postmenopausal women without vertebral fracture and one of postmenopausal women with at least one vertebral fracture. It was found that app.Tb.Sp.SD discriminates fracture subjects from non-fracture patients as well as dual-energy X-ray absorptiometry (DXA) measurements of the radius and the spine, but not as well as DXA of the hip. Using receiver operating characteristic analysis, the area under the curve (AUC) values were 0.67 for app.Tb.Sp.SD, 0.72 for DXA radius, 0.67 for DXA spine and 0.81 for DXA of the hip. A combination of MR indices reached an AUC of 0.75. Age-adjusted odds ratio ranged from 1.85 to 2.03 for app.Tb.N, app.Tb.Sp and app.Tb.Sp.SD (p<0.003). We conclude that in vivo high-resolution MRI not only has the potential of imaging trabecular bone, but in combination with novel metrics may offer new insight into the structural changes occurring in postmenopausal women.

    View details for Web of Science ID 000174450100005

    View details for PubMedID 11905523

  • Gliomas classification by multivariate analysis of in vivo MRI/MRSI data based on recursive partitioning tree and discriminant analysis Li, X. J., Ying, L., Nelson, S. J., IEEE, IEEE IEEE. 2002: 209–12
  • Effects of raloxifene on fracture severity in postmenopausal women with osteoporosis: Results from the MORE study 65th Annual Meeting of the American-College-of-Rheumatology Siris, E., Adachi, J. D., Lu, Y., Fuerst, T., Crans, G. G., Wong, M., Harper, K. D., Genant, H. K. SPRINGER LONDON LTD. 2002: 907–13


    Raloxifene reduces the risk of new vertebral fractures, but its effect on the severity of these new fractures has not been determined. The MORE (Multiple Outcomes of Raloxifene Evaluation) trial studied the effects of placebo, raloxifene 60 or 120 mg/day in 7,705 postmenopausal women with osteoporosis. Radiologists assessed new vertebral fractures from radiographs and graded the fracture severity as normal (no fracture) or mild, moderate or severe. New clinical vertebral fractures were defined as new vertebral fractures associated with symptoms, such as back pain, and confirmed in radiographs. In the total study population, the majority (76.4%) of the women who experienced clinical vertebral fractures were diagnosed with new moderate/severe vertebral fractures. In turn, women with moderate/severe vertebral fractures in the overall population were more likely to experience clinical symptoms suggestive of fracture than were women who had new mild-only vertebral fractures. The incidence of new mild-only and moderate/severe fractures was the same in women without prevalent vertebral fractures, but the incidence of new moderate/severe fractures was 2 to 3 times higher than that for new mild-only fractures in women with prevalent vertebral fractures. Raloxifene 60 mg/day decreased the risk of at least 1 new moderate/severe vertebral fracture by 61% in women without prevalent vertebral fractures [RR 0.39 (95% CI 0.17, 0.69)], and by 37% in women with prevalent vertebral fractures [RR 0.63 (95% CI 0.49, 0.83)] at 3 years. The risk reductions for at least 1 new moderate/severe vertebral fracture were not significantly different between the raloxifene doses, in women with and without prevalent vertebral fractures. The effects of raloxifene on significantly decreasing the risk of new moderate/severe vertebral fractures may explain the risk reduction for new painful clinical vertebral fractures observed with raloxifene, and is particularly important in postmenopausal women with severe osteoporosis who are at higher risk for moderate or severe fractures.

    View details for Web of Science ID 000179554500009

    View details for PubMedID 12415439

  • Changes in calcaneal trabecular bone structure assessed with high-resolution MR imaging in patients with kidney transplantation OSTEOPOROSIS INTERNATIONAL Link, T. M., Saborowski, O., Kisters, K., Kempkes, M., Kosch, M., Newitt, D., Lu, Y., Waldt, S., Majumdar, S. 2002; 13 (2): 119-129


    The purpose of this study was to use high-resolution magnetic resonance (HR-MR) imaging to analyze the trabecular bone structure of the calcaneus in patients before and after renal transplantation and to compare this technique with bone mineral density (BMD) in predicting therapy-induced bone loss and osteoporotic fracture status. HR-MR imaging (voxel size: 0.195 x 0.195 x 1 mm) was performed at 1.5 T with an axial and sagittal orientation in 48 patients after transplantation, 12 patients before renal transplantation and 20 healthy controls. Structure measures analogous to standard histomorphometry and fractal dimension were determined in these images. BMD measurements of the lumbar spine and the proximal femur were obtained in the healthy female controls and the patients. Vertebral and peripheral fracture status were determined in all patients. The structural measures app.BV/TV, Tb.Sp, Tb.Th and Tb.N showed significant differences between controls and patients (p<0.05) while fractal dimension showed no significant differences. Neither the structural measures nor BMD showed significant differences between patients before and after transplantation. Correlations between time after transplantation versus structural measures and BMD were not significant. Differences between fracture and nonfracture patients were significant for the structural measures app.BV/TV, Tb.Sp and Tb.N (axial images) as well as for app.Tb.Th (sagittal images) and spine BMD (p<0.05) but not for hip BMD. Using odds ratios the strongest discriminators between patients with and without fractures were app. BV/TV, app.Tb.Sp (axial images) and app.Tb.Th (sagittal images), even after adjustment for age and BMD. Using receiver operating characteristic analysis the highest diagnostic performance was found for a combination of BMD and structural measures. In conclusion, our results indicate that structural measures obtained from HR-MR images may be used to characterize fracture incidence in kidney transplant patients; the best results, however, are obtained using a combination of BMD and structural measures.

    View details for Web of Science ID 000174450100004

    View details for PubMedID 11905522

  • Focal fatty infiltration of the liver: Analysis of prevalence and CT findings in children and young adults AMERICAN JOURNAL OF ROENTGENOLOGY Kammen, B. F., Pacharn, P., Thoeni, R. F., Lu, Y., Qayyum, A., Coakly, F., Gooding, C. A., Brasch, R. C. 2001; 177 (5): 1035-1039


    Focal fatty infiltration of the liver, a benign entity that can be confused with a malignant lesion, is well characterized in adults but not in children. The goal of this study was to determine by CT the prevalence and characteristics of focal fatty infiltration in children and young adults.We retrospectively analyzed 305 consecutive contrast-enhanced abdominal CT examinations of 218 children and young adults with no known liver disease, performed during 2 years at our institution, to identify focal fatty infiltration of the liver. The imaging criterion for focal fatty infiltration of the liver on helical CT was a geometric or ovoid low-attenuation area adjacent to the falciform ligament, gallbladder fossa, or porta hepatis. If a patient's findings met the CT criterion for focal fatty infiltration of the liver, all previous abdominal CT and MR imaging examinations performed for that patient were reviewed to assess the evolution of focal fatty infiltration of the liver.Of 218 children and young adults, 20 (9.2%) met the CT criterion for focal fatty infiltration of the liver. In our population, focal fatty infiltration of the liver was identified only adjacent to the falciform ligament. The prevalence of focal fatty infiltration of the liver increased significantly with advancing age: 0% for ages 1 month-4 years; 7.3% for 5-9 years; 10.2% for 10-14 years, and 25.6% for 15-19 years (p < 0.0001).Focal fatty infiltration of the liver was identified in 9.2% of patients in our population, and occurrence of this lesion in children increases significantly with advancing age. However, focal fatty infiltration of the liver is uncommon in infants and young children and should be a diagnosis of exclusion.

    View details for Web of Science ID 000171732700013

    View details for PubMedID 11641164

  • Cost-effective methods in identifying systemic lupus erythematosus patients with low bone densities. Lu, Y., Shepherd, J. A., Von Scheven, E., Genent, H. K. AMER SOC BONE & MINERAL RES. 2001: S461
  • Three-dimensional proton MR spectroscopic imaging of premature and term neonates AMERICAN JOURNAL OF NEURORADIOLOGY Vigneron, D. B., Barkovich, A. J., Noworolski, S. M., von dem Bussche, M., Henry, R. G., Lu, Y., Partridge, J. C., Gregory, G., Ferriero, D. M. 2001; 22 (7): 1424-1433


    Previous studies have primarily used single-voxel techniques to obtain MR spectra from the neonatal brain. In this study, we applied 3D MR spectroscopic imaging techniques to detect the spatial distribution of MR spectroscopic imaging-detectable compounds in premature and term infants. The goals were to test the feasibility of obtaining 3D MR spectroscopic images of newborns, assess the spatial variations of metabolite levels, and determine age-dependent differences in MR spectroscopic imaging data.MR spectroscopic imaging data were acquired from nine premature (postconceptional age, 30-34 weeks) and eight term (postconceptional age, 38-42 weeks) neonates, all with normal clinical and neurologic outcomes. A specialized point-resolved spectroscopy sequence with very selective saturation pulses was used to select a region encompassing the majority of the brain. Phase encoding in three dimensions was performed in a 17-minute acquisition time to obtain 3D spectral arrays with a 1.0 cm(3) nominal spatial resolution.This study showed the feasibility of detecting the 3D distributions of choline, creatine, and N-acetylaspartate resonances in the neonatal brain. Significant spectral differences were detected among anatomic locations and between the premature and term groups.This initial study indicates that 3D MR spectroscopic imaging of the neonatal brain can detect anatomic and age-dependent variations in metabolite levels. This technique seems to be a powerful tool to assess the metabolic differences between anatomic regions and to follow the changes in cellular metabolites with brain maturation. This study also indicates the need for determining topologic and age-matched normative values before metabolic abnormalities in neonates can be accurately assessed by MR spectroscopy.

    View details for Web of Science ID 000170437200036

    View details for PubMedID 11498441

  • MRI phenotype is associated with response to doxorubicin and cyclophosphamide neoadjuvant chemotherapy in stage III breast cancer ANNALS OF SURGICAL ONCOLOGY Esserman, L., Kaplan, E., Partridge, S., Tripathy, D., Rugo, H., Park, J., Hwang, S., Kuerer, H., Sudilovsky, D., Lu, Y., Hylton, N. 2001; 8 (6): 549-559


    The preferred management for women with stage II or locally advanced breast cancer (LABC) is neoadjuvant chemotherapy. Pathologic response to chemotherapy has been shown to be an excellent predictor of outcome. Surrogates that can predict pathologic response and outcome will fuel future changes in management. Magnetic resonance imaging (MRI) demonstrates that patients with LABC have distinct tumor patterns. We investigated whether or not these patterns predict response to therapy.Thirty-three women who received neoadjuvant doxorubicin and cyclophosphamide chemotherapy for 4 cycles and serial breast MRI scans before and after therapy were evaluated for this study. Response to therapy was measured by change in the longest diameter on the MRI.Five distinct imaging patterns were identified: circumscribed mass, nodular tissue infiltration diffuse tissue infiltration, patchy enhancement, and septal spread. The likelihood of a partial or complete response as measured by change in longest diameter was 77%, 37.5%, 20%, and 25%, respectively.MRI affords three-dimensional characterization of tumors and has revealed distinct patterns of tumor presentation that predict response. A multisite trial is being planned to combine imaging and genetic information in an effort to better understand and predict response and, ultimately, to tailor therapy and direct the use of novel agents.

