Biostatistics Commons^™

Designing The Search Trial: Ph250b In Practice, Laura Balzer

Laura B. Balzer

No abstract provided.

Regression Trees For Longitudinal Data, Madan Gopal Kundu, Jaroslaw Harezlak

COBRA Preprint Series

Often when a longitudinal change is studied in a population of interest we find that changes over time are heterogeneous (in terms of time and/or covariates' effect) and a traditional linear mixed effect model [Laird and Ware, 1982] on the entire population assuming common parametric form for covariates and time may not be applicable to the entire population. This is usually the case in studies when there are many possible predictors influencing the response trajectory. For example, Raudenbush [2001] used depression as an example to argue that it is incorrect to assume that all the people in a given population …

Net Reclassification Index: A Misleading Measure Of Prediction Improvement, Margaret Sullivan Pepe, Holly Janes, Kathleen F. Kerr, Bruce M. Psaty

UW Biostatistics Working Paper Series

The evaluation of biomarkers to improve risk prediction is a common theme in modern research. Since its introduction in 2008, the net reclassification index (NRI) (Pencina et al. 2008, Pencina et al. 2011) has gained widespread use as a measure of prediction performance with over 1,200 citations as of June 30, 2013. The NRI is considered by some to be more sensitive to clinically important changes in risk than the traditional change in the AUC (Delta AUC) statistic (Hlatky et al. 2009). Recent statistical research has raised questions, however, about the validity of conclusions based on the NRI. (Hilden and …

Never Smokers -- Are They More Sensitive To The Respiratory Health Effects Of Ambient Air Pollution?, Zuhair Saleh Natto

Loma Linda University Electronic Theses, Dissertations & Projects

Background: Several studies show an association between ambient particulate matter (PM) and all-cause mortality. The Adventist Health and Smog 1 (AHSMOG-1) study (N=6,338) has previously found associations between ambient air pollution and incident chronic obstructive pulmonary disease (COPD) using the spatial interpolation method from the three nearest fixed monitoring stations to residence and workplace. However, few studies have assessed the risk of death among disease specific subgroups such as those with COPD.

Objectives: The aims of this study were 1) to assess the effect of chronic exposure to ambient air pollutants on risk of all-cause mortality among persons with COPD …

Analysis Of Subgroup Data Of Clinical Trials, Kao-Tai Tsai, Karl E. Peace

Biostatistics Faculty Publications

Large randomized controlled clinical trials are the gold standard to evaluate and compare the effects of treatments. It is common practice for investigators to explore and even attempt to compare treatments, beyond the first round of primary analyses, for various subsets of the study populations based on scientific or clinical interests to take advantage of the potentially rich information contained in the clinical database. Although subjects are randomized to treatment groups in clinical trials, this does not imply the same degree of randomization among sub-populations of the original trials. Therefore, comparisons of treatments in sub-populations may not produce fair and …

Associations Of Smoking Status And Serious Psychological Distress With Chronic Obstructive Pulmonary Disease, Ke-Sheng Wang, Liang Wang, Shimin Zheng, Long-Yang Wu

ETSU Faculty Works

Background: Chronic obstructive pulmonary disease (COPD) has been a major public health problem due to its high prevalence, morbidity, and mortality. Smoking is a major risk factor for COPD, while serious psychological distress (SPD) is prevalent among COPD patients. However, no study focusing on the effect of SPD on COPD has been so far conducted, while few studies have focused on the associations of SPD and behavioral factors with COPD by smoking status.

Objectives: This study aimed to examine the associations of SPD and behavioral factors (such as smoking and physical activity) with COPD.

