Biostatistics Commons^™

An Efficient Basket Trial Design, Kristen Cunanan, Alexia Iasonos, Ronglai Shen, Colin B. Begg, Mithat Gonen

Memorial Sloan-Kettering Cancer Center, Dept. of Epidemiology & Biostatistics Working Paper Series

The landscape for early phase cancer clinical trials is changing dramatically due to the advent of targeted therapy. Increasingly, new drugs are designed to work against a target such as the presence of a specific tumor mutation. Since typically only a small proportion of cancer patients will possess the mutational target, but the mutation is present in many different cancers, a new class of basket trials is emerging, whereby the drug is tested simultaneously in different baskets, i.e., sub-groups of different tumor types. Investigators not only desire to test whether the drug works, but also to determine which types of …

Variable Selection For Case-Cohort Studies With Failure Time Outcome, Andy Ni, Jianwen Cai, Donglin Zeng

Memorial Sloan-Kettering Cancer Center, Dept. of Epidemiology & Biostatistics Working Paper Series

Case-cohort designs are widely used in large cohort studies to reduce the cost associated with covariate measurement. In many such studies the number of covariates is very large, so an efficient variable selection method is necessary. In this paper, we study the properties of variable selection using the smoothly clipped absolute deviation penalty in a case-cohort design with a diverging number of parameters. We establish the consistency and asymptotic normality of the maximum penalized pseudo-partial likelihood estimator, and show that the proposed variable selection procedure is consistent and has an asymptotic oracle property. Simulation studies compare the finite sample performance …

Leveraging Contact Network Structure In The Design Of Cluster Randomized Trials, Guy Harling, Rui Wang, Jukka-Pekka Onnela, Victor Degruttola

Harvard University Biostatistics Working Paper Series

Background: In settings like the Ebola epidemic, where proof-of-principle trials have succeeded but questions remain about the effectiveness of different possible modes of implementation, it may be useful to develop trials that not only generate information about intervention effects but also themselves provide public health benefit. Cluster randomized trials are of particular value for infectious disease prevention research by virtue of their ability to capture both direct and indirect effects of intervention; the latter of which depends heavily on the nature of contact networks within and across clusters. By leveraging information about these networks – in particular the degree …

Using Validation Data To Adjust The Inverse Probability Weighting Estimator For Misclassified Treatment, Danielle Braun, Corwin Zigler, Francesca Dominici, Malka Gorfine

Harvard University Biostatistics Working Paper Series

The inverse probability weighting (IPW) estimator is widely used to estimate the treatment effect in observational studies in which patient characteristics might not be balanced by treatment group. The estimator assumes that treatment assignment, is error-free, but in reality treatment assignment can be measured with error. This arises in the context of comparative effectiveness research, using administrative data sources in which accurate procedural or billing codes are not always available. We show the bias introduced to the estimator when using error-prone treatment assignment, and propose an adjusted estimator using a validation study to eliminate this bias. In simulations, we explore …

Estimation And Inference For The Mediation Proportion, Daniel Nevo, Xiaomei Liao, Donna Spiegelman

Harvard University Biostatistics Working Paper Series

In epidemiology, public health and social science, mediation analysis is often undertaken to investigate the extent to which the effect of a risk factor on an outcome of interest is mediated by other covariates. A pivotal quantity of interest in such an analysis is the mediation proportion. A common method for estimating it, termed the "difference method'', compares estimates from models with and without the hypothesized mediator. However, rigorous methodology for estimation and statistical inference for this quantity has not previously been available. We formulated the problem for the Cox model and generalized linear models, and utilize a data duplication …

A Cautionary Note On The Effect Of Treatment Misclassification On The Average Treatment Effect, Danielle Braun, Corwin Zigler, Malka Gorfine, Francesca Dominici

Harvard University Biostatistics Working Paper Series

Comparative effectiveness research often relies on large administrative data, such as claims data. Methods to estimate treatment effects assume that treatment assignment is error-free, but in reality the inaccuracy of procedural or billing codes frequently misclassifies patients into treatment groups. Propensity score methods are widely used to analyze observational studies in which patient characteristics might not be balanced by treatment group. We evaluate the impact of treatment misclassification on 1) propensity score estimation; 2) treatment effect estimation conditional on propensity score estimation and implementation. We focus on three common propensity score implementations: subclassification, matching, and inverse probability of treatment weighting …