    View details for Web of Science ID 000169879500014

    View details for PubMedID 11456056

  • Congenital diaphragmatic hernia: Prenatal evaluation with MR lung volumetry-preliminary experience RADIOLOGY Paek, B. W., Coakley, F. V., Lu, Y., Filly, R. A., Lopoo, J. B., Qayyum, A., Harrison, M. R., Albanese, C. T. 2001; 220 (1): 63-67


    To determine the interobserver variability of prenatal magnetic resonance (MR) lung volumetry and to assess the value of MR lung volumetric findings as predictors of outcome in fetuses with congenital diaphragmatic hernia.Prenatal MR imaging was performed in 26 fetuses with unilateral congenital diaphragmatic hernia. Two independent observers performed planimetric measurement of lung volume. Relative lung volume was calculated as the observed total lung volume expressed as a percentage of the total lung volume predicted from fetal size. Relative lung volume was correlated with the ultrasonographic lung-head ratio in left-sided congenital diaphragmatic hernias evaluated before 27 weeks gestation (n = 21) and with pregnancy outcome in all cases of isolated left-sided congenital diaphragmatic hernia without prenatal intervention (n = 11).Observers demonstrated excellent agreement in total lung volume measurements at MR imaging, with an intraclass correlation coefficient of 0.95. Relative lung volume was positively correlated with lung-head ratio (r = 0.78, P <.001). By using rank order analysis in the pregnancy outcome group, relative lung volume was predictive of prognosis (P <.05) when adjusted for gestational age at delivery and birth weight. Three of four fetuses with a relative lung volume of less than 40% died.Interobserver agreement is high at MR lung volumetry, and its findings are predictive of outcome in fetuses with isolated left-sided congenital diaphragmatic hernia.

    View details for Web of Science ID 000169468400009

    View details for PubMedID 11425973

  • Measuring the academic radiologist's clinical productivity: Applying RVU adjustment factors ACADEMIC RADIOLOGY Arenson, R. L., Lu, Y., Elliott, S. C., Jovais, C., Avrin, D. E. 2001; 8 (6): 533-540


    To improve understanding of academic radiologists' clinical workloads, the Society of Chairmen of Academic Radiology Departments (SCARD) performed surveys to collect workload data for radiologists in 20 departments; workload was measured in relative value units (RVUs) per full-time equivalent (FTE). Although they were useful for comparisons within some subspecialties, the workload data proved inadequate for comparisons across sections, and adjustment factors were needed for each Current Procedure Terminology (CPT) code.All CPT codes for examinations were divided into groups with similar radiologist work effort. Focusing on radiologists who worked almost exclusively in each group, the authors created adjustment factors by using data from the individual radiologists at each institution.The adjustment factors are 0.50 for angiography, 0.58 for computed tomography and magnetic resonance imaging, and 1.0 for nuclear medicine, plain radiography, and special procedures (no adjustment needed for these groups). These factors are multiplied by the work RVUs for each examination to create the adjusted workload RVUs.The SCARD survey provided very useful clinical workload data, with workload measured in work RVUs per FTE for specific subspecialty sections. The new adjusted workload RVUs allow comparison of radiologists' workload across subspecialties.

    View details for Web of Science ID 000168911900014

    View details for PubMedID 11394549

  • Measuring the academic radiologist's clinical productivity: Survey results for subspecialty sections ACADEMIC RADIOLOGY Arenson, R. L., Lu, Y., Elliott, S. C., Jovais, C., Avrin, D. E. 2001; 8 (6): 524-532


    The purpose of this project was to understand better the academic radiologist's clinical workload in order to determine faculty staffing requirements more accurately.Surveys performed by the Society of Chairmen of Academic Radiology Departments (SCARD) collected data for radiologists in 20 departments in 1996 and 1998; the data included work relative value units (RVUs) per full-time equivalent (FTE). Radiologists in each subspecialty were compared with their counterparts in other departments. The data were collected for each radiologist. Summary statistics showing averages, medians, and quartiles were used to describe workload (in RVUs per FTE) for each department and each subspecialty.Overall, the average clinical workload was 4,458 RVU/FTE, with 0.62 RVU per procedure. In those sections for which the faculty performed similar types of procedures across departments, the results were useful. The workload data, however, proved inadequate to compare across subspecialty sections. Between 1996 and 1998, the workload increased from 3,790 to 4,458 RVU/FTE.The SCARD survey provided very useful clinical workload data, measured in work RVUs per FTE for specific subspecialty sections. At practically all surveyed institutions, increasing clinical workload is competing with academic activities.

    View details for Web of Science ID 000168911900013

    View details for PubMedID 11394548

  • Quantitative US of the calcaneus: Cutoff levels for the distinction of healthy and osteoporotic individuals Radiology Grampp S, Henk C; Lu Y; Krestan C; Resch H; Kainberger F; Youssefzadeh S; Vorbeck F; Imhof H 2001; 220 (2): 400-5
  • Prediction of deep myometrial invasion in patients with endometrial cancer: Clinical utility of contrast-enhanced MR imaging - A meta-analysis and Bayesian analysis 85th Annual Meeting and Scientific Assembly of the Radiological-Society-of-North-America (RSNA) Frei, K. A., Kinkel, K., Bonel, H. M., Lu, Y., Zaloudek, C., Hricak, H. RADIOLOGICAL SOC NORTH AMERICA. 2000: 444–49


    To determine if, in a patient with an endometrial cancer, in addition to the knowledge of tumor grade, preoperative magnetic resonance (MR) imaging findings contribute to treatment stratification and specialist referral.By using a MEDLINE literature search and institutional pathology reports, pretest probabilities for myometrial invasion were correlated with tumor grade. Likelihood ratios (LRs) were obtained through summary receiver operating characteristics.The mean pretest probabilities of deep myometrial invasion were derived from seven articles (1,875 patients) and from 125 institutional pathology reports. LRs for the prediction of myometrial invasion with contrast-enhanced MR imaging were derived from nine studies (742 patients); positive and negative LRs were 10.11 and 0.1, respectively. The mean weighted pretest probabilities of deep myometrial invasion in patients with tumor grades 1, 2, or 3 were 13%, 35%, or 54%, respectively. Posttest probabilities of deep myometrial invasion for grades 1, 2, or 3 increased to 60%, 84%, or 92%, respectively, for positive and decreased to 1%, 5%, or 10%, respectively, for negative MR imaging findings.Use of contrast-enhanced MR imaging significantly affects the posttest probability of deep myometrial invasion in patients with all grades of endometrial cancer and could be used to select patients for specialist referral.

    View details for Web of Science ID 000088430800022

    View details for PubMedID 10924568

  • Sextant localization of prostate cancer: Comparison of sextant biopsy, magnetic resonance imaging and magnetic resonance spectroscopic imaging with step section histology JOURNAL OF UROLOGY Wefer, A. E., Hricak, H., Vigneron, D. B., Coakley, F. V., Lu, Y., Wefer, J., Mueller-Lisse, U., Carroll, P. R., Kurhanewicz, J. 2000; 164 (2): 400-404


    We compared the accuracy of endorectal magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging with that of sextant biopsy for the sextant localization of prostate cancer.Sextant biopsy, MRI, magnetic resonance spectroscopic imaging and radical prostatectomy with step section histology were done in 47 patients with prostate cancer. For each sextant we categorized biopsy and imaging results as positive or negative for cancer. Step section histology was used as the standard of reference.For sextant localization of prostate cancer MRI and magnetic resonance spectroscopic imaging were more sensitive but less specific than biopsy (67% and 76% versus 50%, and 69% and 68% versus 82%, respectively). The sensitivity of sextant biopsy was significantly less in the prostate apex than in the mid prostate or prostate base (38% versus 52% and 62%, respectively). MRI and magnetic resonance spectroscopic imaging had similar efficacy throughout the prostate compared with biopsy only as well as better sensitivity and specificity in the prostate apex (60% and 75%, and 86% and 68%, respectively). A positive biopsy or imaging result had 94% sensitivity for cancer and concordant positivity by all 3 tests was highly specific at 98%.Overall MRI and magnetic resonance spectroscopic imaging have accuracy similar to biopsy for intraprostatic localization of cancer and they are more accurate than biopsy in the prostate apex. These 2 imaging modalities may supplement biopsy results by increasing physician confidence when evaluating intraprostatic tumor location, which may be important for planning disease targeted therapy.

    View details for Web of Science ID 000088126200033

    View details for PubMedID 10893595

  • Normal and hypoplastic fetal lungs: Volumetric assessment with prenatal single-shot rapid acquisition with relaxation enhancement MR imaging RADIOLOGY Coakley, F. V., Lopoo, J. B., Lu, Y., Hricak, H., Albanese, C. T., Harrison, M. R., Filly, R. A. 2000; 216 (1): 107-111


    To determine which parameters are most closely correlated with normal fetal total lung volume and to investigate the use of these parameters in the evaluation of fetal pulmonary hypoplasia.Single-shot rapid acquisition with relaxation enhancement (RARE) magnetic resonance (MR) imaging was used to perform planimetric measurement of total lung volume in 46 fetuses at 18-32 weeks gestation. Total lung volume was correlated with gestational age, and biometric parameters in fetuses were correlated with normal chest findings at ultrasonography (US) (n = 24). This analysis was used to evaluate relative lung volume in fetuses suspected of having pulmonary hypoplasia (n = 22).Normal fetal total lung volume was strongly correlated with liver volume measured at MR imaging (r = 0.94), fetal weight estimated at US (r = 0.93), head circumference measured at US (r = 0.90), and gestational age (r = 0.87). In fetuses suspected of having pulmonary hypoplasia, the relative lung volume varied from 4.6% to 81.6% when the observed total lung volume was expressed as a percentage of the predicted total lung volume.Normal fetal total lung volume is strongly correlated with biometric measurements. Relative fetal lung volume can be calculated by expressing the observed volume as a percentage of the predicted volume calculated from biometric measurements; knowledge of the relative fetal lung volume assists in the confirmation and quantification of fetal pulmonary hypoplasia.

    View details for Web of Science ID 000087829500015

    View details for PubMedID 10887234

  • Comparison of six calcaneal quantitative ultrasound devices: Precision and hip fracture discrimination OSTEOPOROSIS INTERNATIONAL Njeh, C. F., Hans, D., Li, J., Fan, B., Fuerst, T., He, Y. Q., Tsuda-Futami, E., Lu, Y., Wu, C. Y., Genant, H. K. 2000; 11 (12): 1051-1062


    Quantitative ultrasound (QUS) is now accepted as a useful tool in the management of osteoporosis. There are a variety of QUS devices clinically available with a number of differences among them, including their coupling methods, parameter calculation algorithms and sites of measurement. This study evaluated the abilities of six calcaneal QUS devices to discriminate between normal and hip-fractured subjects compared with the established method of dual-energy X-ray absorptiometry (DXA). The short-term and mid-term precisions of these devices were also determined. Thirty-five women (mean age 74.5+/-7.9 years) who had sustained a hip fracture within the past 3 years, and 35 age-matched controls (75.8+/-5.6 years) were recruited. Ultrasound measurements were acquired using six ultrasound devices: three gel-coupled and three water-coupled devices. Bone mineral density was measured at the hip using DXA. Discrimination of fracture patients versus controls was assessed using logistic regression analysis (expressed as age- and BMI-adjusted odds ratios per standard deviation decrease with 95% confidence interval) and receiver operating characteristics (ROC) curve analysis. Measurement precision was standardized to the biological range (sCV). The sCV ranged from 3.14% to 5.5% for speed of sound (SOS) and from 2.45% to 6.01% for broadband ultrasound attenuation (BUA). The standardized medium-term precision ranged from 4.33% to 8.43% for SOS and from 2.77% to 6.91% for BUA. The pairwise Pearson correlation coefficients between different devices was highly significant (SOS, r = 0.79-0.93; BUA, r = 0.71-0.92). QUS variables correlated weakly, though significantly, with femoral BMD (SOS, r = 0.30-0.55; BUA, r = 0.35-0.61). The absolute BUA and SOS values varied among devices. The gel-coupled devices generally had a higher SOS than water-coupled devices. Bone mineral density (BMD) and BUA were weakly correlated with weight (r = 0.48-0.57 for BMD and r = 0.18-0.54 for BUA), whereas SOS was independent of weight. All the QUS devices gave similar, statistically significant hip fracture discrimination for both SOS and BUA measures. The odds ratios for SOS (2.1-2.8) and BUA (2.4-3.4) were comparable to those for femoral BMD (2.6-3.5), as were the area under the curve (SOS, 0.65-0.71; BUA, 0.62-0.71; BMD, 0.65-0.74) from ROC analysis. Within the limitation of the sample size all devices show similar diagnostic sensitivity.

