Biostatistics Commons^™

Analysis Of Covariance (Ancova) In Randomized Trials: More Precision, Less Conditional Bias, And Valid Confidence Intervals, Without Model Assumptions, Bingkai Wang, Elizabeth Ogburn, Michael Rosenblum

Johns Hopkins University, Dept. of Biostatistics Working Papers

Covariate adjustment" in the randomized trial context refers to an estimator of the average treatment effect that adjusts for chance imbalances between study arms in baseline variables (called “covariates"). The baseline variables could include, e.g., age, sex, disease severity, and biomarkers. According to two surveys of clinical trial reports, there is confusion about the statistical properties of covariate adjustment. We focus on the ANCOVA estimator, which involves fitting a linear model for the outcome given the treatment arm and baseline variables, and trials with equal probability of assignment to treatment and control. We prove the following new (to the best …

Cross-Sectional Hiv Incidence Estimation Accounting For Heterogeneity Across Communities, Yuejia Xu, Oliver B. Laeyendecker, Rui Wang

Harvard University Biostatistics Working Paper Series

No abstract provided.

Robust Inference For The Stepped Wedge Design, James P. Hughes, Patrick J. Heagerty, Fan Xia, Yuqi Ren

UW Biostatistics Working Paper Series

Based on a permutation argument, we derive a closed form expression for an estimate of the treatment effect, along with its standard error, in a stepped wedge design. We show that these estimates are robust to misspecification of both the mean and covariance structure of the underlying data-generating mechanism, thereby providing a robust approach to inference for the treatment effect in stepped wedge designs. We use simulations to evaluate the type I error and power of the proposed estimate and to compare the performance of the proposed estimate to the optimal estimate when the correct model specification is known. The …

Robust Estimation Of The Average Treatment Effect In Alzheimer's Disease Clinical Trials, Michael Rosenblum, Aidan Mcdermont, Elizabeth Colantuoni

Johns Hopkins University, Dept. of Biostatistics Working Papers

The primary analysis of Alzheimer's disease clinical trials often involves a mixed-model repeated measure (MMRM) approach. We consider another estimator of the average treatment effect, called targeted minimum loss based estimation (TMLE). This estimator is more robust to violations of assumptions about missing data than MMRM.

We compare TMLE versus MMRM by analyzing data from a completed Alzheimer's disease trial data set and by simulation studies. The simulations involved different missing data distributions, where loss to followup at a given visit could depend on baseline variables, treatment assignment, and the outcome measured at previous visits. The TMLE generally has improved …

Incorporating Historical Models With Adaptive Bayesian Updates, Philip S. Boonstra, Ryan P. Barbaro

The University of Michigan Department of Biostatistics Working Paper Series

This paper considers Bayesian approaches for incorporating information from a historical model into a current analysis when the historical model includes only a subset of covariates currently of interest. The statistical challenge is two-fold. First, the parameters in the nested historical model are not generally equal to their counterparts in the larger current model, neither in value nor interpretation. Second, because the historical information will not be equally informative for all parameters in the current analysis, additional regularization may be required beyond that provided by the historical information. We propose several novel extensions of the so-called power prior that adaptively …

A Spline-Assisted Semiparametric Approach To Nonparametric Measurement Error Models, Fei Jiang, Yanyuan Ma

COBRA Preprint Series

Nonparametric estimation of the probability density function of a random variable measured with error is considered to be a difficult problem, in the sense that depending on the measurement error prop- erty, the estimation rate can be as slow as the logarithm of the sample size. Likewise, nonparametric estimation of the regression function with errors in the covariate suffers the same possibly slow rate. The traditional methods for both problems are based on deconvolution, where the slow convergence rate is caused by the quick convergence to zero of the Fourier transform of the measurement error density, which, unfortunately, appears in …

Technical Considerations In The Use Of The E-Value, Tyler J. Vanderweele, Peng Ding, Maya Mathur

Harvard University Biostatistics Working Paper Series

The E-value is defined as the minimum strength of association on the risk ratio scale that an unmeasured confounder would have to have with both the exposure and the outcome, conditional on the measured covariates, to explain away the observed exposure-outcome association. We have elsewhere proposed that the reporting of E-values for estimates and for the limit of the confidence interval closest to the null become routine whenever causal effects are of interest. A number of questions have arisen about the use of E-value including questions concerning the interpretation of the relevant confounding association parameters, the nature of the transformation …