The Myth Of Making Inferences For An Overall Treatment Efficacy With Data From Multiple Comparative Studies Via Meta-Analysis, Takahiro Hasegawa, Brian Claggett, Lu Tian, Scott D. Solomon, Marc A. Pfeffer, Lee-Jen Wei

Harvard University Biostatistics Working Paper Series

Meta analysis techniques, if applied appropriately, can provide a summary of the totality of evidence regarding an overall difference between a new treatment and a control group using data from multiple comparative clinical studies. The standard meta analysis procedures, however, may not give a meaningful between-group difference summary measure or identify a meaningful patient population of interest, especially when the fixed effect model assumption is not met. Moreover, a single between-group comparison measure without a reference value obtained from patients in the control arm would likely not be informative enough for clinical decision making. In this paper, we propose a …

Moving Beyond The Conventional Stratified Analysis To Estimate An Overall Treatment Efficacy With The Data From A Comparative Randomized Clinical Study, Lu Tian, Fei Jiang, Takahiro Hasegawa, Hajime Uno, Marc Alan Pfeffer, L.J. Wei

Harvard University Biostatistics Working Paper Series

No abstract provided.

Detectable Viral Load In Late Pregnancy Among Women In The Rwanda Option B+ Pmtct Program: Enrollment Results From The Kabeho Study., Michelle M Gill, Heather J Hoffman, Emily A Bobrow, Placidie Mugwaneza, Dieudonne Ndatimana, Gilles F Ndayisaba, Cyprien Baribwira, Laura Guay, Anita Asiimwe

Epidemiology Faculty Publications

There are limited viral load (VL) data available from programs implementing "Option B+," lifelong antiretroviral treatment (ART) to all HIV-positive pregnant and postpartum women, in resource-limited settings. Extent of viral suppression from a prevention of mother-to-child transmission of HIV program in Rwanda was assessed among women enrolled in the Kigali Antiretroviral and Breastfeeding Assessment for the Elimination of HIV (Kabeho) Study. ARV drug resistance testing was conducted on women with VL>2000 copies/ml. In April 2013-January 2014, 608 pregnant or early postpartum HIV-positive women were enrolled in 14 facilities. Factors associated with detectable enrollment VL (>20 copies/ml) were examined …

Male Pattern Baldness In Relation To Prostate Cancer–Specific Mortality: A Prospective Analysis In The Nhanes I Epidemiologic Follow-Up Study, Cindy Ke Zhou, Paul H Levine, Sean D. Cleary, Heather J. Hoffman, Barry I Graubard, Michael B. Cook

Epidemiology Faculty Publications

We used male pattern baldness as a proxy for long-term androgen exposure and investigated the association of dermatologist-assessed hair loss with prostate cancer–specific mortality in the first National Health and Nutrition Examination Survey Epidemiologic Follow-up Study. From the baseline survey (1971–1974), we included 4,316 men who were 25–74 years of age and had no prior cancer diagnosis. We estimated hazard ratios and used Cox proportional hazards regressions with age as the time metric and baseline hazard stratified by baseline age. A hybrid framework was used to account for stratification and clustering of the sample design, with adjustment for the variables …

Socioecological Factors Influencing Women's Hiv Risk In The United States: Qualitative Findings From The Women's Hiv Seroincidence Study (Hptn 064)., Paula M Frew, Kimberly Parker, Linda Vo, Danielle Haley, Ann O'Leary, Dazon Dixon Diallo, Carol E Golin, Irene Kuo, Lydia Soto-Torres, Jing Wang, Adaora A Adimora, Laura A Randall, Carlos Del Rio, Sally Hodder, Hiv Prevention Trials Network 064 (Htpn) Study Team.

Epidemiology Faculty Publications

BACKGROUND: We sought to understand the multilevel syndemic factors that are concurrently contributing to the HIV epidemic among women living in the US. We specifically examined community, network, dyadic, and individual factors to explain HIV vulnerability within a socioecological framework.