Materials and Methods: Weighted logistic regression …

Normalization Techniques For Statistical Inference From Magnetic Resonance Imaging, Russell T. Shinohara, Elizabeth M. Sweeney, Jeff Goldsmith, Navid Shiee, Farrah J. Mateen, Peter A. Calabresi, Samson Jarso, Dzung L. Pham, Daniel S. Reich, Ciprian M. Crainiceanu

UPenn Biostatistics Working Papers

While computed tomography and other imaging techniques are measured in absolute units with physical meaning, magnetic resonance images are expressed in arbitrary units that are difficult to interpret and differ between study visits and subjects. Much work in the image processing literature on intensity normalization has focused on histogram matching and other histogram mapping techniques, with little emphasis on normalizing images to have biologically interpretable units. Furthermore, there are no formalized principles or goals for the crucial comparability of image intensities within and across subjects. To address this, we propose a set of criteria necessary for the normalization of images. …

Plasma S-Adenosylmethionine, Dnmt Polymorphisms, And Peripheral Blood Line-1 Methylation Among Healthy Chinese Adults In Singapore, Maki Inoue-Choi, Heather H. Nelson, Kim Robien, Erland Arning, Teodoro Bottiglieri, Woon-Puay Koh, Jian-Min Yuan

Epidemiology Faculty Publications

Background

Global hypomethylation of repetitive DNA sequences is believed to occur early in tumorigenesis. There is a great interest in identifying factors that contribute to global DNA hypomethylation and associated cancer risk. We tested the hypothesis that plasma S-adenosylmethionine (SAM) level alone or in combination with genetic variation in DNA methyltransferases (DNMT1, DNMT3A andDNMT3B) was associated with global DNA methylation extent at long interspersed nucleotide element-1 (LINE-1) sequences.

Methods

Plasma SAM level and LINE-1 DNA methylation index were measured using stored blood samples collected from 440 healthy Singaporean Chinese adults during 1994-1999. Genetic polymorphisms of …

Net Reclassification Indices For Evaluating Risk Prediction Instruments: A Critical Review, Kathleen F. Kerr, Zheyu Wang, Holly Janes, Robyn Mcclelland, Bruce M. Psaty, Margaret S. Pepe

UW Biostatistics Working Paper Series

Background Net Reclassification Indices (NRI) have recently become popular statistics for measuring the prediction increment of new biomarkers.

Methods In this review, we examine the various types of NRI statistics and their correct interpretations. We evaluate the advantages and disadvantages of the NRI approach. For pre-defined risk categories, we relate NRI to existing measures of the prediction increment. We also consider statistical methodology for constructing confidence intervals for NRI statistics and evaluate the merits of NRI-based hypothesis testing.

Conclusions Investigators using NRI statistics should report them separately for events (cases) and nonevents (controls). When there are two risk categories, the …

Bayesian Statistical Methods In Gene-Environment And Gene-Gene Interaction Studies, Changlu Liu

Dissertations & Theses (Open Access)

Complex diseases such as cancer result from multiple genetic changes and environmental exposures. Due to the rapid development of genotyping and sequencing technologies, we are now able to more accurately assess causal effects of many genetic and environmental factors. Genome-wide association studies have been able to localize many causal genetic variants predisposing to certain diseases. However, these studies only explain a small portion of variations in the heritability of diseases. More advanced statistical models are urgently needed to identify and characterize some additional genetic and environmental factors and their interactions, which will enable us to better understand the causes of …

Correlates Of Hiv Acquisition In A Cohort Of Black Men Who Have Sex With Men In The United States: Hiv Prevention Trials Network (Hptn) 061, Beryl A. Koblin, Kenneth H. Mayer, Susan H. Eshleman, Lei Wang, Sharon B. Mannheimer, Carlos Del Rio, Steve Shoptaw, Manya Magnus, Susan Buchbinder, Leo Wilton, Ting-Yuan Liu, Vanessa Cummings, Estelle Piwowar-Manning, Sheldon D. Fields, Sam Griffith, Vanessa Elharrar, Darrell Wheeler

Epidemiology Faculty Publications

Background

Black men who have sex with men (MSM) in the United States (US) are affected by HIV at disproportionate rates compared to MSM of other race/ethnicities. Current HIV incidence estimates in this group are needed to appropriately target prevention efforts.