    View details for Web of Science ID 000167086200008

    View details for PubMedID 11256897

  • Assessment of a new quantitative ultrasound calcaneus measurement: Precision and discrimination of hip fractures in elderly women compared with dual X-ray absorptiometry OSTEOPOROSIS INTERNATIONAL He, Y. Q., Fan, B., Hans, D., Li, J., Wu, C. Y., Njeh, C. F., Zhao, S., Lu, Y., Tsuda-Futami, E., Fuerst, T., Genant, H. K. 2000; 11 (4): 354-360


    The incidence of osteoporotic hip fracture increases in postmenopausal women with low hip bone mineral density (BMD). Dual X-ray absorptiometry (DXA) is the most commonly used technique for the assessment of bone status and provides good measurement precision. However, DXA affords little information about bone architecture. Quantitative ultrasound (QUS) systems have been developed to evaluate bone status for assessment of fracture risk. Our study was designed to assess a new QUS system from Hologic, the Sahara; to compare it with a previous model, the Walker-Sonix UBA 575+; and to investigate whether it is able to discriminate between women with and without fracture. Using both ultrasound devices, the measurements were performed at the heels of 33 postmenopausal women who had recently sustained hip fracture. A control group of 35 age-matched postmenopausal women was recruited for comparison. The total, neck and trochanter femoral BMD values were assessed using DXA for both groups. QUS and DXA measurements were significantly lower in fractured patients (p < 0.005) than in the control group. The short-term, mid-term and standardized short-term precisions were used to evaluate the reproducibility of the two QUS systems. The Sahara showed a better standardized coefficient of variation for broadband ultrasound attenuation (BUA) than did the UBA 575+ (p < 0.001). The correlation of BUA and speed of sound (SOS) between the two QUS devices was highly significant, with an r value of 0.92 for BUA and 0.91 for SOS. However, the correlation between DXA and ultrasound parameters ranged from 0.28 to 0.44. We found that ultrasound measurements at the heel were significant discriminators of hip fractures with odds ratios (OR) ranging from 2.7 to 3.2. Even after adjusting the logistic regressions for total, neck or trochanter femoral BMD, QUS variables were still significant independent discriminators of hip fracture. The areas under the ROC curves of each ultrasound parameter ranged from 0.75 to 0.78, and compared very well with femoral neck BMD (p > 0.05). In conclusion, our study indicated that the calcaneal QUS variables, as measured by the Sahara system can discriminate hip fracture patients equally as well as hip DXA.

    View details for Web of Science ID 000088246900010

    View details for PubMedID 10928226

  • US charaterization of ovarian masses, a meta-analysis Radiology Kinkel K, Hricak H; Lu Y; Tsuda K; Filly RA 2000; 217: 803-811
  • MR imaging of the breast in patients with positive margins after lumpectomy: Influence of the time interval between lumpectomy and MR imaging American Journal of Roentgenology Frei, K., Kinkel K; Bonel HM; Lu Y; Esserman LJ; Hylton NM 2000; 175 (6): 1577-84
  • Changes in calcaneal trabecular bone structure after heart transplantation: An MR imaging study Radiology Link T, Lotter A; Beyer F; Christiansen S; Newitt D; Lu Y; Schmid C; Majumdar S 2000; 217: 855-862.
  • Radiologic staging in patients with endometrial cancer: A meta-analysis RADIOLOGY Kinkel, K., Kaji, Y., Yu, K. K., Segal, M. R., Lu, Y., Powell, C. B., Hricak, H. 1999; 212 (3): 711-718


    To apply a meta-analysis to compare the utility of computed tomography (CT), ultrasonography (US), and magnetic resonance (MR) imaging in staging endometrial cancer.Data were obtained from a MEDLINE literature search and from manual reviews of article bibliographies. Articles were selected that included results in patients with proved endometrial cancer and imaging-histopathologic correlation and that presented data that allowed calculation of contingency tables. Data for the imaging evaluation of myometrial and cervical invasion were abstracted independently by two authors. Data on year of publication, International Federation of Gynecology and Obstetrics (FIGO) stage distribution, and methodologic quality were also collected. A subgroup analysis was performed to compare contrast medium-enhanced MR imaging with nonenhanced MR imaging, US, and CT.Six studies met the inclusion criteria for CT; 16, for US; and 25, for MR imaging. Summary receiver operating characteristic analysis showed no significant differences in the overall performance of CT, US, and MR imaging. In the assessment of myometrial invasion, however, contrast-enhanced MR imaging performed significantly better than did nonenhanced MR imaging or US (P < .002) and demonstrated a trend toward better results, as compared with CT. The lack of data on the assessment of cervical invasion at CT or US prevented meta-analytic comparison with data obtained at MR imaging. Results were not influenced by year of publication, FIGO stage distribution, or methodologic quality.Although US, CT, or MR imaging can be used in the pretreatment evaluation of endometrial cancer, contrast-enhanced MR imaging offers "one-stop" examination with the highest efficacy.

    View details for Web of Science ID 000082196600019

    View details for PubMedID 10478237

  • When to combine two DXA measurements? Lu, Y., Hans, D., Zhao, S., Genant, H. K. AMER SOC BONE & MINERAL RES. 1999: S201
  • Correlation of vertebral fracture among vertebral levels. Zhao, S. J., Lu, Y., Wu, C. Y., Wu, J., Gnant, H. K. AMER SOC BONE & MINERAL RES. 1999: S203
  • MR imaging of the arthritic rabbit knee joint using albumin (Gd-DTPA)(30) with correlation to histopathology MAGNETIC RESONANCE IMAGING van Dijke, C. F., Peterfy, C. G., Brasch, R. C., Lang, P., Roberts, T. P., Shames, D., Kneeland, J. B., Lu, Y., Mann, J. S., Kapila, S. D., Genant, H. K. 1999; 17 (2): 237-245


    The purpose of this study was to demonstrate a technique, in a pilot study, for measuring abnormal capillary permeability in synovial tissue of rabbit arthritic knees using dynamic MRI with a gadolinium-based blood pool agent. Arthritis, simulating rheumatoid arthritis, was induced in knees of 8 rabbits by intra-articular injection of carrageenan (n = 4) or ovalbumin (n = 4). Sequential fat presaturated T1-weighted Spoiled Grass images were obtained before and up to 30 min after intravenous administration of albumin-(Gd-DTPA)30. Estimates of synovial tissue plasma-volume (PV), fractional-leak-rate (FLR), and permeability-surface-area-product (PS) were computed. Histologic correlation was obtained in the corresponding regions. Dynamic MRI showed extravasation of albumin-(Gd-DTPA)30 into hypertrophic synovium in six of the eight arthritic knees. Histologic examination of these six knees showed markedly inflamed synovium. The two knees that did not show abnormal vascular permeability contained non-hypertrophic synovium. None of the rabbits showed abnormal permeability in muscle. MRI derived microvascular characteristics (PV, FLR and PS) correlated positively (r2 = 0.51, 0.97 and 0.86) with the histology. Factors involving the structural and functional microvascular characteristics of synovial tissue can be estimated non-invasively using albumin-(Gd-DTPA)30. This technique may be useful for monitoring disease progression and treatment response in rheumatoid arthritis.

    View details for Web of Science ID 000078166100010

    View details for PubMedID 10215479

  • Diagnostic agreement of quantitative sonography of the calcaneus with dual X-ray absorptiometry of the spine and femur American Journal of Roentgenology Grampp, S., Henk CB; Fuerst TP; Lu Y; Bader TR; Kainberger F; Genant HK 1999; 173 (2): 329-34
  • Ultrasound velocity of trabecular cubes reflects mainly bone density and elasticity CALCIFIED TISSUE INTERNATIONAL Hans, D., Wu, C., Njeh, C. F., Zhao, S., Augat, P., Newitt, D., Link, T., Lu, Y., Majumdar, S., Genant, H. K. 1999; 64 (1): 18-23


    Studies have indicated that quantitative ultrasound (QUS) variables may be influenced by the mechanical properties of bone which in turn are determined by bone's material and structural properties. However, from these studies it is unclear what role density, elasticity, and structure play in determining velocity. Eighteen defatted, 12-mm cubic trabecular bone specimens were cut from cadaveric specimens. Amplitude-dependent speed of sound (SOS) using a single point QUS system was assessed in three orthogonal axes. Magnetic resonance images were obtained, from which measures of apparent trabeuclar structure were derived. The specimens were nondestructively tested in compression along three orthogonal axes defined by the sides of the cubes. The elastic modulus (in the three directions) and the strength (in one direction) were determined. Trabecular BMD was measured by quantitative computed tomography. SOS varied significantly with direction of measurement, with the highest value in the axial direction (axial:1715 m/s, sagittal: 1662 m/second, and coronal: 1676 m/s). SOS of each of the three axes was generally associated with the various mechanical (r = 0.30-0.87), density (r = 0.81-0.93), and bone structural variables (0.3-0.8). However, after adjusting the SOS correlations by density, only the correlation with elasticity remained significant in the coronal direction. BMD alone explained 88-93% of variance in SOS whereas in the multivariate model, BMD plus elasticity and/or anisotropic variables explained 96-98% of the variance in SOS. Variability of SOS is explained mostly by density and to a small extent by elasticity or anisotropy. Since only 2-6% of the variance of the QUS measurement is not explained by density and elasticity, one could conclude that the remaining variance reflects other properties of bone or perhaps simply measurement error. Evidence that these other properties may be structure related is only found in the anisotropy of QUS parameter.

    View details for Web of Science ID 000077789200003

    View details for PubMedID 9868278

  • Trabecular bone mineral and calculated structure of human bone specimens scanned by peripheral quantitative computed tomography: Relation to biomechanical properties JOURNAL OF BONE AND MINERAL RESEARCH Jiang, Y. B., Zhao, J. N., Augat, P., Ouyang, X. L., Lu, Y., Majumdar, S., Genant, H. K. 1998; 13 (11): 1783-1790


    The relationship of cortical bone mineral density (BMD), and geometry to bone strength has been well documented. In this study, we used peripheral quantitative computerized tomography (pQCT) to acquire trabecular BMD and high-resolution images of trabeculae from specimens to determine their relationship with biomechanical properties. Fifty-eight human cubic trabecular bone specimens, including 26 from the vertebral bodies, were scanned in water and air. Trabecular structure was quantitated using software developed with Advanced Visual Systems interfaced on a Sun/Sparc Workstation. BMD was also obtained using a whole-body computerized tomography scanner (QCT). Nondestructive testing of the specimens was performed to assess their elastic modulus. QCT and pQCT measurements of BMD of specimens in water were strongly correlated (r2 = 0.95, p < 0.0001), with a slope (0.96) statistically not significantly different from 1. Strong correlations were found between pQCT measurements of specimens in water and in air, for BMD (r2 = 0.96, p < 0.0001), and for apparent trabecular structural parameters (r2 = 0.89-0.93, p < 0.0001). Correlations were moderate between BMD and apparent trabecular structural parameters (r2 = 0.37-0.64, p < 0.0001). Precision as coefficient of variation (CV) and standardized coefficient of variation (SCV) for these measurements was < 5%. For the vertebral specimens, the correlation was higher between elastic modulus and BMD (r2 = 0.76,p < 0.0001) than between elastic modulus and apparent trabecular structural parameters (r2 = 0.58-0.72, p < 0.0001), while the addition of apparent trabecular nodes and branches to BMD in a multivariate regression model significantly increased the correlation with the elastic modulus (r2 = 0.86, p < 0.01). Thus, pQCT can comparably and reproducibly measure trabecular bone mineral in water or air, and trabecular structure can be quantitated from pQCT images. The combination of volumetric BMD with trabecular structural parameters rather than either alone improves the prediction of biomechanical properties. Such a noninvasive approach may be useful for the preclinical study of osteoporosis.