METHODS: We gathered qualitative data (120 interviews and 31 focus groups) from a subset of women ages 18-44 years (N = 2,099) enrolled in the HPTN 064 HIV seroincidence estimation study across 10 US communities. We analyzed data from 4 diverse locations: Atlanta, New York City (the Bronx), Raleigh, and Washington, DC. Data were thematically coded using grounded theory methodology. …

Improving Hiv Surveillance Data For Public Health Action In Washington, Dc: A Novel Multiorganizational Data-Sharing Method, Joanne Ocampo, J. C. Smart, Adam Allston, Reshma Bhattacharjee, Sahithi Boggavarapu, Amanda D. Castel, +13 More

GW Biostatistics Center

Background: The National HIV/AIDS Strategy calls for active surveillance programs for human immunodeficiency virus (HIV) to more accurately measure access to and retention in care across the HIV care continuum for persons living with HIV within their jurisdictions and to identify persons who may need public health services. However, traditional public health surveillance methods face substantial technological and privacy-related barriers to data sharing.

Objective: This study developed a novel data-sharing approach to improve the timeliness and quality of HIV surveillance data in three jurisdictions where persons may often travel across the borders of the District of Columbia, Maryland, and Virginia. …

Skin Collagen Fluorophore Lw-1 Versus Skin Fluorescence As Markers For The Long-Term Progression Of Subclinical Macrovascular Disease In Type 1 Diabetes., David R Sell, Wanjie Sun, Xiaoyu Gao, Christopher Strauch, John M. Lachin, Patricia A Cleary, Saul Genuth, Ddit/Edic Research Group, Vincent M Monnier

GW Biostatistics Center

BACKGROUND: Skin collagen Long Wavelength Fluorescence (LWF) is widely used as a surrogate marker for accumulation of advanced glycation end-products. Here we determined the relationship of LWF with glycemia, skin fluorescence, and the progression of complications during EDIC in 216 participants from the DCCT.

METHODS: LW-1 and collagen-linked fluorescence (CLF) were measured by either High Performance Liquid Chromatography (HPLC) with fluorescence detection (LW-1) or total fluorescence of collagenase digests (CLF) in insoluble skin collagen extracted from skin biopsies obtained at the end of the DCCT (1993). Skin intrinsic fluorescence (SIF) was noninvasively measured on volar forearm skin at EDIC year …

D-Dimer Levels Before Hiv Seroconversion Remain Elevated Even After Viral Suppression And Are Associated With An Increased Risk Of Non-Aids Events, Matthew S Freiberg, Ionut Bebu, Russell Tracy, Kaku So-Armah, Jason Okulicz, Anuradha Ganesan, Adam Armstrong, Thomas O'Bryan, David Rimland, Amy C Justice, Brian K Agan

GW Biostatistics Center

The mechanism underlying the excess risk of non-AIDS diseases among HIV infected people is unclear. HIV associated inflammation/hypercoagulability likely plays a role. While antiretroviral therapy (ART) may return this process to pre-HIV levels, this has not been directly demonstrated. We analyzed data/specimens on 249 HIV+ participants from the US Military HIV Natural History Study, a prospective, multicenter observational cohort of >5600 active duty military personnel and beneficiaries living with HIV. We used stored blood specimens to measure D-dimer and Interleukin-6 (IL-6) at three time points: pre-HIV seroconversion, ≥6 months post-HIV seroconversion but prior to ART initiation, and ≥6 months post-ART …

Generalized Confidence Intervals And Fiducial Intervals For Some Epidemiological Measures., Ionut Bebu, G. Luta, T. Mathew, B. K. Agan

GW Biostatistics Center

For binary outcome data from epidemiological studies, this article investigates the interval estimation of several measures of interest in the absence or presence of categorical covariates. When covariates are present, the logistic regression model as well as the log-binomial model are investigated. The measures considered include the common odds ratio (OR) from several studies, the number needed to treat (NNT), and the prevalence ratio. For each parameter, confidence intervals are constructed using the concepts of generalized pivotal quantities and fiducial quantities. Numerical results show that the confidence intervals so obtained exhibit satisfactory performance in terms of maintaining the coverage probabilities …

Significance Of Epicardial And Intrathoracic Adipose Tissue Volume Among Type 1 Diabetes Patients In The Dcct/Edic: A Pilot Study., Sirous Darabian, Jye-Yu C Backlund, Patricia A Cleary, Nasim Sheidaee, Ionut Bebu, John M. Lachin, Matthew J Budoff, Dcct/Edic Research Group

GW Biostatistics Center

Introduction

Type 1 diabetes (T1DM) patients are at increased risk of coronary artery disease (CAD). This pilot study sought to evaluate the relationship between epicardial adipose tissue (EAT) and intra-thoracic adipose tissue (IAT) volumes and cardio-metabolic risk factors in T1DM.

