Statistics and Probability Commons^™

Diagnosing And Responding To Violations In The Positivity Assumption, Maya L. Petersen, Kristin Porter, Susan Gruber, Yue Wang, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

The assumption of positivity or experimental treatment assignment requires that observed treatment levels vary within confounder strata. This article discusses the positivity assumption in the context of assessing model and parameter-specific identifiability of causal effects. Positivity violations occur when certain subgroups in a sample rarely or never receive some treatments of interest. The resulting sparsity in the data may increase bias with or without an increase in variance and can threaten valid inference. The parametric bootstrap is presented as a tool to assess the severity of such threats and its utility as a diagnostic is explored using simulated data. Several …

Longitudinal Penalized Functional Regression, Jeff Goldsmith, Ciprian M. Crainiceanu, Brian Caffo, Daniel Reich

Johns Hopkins University, Dept. of Biostatistics Working Papers

We propose a new regression model and inferential tools for the case when both the outcome and the functional exposures are observed at multiple visits. This data structure is new but increasingly present in applications where functions or images are recorded at multiple times. This raises new inferential challenges that cannot be addressed with current methods and software. Our proposed model generalizes the Generalized Linear Mixed Effects Model (GLMM) by adding functional predictors. Smoothness of the functional coefficients is ensured using roughness penalties estimated by Restricted Maximum Likelihood (REML) in a corresponding mixed effects model. This method is computationally feasible …

On Two-Stage Hypothesis Testing Procedures Via Asymptotically Independent Statistics, James Dai, Charles Kooperberg, Michael L. Leblanc, Ross Prentice

UW Biostatistics Working Paper Series

Kooperberg and LeBlanc (2008) proposed a two-stage testing procedure to screen for significant interactions in genome-wide association (GWA) studies by a soft threshold on marginal associations (MA), though its theoretical properties and generalization have not been elaborated. In this article, we discuss conditions that are required to achieve strong control of the Family-Wise Error Rate (FWER) by such procedures for low or high-dimensional hypothesis testing. We provide proof of asymptotic independence of marginal association statistics and interaction statistics in linear regression, logistic regression, and Cox proportional hazard models in a randomized clinical trial (RCT) with a rare event. In case-control …

Stratifying Subjects For Treatment Selection With Censored Event Time Data From A Comparative Study, Lihui Zhao, Tianxi Cai, Lu Tian, Hajime Uno, Scott D. Solomon, L. J. Wei

Harvard University Biostatistics Working Paper Series

No abstract provided.

Mixed Effect Poisson Log-Linear Models For Clinical And Epidemiological Sleep Hypnogram Data, Bruce J. Swihart, Brian S. Caffo Phd, Ciprian Crainiceanu Phd, Naresh M. Punjabi Phd, Md

Johns Hopkins University, Dept. of Biostatistics Working Papers

Bayesian Poisson log-linear multilevel models scalable to epidemiological studies are proposed to investigate population variability in sleep state transition rates. Hierarchical random effects are used to account for pairings of individuals and repeated measures within those individuals, as comparing diseased to non-diseased subjects while minimizing bias is of importance. Essentially, non-parametric piecewise constant hazards are estimated and smoothed, allowing for time-varying covariates and segment of the night comparisons. The Bayesian Poisson regression is justified through a re-derivation of a classical algebraic likelihood equivalence of Poisson regression with a log(time) offset and survival regression assuming exponentially distributed survival times. Such re-derivation …

On Two-Stage Hypothesis Testing Procedures Via Asymptotically Independent Statistics, James Y. Dai, Charles Kooperberg, Michael Leblanc, Ross L. Prentice

UW Biostatistics Working Paper Series

Kooperberg08 proposed a two-stage testing procedure to screen for significant interactions in genome-wide association (GWA) studies by a soft threshold on marginal associations (MA), though its theoretical properties and generalization have not been elaborated. In this article, we discuss conditions that are required to achieve strong control of the Family-Wise Error Rate (FWER) by such procedures for low or high-dimensional hypothesis testing. We provide proof of asymptotic independence of marginal association statistics and interaction statistics in linear regression, logistic regression, and Cox proportional hazard models in a randomized clinical trial (RCT) with a rare event. In case-control studies nested within …

A Perturbation Method For Inference On Regularized Regression Estimates, Jessica Minnier, Lu Tian, Tianxi Cai

Harvard University Biostatistics Working Paper Series

No abstract provided.