    View details for Web of Science ID 000076526500020

    View details for PubMedID 9797489

  • Morphometric texture analysis of spinal trabecular bone structure assessed using orthogonal radiographic projections MEDICAL PHYSICS Ouyang, X. L., Majumdar, S., Link, T. M., Lu, Y., Augat, P., Lin, J., Newitt, D., Genant, H. K. 1998; 25 (10): 2037-2045


    The measurement of bone microstructure as well as bone mineral density may improve the estimation of bone strength. Cubic specimens (N = 26, 12 mm X 12 mm X 12 mm) of human cadaver vertebrae were cut along three orthogonal anatomic orientations, i.e., superior-inferior (SI), medial-lateral (ML), and anterior-posterior (AP). Contact radiographs of the bone cubes along all three orientations were obtained and then digitized by a laser scanner with pixel size of 50 microns x 50 microns. The specimens were tested in compression along the 3 orthogonal orientations and the Young's modulus (YM) was calculated for each direction. Quantitative computed tomography (QCT) was used to obtain a measure of trabecular bone mineral density (BMD). Global gray level thresholding and local thresholding algorithms were used to extract the trabecular bone network. Apparent trabecular bone fraction (ABV/TV), mean intercept length (I.TH), mean intercept separation (I.SP), and number of nodes (N.ND) were measured from the extracted trabecular network. Fractal dimension (Fr.D) of the trabecular bone texture was also measured. Paired t-tests showed that the mean values of each texture parameter (except ABV/TV) and of YM along the SI direction were significantly different (p < 0.05) from those along the ML and AP direction. However, the mean values along the ML and AP directions were not significantly different. Multivariate regression of YM as a function of the texture parameters and BMD showed that without adjusting for the effect of BMD, YM was significantly explained by all the texture parameters (R2 = 0.2-0.6). When BMD was included in the regression, although the variations in YM of ML, AP, and SI orientations could be explained by BMD alone, some of the texture parameters did improve the overall prediction of the biomechanical properties, while, some parameters such as ABV/TV and Fr.D in the ML orientation showed a more significant overall effect in explaining mechanical strength than did BMD. In conclusion, trabecular texture parameters correlated significantly with BMD and YM. Trabecular texture parameters from projectional radiographs reflect the anisotropy of trabecular structure. Quantitative radiographic assessment of trabecular structure using fine-detail radiography can potentially improve the estimation of bone strength.

    View details for Web of Science ID 000076452500029

    View details for PubMedID 9800713

  • Correlation of dynamic contrast-enhanced MR imaging with histologic tumor grade: Comparison of macromolecular and small-molecular contrast media 40th Annual Meeting of the Society-for-Pediatric-Radiology Daldrup, H., Shames, D. M., Wendland, M., Okuhata, Y., Link, T. M., Rosenau, W., Lu, Y., Brasch, R. C. AMER ROENTGEN RAY SOC. 1998: 941–49


    The endothelial integrity of microvessels is disrupted in malignant tumors. Quantitative assays of tumor microvascular characteristics based on dynamic MR imaging were correlated with histopathologic grade in mammary soft-tissue tumors.A spectrum of tumors, benign through highly malignant, was induced in 33 female rats by administration of N-ethyl-N-nitrosourea, a potent carcinogen. Dynamic contrast-enhanced MR imaging was performed using a small-molecular contrast medium (gadopentetate, molecular weight = 0.5 kDa) and a macromolecular contrast medium (albumin-(Gd-DTPA)30, molecular weight = 92 kDa) at an interval of 1-2 days. Permeability surface area product (PS), as estimated by the corresponding endothelial transfer coefficient (K(PS)), and fractional plasma volume (fPV) were calculated for each tumor and each contrast agent using a two-compartment bidirectional kinetic model. MR imaging microvascular characteristics were correlated with histopathologic tumor grade.Tumor permeability to macromolecular contrast medium, characterized by K(PS), showed a highly positive correlation with tumor grade (r2 = .76, p < 10(-10)). K(PS) values were zero for all benign and some low-grade carcinomas, greater than zero in all other carcinomas, and increased in magnitude with higher tumor grade. A considerably smaller but significantly positive correlation was found between fPV and tumor grade using macromolecular contrast medium (r2 = .25, p < .003). No correlation between K(PS) or fPV values and tumor grade was found using gadopentetate (r2 = .01, p > .95 and r2 = .03, p > .15, respectively).Quantitative tumor microvascular permeability assays generated with macromolecular MR imaging contrast medium correlate closely with histologic tumor grade. No significant correlation is found using small-molecular gadopentetate.

    View details for Web of Science ID 000076117300007

    View details for PubMedID 9762973

  • Assessment of rheumatoid arthritis using a modified scoring method on digitized and original radiographs ARTHRITIS AND RHEUMATISM Genant, H. K., Jiang, Y. B., Peterfy, C., Lu, Y., Redei, J., Countryman, P. J. 1998; 41 (9): 1583-1590


    The results of different readers' interpretations of laser-digitized hand radiographs versus original radiographs were compared to determine the reproducibility of scoring of erosions (ERO), joint space narrowing (JSN), and their combination (ERO + JSN) in patients with rheumatoid arthritis (RA).Standardized radiographs of both hands were obtained at 2 visits (baseline and 6-24-month followup) from 30 patients with established RA. Conventional and laser-digitized (pixel sizes 50 microm and 100 microm) radiographs were scored independently by 3 experienced and trained radiologists who were blinded to the order of the visits. Scoring of radiographs was based on the validated Genant grading system.Intertechnique (intrareader) correlation coefficients at baseline were 0.90-0.93 for scoring of ERO, 0.90-0.94 for scoring of JSN, and 0.92-0.95 for ERO + JSN; for scoring of progression between baseline and followup, these values were 0.93-0.97, 0.87-0.95, and 0.93-0.97, respectively. Interreader (intratechnique) correlation coefficients at baseline were 0.82-0.96 for scoring of ERO, 0.69-0.91 for scoring of JSN, and 0.80-0.95 for ERO + JSN; for scoring of progression between baseline and followup, these values were 0.90-0.97, 0.80-0.92, and 0.90-0.95, respectively. Intrareader (intratechnique) correlation coefficients were 0.90-0.97 for scoring of the original radiographs and 0.90-0.98 for scoring of the digitized images at 100 microm.Using this modified grading system, scoring of RA progression directly from paired, high-resolution monitors of laser-digitized images of the hands provided highly reproducible results, comparable to those obtained from the original radiographs. Thus, this method may have useful applications in clinical trials involving RA.

    View details for Web of Science ID 000076066400007

    View details for PubMedID 9751090

  • In vivo high resolution MRI of the calcaneus: Differences in trabecular structure in osteoporosis patients JOURNAL OF BONE AND MINERAL RESEARCH Link, T. M., Majumdar, S., Augat, P., Lin, J. C., Newitt, D., Lu, Y., Lane, N. E., Genant, H. K. 1998; 13 (7): 1175-1182


    The purpose of this study was to use high resolution (HR) magnetic resonance (MR) images of the calcaneus to investigate the trabecular structure of patients with and without osteoporotic hip fractures and to compare these techniques with bone mineral density (BMD) in differentiating fracture and nonfracture patients. Axial and sagittal HR MR images of the calcaneus were obtained in 50 female (23 postmenopausal patients with osteoporotic hip fractures and 27 postmenopausal controls). A three-dimensional gradient-echo sequence was used with a slice thickness of 500 micron and in plane resolution of 195 x 195 micron. Texture analysis was performed using morphological features, analogous to standard histomorphometry and fractal dimension. Additionally, BMd measurements of the hip (dual-energy X-ray absorptiometry) were obtained in all patients. Significant differences between both patient groups were obtained using morphological parameters and fractal dimension as well as hip BMD (p < 0.05). Odds ratios for the texture parameters apparent (app.) bone volume/total volume and app. trabecular separation were higher than for hip BMD. Receiver operator characteristic values of texture measures and hip BMD were comparable. In conclusion, trabecular structure measures derived from HR MR images of the calcaneus can differentiate between postmenopausal women with and without osteoporotic hip fractures.

    View details for Web of Science ID 000074507800014

    View details for PubMedID 9661082

  • High-resolution magnetic resonance imaging: Three-dimensional trabecular bone architecture and biomechanical properties BONE Majumdar, S., Kothari, M., Augat, P., Newitt, D. C., Link, T. M., Lin, J. C., Lang, T., Lu, Y., Genant, H. K. 1998; 22 (5): 445-454


    The purpose of this study was to use high-resolution magnetic resonance (MR) imaging combined with image analysis to investigate the three-dimensional (3D) trabecular structure, anisotropy, and connectivity of human vertebral, femoral, and calcaneal specimens. The goal was to determine whether: (a) MR-derived measures depict known skeletal-site-specific differences in architecture and orientation of trabeculae; (b) 3D architectural parameters combined with bone mineral density (BMD) improve the prediction of the elastic modulus using a fabric tensor formulation; (c) MR-derived 3D architectural parameters combined with BMD improve the prediction of strength using a multiple regression model, and whether these results corresponded to the results obtained using higher resolution depictions of trabecular architecture. A total of 94 specimens (12 x 12 x 12 mm cubes) consisting of trabecular bone only were obtained, of which there were 7 from the calcaneus, 15 from distal femur, 47 from the proximal femur, and 25 from the vertebral bodies. MR images were obtained using a 1.5 Tesla MR scanner at a spatial resolution of 117 x 117 x 300 microm. Additionally, BMD was determined using quantitative computed tomography (QCT), and the specimens were nondestructively tested and the elastic modulus (YM) was measured along three orthogonal axes corresponding to the anatomic superior-inferior (axial), medial-lateral (sagittal), and anterior-posterior (coronal) directions. A subset of the specimens (n=67) was then destructively tested in the superior-inferior (axial) direction to measure the ultimate compressive strength. The MR images were segmented into bone and marrow phases and then analyzed in 3D. Ellipsoids were fitted to the mean intercept lengths, using single value decomposition and the primary orientation of the trabeculae and used to calculate the anisotropy of trabecular architecture. Stereological measures were derived using a previously developed model and measures such as mean trabecular width, spacing, and number were derived. Because the spatial resolution of MR images is comparable to trabecular bone dimensions, these measures may be subject to partial volume effects and were thus treated as apparent measures, such as BV/TV, Tb.Sp, Tb.N, and Tb.Th rather than absolute measures, as would be derived from histomorphometry. In addition, in a subset of specimens, the Euler number per unit volume was determined to characterize the connectivity of the trabecular network. There were significant differences in the BMD, trabecular architectural measures, elastic modulus, and strength at the different skeletal sites. The primary orientation axes for most of the specimens was the anatomic superior-inferior (axial) direction. Using the fabric tensor formulation, in addition to BMD, improved the prediction of YM (SI), while including some of the architectural parameters significantly improved the prediction of strength. In comparing MR-derived 3D measures with those obtained from 20 microm optical images (n=18; 9 vertebrae, 9 femur specimens), good correlations were found for the apparent Tb.Sp and Tb.N, moderate correlation was seen for the apparent BV/TV, and poor correlation was found for the apparent Tb.Th. Using these higher resolution images, the fabric tensor formulation for predicting the elastic modulus also showed improved correlation between the measured and calculated modulus in the axial (SI) direction. In summary, high-resolution MR images may be used to assess 3D architecture of trabecular bone, and the inclusion of some of the 3D architectural measures provides an improved assessment of biomechanical properties. Further studies are clearly warranted to establish the role of architecture in predicting overall bone quality, and the role of trabecular architecture measures in clinical practice. (ABSTRACT TRUNCATED)