Method

EAT/IAT volumes in 100 patients, underwent non-contrast cardiac computed tomography in the Diabetes Control and Complications Trial /Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study were measured by a certified reader. Fat was defined as pixels’ density of -30 to -190 Hounsfield Unit. The associations were assessed using–Pearson partial correlation and linear regression models adjusted for gender and age …

Lymphoblastoid Cell Lines As A Tool To Study Inter-Individual Differences In The Response To Glucose., Michael A Grassi, Vidhya R Rao, Siquan Chen, Dingcai Cao, Xiaoyu Gao, Patricia A. Cleary, R Stephanie Huang, Andrew D Paterson, Rama Natarajan, Jalees Rehman, Timothy S Kern

GW Biostatistics Center

BACKGROUND: White blood cells have been shown in animal studies to play a central role in the pathogenesis of diabetic retinopathy. Lymphoblastoid cells are immortalized EBV-transformed primary B-cell leukocytes that have been extensively used as a model for conditions in which white blood cells play a primary role. The purpose of this study was to investigate whether lymphoblastoid cell lines, by retaining many of the key features of primary leukocytes, can be induced with glucose to demonstrate relevant biological responses to those found in diabetic retinopathy.

METHODS: Lymphoblastoid cell lines were obtained from twenty-three human subjects. Differences between high and …

Importance Of Hereditary And Selected Environmental Risk Factors In The Etiology Of Inflammatory Breast Cancer: A Case-Comparison Study., Roxana Moslehi, Elizabeth Freedman, Nur Zeinomar, Carmela Veneroso, Paul H. Levine

Epidemiology Faculty Publications

BACKGROUND: To assess the importance of heredity in the etiology of inflammatory breast cancer (IBC), we compared IBC patients to several carefully chosen comparison groups with respect to the prevalence of first-degree family history of breast cancer.

METHODS: IBC cases (n = 141) were compared to non-inflammatory breast cancer cases (n = 178) ascertained through George Washington University (GWU) with respect to the prevalence of first-degree family history of breast cancer and selected environmental/lifestyle risk factors for breast cancer. Similar comparisons were conducted with subjects from three case-control studies: breast cancer cases (n = 1145) and unaffected controls (n = …

Importance Of Hereditary And Selected Environmental Risk Factors In The Etiology Of Inflammatory Breast Cancer: A Case-Comparison Study., Roxana Moslehi, Elizabeth Freedman, Nur Zeinomar, Carmela Veneroso, Paul H. Levine

Epidemiology Faculty Publications

BACKGROUND: To assess the importance of heredity in the etiology of inflammatory breast cancer (IBC), we compared IBC patients to several carefully chosen comparison groups with respect to the prevalence of first-degree family history of breast cancer.

METHODS: IBC cases (n = 141) were compared to non-inflammatory breast cancer cases (n = 178) ascertained through George Washington University (GWU) with respect to the prevalence of first-degree family history of breast cancer and selected environmental/lifestyle risk factors for breast cancer. Similar comparisons were conducted with subjects from three case-control studies: breast cancer cases (n = 1145) and unaffected controls (n = …

Interruptions Of Antiretroviral Therapy In Children And Adolescents With Hiv Infection In Clinical Practice: A Retrospective Cohort Study In The Usa., Natella Rakhmanina, Kam S Lam, Jaclyn Hern, Heather A. Young, Alex Walters, Amanda D. Castel

Epidemiology Faculty Publications

INTRODUCTION: Changes in combination antiretroviral therapy (cART) throughout childhood challenge the continuity of paediatric HIV treatment. This study aimed to evaluate the prevalence of treatment interruption (TI), including lamivudine (3TC) monotherapy, and the relationship of TI to virologic and immunologic parameters in HIV-infected paediatric patients.

METHODS: Nested within a prospective observational study of a city-wide cohort of HIV-infected persons in the District of Columbia, this sub-study collected retrospective data on antiretroviral therapy, enrolment (endpoint) and historic (lifelong) CD4 counts and HIV RNA viral load (VL) of the paediatric cohort. TI was defined as interruption of cART ≥4 consecutive weeks. Data …