Principled Sure Independence Screening For Cox Models With Ultra-High-Dimensional Covariates, Sihai Dave Zhao, Yi Li

Harvard University Biostatistics Working Paper Series

No abstract provided.

A Unified Approach To Modeling Multivariate Binary Data Using Copulas Over Partitions, Bruce J. Swihart, Brian Caffo, Ciprian Crainiceanu

Johns Hopkins University, Dept. of Biostatistics Working Papers

Many seemingly disparate approaches for marginal modeling have been developed in recent years. We demonstrate that many current approaches for marginal modeling of correlated binary outcomes produce likelihoods that are equivalent to the proposed copula-based models herein. These general copula models of underlying latent threshold random variables yield likelihood based models for marginal fixed effects estimation and interpretation in the analysis of correlated binary data. Moreover, we propose a nomenclature and set of model relationships that substantially elucidates the complex area of marginalized models for binary data. A diverse collection of didactic mathematical and numerical examples are given to illustrate …

Improving Statistical Analysis Of Prospective Clinical Trials In Stem Cell Transplantation. An Inventory Of New Approaches In Survival Analysis, Aurelien Latouche

COBRA Preprint Series

The CLINT project is an European Union funded project, run as a specific support action, under the sixth framework programme. It is a 2 year project aimed at supporting the European Group for Blood and Marrow Transplantation (EBMT) to develop its infrastructure for the conduct of trans-European clinical trials in accordance with the EU Clinical Trials Directive, and to facilitate International prospective clinical trials in stem cell transplantation. The initial task is to create an inventory of the existing biostatistical literature on new approaches to survival analyses that are not currently widely utilised. The estimation of survival endpoints is introduced, …

Estimation Of Causal Effects Of Community Based Interventions, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

Suppose one assigns two interventions to a small number K of different populations or communities, and one measures covariates and outcomes on a random sample of independent individuals from each of the K populations. We investigate the problem of identification and estimation of the causal effect of the choice of intervention assigned at the community level, and, if the intervention is time-dependent, the causal effect of the changes in the intervention at time t, on the outcome. The challenge one is confronted with is that different populations have different environmental factors and that the intervention and environment are assigned to …

Modeling Menstrual Cycle Length And Variability At The Approach Of Menopause Using Bayesian Changepoint Models, Xiaobi Huang, Michael R. Elliott, Sioban D. Harlow

The University of Michigan Department of Biostatistics Working Paper Series

As women approach menopause, the patterns of their menstruation cycle lengths change. To study these changes, we need to jointly model both the mean and variability of the cycle length. The model incorporates separate mean and variance change points for each woman and a hierarchical model to link them together, along with regression components to include predictors of menopausal onset such as age at menarche and parity. Data are from TREMIN, an ongoing 70-year old longitudinal study that has obtained menstrual calendar data of women throughout their reproductive life course. An additional complexity arises from the fact that these calendars …

Optimizing Randomized Trial Designs To Distinguish Which Subpopulations Benefit From Treatment, Michael Rosenblum, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

It is a challenge to evaluate experimental treatments where it is suspected that the treatment effect may only be strong for certain subpopulations, such as those having a high initial severity of disease, or those having a particular gene variant. Standard randomized controlled trials can have low power in such situations. They also are not optimized to distinguish which subpopulations benefit from a treatment. With the goal of overcoming these limitations, we consider randomized trial designs in which the criteria for patient enrollment may be changed, in a preplanned manner, based on interim analyses. Since such designs allow data-dependent changes …

Multi-State Life Tables, Equilibrium Prevalence, And Baseline Selection Bias, Paula Diehr, David Yanez

UW Biostatistics Working Paper Series

Consider a 3-state system with one absorbing state, such as Healthy, Sick, and Dead. If the system satisfies the 1-step Markov conditions, the prevalence of the Healthy state will converge to a value that is independent of the initial distribution. This equilibrium prevalence and its variance are known under the assumption of time homogeneity, and provided reasonable estimates in the time non-homogeneous systems studied. Here, we derived the equilibrium prevalence for a system with more than three states. Under time homogeneity, the equilibrium prevalence distribution was shown to be an eigenvector of a partition of the matrix of transition probabilities. …

The Strength Of Statistical Evidence For Composite Hypotheses: Inference To The Best Explanation, David R. Bickel