Methods

From July 2009 to October 2010, Black MSM reporting unprotected anal intercourse with a man in the past six months were enrolled and followed for one year in six US cities for a feasibility study of a multi-component intervention to reduce HIV infection. HIV incidence based on HIV seroconversion was calculated as number of events/100 person-years. Multivariate proportional …

Testing The Relative Performance Of Data Adaptive Prediction Algorithms: A Generalized Test Of Conditional Risk Differences, Benjamin A. Goldstein, Eric Polley, Farren Briggs, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

In statistical medicine comparing the predictability or fit of two models can help to determine whether a set of prognostic variables contains additional information about medical outcomes, or whether one of two different model fits (perhaps based on different algorithms, or different set of variables) should be preferred for clinical use. Clinical medicine has tended to rely on comparisons of clinical metrics like C-statistics and more recently reclassification. Such metrics rely on the outcome being categorical and utilize a specific and often obscure loss function. In classical statistics one can use likelihood ratio tests and information based criterion if the …

Attributing Effects To Interactions, Tyler J. Vanderweele, Eric J. Tchetgen Tchetgen

Harvard University Biostatistics Working Paper Series

A framework is presented which allows an investigator to estimate the portion of the effect of one exposure that is attributable to an interaction with a second exposure. We show that when the two exposures are independent, the total effect of one exposure can be decomposed into a conditional effect of that exposure and a component due to interaction. The decomposition applies on difference or ratio scales. We discuss how the components can be estimated using standard regression models, and how these components can be used to evaluate the proportion of the total effect of the primary exposure attributable to …

The Estimation And Evaluation Of Optimal Thresholds For Two Sequential Testing Strategies, Amber R. Wilk

Theses and Dissertations

Many continuous medical tests often rely on a threshold for diagnosis. There are two sequential testing strategies of interest: Believe the Positive (BP) and Believe the Negative (BN). BP classifies a patient positive if either the first test is greater than a threshold θ1 or negative on the first test and greater than θ2 on the second test. BN classifies a patient positive if the first test is greater than a threshold θ3 and greater than θ4 on the second test. Threshold pairs θ = (θ1, θ2) or (θ3, θ4), depending on strategy, are defined as optimal if they maximized …

Sample Size Considerations In The Design Of Cluster Randomized Trials Of Combination Hiv Prevention, Rui Wang, Ravi Goyal, Quanhong Lei, M. Essex, Victor Degruttola

Harvard University Biostatistics Working Paper Series

No abstract provided.

Cardiovascular Outcome Trials In Type 2 Diabetes And The Sulphonylurea Controversy: Rationale For The Active-Comparator Carolina Trial, Julio Rosenstock, Nikolaus Marx, Steven E. Kahn, Bernard Zinman, John J. Kastelein, John M. Lachin, Erich Bluhmki, Sanjay Patel, Odd-Erik Johansen, Hans-Jurgen Woerle

Epidemiology Faculty Publications

Sulphonylureas (SUs) are widely used glucose-lowering agents in type 2 diabetes mellitus (T2DM) with apparent declining efficacy over time. Concerns have been raised from observational retrospective studies on the cardiovascular (CV) safety of SUs but there are few long-term data on CV outcomes from randomized controlled trials (RCTs) involving the use of this class of agents. Most of the observational studies and registry data are conflicting and vary with study population and methodology used for analyses. To address the SU controversy, we reviewed the recently published literature (until end of the year 2011) to evaluate the impact of SUs on …

Fast Covariance Estimation For High-Dimensional Functional Data, Luo Xiao, David Ruppert, Vadim Zipunnikov, Ciprian Crainiceanu

Johns Hopkins University, Dept. of Biostatistics Working Papers

For smoothing covariance functions, we propose two fast algorithms that scale linearly with the number of observations per function. Most available methods and software cannot smooth covariance matrices of dimension J x J with J>500; the recently introduced sandwich smoother is an exception, but it is not adapted to smooth covariance matrices of large dimensions such as J \ge 10,000. Covariance matrices of order J=10,000, and even J=100,000$ are becoming increasingly common, e.g., in 2- and 3-dimensional medical imaging and high-density wearable sensor data. We introduce two new algorithms that can handle very large covariance matrices: 1) FACE: a …

Soft Null Hypotheses: A Case Study Of Image Enhancement Detection In Brain Lesions, Haochang Shou, Russell T. Shinohara, Han Liu, Daniel Reich, Ciprian Crainiceanu