Optimized Adaptive Enrichment Designs For Multi-Arm Trials: Learning Which Subpopulations Benefit From Different Treatments, Jon Arni Steingrimsson, Joshua Betz, Tiachen Qian, Michael Rosenblum

Johns Hopkins University, Dept. of Biostatistics Working Papers

We consider the problem of designing a randomized trial for comparing two treatments versus a common control in two disjoint subpopulations. The subpopulations could be defined in terms of a biomarker or disease severity measured at baseline. The goal is to determine which treatments benefit which subpopulations. We develop a new class of adaptive enrichment designs tailored to solving this problem. Adaptive enrichment designs involve a preplanned rule for modifying enrollment based on accruing data in an ongoing trial. The proposed designs have preplanned rules for stopping accrual of treatment by subpopulation combinations, either for efficacy or futility. The motivation …

Phase Ii Adaptive Enrichment Design To Determine The Population To Enroll In Phase Iii Trials, By Selecting Thresholds For Baseline Disease Severity, Yu Du, Gary L. Rosner, Michael Rosenblum

Johns Hopkins University, Dept. of Biostatistics Working Papers

We propose and evaluate a two-stage, phase 2, adaptive clinical trial design. Its goal is to determine whether future phase 3 (confirmatory) trials should be conducted, and if so, which population should be enrolled. The population selected for phase 3 enrollment is defined in terms of a disease severity score measured at baseline. We optimize the phase 2 trial design and analysis in a decision theory framework. Our utility function represents a combination of the cost of conducting phase 3 trials and, if the phase 3 trials are successful, the improved health of the future population minus the cost of …

Power Calculation For Cross-Sectional Stepped Wedge Cluster-Randomized Trials With Variable Cluster Sizes, Linda J. Harrison, Tom Chen, Rui Wang

Harvard University Biostatistics Working Paper Series

Standard sample size calculation formulas for Stepped Wedge Cluster Randomized Trials (SW-CRTs) assume that cluster sizes are equal. When cluster sizes vary substantially, ignoring this variation may lead to an under-powered study. We investigate the relative efficiency of a SW-CRT with varying cluster sizes to equal cluster sizes, and derive variance estimators for the intervention effect that account for this variation under the assumption of a mixed effects model; a commonly-used approach for analyzing data from cluster randomized trials. When cluster sizes vary, the power of a SW-CRT depends on the order in which clusters receive the intervention, which is …

Using Multilevel Outcomes To Construct And Select Biomarker Combinations For Single-Level Prediction, Allison Meisner, Chirag R. Parikh, Kathleen F. Kerr

UW Biostatistics Working Paper Series

Biomarker studies may involve a multilevel outcome, such as no, mild, or severe disease. There is often interest in predicting one particular level of the outcome due to its clinical significance. The standard approach to constructing biomarker combinations in this context involves dichotomizing the outcome and using a binary logistic regression model. We assessed whether information can be usefully gained from instead using more sophisticated regression methods. Furthermore, it is often necessary to select among several candidate biomarker combinations. One strategy involves selecting a combination on the basis of its ability to predict the outcome level of interest. We propose …

Constructing A Confidence Interval For The Fraction Who Benefit From Treatment, Using Randomized Trial Data, Emily J. Huang, Ethan X. Fang, Daniel F. Hanley, Michael Rosenblum

Johns Hopkins University, Dept. of Biostatistics Working Papers

The fraction who benefit from treatment is the proportion of patients whose potential outcome under treatment is better than that under control. Inference on this parameter is challenging since it is only partially identifiable, even in our context of a randomized trial. We propose a new method for constructing a confidence interval for the fraction, when the outcome is ordinal or binary. Our confidence interval procedure is pointwise consistent. It does not require any assumptions about the joint distribution of the potential outcomes, although it has the flexibility to incorporate various user-defined assumptions. Unlike existing confidence interval methods for partially …

Comparison Of Adaptive Randomized Trial Designs For Time-To-Event Outcomes That Expand Versus Restrict Enrollment Criteria, To Test Non-Inferiority, Josh Betz, Jon Arni Steingrimsson, Tianchen Qian, Michael Rosenblum