    View details for Web of Science ID 000073394300002

    View details for PubMedID 9600777

  • Assessment of bone mineral at appendicular sites in females with fractures of the proximal femur BONE Augat, P., Fan, B., Lane, N. E., Lang, T. F., LeHir, P., Lu, Y., Uffmann, M., Genant, H. K. 1998; 22 (4): 395-402


    The prediction of hip fractures by measurements at remote sites or the improvement of predictive power by measurements at multiple sites could potentially increase the success of osteoporosis screening programs. In a cross-sectional study on 137 postmenopausal women, we tested the hypothesis that bone assessment at the hip, the forearm, and the tibia are independently associated with osteoporotic fractures of the hip. Bone mineral densities, geometric features, and ultrasound properties were determined with hip dual X-ray absorptiometry, forearm peripheral quantitative computed tomography (QCT), and tibia speed of sound measurement. While the odds ratios for fracture discrimination per standard deviation decrease ranged between 3 and 4 for measurements at the hip, they were only 1.8 at the forearm and 1.4 at the tibia. Measurements at the tibia or the forearm were neither independently associated with osteoporotic hip fractures (p > 0.05) nor could any combination of measurements significantly increase the power for the identification of fractures as measured with receiver operating curves. Women who sustained trochanteric fractures were characterized by a generalized loss of bone mineral. Cervical fractures were associated with a decrease of bone mineral density at the hip, but no significant alterations in bone mass or geometric properties were observed at the tibia or at the forearm. Fracture risk prediction at the hip is therefore preferably performed by measurements at the hip itself. Peripheral QCT at the distal radius and tibial ultrasound seem capable of depicting women with an increased risk for trochanteric but not for cervical fractures. The risk assessment appears not to be improved by including information of cortical or geometric properties of the forearm.

    View details for Web of Science ID 000072854800015

    View details for PubMedID 9556141

  • Ultrasound characterization of bone demineralization CALCIFIED TISSUE INTERNATIONAL Wu, C., Gluer, C., Lu, Y., Fuerst, T., Hans, D., Genant, H. K. 1998; 62 (2): 133-139


    Quantitative ultrasound (QUS) assessment of bone may permit an assessment of bone properties currently not available by bone densitometry techniques. To explore the effects of the quantity of bone mineral on acoustic parameters, we carried out an in vitro study of the impact of demineralization on attenuation of ultrasound in trabecular bone. Ten fresh cubes of trabecular bone obtained from bovine distal femurs were progressively demineralized using formic acid solution. The progression of demineralization was controlled by monitoring the specimen bone mineral density (BMD) using dual x-ray absorptiometry (DXA). At five stages of demineralization-0% (baseline), 25%, 50%, 75%, and 100% (all mineral removed)-the US properties of the specimens were assessed (Walker Sonix UBA 575+). The US parameters investigated were broadband ultrasound attenuation (BUA) and ultrasound attenuation in bone (UAB). Both DXA and QUS measurements were made along the three orthogonal axes of each cube. Our results demonstrated significant variability in both BUA and UAB along the three principle axes of the cubes whereas BMD did not differ in the different directions. A strong but nonlinear correlation was found between BMD and US attenuation. A reduction in BMD to 50% of the baseline values resulted in BUA (UAB) reduction to 25% and 19%, respectively. A random effect model analysis supported a multiplicative relationship between BMD and the US parameters. US attenuation is a sensitive indicator of bone mineral changes with nonlinear dependence on bone mineral loss. Bone collagen structure reinforced by hydroxyapatite crystal accounts for fundamental US characteristics. Ultrasound attenuation associated with trabecular orientation is basically dominated by the mineral spread in a collagen framework.

    View details for Web of Science ID 000071473900009

    View details for PubMedID 9437046

  • Correlation of dynamic contrast-enhanced magnetic resonance imaging with histologic tumor grade: comparison of macromolecular and small-molecular contrast media PEDIATRIC RADIOLOGY Daldrup, H., Shames, D. M., Wendland, M., Okuhata, Y., Link, T. M., Rosenau, W., Lu, Y., Brasch, R. C. 1998; 28 (2): 67-78


    The endothelial integrity of microvessels is disrupted in malignant tumors. Quantitative assays of tumor microvascular characteristics based on dynamic magnetic resonance imaging (MRI) were correlated with histopathologic grade in mammary soft tissue tumors.A spectrum of tumors, benign through highly malignant, was induced in 33 female rats by administration of N -ethyl-N -nitrosourea (ENU), a potent carcinogen. Dynamic contrast-enhanced MRI was performed using a small-molecular contrast medium [gadopentetate, MW = 0.5 kDa] and a macromolecular contrast medium [albumin-(Gd-DTPA)30, MW = 92 kDa] at an interval of 1-2 days. Permeability surface area product (PS), as estimated by the corresponding endothelial transfer coefficient (KPS), and fractional plasma volume (fPV) were calculated for each tumor and each contrast agent using a two-compartment bi-directional kinetic model. MRI microvascular characteristics were correlated with histopathologic tumor grade.Tumor permeability to macromolecular contrast medium, characterized by KPS, showed a highly positive correlation with tumor grade (r 2 = 0.76, P < 10(-10)). KPS values were zero for all benign and some low-grade carcinomas, greater than zero in all other carcinomas, and increased in magnitude with higher tumor grade. A considerably smaller but significantly positive correlation was found between fPV and tumor grade using macromolecular contrast medium (r 2 = 0.25, P < 0.003). No correlation between KPS or fPV values and tumor grade was found using gadopentetate (r 2 = 0.01, P > 0.95 and r2 = 0.03, P > 0.15, respectively).Quantitative tumor microvascular permeability assays generated with macromolecular MRI contrast medium correlate closely with histologic tumor grade. No significant correlation is found using small-molecular gadopentetate.

    View details for Web of Science ID 000072138600001

    View details for PubMedID 9472047

  • How can we measure bone quality? BAILLIERES CLINICAL RHEUMATOLOGY Hans, D., Fuerst, T., Lang, T., Majumdar, S., Lu, Y., Genant, H. K., Gluer, C. 1997; 11 (3): 495-515


    Osteoporosis is a systematic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue. This leads to diminished biomechanical competence of the skeleton and is associated with low-trauma or atraumatic fractures. In the past decade, considerable progress has been made in the development of methods for assessing the skeleton non-invasively, so that osteoporosis can be better managed. While dual X-ray absorptiometry (DXA) is still the preferred methodology, several limitations will be addressed. Another densitometric technique which is widely accepted for diagnosis of spinal osteoporosis is single energy QCT. Measurements of vertebral trabecular bone mineral density (BMD) demonstrate larger percentage decrements between vertebrally-fractured subjects and normal controls, and confer higher relative risks for vertebral fracture than either anteroposterior or lateral DXA measurements. As an emerging alternative to photon absorptiometry techniques, there is a growing interest in the use of quantitative ultrasound (QUS) measurements for the non-invasive assessment of osteoporotic fracture risk in the management of osteoporosis. The attractiveness of QUS lies in the fact that indirect and in vitro experience has suggested that ultrasound may give information not only about BMD but also about architecture and elasticity. Whether or not combining QUS and DXA improve fracture prediction is still unclear and needs further analysis. Due to the growing evidence supporting the use of QUS in osteoporosis and the large number of QUS devices already on the market, a general clinical consensus on the application of QUS is urgently needed. Other techniques that are less widely used for the management of osteoporosis. For example, peripheral quantitative computed tomography, quantitative magnetic resonance (QMR) and magnetic resonance microscopy are promising tools for the evaluation of the skeleton. For example, the ability of QMR and high resolution magnetic resonance imaging has been explored and shows promise as a technique for assessing trabecular bone structure in osteoporosis.

    View details for Web of Science ID A1997YB23700005

    View details for PubMedID 9367034

  • Volumetric quantitative computed tomography of the proximal femur: Precision and relation to bone strength 1996 World Congress on Osteoporosis Lang, T. F., Keyak, J. H., Heitz, M. W., Augat, P., Lu, Y., Mathur, A., Genant, H. K. ELSEVIER SCIENCE INC. 1997: 101–8


    We have developed a three-dimensional computed tomography (CT) scanning and image analysis method for measurement of trabecular and integral bone mineral density (BMD) and geometry in automatically determined femoral-neck and trochanteric subregions of the proximal femur. We measured the correlation of the density and geometry variables to femoral strength assessed in vitro under loading simulating a single-limb condition and a fall to the side. While BMD alone accounted for 48%-77% of the variability in strength for the stance loading configuration, femoral neck cross-sectional area (minCSA) and femoral neck axis length (FNAL) also contributed independently to femoral strength, and a combination of BMD and geometry variables explained 87%-93% of the variance in the data. For the fall loading configuration, trochanteric trabecular BMD alone explained 87% of the variability of strength. The reproducibility in vivo of the technique was assessed in a group of seven postmenopausal women, who underwent repeat scans with repositioning. For trabecular BMD, the precision was 1.1% and 0.6% for the femoral neck and trochanteric subregions, respectively, compared to 3.3% and 1.6% for the corresponding integral envelopes. Thus, trabecular BMD measurements were reproducible and highly correlated to biomechanical strength measurements. These results support further exploration of quantitative CT for assessment of osteoporosis at the proximal femur.

    View details for Web of Science ID A1997XH43800015

    View details for PubMedID 9213015

  • Comparisons of noninvasive bone mineral measurements in assessing age-related loss, fracture discrimination, and diagnostic classification XIth International Workshop on Bone Densitometry Grampp, S., Genant, H. K., Mathur, A., Lang, P., Jergas, M., Takada, M., Gluer, C. C., Lu, Y., Chavez, M. BLACKWELL SCIENCE INC. 1997: 697–711


    The purpose of this study was to examine the commonly available methods of noninvasively assessing bone mineral status across three defined female populations to examine their interrelationships, compare their respective abilities to reflect age- and menopause-related bone loss, discriminate osteoporotic fractures, and classify patients diagnostically. A total of 47 healthy premenopausal (age 33 +/- 7 years), 41 healthy postmenopausal (age 64 +/- 9 years), and 36 osteoporotic postmenopausal (age 70 +/- 6 years) women were examined with the following techniques: (1) quantitative computed tomography of the L1-L4 lumbar spine for trabecular (QCT TRAB BMD) and integral (QCT INTG BMD) bone mineral density (BMD); (2) dual X-ray absorptiometry of the L1-L4 posterior-anterior (DXA PA BMD) and L2-L4 lateral (DXA LAT BMD) lumbar spine, of the femoral neck (DXA NECK BMD) and trochanter (DXA TROC BMD), and of the ultradistal radius (DXA UD BMD) for integral BMD; (3) peripheral QCT of the distal radius for trabecular BMD (pQCT TRAB BMD) and cortical bone mineral content (BMC) (pQCT CORT BMC); (4) two radiographic absorptiometric techniques of the metacarpal (RA METC BMD) and phalanges (RA PHAL BMD) for integral BMD; and (5) two quantitative ultrasound devices (QUS) of the calcaneus for speed of sound (SOS CALC) and broadband ultrasound attenuation (BUA CALC). In general, correlations ranged from (r = 0.10-0.93) among different sites and techniques. We found that pQCT TRAB BMD correlated poorly (r < or = 0.46) with all other measurements except DXA UD BMD (r = 0.62,p < or = 0.0001) and RA PHAL BMD (r = 0.52, p < or = 0.0001). The strongest correlation across techniques was between QCT INT BMD and DXA LAT BMD (r = 0.87, p < or = 0.0001), and the weakest correlation within a technique was between pQCT TRAB BMD and pQCT CORT BMC (r = 0.25,p < or = 0.05). Techniques showing the highest correlations with age in the healthy groups also showed the greatest differences among groups. They also showed the best discrimination (as measured by the odds ratios) for the distinction between healthy postmenopausal and osteoporotic postmenopausal groups based on age-adjusted logistic regression analysis. For each anatomic site, the techniques providing the best results were: (1) spine, QCT TRAB BMD (annual loss, -1.2% [healthy premenopausal and healthy postmenopausal]); Student's t-value [not the T score], 5.4 [healthy postmenopausal vs. osteoporotic postmenopausal]; odds ratio, 43 [age-adjusted logistic regression for healthy postmenopausal vs. osteoporotic postmenopausal]); (2) hip, DXA TROC BMD (-0.46; 3.5; 2.2); (3) radius, DXA UD BMD (-0.44; 3.3; 1.9) and pQCT, CORT BMC (-0.72; 2.9; 1.7); (4) hand, RA PHAL (-0.51; 3.6; 2.0); and (5) calcaneus, SOS (-0.09; 3.4; 2.1) and BUA (-0.52; 2.6; 1.7). Despite these performance trends, the differences among sites and techniques were statistically insignificant (p > 0.05) using age-adjusted receiver operating characteristic (ROC) curve analysis. Nevertheless, kappa score analysis (using -2.0 T score as the cut-off value for osteopenia and -2.5 T score for osteoporosis) showed that in general the diagnostic agreement among these measurements in classifying women as osteopenic or osteoporotic was poor, with kappa scores averaging about 0.4 (exceptions were QCT TRAB/INTG BMD, DXA LAT BMD, and RA PHAL BMD, with kappa scores ranging from 0.63 to 0.89). Often different patients were estimated at risk by using different measurement sites or techniques.

