Statistics and Probability Commons^™

Nonparametric And Semiparametric Group Sequential Methods For Comparing Accuracy Of Diagnostic Tests, Liansheng Tang, Scott S. Emerson, Xiao-Hua Zhou

UW Biostatistics Working Paper Series

Comparison of the accuracy of two diagnostic tests using the receiver operating characteristic (ROC) curves from two diagnostic tests has been typically conducted using fixed sample designs. On the other hand, the human experimentation inherent in a comparison of diagnostic modalities argues for periodic monitoring of the accruing data to address many issues related to the ethics and efficiency of the medical study. To date, very little research has been done in the use of sequential sampling plans for comparative ROC studies, even when these studies may use expensive and unsafe diagnostic procedures. In this paper, we propose a nonparametric …

A Bayesian Image Analysis Of The Change In Tumor/Brain Contrast Uptake Induced By Radiation Via Reversible Jump Markov Chain Monte Carlo, Xiaoxi Zhang, Tim Johnson, Roderick J.A. Little

The University of Michigan Department of Biostatistics Working Paper Series

This work is motivated by a pilot study on the change in tumor/brain contrast uptake induced by radiation via quantitative Magnetic Resonance Imaging. The results inform the optimal timing of administering chemotherapy in the context of radiotherapy. A noticeable feature of the data is spatial heterogeneity. The tumor is physiologically and pathologically distinct from surrounding healthy tissue. Also, the tumor itself is usually highly heterogeneous. We employ a Gaussian Hidden Markov Random Field model that respects the above features. The model introduces a latent layer of discrete labels from an Markov Random Field (MRF) governed by a spatial regularization parameter. …

A Note On Targeted Maximum Likelihood And Right Censored Data, Mark J. Van Der Laan, Daniel Rubin

U.C. Berkeley Division of Biostatistics Working Paper Series

A popular way to estimate an unknown parameter is with substitution, or evaluating the parameter at a likelihood based fit of the data generating density. In many cases, such estimators have substantial bias and can fail to converge at the parametric rate. van der Laan and Rubin (2006) introduced targeted maximum likelihood learning, removing these shackles from substitution estimators, which were made in full agreement with the locally efficient estimating equation procedures as presented in Robins and Rotnitzsky (1992) and van der Laan and Robins (2003). This note illustrates how targeted maximum likelihood can be applied in right censored data …

Detailed Version: Analyzing Direct Effects In Randomized Trials With Secondary Interventions: An Application To Hiv Prevention Trials, Michael A. Rosenblum, Nicholas P. Jewell, Mark J. Van Der Laan, Stephen Shiboski, Ariane Van Der Straten, Nancy Padian

U.C. Berkeley Division of Biostatistics Working Paper Series

This is the detailed technical report that accompanies the paper “Analyzing Direct Effects in Randomized Trials with Secondary Interventions: An Application to HIV Prevention Trials” (an unpublished, technical report version of which is available online at http://www.bepress.com/ucbbiostat/paper223).

The version here gives full details of the models for the time-dependent analysis, and presents further results in the data analysis section. The Methods for Improving Reproductive Health in Africa (MIRA) trial is a recently completed randomized trial that investigated the effect of diaphragm and lubricant gel use in reducing HIV infection among susceptible women. 5,045 women were randomly assigned to either the …

A Smoothing Approach To Data Masking, Yijie Zhous, Francesca Dominici, Thomas A. Louis

Johns Hopkins University, Dept. of Biostatistics Working Papers

Individual-level data are often not publicly available due to confidentiality. Instead, masked data are released for public use. However, analyses performed using masked data may produce invalid statistical results such as biased parameter estimates or incorrect standard errors. In this paper, we propose a data masking method using spatial smoothing, and we investigate the bias of parameter estimates resulting from analyses using the masked data for Generalized Linear Models (GLM). The method allows for varying both the form and the degree of masking by utilizing a smoothing weight function and a smoothness parameter. We show that data masking by using …

Optimal Propensity Score Stratification, Jessica A. Myers, Thomas A. Louis

Johns Hopkins University, Dept. of Biostatistics Working Papers

Stratifying on propensity score in observational studies of treatment is a common technique used to control for bias in treatment assignment; however, there have been few studies of the relative efficiency of the various ways of forming those strata. The standard method is to use the quintiles of propensity score to create subclasses, but this choice is not based on any measure of performance either observed or theoretical. In this paper, we investigate the optimal subclassification of propensity scores for estimating treatment effect with respect to mean squared error of the estimate. We consider the optimal formation of subclasses within …