Johns Hopkins University, Dept. of Biostatistics Working Papers

Adaptive enrichment designs involve preplanned rules for modifying patient enrollment criteria based on data accrued in an ongoing trial. These designs may be useful when it is suspected that a subpopulation, e.g., defined by a biomarker or risk score measured at baseline, may benefit more from treatment than the complementary subpopulation. We compare two types of such designs, for the case of two subpopulations that partition the overall population. The first type starts by enrolling the subpopulation where it is suspected the new treatment is most likely to work, and then may expand inclusion criteria if there is early evidence …

Nonparametric Variable Importance Assessment Using Machine Learning Techniques, Brian D. Williamson, Peter B. Gilbert, Noah Simon, Marco Carone

UW Biostatistics Working Paper Series

In a regression setting, it is often of interest to quantify the importance of various features in predicting the response. Commonly, the variable importance measure used is determined by the regression technique employed. For this reason, practitioners often only resort to one of a few regression techniques for which a variable importance measure is naturally defined. Unfortunately, these regression techniques are often sub-optimal for predicting response. Additionally, because the variable importance measures native to different regression techniques generally have a different interpretation, comparisons across techniques can be difficult. In this work, we study a novel variable importance measure that can …

Combining Biomarkers By Maximizing The True Positive Rate For A Fixed False Positive Rate, Allison Meisner, Marco Carone, Margaret Pepe, Kathleen F. Kerr

UW Biostatistics Working Paper Series

Biomarkers abound in many areas of clinical research, and often investigators are interested in combining them for diagnosis, prognosis and screening. In many applications, the true positive rate for a biomarker combination at a prespecified, clinically acceptable false positive rate is the most relevant measure of predictive capacity. We propose a distribution-free method for constructing biomarker combinations by maximizing the true positive rate while constraining the false positive rate. Theoretical results demonstrate good operating characteristics for the resulting combination. In simulations, the biomarker combination provided by our method demonstrated improved operating characteristics in a variety of scenarios when compared with …

Developing Biomarker Combinations In Multicenter Studies Via Direct Maximization And Penalization, Allison Meisner, Chirag R. Parikh, Kathleen F. Kerr

UW Biostatistics Working Paper Series

When biomarker studies involve patients at multiple centers and the goal is to develop biomarker combinations for diagnosis, prognosis, or screening, we consider evaluating the predictive capacity of a given combination with the center-adjusted AUC (aAUC), a summary of conditional performance. Rather than using a general method to construct the biomarker combination, such as logistic regression, we propose estimating the combination by directly maximizing the aAUC. Furthermore, it may be desirable to have a biomarker combination with similar predictive capacity across centers. To that end, we allow for penalization of the variability in center-specific performance. We demonstrate good asymptotic properties …

Biomarker Combinations For Diagnosis And Prognosis In Multicenter Studies: Principles And Methods, Allison Meisner, Chirag R. Parikh, Kathleen F. Kerr

UW Biostatistics Working Paper Series

Many investigators are interested in combining biomarkers to predict an outcome of interest or detect underlying disease. This endeavor is complicated by the fact that many biomarker studies involve data from multiple centers. Depending upon the relationship between center, the biomarkers, and the target of prediction, care must be taken when constructing and evaluating combinations of biomarkers. We introduce a taxonomy to describe the role of center and consider how a biomarker combination should be constructed and evaluated. We show that ignoring center, which is frequently done by clinical researchers, is often not appropriate. The limited statistical literature proposes using …

Optimal, Two Stage, Adaptive Enrichment Designs For Randomized Trials Using Sparse Linear Programming, Michael Rosenblum, Xingyuan Fang, Han Liu

Johns Hopkins University, Dept. of Biostatistics Working Papers

Adaptive enrichment designs involve preplanned rules for modifying enrollment criteria based on accruing data in a randomized trial. We focus on designs where the overall population is partitioned into two predefined subpopulations, e.g., based on a biomarker or risk score measured at baseline. The goal is to learn which populations benefit from an experimental treatment. Two critical components of adaptive enrichment designs are the decision rule for modifying enrollment, and the multiple testing procedure. We provide a general method for simultaneously optimizing these components for two stage, adaptive enrichment designs. We minimize the expected sample size under constraints on power …

Estimating Autoantibody Signatures To Detect Autoimmune Disease Patient Subsets, Zhenke Wu, Livia Casciola-Rosen, Ami A. Shah, Antony Rosen, Scott L. Zeger