Johns Hopkins University, Dept. of Biostatistics Working Papers

This work is motivated by a study of a population of multiple sclerosis (MS) patients using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to identify active brain lesions. At each visit, a contrast agent is administered intravenously to a subject and a series of images is acquired to reveal the location and activity of MS lesions within the brain. Our goal is to identify and quantify lesion enhancement location at the subject level and lesion enhancement patterns at the population level. With this example, we aim to address the difficult problem of transforming a qualitative scientific null hypothesis, such as "this …

Phylogenetic Linkage Among Hiv-Infected Village Residents In Botswana: Estimation Of Clustering Rates In The Presence Of Missing Data, Nicole Bohme Carnegie, Rui Wang, Vladimir Novitsky, Victor G. Degruttola

Harvard University Biostatistics Working Paper Series

No abstract provided.

Statistical Inference For Data Adaptive Target Parameters, Mark J. Van Der Laan, Alan E. Hubbard, Sara Kherad Pajouh

U.C. Berkeley Division of Biostatistics Working Paper Series

Consider one observes n i.i.d. copies of a random variable with a probability distribution that is known to be an element of a particular statistical model. In order to define our statistical target we partition the sample in V equal size sub-samples, and use this partitioning to define V splits in estimation-sample (one of the V subsamples) and corresponding complementary parameter-generating sample that is used to generate a target parameter. For each of the V parameter-generating samples, we apply an algorithm that maps the sample in a target parameter mapping which represent the statistical target parameter generated by that parameter-generating …

When To Start Antiretroviral Therapy: The Need For An Evidence Base During Early Hiv Infection, James D. Lundgren, Abdel G. Babiker, Fred M. Gordin, Alvaro H. Borges, James D. Neaton

Epidemiology Faculty Publications

Background

Strategies for use of antiretroviral therapy (ART) have traditionally focused on providing treatment to persons who stand to benefit immediately from initiating the therapy. There is global consensus that any HIV+ person with CD4 counts less than 350 cells/μl should initiate ART. However, it remains controversial whether ART is indicated in asymptomatic HIV-infected persons with CD4 counts above 350 cells/μl, or whether it is more advisable to defer initiation until the CD4 count has dropped to 350 cells/μl. The question of when the best time is to initiate ART during early HIV infection has always been vigorously debated. The …

Restricted Likelihood Ratio Tests For Functional Effects In The Functional Linear Model, Bruce J. Swihart, Jeff Goldsmith, Ciprian M. Crainiceanu

Johns Hopkins University, Dept. of Biostatistics Working Papers

The goal of our article is to provide a transparent, robust, and computationally feasible statistical approach for testing in the context of scalar-on-function linear regression models. In particular, we are interested in testing for the necessity of functional effects against standard linear models. Our methods are motivated by and applied to a large longitudinal study involving diffusion tensor imaging of intracranial white matter tracts in a susceptible cohort. In the context of this study, we conduct hypothesis tests that are motivated by anatomical knowledge and which support recent findings regarding the relationship between cognitive impairment and white matter demyelination. R-code …

Augmentation Of Propensity Scores For Medical Records-Based Research, Mikel Aickin

COBRA Preprint Series

Therapeutic research based on electronic medical records suffers from the possibility of various kinds of confounding. Over the past 30 years, propensity scores have increasingly been used to try to reduce this possibility. In this article a gap is identified in the propensity score methodology, and it is proposed to augment traditional treatment-propensity scores with outcome-propensity scores, thereby removing all other aspects of common causes from the analysis of treatment effects.

A Versatile Test For Equality Of Two Survival Functions Based On Weighted Differences Of Kaplan-Meier Curves, Hajime Uno, Lu Tian, Brian Claggett, L. J. Wei

Harvard University Biostatistics Working Paper Series

With censored event time observations, the logrank test is the most popular tool for testing the equality of two underlying survival distributions. Although this test is asymptotically distribution-free, it may not be powerful when the proportional hazards assumption is violated. Various other novel testing procedures have been proposed, which generally are derived by assuming a class of specific alternative hypotheses with respect to the hazard functions. The test considered by Pepe and Fleming (1989) is based on a linear combination of weighted differences of two Kaplan-Meier curves over time and is a natural tool to assess the difference of two …