Multiple Model Evaluation Absent The Gold Standard Via Model Combination, Edwin J. Iversen, Jr., Giovanni Parmigiani, Sining Chen

Johns Hopkins University, Dept. of Biostatistics Working Papers

We describe a method for evaluating an ensemble of predictive models given a sample of observations comprising the model predictions and the outcome event measured with error. Our formulation allows us to simultaneously estimate measurement error parameters, true outcome — aka the gold standard — and a relative weighting of the predictive scores. We describe conditions necessary to estimate the gold standard and for these estimates to be calibrated and detail how our approach is related to, but distinct from, standard model combination techniques. We apply our approach to data from a study to evaluate a collection of BRCA1/BRCA2 gene …

Analyzing Direct Effects In Randomized Trials With Secondary Interventions , Michael Rosenblum, Nicholas P. Jewell, Mark J. Van Der Laan, Stephen Shiboski, Ariane Van Der Straten, Nancy Padian

U.C. Berkeley Division of Biostatistics Working Paper Series

The Methods for Improving Reproductive Health in Africa (MIRA) trial is a recently completed randomized trial that investigated the effect of diaphragm and lubricant gel use in reducing HIV infection among susceptible women. 5,045 women were randomly assigned to either the active treatment arm or not. Additionally, all subjects in both arms received intensive condom counselling and provision, the "gold standard" HIV prevention barrier method. There was much lower reported condom use in the intervention arm than in the control arm, making it difficult to answer important public health questions based solely on the intention-to-treat analysis. We adapt an analysis …

Roc Surfaces In The Presence Of Verification Bias, Yueh-Yun Chi, Xiao-Hua (Andrew) Zhou

UW Biostatistics Working Paper Series

In diagnostic medicine, the Receiver Operating Characteristic (ROC) surface is one of the established tools for assessing the accuracy of a diagnostic test in discriminating three disease states, and the volume under the ROC surface has served as a summary index for diagnostic accuracy. In practice, the selection for definitive disease examination may be based on initial test measurements, and induces verification bias in the assessment. We propose here a nonparametric likelihood-based approach to construct the empirical ROC surface in the presence of differential verification, and to estimate the volume under the ROC surface. Estimators of the standard deviation are …

Comparing Trends In Cancer Rates Across Overlapping Regions, Yi Li, Ram C. Tiwari

Harvard University Biostatistics Working Paper Series

No abstract provided.

Effective Communication Of Standard Errors And Confidence Intervals, Thomas A. Louis, Scott L. Zeger

Johns Hopkins University, Dept. of Biostatistics Working Papers

We recommend a format for communicating an estimate with its standard error or confidence interval. The format reinforces that the associated variability is an inseparable component of the estimate and it substantially improves clarity in tabular displays.

Correcting Instrumental Variables Estimators For Systematic Measurement Error, Stijn Vansteelandt, Manoochehr Babanezhad, Els Goetghebeur

Harvard University Biostatistics Working Paper Series

No abstract provided.

Inference For Survival Curves With Informatively Coarsened Discrete Event-Time Data: Application To Alive, Michelle Shardell, Daniel O. Scharfstein, David Vlahov, Noya Galai

Johns Hopkins University, Dept. of Biostatistics Working Papers

In many prospective studies, including AIDS Link to the Intravenous Experience (ALIVE), researchers are interested in comparing event-time distributions (e.g.,for human immunodeficiency virus seroconversion) between a small number of groups (e.g., risk behavior categories). However, these comparisons are complicated by participants missing visits or attending visits off schedule and seroconverting during this absence. Such data are interval-censored, or more generally,coarsened. Most analysis procedures rely on the assumption of non-informative censoring, a special case of coarsening at random that may produce biased results if not valid. Our goal is to perform inference for estimated survival functions across a small number of …

Effectively Combining Independent 2 X 2 Tables For Valid Inferences In Meta Analysis With All Available Data But No Artificial Continuity Corrections For Studies With Zero Events And Its Application To The Analysis Of Rosiglitazone's Cardiovascular Disease Related Event Data, Lu Tian, Tianxi Cai, Nikita Piankov, Pierre-Yves Cremieux, L. J. Wei

Harvard University Biostatistics Working Paper Series

No abstract provided.