Johns Hopkins University, Dept. of Biostatistics Working Papers

Autoimmune diseases are characterized by highly specific immune responses against molecules in self-tissues. Different autoimmune diseases are characterized by distinct immune responses, making autoantibodies useful for diagnosis and prediction. In many diseases, the targets of autoantibodies are incompletely defined. Although the technologies for autoantibody discovery have advanced dramatically over the past decade, each of these techniques generates hundreds of possibilities, which are onerous and expensive to validate. We set out to establish a method to greatly simplify autoantibody discovery, using a pre-filtering step to define subgroups with similar specificities based on migration of labeled, immunoprecipitated proteins on sodium dodecyl sulfate …

Evaluation Of Progress Towards The Unaids 90-90-90 Hiv Care Cascade: A Description Of Statistical Methods Used In An Interim Analysis Of The Intervention Communities In The Search Study, Laura Balzer, Joshua Schwab, Mark J. Van Der Laan, Maya L. Petersen

U.C. Berkeley Division of Biostatistics Working Paper Series

WHO guidelines call for universal antiretroviral treatment, and UNAIDS has set a global target to virally suppress most HIV-positive individuals. Accurate estimates of population-level coverage at each step of the HIV care cascade (testing, treatment, and viral suppression) are needed to assess the effectiveness of "test and treat" strategies implemented to achieve this goal. The data available to inform such estimates, however, are susceptible to informative missingness: the number of HIV-positive individuals in a population is unknown; individuals tested for HIV may not be representative of those whom a testing intervention fails to reach, and HIV-positive individuals with a viral …

It's All About Balance: Propensity Score Matching In The Context Of Complex Survey Data, David Lenis, Trang Q. ;Nguyen, Nian Dong, Elizabeth A. Stuart

Johns Hopkins University, Dept. of Biostatistics Working Papers

Many research studies aim to draw causal inferences using data from large, nationally representative survey samples, and many of these studies use propensity score matching to make those causal inferences as rigorous as possible given the non-experimental nature of the data. However, very few applied studies are careful about incorporating the survey design with the propensity score analysis, which may mean that the results don’t generate population inferences. This may be because few methodological studies examine how to best combine these methods. Furthermore, even fewer of the methodological studies incorporate different non-response mechanisms in their analysis. This study examines methods …

Estimating The Probability Of Clonal Relatedness Of Pairs Of Tumors In Cancer Patients, Audrey Mauguen, Venkatraman E. Seshan, Irina Ostrovnaya, Colin B. Begg

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

Next generation sequencing panels are being used increasingly in cancer research to study tumor evolution. A specific statistical challenge is to compare the mutational profiles in different tumors from a patient to determine the strength of evidence that the tumors are clonally related, i.e. derived from a single, founder clonal cell. The presence of identical mutations in each tumor provides evidence of clonal relatedness, although the strength of evidence from a match is related to how commonly the mutation is seen in the tumor type under investigation. This evidence must be weighed against the evidence in favor of independent tumors …

Predicting Future Years Of Life, Health, And Functional Ability: A Healthy Life Calculator For Older Adults, Paula Diehr, Michael Diehr, Alice M. Arnold, Laura Yee, Michelle C. Odden, Calvin H. Hirsch, Stephen Thielke, Bruce Psaty, W Craig Johnson, Jorge Kizer, Anne B. Newman

UW Biostatistics Working Paper Series

Introduction

Planning for the future would be easier if we knew how long we will live and, more importantly, how many years we will be healthy and able to enjoy it. There are few well-documented aids for predicting our future health. We attempted to meet this need for persons 65 years of age and older.

Methods

Data came from the Cardiovascular Health Study, a large longitudinal study of older adults that began in 1990. Years of life (YOL) were defined by measuring time to death. Years of healthy life (YHL) were defined by an annual question about self-rated health, and …

Quantifying The Totality Of Treatment Effect With Multiple Event-Time Observations In The Presence Of A Terminal Event From A Comparative Clinical Study, Brian Claggett, Lu Tian, Haoda Fu, Scott D. Solomon, L. J. Wei

Harvard University Biostatistics Working Paper Series

To evaluate the totality of one treatment's benefit/risk profile relative to an alternative treatment via a longitudinal comparative clinical study, the timing and occurrence of multiple clinical events are typically collected during the patient's followup. These multiple observations reflect the patient's disease progression/burden over time. The standard practice is to create a composite endpoint from the multiple outcomes, the timing of the occurrence of the first clinical event, to evaluate the treatment via the standard survival analysis techniques. By ignoring all events after the composite outcome, this type of assessment may not be ideal. Various parametric or semi-parametric procedures have …