COBRA Preprint Series

A general function to quantify the weight of evidence in a sample of data for one hypothesis over another is derived from the law of likelihood and from a statistical formalization of inference to the best explanation. For a fixed parameter of interest, the resulting weight of evidence that favors one composite hypothesis over another is the likelihood ratio using the parameter value consistent with each hypothesis that maximizes the likelihood function over the parameter of interest. Since the weight of evidence is generally only known up to a nuisance parameter, it is approximated by replacing the likelihood function with …

Model-Robust Regression And A Bayesian `Sandwich' Estimator, Adam A. Szpiro, Kenneth M. Rice, Thomas Lumley

UW Biostatistics Working Paper Series

The published version of this paper in Annals of Applied Statistics (Vol. 4, No. 4 (2010), 2099–2113) is available from the journal web site at http://dx.doi.org/10.1214/10-AOAS362.

We present a new Bayesian approach to model-robust linear regression that leads to uncertainty estimates with the same robustness properties as the Huber-White sandwich estimator. The sandwich estimator is known to provide asymptotically correct frequentist inference, even when standard modeling assumptions such as linearity and homoscedasticity in the data-generating mechanism are violated. Our derivation provides a compelling Bayesian justification for using this simple and popular tool, and it also clarifies what is being estimated …

The Use Of Propensity Scores To Assess The Generalizability Of Results From Randomized Trials, Elizabeth A. Stuart, Stephen R. Cole, Catherine P. Bradshaw, Philip J. Leaf

Johns Hopkins University, Dept. of Biostatistics Working Papers

Randomized trials remain the most accepted design for estimating the effects of interventions, but they do not necessarily answer a question of primary interest: Will the program be effective in a target population in which it may be implemented? In other words,are the results generalizable? There has been very little statistical research on how to assess the generalizability, or "external validity," of randomized trials. We propose the use of propensity-score-based metrics to quantify the similarity of the participants in a randomized trial and a target population. In this setting the propensity score model predicts participation in the randomized trial, given …

Powerful Snp Set Analysis For Case-Control Genome Wide Association Studies, Michael C. Wu, Peter Kraft, Michael P. Epstein, Deanne M. Taylor, Stephen J. Chanock, David J. Hunter, Xihong Lin

Harvard University Biostatistics Working Paper Series

No abstract provided.

Asymptotic Properties Of The Sequential Empirical Roc And Ppv Curves, Joseph S. Koopmeiners, Ziding Feng

UW Biostatistics Working Paper Series

The receiver operating characteristic (ROC) curve, the positive predictive value (PPV) curve and the negative predictive value (NPV) curve are three common measures of performance for a diagnostic biomarker. The independent increments covariance structure assumption is common in the group sequential study design literature. Showing that summary measures of the ROC, PPV and NPV curves have an independent increments covariance structure will provide the theoretical foundation for designing group sequential diagnostic biomarker studies. The ROC, PPV and NPV curves are often estimated empirically to avoid assumptions about the distributional form of the biomarkers. In this paper we derive asymptotic theory …

The Linkset Model For 2^N Contingency Tables, Mikel Aickin

COBRA Preprint Series

Abstract The linkset model is defined for parametrizing the general 2^n contingency table. The linkset parameters are designed to represent latent influences that promote the co-occurrences of binary events beyond that explained by chance. Linkages involving 2 through n binary variables are included in this parametrization. The intent of this process is to elucidate the patterns of linkage, no matter how complex they might be, rather than to fit simplifying models. The relationship between linkset parameters and the natural parameters for a 2n table are derived, and large sample inference methods are provided. Examples are given from medical diagnostics, survival …

Estimating Causal Effects In Trials Involving Multi-Treatment Arms Subject To Non-Compliance: A Bayesian Frame-Work, Qi Long, Roderick J. Little, Xihong Lin

Harvard University Biostatistics Working Paper Series

No abstract provided.