    View details for Web of Science ID A1997WW90700001

    View details for PubMedID 9144335

  • HIV prevention among Zambian adolescents: Developing a value utilization/norm change model Social Science and Medicine Fledman DA, OHara P; Baboo KS; Chitalu NW; Lu Y 1997; 44: 455-468
  • Biomechanical strength versus spinal trabecular bone structure assessed using contact radiography and texture analysis Medical Imaging 1997 Symposium - Image Processing Ouyang, X. L., Lin, J., Link, T., Augat, P., Lu, Y., Newitt, D., Lang, T., Genant, H. K., Majumdar, S. SPIE - INT SOC OPTICAL ENGINEERING. 1997: 165–174
  • Surgically defined prognostic parameters in patients with early cervical carcinoma - A multivariate survival tree analysis CANCER Sevin, B. U., Lu, Y., Bloch, D. A., Nadji, M., Koechli, O. R., Averette, H. E. 1996; 78 (7): 1438-1446


    This study was performed to identify a statistical combination of independent pathologic and clinical features that best predict 5-year disease free survival (DFS) in patients with early stage cervical carcinoma treated by radical hysterectomy. The main goal of the study was to identify subsets of patients based on risk factors with maximal differences in DFS.Three hundred and seventy patients were found for whom complete clinical and pathologic material, including cone and cervical biopsies, were available for analysis. Variables studied included age, weight, race, marital status, economic status, tumor size (TS), depth of invasion (DI), lymph-vascular space involvement (LVSI), cell type, tumor grade, lymph node metastasis (LNM), and number of lymph nodes removed. Patients with LNM, parametrial involvement, and positive or close surgical margins were offered postoperative radiation. After excluding patients with microinvasive and small cell carcinoma, data from the remaining 301 patients were submitted to univariate and multivariate analyses to define those variables that best predict DFS.Univariate analysis showed that, ranked by degree of significance, DI, TS, LVSI, LNM, tumor volume (TV) and clinical stage were significant in predicting survival. Significant (P < 0.05) single parameters and other variables considered important were chosen for multivariate analysis, including the creation of a survival tree. With this method, DI (< or = 6 mm and > 2 cm), LVSI, age (> or = 40 yrs), and LNM were found to be the best combination of risk factors to define prognosis.The multivariate survival tree analysis maximally separates patients with early stage invasive carcinoma of the cervix into 3 subgroups with 5-year DFS of 91%, 68%, and 43%, respectively. The authors excluded patients with microinvasive carcinoma (SGO, Society of Gynecologic Oncologists), who have an excellent DFS of 100%, and patients with small carcinoma, who have a poor DFS of 36.4% based on cell type alone, to define independent risk factors that maximally separate the remaining patients by DSF. The survival tree prognostic scoring system is easy to apply, and only requires DI (mm), LVSI (+, -), LNM, and age to assign an individual patient to one of three risk groups.

    View details for Web of Science ID A1996VJ53600010

    View details for PubMedID 8839549

  • Efficacy of radical hysterectomy as treatment for patients with small cell carcinoma of the cervix CANCER Sevin, B. U., Method, M. W., Nadji, M., Lu, Y., Averette, H. A. 1996; 77 (8): 1489-1493


    This study was performed to identify pathologic and clinical features that best predict disease free survival of patients with early stage small cell carcinoma of the cervix treated by radical hysterectomy.Three hundreds and seventy patients with cervical carcinoma were analyzed retrospectively to define those variable that best predict disease free survival (DFS). Variables included age, weight, race, marital status, economic status, tumor size, depth of invasion (DI), lymph-vascular space involvement (LVSI), cell type, tumor grade, lymph node metastasis (LNM), and total number of lymph nodes removed. Patients with lymph node metastasis, parametrial involvement, and positive or close surgical margins were offered postoperative radiation.Twelve patients were found to have small cell carcinoma (3.2%). One patient had microinvasive carcinoma of the cervix (MIC) as defined by the Society of Gynecologic Oncologists with a depth of invasion of 3 mm or less and no lymph-vascular space invasion, and has been reported previously. A detailed analysis of the other patients with nonsmall cell carcinoma is presented separately. Five patients achieved a DFS of at least 5 years, whereas 7 patients died with disease. Excluding the patient with MIC, the 5-year DFS rate was 36.4%.Relative to other cell types, small cell carcinomas of the cervix is an aggressive neoplasm with a higher rate of LVSI and LNM despite smaller DI and tumor size. These data suggest that multimodality therapy, combining radical surgery and radiation with cytotoxic chemotherapy, may provide these patients with the best chance for cure.

    View details for Web of Science ID A1996UD43000010

    View details for PubMedID 8608533

  • Aspiration cytology of neoplastic and non-neoplastic ovarian cysts: Is it accurate? INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY Ganjei, P., Dickinson, B., Harrison, T. A., Nassiri, M., Lu, Y. 1996; 15 (2): 94-101


    To evaluate the role of aspiration cytology in the distinction between neoplastic and non-neoplastic ovarian cysts, we examined the cytology of 81 aspirates from 80 women 14-67 years of age. We then correlated results with subsequent histology or the clinical follow-up. Aspiration were performed during laparoscopy (32 cases) or immediately after surgical removal of the tumors (49 cases). The cysts ranged in size from 1.0 to 43.0 cm. Papanicolaou-stained cytospin preparations of samples were evaluated, and the lesions were classified into non-neoplastic (68 cases), benign neoplasms (four cases), and malignant neoplasms (nine cases). Cytologic impressions were correlated with histologic findings in 74 cases and with the clinical follow-up in the remaining seven. Nine of the 12 (75%) cystadenocarcinomas, including two serous neoplasms of low malignant potential (LMP), were correctly diagnosed as malignant by cytology. There were no false-positive results. On the other hand, of the 26 benign neoplasms (19 cystadenomas and seven mature cystic teratomas), only four teratomas (15%) could be subclassified specifically. The remaining 68 aspirates were classified as non-neoplastic. Seventy-seven percent of all proven non-neoplastic cysts measured < 8.0 cm, whereas 77% of all benign and malignant neoplastic cysts were > 8.0 cm. The overall diagnostic accuracy was improved from 63% to 69% when cyst size was taken into consideration. In malignant cysts the diagnostic sensitivity was 75%, specificity 100%, and overall accuracy 96%. We arrived at the following conclusions: Aspiration cytology is an accurate predictor of malignancy in ovarian cystic lesions, but because the sensitivity of the technique is not high enough, one should not rely on aspiration cytology alone; The differential diagnosis between cystadenocarcinomas and tumors of low malignant potential cannot be made by cytology; Although it is difficult to distinguish between benign neoplasms and non-neoplastic benign cysts, diagnostic accuracy will improve when the size of the lesion is considered; Aspiration cytology can provide particularly useful information in young women with functional cysts of the ovary to avoid an unnecessary operation; Acellular cyst fluids should not be considered nondiagnostic because they represent benign cysts in the majority of cases; false-negative results of fine-needle aspiration of cystic ovarian lesions is usually due to low cellularity of the sample and secondary degenerative changes; negative fine-needle aspiration results should be followed clinically.

    View details for Web of Science ID A1996UE29000002

    View details for PubMedID 8786211

  • Assessment of calcaneal structure by MRI: Comparison with DXA and QUS measurements 1996 World Congress on Osteoporosis Ouyang, X., Lang, P., Engleke, K., Selby, K., Lu, Y., Mathur, A., Gindele, A., Klifa, C., Chen, M., Fan, B., Hottya, G., Majumdar, S., Genant, H. K. ELSEVIER SCIENCE PUBL B V. 1996: 215–221
  • PROGNOSTIC FACTORS OF EARLY-STAGE CERVICAL-CANCER TREATED BY RADICAL HYSTERECTOMY 5th National Conference of the American-Cancer-Society on Gynecologic Cancers Sevin, B. U., Nadji, M., Lampe, B., Lu, Y., Hilsenbeck, S., Koechli, O. R., Averette, H. E. WILEY-LISS. 1995: 1978–86


    This study was performed to identify pathologic and clinical features that best correlate with lymph node metastasis and disease free survival among patients with Stage I and II cervical cancer treated by radical hysterectomy.Three hundred-seventy patients with complete clinical information and pathologic material, including cone and cervical biopsies, were selected for analysis. Of these patients, 301 with clinical stages I and II disease were the subject of this paper. The results of patients with microinvasive carcinoma of the cervix, as defined by the Society of Gynecologic Oncologists (depth of invasion < or = 3 mm and no lymph node vascular space invasion), were reported previously and excluded from this analysis. Patients with small cell carcinoma of the cervix were found to have a very poor prognosis (disease free 5-year survival of 36%) and were also excluded from this analysis (Sevin BU, Nadji M, Metkoch MW, Lu Y, Averette HE. Unpublished data, 1995). Variables studied were patient age, weight, race, marital status, and economic status; tumor size; depth of invasion; lymph node-vascular space involvement; cell type; tumor grade; lymph node metastasis; and number of lymph nodes removed. The influence of these variables on survival was examined by univariate analysis with use of Cox's regression model and the log rank test for comparison of survival curves.Factors that predict disease free survival, ranked by degree of significance, were depth of invasion, tumor size, lymph node-vascular space invasion, number of positive nodes, tumor volume, clinical stage, and tumor extension to the vagina or surgical margins.Radical hysterectomy and bilateral lymphadenectomy is standard therapy for patients with Stage IB and IIA carcinoma of the cervix. A variety of surgically defined risk factors predict 5-year disease free survival, and many of these factors are related. Identification of independent risk factors requires a multivariate analysis of data.