Tuning Parameter Selection In Cox Proportional Hazards Model With A Diverging Number Of Parameters, Andy Ni, Jianwen Cai

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

Regularized variable selection is a powerful tool for identifying the true regression model from a large number of candidates by applying penalties to the objective functions. The penalty functions typically involve a tuning parameter that control the complexity of the selected model. The ability of the regularized variable selection methods to identify the true model critically depends on the correct choice of the tuning parameter. In this study we develop a consistent tuning parameter selection method for regularized Cox's proportional hazards model with a diverging number of parameters. The tuning parameter is selected by minimizing the generalized information criterion. We …

Variance Prior Specification For A Basket Trial Design Using Bayesian Hierarchical Modeling, Kristen Cunanan, Alexia Iasonos, Ronglai Shen, Mithat Gonen

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

Background: In the era of targeted therapies, clinical trials in oncology are rapidly evolving, wherein patients from multiple diseases are now enrolled and treated according to their genomic mutation(s). In such trials, known as basket trials, the different disease cohorts form the different baskets for inference. Several approaches have been proposed in the literature to efficiently use information from all baskets while simultaneously screening to find individual baskets where the drug works. Most proposed methods are developed in a Bayesian paradigm that requires specifying a prior distribution for a variance parameter, which controls the degree to which information is shared …

Optimized Variable Selection Via Repeated Data Splitting, Marinela Capanu, Colin B. Begg, Mithat Gonen

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

We introduce a new variable selection procedure that repeatedly splits the data into two sets, one for estimation and one for validation, to obtain an empirically optimized threshold which is then used to screen for variables to include in the final model. Simulation results show that the proposed variable selection technique enjoys superior performance compared to candidate methods, being amongst those with the lowest inclusion of noisy predictors while having the highest power to detect the correct model and being unaffected by correlations among the predictors. We illustrate the methods by applying them to a cohort of patients undergoing hepatectomy …

Mediation Analysis For Censored Survival Data Under An Accelerated Failure Time Model, Isabel Fulcher, Eric J. Tchetgen Tchetgen, Paige Williams

Harvard University Biostatistics Working Paper Series

Recent advances in causal mediation analysis have formalized conditions for estimating direct and indirect effects in various contexts. These approaches have been extended to a number of models for survival outcomes including accelerated failure time (AFT) models which are widely used in a broad range of health applications given their intuitive interpretation. In this setting, it has been suggested that under standard assumptions, the “difference” and “product” methods produce equivalent estimates of the indirect effect of exposure on the survival outcome. We formally show that these two methods may produce substantially different estimates in the presence of censoring or truncation, …

Studying The Optimal Scheduling For Controlling Prostate Cancer Under Intermittent Androgen Suppression, Sunil K. Dhar, Hans R. Chaudhry, Bruce G. Bukiet, Zhiming Ji, Nan Gao, Thomas W. Findley

Harvard University Biostatistics Working Paper Series

This retrospective study shows that the majority of patients’ correlations between PSA and Testosterone during the on-treatment period is at least 0.90. Model-based duration calculations to control PSA levels during off-treatment are provided. There are two pairs of models. In one pair, the Generalized Linear Model and Mixed Model are both used to analyze the variability of PSA at the individual patient level by using the variable “Patient ID” as a repeated measure. In the second pair, Patient ID is not used as a repeated measure but additional baseline variables are included to analyze the variability of PSA.

Improving Power In Group Sequential, Randomized Trials By Adjusting For Prognostic Baseline Variables And Short-Term Outcomes, Tianchen Qian, Michael Rosenblum, Huitong Qiu

Johns Hopkins University, Dept. of Biostatistics Working Papers

In group sequential designs, adjusting for baseline variables and short-term outcomes can lead to increased power and reduced sample size. We derive formulas for the precision gain from such variable adjustment using semiparametric estimators for the average treatment effect, and give new results on what conditions lead to substantial power gains and sample size reductions. The formulas reveal how the impact of prognostic variables on the precision gain is modified by the number of pipeline participants, analysis timing, enrollment rate, and treatment effect heterogeneity, when the semiparametric estimator uses correctly specified models. Given set prognostic value of baseline variables and …