Biomarker Discovery Using Targeted Maximum Likelihood Estimation: Application To The Treatment Of Antiretroviral Resistant Hiv Infection, Oliver Bembom, Maya L. Petersen , Soo-Yon Rhee , W. Jeffrey Fessel , Sandra E. Sinisi, Robert W. Shafer, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

Researchers in clinical science and bioinformatics frequently aim to learn which of a set of candidate biomarkers is important in determining a given outcome, and to rank the contributions of the candidates accordingly. This article introduces a new approach to research questions of this type, based on targeted maximum likelihood estimation of variable importance measures.

The methodology is illustrated using an example drawn from the treatment of HIV infection. Specifically, given a list of candidate mutations in the protease enzyme of HIV, we aim to discover mutations that reduce clinical virologic response to antiretroviral regimens containing the protease inhibitor lopinavir. …

A Censored Multinomial Regression Model For Perinatal Mother To Child Transmission Of Hiv, Charlotte C. Gard, Elizabeth R. Brown

UW Biostatistics Working Paper Series

In studies designed to estimate rates of perinatal mother to child transmission of HIV, HIV assays are scheduled at multiple points in time. Still infection status for some infants at some time points is often unknown, particularly when interim analyses are conducted. Logistic regression and Cox proportional hazards regression are commonly used to estimate covariate-adjusted transmission rates, but their methods for handling missing data may be inadequate. Here, we propose using censored multinomial regression models to estimate cumulative and conditional rates of HIV transmission. Through simulation, we show that the proposed methods perform better than standard logistic models in terms …

An Example Of How To Write The Statistical Section Of A Bioequivalence Study Protocol For Fda Review, William F. Mccarthy

COBRA Preprint Series

This paper provides a detailed example of how one should write the statistical section of a bioequivalence study protocol for FDA review. Three forms of bioequivalence are covered: average bioequivalence (ABE), population bioequivalence (PBE) and individual bioequivalence (IBE). The method of analysis is based on Jones and Kenward (2003) and a modification of their SAS Macro is provided.

Empirical Efficiency Maximization, Daniel B. Rubin, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

It has long been recognized that covariate adjustment can increase precision, even when it is not strictly necessary. The phenomenon is particularly emphasized in clinical trials, whether using continuous, categorical, or censored time-to-event outcomes. Adjustment is often straightforward when a discrete covariate partitions the sample into a handful of strata, but becomes more involved when modern studies collect copious amounts of baseline information on each subject.

The dilemma helped motivate locally efficient estimation for coarsened data structures, as surveyed in the books of van der Laan and Robins (2003) and Tsiatis (2006). Here one fits a relatively small working model …

Variable Selection For Nonparametric Varying-Coefficient Models For Analysis Of Repeated Measurements, Lifeng Wang, Hongzhe Li

UPenn Biostatistics Working Papers

Nonparametric varying-coefficient models are commonly used for analysis of data measured repeatedly over time, including longitudinal and functional responses data. While many procedures have been developed for estimating the varying-coefficients, the problem of variable selection for such models has not been addressed. In this article, we present a regularized estimation procedure for variable selection for such nonparametric varying-coefficient models using basis function approximations and a group smoothly clipped absolute deviation penalty (gSCAD). This gSCAD procedure simultaneously selects significant variables with time-varying effects and estimates unknown smooth functions using basis function approximations. With appropriate selection of the tuning parameters, we have …

Adjustment To The Mcnemar’S Test For The Analysis Of Clustered Matched-Pair Data, William F. Mccarthy

COBRA Preprint Series

This paper presents how one can adjust the McNemar’s test for the analysis of clustered matched-pair data. A McNemar’s-like table for K clusters of matched-pair data is used.

Assessment Of Sample Size And Power For The Analysis Of Clustered Matched-Pair Data, William F. Mccarthy

COBRA Preprint Series

This paper outlines how one can determined the sample size or power of a study design that is based on clustered matched-pair data. Detailed examples are provided.