Subsemble: An Ensemble Method For Combining Subset-Specific Algorithm Fits, Stephanie Sapp, Mark J. Van Der Laan, John Canny

U.C. Berkeley Division of Biostatistics Working Paper Series

Ensemble methods using the same underlying algorithm trained on different subsets of observations have recently received increased attention as practical prediction tools for massive datasets. We propose Subsemble: a general subset ensemble prediction method, which can be used for small, moderate, or large datasets. Subsemble partitions the full dataset into subsets of observations, fits a specified underlying algorithm on each subset, and uses a clever form of V-fold cross-validation to output a prediction function that combines the subset-specific fits. We give an oracle result that provides a theoretical performance guarantee for Subsemble. Through simulations, we demonstrate that Subsemble can be …

Targeted Maximum Likelihood Estimation For Dynamic And Static Longitudinal Marginal Structural Working Models, Maya L. Petersen, Joshua Schwab, Susan Gruber, Nello Blaser, Michael Schomaker, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

This paper describes a targeted maximum likelihood estimator (TMLE) for the parameters of longitudinal static and dynamic marginal structural models. We consider a longitudinal data structure consisting of baseline covariates, time-dependent intervention nodes, intermediate time-dependent covariates, and a possibly time dependent outcome. The intervention nodes at each time point can include a binary treatment as well as a right-censoring indicator. Given a class of dynamic or static interventions, a marginal structural model is used to model the mean of the intervention specific counterfactual outcome as a function of the intervention, time point, and possibly a subset of baseline covariates. Because …

Varying Index Coefficient Models, Shujie Ma, Peter Xuekun Song

The University of Michigan Department of Biostatistics Working Paper Series

It has been a long history of utilizing interactions in regression analysis to investigate interactive effects of covariates on response variables. In this paper we aim to address two kinds of new challenges resulted from the inclusion of such high-order effects in the regression model for complex data. The first kind arises from a situation where interaction effects of individual covariates are weak but those of combined covariates are strong, and the other kind pertains to the presence of nonlinear interactive effects. Generalizing the single index coefficient regression model (Xia and Li, 1999), we propose a new class of semiparametric …

Balancing Score Adjusted Targeted Minimum Loss-Based Estimation, Samuel D. Lendle, Bruce Fireman, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

Adjusting for a balancing score is sufficient for bias reduction when estimating causal effects including the average treatment effect and effect among the treated. Estimators that adjust for the propensity score in a nonparametric way, such as matching on an estimate of the propensity score, can be consistent when the estimated propensity score is not consistent for the true propensity score but converges to some other balancing score. We call this property the balancing score property, and discuss a class of estimators that have this property. We introduce a targeted minimum loss-based estimator (TMLE) for a treatment specific mean with …

Optimal Tests Of Treatment Effects For The Overall Population And Two Subpopulations In Randomized Trials, Using Sparse Linear Programming, Michael Rosenblum, Han Liu, En-Hsu Yen

Johns Hopkins University, Dept. of Biostatistics Working Papers

We propose new, optimal methods for analyzing randomized trials, when it is suspected that treatment effects may differ in two predefined subpopulations. Such sub-populations could be defined by a biomarker or risk factor measured at baseline. The goal is to simultaneously learn which subpopulations benefit from an experimental treatment, while providing strong control of the familywise Type I error rate. We formalize this as a multiple testing problem and show it is computationally infeasible to solve using existing techniques. Our solution involves a novel approach, in which we first transform the original multiple testing problem into a large, sparse linear …

Estimating Effects On Rare Outcomes: Knowledge Is Power, Laura B. Balzer, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

Many of the secondary outcomes in observational studies and randomized trials are rare. Methods for estimating causal effects and associations with rare outcomes, however, are limited, and this represents a missed opportunity for investigation. In this article, we construct a new targeted minimum loss-based estimator (TMLE) for the effect of an exposure or treatment on a rare outcome. We focus on the causal risk difference and statistical models incorporating bounds on the conditional risk of the outcome, given the exposure and covariates. By construction, the proposed estimator constrains the predicted outcomes to respect this model knowledge. Theoretically, this bounding provides …