    View details for Web of Science ID A1995TE56300011

    View details for PubMedID 8634988



    We assessed the impact of various forms of spinal degenerative joint disease (DJD) on bone mineral density (BMD) measured by quantitative computed tomography (QCT) and dual X-ray absorptiometry (DXA) in a group of postmenopausal women. Lateral (T4-L4) and AP (L1-L4) spinal radiographs were reviewed for fracture and DJD in 209 women (mean age 62.6 +/- 6.7). The severity of DJD findings was graded as 0, 1, or 2 on the lumbar films, except for vertebral osteophytes which were graded from 0 to 3. Vertebral fractures were defined semiquantitatively as approximately 20% reduction in anterior, middle, or posterior vertebral height. BMD was measured in all subjects by QCT and DXA, including posteroanterior DXA (PA-DXA), lateral DXA (L-DXA) and midlateral DXA (mL-DXA). When BMD was measured by QCT and mL-DXA in the 168 women without fractures, no significant differences were found between women with and those without DJD. However, BMD by PA-DXA was significantly higher in women with DJD changes, particularly when osteophytes were present at the vertebral bodies or facet joints. BMD by L-DXA was less affected by DJD. For this measurement a significant increase in BMD was only noted in subjects with vertebral osteophytes. Multivariate analysis of variance (MANOVA) showed that BMD by QCT and mL-DXA was not affected by DJD. In contrast, for all women, BMD by PA- and L-DXA was affected more by DJD than by fracture status. Chi-square testing demonstrated no significant relationships between vertebral fractures and any of the DJD changes. We conclude that QCT and mL-DXA are superior to PA-DXA and L-DXA in detecting bone loss in patients with DJD. Thus, for these patients, BMD assessment by QCT or mL-DXA may be advisable.

    View details for Web of Science ID A1995RQ40800002

    View details for PubMedID 8574931

  • MICRONUTRIENTS AND HIV-1 DISEASE PROGRESSION AIDS Baum, M. K., Shorposner, G., Lu, Y., Rosner, B., Sauberlich, H. E., Fletcher, M. A., Szapocznik, J., Eisdorfer, C., Buring, J. E., Hennekens, C. H. 1995; 9 (9): 1051-1056


    To determine whether nutritional status affects immunological markers of HIV-1 disease progression.A longitudinal study, to evaluate the relationship between plasma levels of nutrients and CD4 cell counts, along and in combination with beta 2-microglobulin (beta 2M; AIDS index) over an 18-month follow-up.Biochemical measurements of nutritional status including plasma proteins, zinc, iron and vitamins B1, B2, B6, B12 (cobalamin), A, E, C and folate and immunological markers [lymphocyte subpopulations (CD4) and beta 2M] were obtained in 108 HIV-1-seropositive homosexual men at baseline and over three 6-month time periods. Changes in nutrient status (e.g., normal to deficient, deficient to normal), were compared with immunological parameters in the same time periods using an autoregressive model.Development of deficiency of vitamin A or vitamin B12 was associated with a decline in CD4 cell count (P = 0.0255 and 0.0377, respectively), while normalization of vitamin A, vitamin B12 and zinc was associated with higher CD4 cell counts (P = 0.0492, 0.0061 and 0.0112, respectively). These findings were largely unaffected by zidovudine use. For vitamin B12, low baseline status significantly predicted accelerated HIV-1 disease progression determined by CD4 cell count (P = 0.041) and the AIDS index (P = 0.005).These data suggest that micronutrient deficiencies are associated with HIV-1 disease progression and raise the possibility that normalization might increase symptom-free survival.

    View details for Web of Science ID A1995RU01300010

    View details for PubMedID 8527077



    Cartilage loss is central to the development of joint failure in arthritis. However, radiographic assessment of cartilage loss is highly unreliable. This study examined the accuracy and reproducibility of a noninvasive technique for quantifying the volume of articular cartilage in the metacarpophalangeal joints of the hand by use of three-dimensional (3D) MR imaging.Eight metacarpophalangeal joints (four normal, one rheumatoid arthritic, and three normal cadaveric) each were imaged three times with a 1.5-T clinical MR imaging scanner with a small partial volume coil and a fat-saturated 3D spoiled gradient-echo sequence optimized for delineating articular cartilage. The volumes of cartilage over the metacarpal and phalangeal surfaces were quantified by summing the voxels within segmented 3D reconstructions of the images. Cartilage volumes in the three cadaver joints also were estimated by scraping cartilage off the articular surfaces and measuring water displacement in graduated cylinders. These values were used as the gold standard for assessing the accuracy of cartilage volume quantification by MR imaging.The fat-saturated sequence discriminated the articular cartilage from adjacent joint structures with high contrast and high spatial resolution. Cartilage volumes determined by MR imaging for the different subjects ranged from 115 microliters to 222 microliters for metacarpal cartilage and from 34 microliters to 86 microliters for proximal phalangeal cartilage. Accuracy errors for quantifying cartilage volume by MR imaging were -1.8% (95% confidence interval, -3.5% to -0.7%) for metacarpal cartilage and 9.1% (4.3% to 14.7%) for proximal phalangeal cartilage. Reproducibility errors were 5.2% (95% confidence interval, 2.9% to 7.6%) and 9.9% (5.4% to 15.1%), respectively.Fat-suppressed T1-weighted 3D MR imaging provides sufficient contrast and spatial resolution to allow accurate and reproducible quantification of articular cartilage volume in the metacarpophalangeal joints of the hand. This technique may be useful for monitoring cartilage loss in patients with arthritis.

    View details for Web of Science ID A1995RJ95900028

    View details for PubMedID 7618560



    Elevation of IgE has been associated with T-cell dysregulation and with the occurrence of opportunistic infections in patients with acquired immunodeficiency syndrome. The precise cause of IgE overproduction during the early stages of human immunodeficiency virus (HIV)-1 disease, however, has not been established. In light of reports demonstrating that IgE production may be affected by vitamin E levels in an animal model, we evaluated nutritional status in relationship to plasma IgE levels and immune parameters in 100 asymptomatic HIV-1-seropositive and 42 HIV-1-seronegative homosexual men. Approximately 18% of the HIV-1-seropositive population demonstrated biochemical evidence of plasma vitamin E deficiency (< 5 micrograms/ml). Subsequent analysis of available samples indicated a dramatic elevation of IgE levels (308 +/- 112 IU/ml) in vitamin E-deficient seropositive subjects (n = 9) as compared with age and CD4-matched HIV-1-seropositive persons with adequate vitamin E levels (n = 16, 118.1 +/- 41.1 IU/ml) and significantly lower levels (59.5 +/- 15.7 IU/ml) in HIV-1-seronegative men (n = 20, p = 0.01). This effect, which was independent of CD4 cell count, did not appear to be influenced by atopic or gastrointestinal parasitic disease. The low plasma vitamin E levels were related at least in part to dietary intake (r = 0.552, p = 0.01), suggesting that supplementation may be warranted in HIV-1-infected persons in whom vitamin E deficiency develops. Analysis of covariance revealed a strong relationship between IgE levels and CD8 cell counts (p < 0.006), and between IgE level and vitamin E deficiency (p < 0.039).(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1995QT46800015

    View details for PubMedID 7722170

  • IMMUNOGLOBULIN-E LEVELS IN RELATIONSHIP TO HIV-1 DISEASE, ROUTE OF INFECTION, AND VITAMIN-E STATUS ALLERGY MIGUEZBURBANO, M. J., Shorposner, G., Fletcher, M. A., Lu, Y., Moreno, J. N., CARCAMO, C., Page, B., Quesada, J., Sauberlich, H., Baum, M. K. 1995; 50 (2): 157-161


    Our recent studies have demonstrated that in early HIV-1 infection, elevation of plasma immunoglobulin E (IgE) levels precedes the decline of CD4 cell count and is influenced by vitamin E status. In order to further investigate the role of IgE elevation in HIV-1 infection, we determined IgE levels in HIV-1-seropositive and -seronegative intravenous drug users (IDUs) (n = 38), in relationship to cellular and humoral immune function, liver enzymes, and vitamin E status. To examine the possible impact of the route of HIV-1 infection on IgE levels, comparisons between the cohorts of the HIV-1-seropositive and -seronegative IDUs and homosexual men (n = 45) were also conducted. All HIV-1-seropositive participants had significantly higher (P = 0.003) IgE levels than the HIV-1-seronegative subjects. The HIV-1-seropositive IDUs, moreover, demonstrated significantly higher (P = 0.01) IgE levels than HIV-1-seropositive homosexual men, despite similar CD4 cell counts. Stepwise regression analysis was used to evaluate the possible variables contributing to the IgE variation. HIV-1 status (P = 0.0009), intravenous drug use (P = 0.014), CD8 cell counts (P = 0.0001), plasma level of vitamin E (P = 0.006), and alcohol intake (P = 0.047) were significant, accounting for 71% of the IgE elevation. These findings suggest that IgE may serve as a sensitive marker to reflect the evolution of HIV-1 disease in individuals from different risk groups.

    View details for Web of Science ID A1995QW19200010

    View details for PubMedID 7604939

  • Spinal bone mineral assessment in postmenopausal women: A comparison between dual X-ray absorptiometry and quantitative computed tomography OSTEOPOROSIS INTERNATIONAL Yu, W., Gluer, C. C., Grampp, S., Jergas, M., Fuerst, T., Wu, C. Y., Lu, Y., Fan, B., Genant, H. K. 1995; 5 (6): 433-439


    We compared quantitative computed tomography (QCT) and dual X-ray absorptiometry (DXA) with respect to their ability to discriminate subjects with and without prevalent vertebral fractures. In 240 post-menopausal women (mean age 63.7 +/- 6.9 years) lateral spine radiographs (T4-L4) were reviewed for the presence of vertebral fracture. Using a semiquantitative technique to grade the severity of vertebral deformities, we classified fractures as mild, moderate or severe (grade 1 to 3, respectively). Postero-anterior DXA (PA-DXA) and lateral DXA (L-DXA) measurements (L2-4) as well as QCT measurements of the lumbar spine (T12-L3 or L1-14) were obtained in all women. Seventy-two women were diagnosed with at least one fracture, and of these 40 were graded as mild. Comparing normal women with fractured women, we found the area under the receiver operating characteristics (ROC) curves to be greatest for QCT (0.81), followed by L-DXA (0.72) and PA-DXA (0.65). The differences among all three techniques were significant. Comparing the normal women with women having only mild fractures, the areas under the ROC curves were 0.79, 0.73 and 0.63 for QCT, L-DXA and PA-DXA, respectively. Significant differences existed between QCT and PA-DXA as well as between L-DXA and PA-DXA. Logistic regression analysis also revealed the highest age-adjusted odds ratios for QCT (3.67; 2.25-5.97) while L-DXA and PA-DXA showed substantially lower odds ratios (2.00; 1.39-2.87, and 1.54; 1.11-2.15, respectively). We conclude that low bone density as measured by QCT, PA-DXA or L-DXA is significantly associated with the prevalence of vertebral fractures. Of the methods studied, QCT of trabecular bone offered the best discriminatory capability. L-DXA proved to be superior to PA-DXA in its diagnostic sensitivity, particularly in women with mild fracture. Mild vertebral fractures are associated with decreased spinal bone density and may be regarded as osteoporotic deformities.

    View details for Web of Science ID A1995TN08800004

    View details for PubMedID 8695964



    Radical cystectomy continues to be one of the primary modalities of treatment for locally advanced bladder cancer. However, long-term survival after cystectomy has improved only marginally in the last decade, and still, nearly half of the patients die from the disease within 5 years. Adjuvant treatments such as radiation therapy and chemotherapy have been used, but a clear advantage has not been demonstrated.The authors reviewed 130 patients who underwent radical cystectomy by the same surgeon as treatment for transitional cell carcinoma of the bladder. Morbidity, postoperative mortality, overall survival time, and accuracy of clinical staging as well as the effect of perioperative chemotherapy were evaluated.The overall actuarial survival rate at 2, 5, and 10 years was 80%, 53%, and 45%, respectively. The survival rate based on T-classification at 5 years was 82%, 65%, and 28% for less than pT2, pT2, and greater than pT2, respectively. Regional lymph node status had a significant effect on survival. The 5-year survival rate for all patients with negative nodes was 65%, whereas patients with positive nodes had a 18% 5-year survival rate. The overall clinical staging error was 61.5%, with 41.5% of the cancers understaged. Of the patients with cTis, 60% were found to be of greater extent than pT1 tumors. No apparent survival advantage was noted for those patients who received perioperative chemotherapy when compared with patients who were followed conservatively or received chemotherapy upon relapse. These results, however, are not conclusive because this was an observation study and the number of patients was limited.Only a modest improvement in survival time after radical cystectomy has been observed in the last decade, despite the use of adjuvant treatments such as radiation and chemotherapy. The pathologic (pT) classification is the most accurate prognostic indicator. Clinical errors in classification are common and impair the evaluation of neoadjuvant treatments. A high incidence of invasive tumors of greater extent than pT1 was found among patients with clinical cTis; this supports an aggressive approach when these patients do not respond promptly to intravesical chemotherapy. Prospective randomized studies are needed to evaluate objectively the benefit of perioperative adjuvant treatment in locally advanced transitional cell carcinoma of the bladder.