A Targeted Maximum Likelihood Estimator Of A Causal Effect On A Bounded Continuous Outcome, Susan Gruber, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

Targeted maximum likelihood estimation of a parameter of a data generating distribution, known to be an element of a semiparametric model, involves constructing a parametric model through an initial density estimator with parameter epsilon representing an amount of fluctuation of the initial density estimator, where the score of this fluctuation model at epsilon=0 equals the efficient influence curve/canonical gradient. The latter constraint can be satisfied by many parametric fluctuation models, since it represents only a local constraint of its behavior at zero fluctuation. However, it is very important that the fluctuations stay within the semiparametric model for the observed data …

Super Learner In Prediction, Eric C. Polley, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

Super learning is a general loss based learning method that has been proposed and analyzed theoretically in van der Laan et al. (2007). In this article we consider super learning for prediction. The super learner is a prediction method designed to find the optimal combination of a collection of prediction algorithms. The super learner algorithm finds the combination of algorithms minimizing the cross-validated risk. The super learner framework is built on the theory of cross-validation and allows for a general class of prediction algorithms to be considered for the ensemble. Due to the previously established oracle results for the cross-validation …

Assessing Noninferiority In A Three-Arm Trial Using The Bayesian Approach, Pulak Ghosh, Farouk S. Nathoo, Mithat Gonen, Ram C. Tiwari

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

Non-inferiority trials, which aim to demonstrate that a test product is not worse than a competitor by more than a pre-specified small amount, are of great importance to the pharmaceutical community. As a result, methodology for designing and analyzing such trials is required, and developing new methods for such analysis is an important area of statistical research. The three-arm clinical trial is usually recommended for non-inferiority trials by the Food and Drug Administration (FDA). The three-arm trial consists of a placebo, a reference, and an experimental treatment, and simultaneously tests the superiority of the reference over the placebo along with …

Nonparametric Regression With Missing Outcomes Using Weighted Kernel Estimating Equations, Lu Wang, Andrea Rotnitzky, Xihong Lin

Harvard University Biostatistics Working Paper Series

No abstract provided.

Nonparametric And Semiparametric Analysis Of Current Status Data Subject To Outcome Misclassification, Victor G. Sal Y Rosas, James P. Hughes

UW Biostatistics Working Paper Series

In this article, we present nonparametric and semiparametric methods to analyze current status data subject to outcome misclassification. Our methods use nonparametric maximum likelihood estimation (NPMLE) to estimate the distribution function of the failure time when sensitivity and specificity may vary among subgroups. A nonparametric test is proposed for the two sample hypothesis testing. In regression analysis, we apply the Cox proportional hazard model and likelihood ratio based confidence intervals for the regression coefficients are proposed. Our methods are motivated and demonstrated by data collected from an infectious disease study in Seattle, WA.

Utilizing The Integrated Difference Of Two Survival Functions To Quantify The Treatment Contrast For Designing, Monitoring And Analyzing A Comparative Clinical Study, Lihui Zhao, Lu Tian, Hajime Uno, Scott D. Solomon, Marc A. Pfeffer, J. S. Schindler, L. J. Wei

Harvard University Biostatistics Working Paper Series

No abstract provided.

Recovery Of The Baseline Incidence Density In Censored Time-To-Event Analysis, Mikel Aickin

COBRA Preprint Series

Abstract Time-to-event analyses are often concerned with the effects of explanatory factors on the underlying incidence density, but since there is no intrinsic interest in the form of the incidence density itself, a proportional hazards model is used. When part of the purpose of the analysis is to use actual cumulative incidence for simulation, or for providing informative visual displays of the results, an estimate of the baseline incidence density is required. The usual method for estimating the baseline hazards in Cox’s proportional hazards analysis yields values that are of little use, and furthermore no standard deviations of the estimates …

Efficient Design And Inference For Multi-Stage Randomized Trials Of Individualized Treatment Policies, Ree Dawson, Philip W. Lavori

COBRA Preprint Series

Increased clinical interest in individualized ‘adaptive’ treatment policies has shifted the methodological focus for their development from the analysis of naturalistically observed strategies to experimental evaluation of a pre-selected set of strategies via multi-stage designs. Because multi-stage studies often avoid the ‘curse of dimensionality’ inherent in uncontrolled studies, and hence the need to parametrically smooth trial data, it is not surprising in this context to find direct connections among different methodological approaches. We show by asymptotic and algebraic proof that the maximum likelihood (ML) and optimal semi-parametric estimators of the mean of a treatment policy and its standard error are …

Simple Examples Of Estimating Causal Effects Using Targeted Maximum Likelihood Estimation, Michael Rosenblum, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

We present a brief overview of targeted maximum likelihood for estimating the causal effect of a single time point treatment and of a two time point treatment. We focus on simple examples demonstrating how to apply the methodology developed in (van der Laan and Rubin, 2006; Moore and van der Laan, 2007; van der Laan, 2010a,b). We include R code for the single time point case.