Lachenbruch’S Method For Determining The Sample Size Required For Testing Interactions: How It Compares To Nquery Advisor And O’Brien’S Sas Unifypow., William F. Mccarthy

COBRA Preprint Series

Lachenbruch (1988) proposed a simple method based on the use of orthogonal contrasts to determine the sample size or power for testing main effects and interactions, and uses the normal distribution instead of the non-central F distribution. This method can be used for factorial designs of various size. The example illustrated in this paper considers a 2 x 2 factorial design. This paper will determine both sample size and power of a particular study design with anticipated (assumed) means for each cell of the 2 x 2 factorial design. Lachenbruch’s method will be compared to nQuery Advisor 6.0 (2005) and …

The Existence Of Maximum Likelihood Estimates For The Binary Response Logistic Regression Model, William F. Mccarthy

COBRA Preprint Series

The existence of maximum likelihood estimates for the binary response logistic regression model depends on the configuration of the data points in your data set. There are three mutually exclusive and exhaustive categories for the configuration of data points in a data set: Complete Separation, Quasi-Complete Separation, and Overlap. For this paper, a binary response logistic regression model is considered. A 2 x 2 tabular presentation of the data set to be modeled is provided for each of the three categories mentioned above. In addition, the paper will present an example of a data set whose data points have a …

Regression Analysis Of A Disease Onset Distribution Using Diagnosis Data, Jessica G. Young, Nicholas P. Jewell, Steven J. Samuels

U.C. Berkeley Division of Biostatistics Working Paper Series

We consider methods for estimating the effect of a covariate on a disease onset distribution when the observed data structure consists of right-censored data on diagnosis times and current status data on onset times amongst individuals who have not yet been diagnosed. Dunson and Baird (2001) approached this problem using maximum likelihood, under the assumption that the ratio of the diagnosis and onset distributions is monotonic non-decreasing. As an alternative, we propose a two-step estimator, an extension of the approach of van der Laan, Jewell and Petersen (1997) in the single sample setting, that is computationally much simpler and requires …

The Assessment Of The Degree Of Concordance Between The Observed Values And The Predicted Values Of A Mixed-Effect Model Using “Method Of Comparison” Techniques, William F. Mccarthy, Nan Guo

COBRA Preprint Series

In this paper, we present a methodology for determining the degree of concordance between observed and model-based predicted values of a mixed-effect model. In particular, we will compare the degree to which observed and model-based predicted values agree by using ‘method of comparison’ techniques. We will also present the results of the concordance correlation coefficient (CCC).

Reporting And Interpretation In Genome-Wide Association Studies, Jon Wakefield

UW Biostatistics Working Paper Series

In the context of genome-wide association studies we critique a number of methods that have been suggested for flagging associations for further investigation. The p-value is by far the most commonly used measure, but requires careful calibration when the a priori probability of an association is small, and discards information by not considering the power associated with each test. The q-value is a frequentist method by which the false discovery rate (FDR) may be controlled. We advocate the use of the Bayes factor as a summary of the information in the data with respect to the comparison of the null …

Assessment Of A Cgh-Based Genetic Instability, David A. Engler, Yiping Shen, J F. Gusella, Rebecca A. Betensky

Harvard University Biostatistics Working Paper Series

No abstract provided.

Survival Analysis With Large Dimensional Covariates: An Application In Microarray Studies, David A. Engler, Yi Li

Harvard University Biostatistics Working Paper Series

Use of microarray technology often leads to high-dimensional and low- sample size data settings. Over the past several years, a variety of novel approaches have been proposed for variable selection in this context. However, only a small number of these have been adapted for time-to-event data where censoring is present. Among standard variable selection methods shown both to have good predictive accuracy and to be computationally efficient is the elastic net penalization approach. In this paper, adaptation of the elastic net approach is presented for variable selection both under the Cox proportional hazards model and under an accelerated failure time …

Super Learner, Mark J. Van Der Laan, Eric C. Polley, Alan E. Hubbard

U.C. Berkeley Division of Biostatistics Working Paper Series

Previous articles (van der Laan and Dudoit (2003); van der Laan et al. (2006); Sinisi et al. (2007)) advertised and theoretically validated the use of cross-validation to select among many candidate estimators to compute a so called super learner which outperforms any of the given candidate estimators. The theoretical basis was provided for this super learner based on oracle results for the cross-validation selector (e.g., van der Laan and Dudoit (2003); van der Laan et al. (2006)) and in Sinisi et al. (2007). In addition, these papers contained a practical demonstration of the adaptivity of this so called super learner …

Estimating Time-To-Event From Longitudinal Categorical Data Using Random Effects Markov Models: Application To Multiple Sclerosis Progression, Micha Mandel, Rebecca A. Betensky

Harvard University Biostatistics Working Paper Series

No abstract provided.