    View details for Web of Science ID A1994NC85700024

    View details for PubMedID 8137219



    Geriatric chronic pain patients (age 65 and over) form an increasing percentage of the pain center treatment population. It is therefore important to be able to predict pain center treatment success or failure for these patients; this is the first study to address this concern.Chronic pain patients rated themselves at pain center admission and discharge on 43 rating scales for the areas of pain, functional status, behavioral variables, and other pain center modification categories. The 43 scores at admission were used as potential predictors, while the 43 change scores (from admission to discharge) were the outcome measures to be predicted. Additional possible predictors were 16 other variables that are considered prognostic of treatment outcome, including age, number of surgeries, and prior occupational level. The statistical analysis consisted of a five-step procedure: (a) mathematical techniques were used to remove redundant outcome measures; (b) each of the remaining outcome variables was correlated with the full set of predictor variables; (c) regression techniques were used to predict the outcome variables; (d) these outcome variables were combined into independent factors using factor analysis; and (e) regression techniques were used to predict the factors.The variable-reduction technique was successful in removing 26 of the 43 outcome variables. Factor analysis of change scores of the remaining variables resulted in four factors, which were identified as change in activity, change in pain and behavior, change in constant pain, and change in attitude to pain center goals. The analysis showed that the best predictor of a variable's change score was the initial level of that variable. Regression analysis, using all variables as predictors except initial level, found a number of statistically significant predictors. However, no predictor variable, alone or in combination, was able to account for > 30% of the variance of any outcome measure.These results indicate that we cannot as yet predict geriatric pain center treatment outcome. Potential reasons for these results are discussed.

    View details for Web of Science ID A1994NA10000003

    View details for PubMedID 7514913

  • RETREATMENT OF INTRACRANIAL GLIOMAS SOUTHERN MEDICAL JOURNAL Landy, H. J., Feun, L., Schwade, J. G., Snodgrass, S., Lu, Y., Gutman, F. 1994; 87 (2): 211-214


    Although intracranial gliomas carry a poor long-term prognosis, retreatment at the time of tumor progression may prolong survival and maintain or improve the quality of life. Thirty-three patients who underwent retreatment with surgery, radiotherapy, and chemotherapy were reviewed retrospectively. Median survival after initiation of retreatment was 8 months for glioblastoma, 13 months for anaplastic astrocytoma, 22 months for astrocytoma, and 47 months for oligodendroglioma/mixed glioma. Survival was significantly better for younger patients and for those with better functional status. One third of patients were neurologically improved by surgery. Surgical morbidity was minimal (2.1%); there was no surgical mortality. Chemotherapy and radiotherapy produced expected adverse reactions. Retreatment of intracranial gliomas carries acceptable risk and is beneficial in selected patients. Decisions regarding retreatment must be carefully individualized with consideration of the quality of life and the wishes of the patient and family.

    View details for Web of Science ID A1994MZ12000013

    View details for PubMedID 8115886



    Recent studies indicate that multiple nutritional abnormalities occur relatively early in the course of human immunodeficiency virus (HIV-1) infection. Decreased plasma levels of vitamins B6, B12, A, and E and zinc have been correlated with dietary intake and associated with significant alterations in immune response and cognitive function. To determine the level of intake consistent with normal plasma nutrient levels, we examined nutrition status in relation to food consumption and nutrient supplementation in HIV-1-seropositive (HIV+) and -seronegative (HIV-) homosexual men. The mean level of total intake (diet plus supplements) for all nutrients was significantly higher in HIV+ men. To achieve normal plasma nutrient values, the HIV+ men appeared to require intake in multiples of the recommended dietary allowance (RDA) for vitamins A, E, B6, and B12 and zinc. For the HIV+ men, a relatively high proportion of biochemical deficiency was associated with consumption of vitamin B6 and zinc at the RDA level. Because little evidence of deficiency was observed with elevated intake in both groups, an effective program of nutritional supplementation may be beneficial in maintaining adequate plasma nutrient levels.

    View details for Web of Science ID A1994MR76600004

    View details for PubMedID 8199417

  • NORMAL TRIGLYCERIDE LEVELS IN EARLY HIV-1 INFECTION AIDS Baum, M. K., Shorposner, G., Lu, Y. 1994; 8 (1): 131-132

    View details for Web of Science ID A1994NA43200021

    View details for PubMedID 8011226



    Previous studies have shown that alterations in micronutrient utilization occur in patients with Acquired Immune Deficiency Syndrome. In this study, total plasma fatty acid composition was measured in 36 homosexual men infected with the Human Immunodeficiency Virus 1 (HIV-1) and in 17 HIV-1 seronegative homosexual men in order to evaluate differences associated with early HIV-1 infection. Immunologic assessment included CD4 cell number count and lymphocyte blastogenesis in response to the mitogens phytohemagglutinin (PHA) and pokeweed (PWM). The mean total amount of omega 6 polyunsaturated fatty acids (18:2 and 20:4) was significantly lower in the HIV-1 seropositive subjects (38 +/- 8.1% SD) as compared to HIV-1 seronegative subjects (43 +/- 4.2%; P = 0.0027). This was also reflected in a higher level of total saturated fatty acids (16:0 and 18:0) in HIV-1 seropositive subjects (30 +/- 2.2% vs. 26 +/- 2.8%; P = 0.0001). The ratio of linoleic to arachidonic acid (18:2 to 20:4) was higher in the HIV-1 seropositive group (6.76 +/- 4.88) compared to the HIV-1 seronegative group (4.86 +/- 1.37; P = 0.0213). The response to PHA in seropositive subjects correlated inversely with total plasma omega 6 fatty acids (r = -0.36; P = 0.027), and directly with the 18:2 to 20:4 ratio (r = 0.33; P = 0.046). CD4 cell counts and the response to PWM did not correlate with plasma fatty acid levels in HIV-1 seropositive subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1993LL46900004

    View details for PubMedID 8355587



    Patients with the acquired immunodeficiency syndrome exhibit marked disturbances in lipid metabolism. Because altered lipid metabolism may affect immune processes, this study characterized the lipid profile of asymptomatic individuals infected with the human immunodeficiency virus (HIV-1), in relationship to immune function.Serum levels of triglycerides and cholesterol were determined in 94 asymptomatic HIV-1-infected (Centers for Disease Control stage II, III) homosexual men and 42 healthy seronegative control subjects. Immune assessment included measurements of lymphocyte subpopulations (CD4), immune activation (beta 2-microglobulin), natural killer cell function, and lymphocyte proliferation in response to mitogens phytohemagglutinin and pokeweed. Dietary intake was determined using a semiquantitative food frequency questionnaire.Despite greater consumption of saturated fat and cholesterol, significantly lower levels of total, high-density, and low-density lipoprotein cholesterol were observed in HIV-1-seropositive men, relative to seronegative controls (p < 0.05), with 40% of the HIV-1-infected group demonstrating hypocholesterolemia (less than 150 mg/dL). Low values of total, high-density, and low-density cholesterol were associated with elevated levels of beta 2-microglobulin in HIV-1-seropositive men. No difference between the groups was noted for serum triglycerides. HIV-1-infected subjects did not demonstrate the significant inverse relationship between cholesterol and mitogen response observed in seronegative controls.These findings indicate that low levels of cholesterol are prevalent during the early stages of HIV-1 infection and associated with specific alterations in immune function, suggesting that hypocholesterolemia may be a useful marker of disease progression.

    View details for Web of Science ID A1993LC87400011

    View details for PubMedID 7605397



    Studies of cognitive function in subjects with human immunodeficiency virus type 1 (HIV-1) infection who remain relatively asymptomatic (ie, Centers for Disease Control stages II and III) have provided widely variable estimates of cognitive impairment. In view of the finding that approximately 25% of asymptomatic HIV-1-infected subjects demonstrate either marginal or overt vitamin B12 deficiency, we have investigated plasma vitamin B12 status as a potential cofactor in studies of HIV-1-related cognitive impairment. When cognition was assessed in asymptomatic (Centers for Disease Control stages II and III) HIV-1-infected participants taking into consideration vitamin B12 status, those subjects with low plasma vitamin B12 levels (less than 180 pmol/L) performed more poorly than did those with normal (greater than or equal to 180 pmol/L) vitamin B12 status on specific measures of information processing speed and visuospatial problem-solving skills. These findings suggest that concurrent vitamin B12 deficiency may be a cofactor in subtle cognitive changes observed in the asymptomatic stages of HIV-1 infection. These differences in prevalence of low plasma vitamin B12 levels may help to explain differences among studies in the proportion of HIV-1-infected subjects showing cognitive impairment.

    View details for Web of Science ID A1992HT67800014

    View details for PubMedID 1580812

  • HEPATITIS-C INFECTION IN A PEDIATRIC DIALYSIS POPULATION PEDIATRICS Jonas, M. M., Zilleruelo, G. E., LaRue, S. I., Abitbol, C., Strauss, J., Lu, Y. 1992; 89 (4): 707-709


    A variable prevalence of hepatitis C (HCV) infection has been reported in adult patients on hemodialysis. We have studied HCV infection and associated risk factors in a pediatric dialysis unit. Sera from all 27 patients undergoing either hemodialysis or peritoneal dialysis in our unit were tested for antibody to HCV by enzyme-linked immunosorbent assay, and seropositives were confirmed by recombinant immunoblot assay. Records were reviewed for demographic, biochemical, and risk factor data. From the total of 27 patients (12 male, mean age 20.9 years, range 7.3 to 28.1 years), five were anti-HCV(+) (18.5%). All the anti-HCV(+) patients had been on hemodialysis (69 to 194 months, mean 105 months), while of the 22 anti-HCV(-) patients, only 14 had been on hemodialysis (5 to 209 months, mean 41.4 months), P less than .005. All the anti-HCV(+) patients had received blood transfusions (10 to 124 units, mean 61.4 units) as had 12 of the anti-HCV(-) patients (1 to 54 units, mean 14 units), P less than .02. Of the 5 anti-HCV(+) patients, only one had prior hepatitis B infection; of the 22 anti-HCV(-) patients, three had hepatitis B surface antigen, and no others had evidence of hepatitis B infection. The most predictive risk factor for HCV infection was length of time on hemodialysis. Eleven of the 27 patients (40.7%) had abnormal alanine aminotransferase values, of whom four were anti-HCV(+), three were hepatitis B surface antigen(+), and one was seropositive for antibody to human immunodeficiency virus.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1992HM25300004

    View details for PubMedID 1313556

  • Association of nutritional abnormalities and immune parameters in HIV-1 seronegative homosexual men Journal of Immunology and Infectious Disease Shor-Posner G, Mantero-Atienza E; Beach R; Javier J; Feaster D; Sotomayor M; Cabrejos C; Fletcher MA; Lu Y; Sauberlich H; Baum MK 1992; 2: 209-216
  • Some opportunistic replacement models (in Chinese) Journal of Shanghai Jiaotong University Lu, Y. 1987; 127 (2)