Biostatistics Commons^™

Improving The Quality And Design Of Retrospective Clinical Outcome Studies That Utilize Electronic Health Records, Oliwier Dziadkowiec, Jeffery Durbin, Vignesh Jayaraman Muralidharan, Megan Novak, Brendon Cornett

HCA Healthcare Journal of Medicine

Electronic health records (EHRs) are an excellent source for secondary data analysis. Studies based on EHR-derived data, if designed properly, can answer previously unanswerable clinical research questions. In this paper we will highlight the benefits of large retrospective studies from secondary sources such as EHRs, examine retrospective cohort and case-control study design challenges, as well as methodological and statistical adjustment that can be made to overcome some of the inherent design limitations, in order to increase the generalizability, validity and reliability of the results obtained from these studies.

Sensitivity Analysis For Incomplete Data And Causal Inference, Heng Chen

Statistical Science Theses and Dissertations

In this dissertation, we explore sensitivity analyses under three different types of incomplete data problems, including missing outcomes, missing outcomes and missing predictors, potential outcomes in \emph{Rubin causal model (RCM)}. The first sensitivity analysis is conducted for the \emph{missing completely at random (MCAR)} assumption in frequentist inference; the second one is conducted for the \emph{missing at random (MAR)} assumption in likelihood inference; the third one is conducted for one novel assumption, the ``sixth assumption'' proposed for the robustness of instrumental variable estimand in causal inference.

Novel Inference Methods For Generalized Linear Models Using Shrinkage Priors And Data Augmentation., Arinjita Bhattacharyya

Electronic Theses and Dissertations

Generalized linear models have broad applications in biostatistics and sociology. In a regression setup, the main target is to find a relevant set of predictors out of a large collection of covariates. Sparsity is the assumption that only a few of these covariates in a regression setup have a meaningful correlation with an outcome variate of interest. Sparsity is incorporated by regularizing the irrelevant slopes towards zero without changing the relevant predictors and keeping the resulting inferences intact. Frequentist variable selection and sparsity are addressed by popular techniques like Lasso, Elastic Net. Bayesian penalized regression can tackle the curse of …

Introduction To Research Statistical Analysis: An Overview Of The Basics, Christian Vandever

HCA Healthcare Journal of Medicine

This article covers many statistical ideas essential to research statistical analysis. Sample size is explained through the concepts of statistical significance level and power. Variable types and definitions are included to clarify necessities for how the analysis will be interpreted. Categorical and quantitative variable types are defined, as well as response and predictor variables. Statistical tests described include t-tests, ANOVA and chi-square tests. Multiple regression is also explored for both logistic and linear regression. Finally, the most common statistics produced by these methods are explored.

Shrinkage Priors For Isotonic Probability Vectors And Binary Data Modeling, Philip S. Boonstra, Daniel R. Owen, Jian Kang

The University of Michigan Department of Biostatistics Working Paper Series

This paper outlines a new class of shrinkage priors for Bayesian isotonic regression modeling a binary outcome against a predictor, where the probability of the outcome is assumed to be monotonically non-decreasing with the predictor. The predictor is categorized into a large number of groups, and the set of differences between outcome probabilities in consecutive categories is equipped with a multivariate prior having support over the set of simplexes. The Dirichlet distribution, which can be derived from a normalized cumulative sum of gamma-distributed random variables, is a natural choice of prior, but using mathematical and simulation-based arguments, we show that …

Nonparametric Misclassification Simulation And Extrapolation Method And Its Application, Congjian Liu

College of Graduate Studies: Theses & Dissertations

The misclassification simulation extrapolation (MC-SIMEX) method proposed by Küchenho et al. is a general method of handling categorical data with measurement error. It consists of two steps, the simulation and extrapolation steps. In the simulation step, it simulates observations with varying degrees of measurement error. Then parameter estimators for varying degrees of measurement error are obtained based on these observations. In the extrapolation step, it uses a parametric extrapolation function to obtain the parameter estimators for data with no measurement error. However, as shown in many studies, the parameter estimators are still biased as a result of the parametric extrapolation …

Multiple Imputation Using Influential Exponential Tilting In Case Of Non-Ignorable Missing Data, Kavita Gohil

College of Graduate Studies: Theses & Dissertations

Modern research strategies rely predominantly on three steps, data collection, data analysis, and inference. In research, if the data is not collected as designed, researchers may face challenges of having incomplete data, especially when it is non-ignorable. These situations affect the subsequent steps of evaluation and make them difficult to perform. Inference with incomplete data is a challenging task in data analysis and clinical trials when missing data related to the condition under the study. Moreover, results obtained from incomplete data are prone to biases. Parameter estimation with non-ignorable missing data is even more challenging to handle and extract useful …

Zero-Inflated Longitudinal Mixture Model For Stochastic Radiographic Lung Compositional Change Following Radiotherapy Of Lung Cancer, Viviana A. Rodríguez Romero

Theses and Dissertations

Compositional data (CD) is mostly analyzed as relative data, using ratios of components, and log-ratio transformations to be able to use known multivariable statistical methods. Therefore, CD where some components equal zero represent a problem. Furthermore, when the data is measured longitudinally, observations are spatially related and appear to come from a mixture population, the analysis becomes highly complex. For this matter, a two-part model was proposed to deal with structural zeros in longitudinal CD using a mixed-effects model. Furthermore, the model has been extended to the case where the non-zero components of the vector might a two component mixture …

Semiparametric And Nonparametric Methods For Comparing Biomarker Levels Between Groups, Yuntong Li

Theses and Dissertations--Statistics

Comparing the distribution of biomarker measurements between two groups under either an unpaired or paired design is a common goal in many biomarker studies. However, analyzing biomarker data is sometimes challenging because the data may not be normally distributed and contain a large fraction of zero values or missing values. Although several statistical methods have been proposed, they either require data normality assumption, or are inefficient. We proposed a novel two-part semiparametric method for data under an unpaired setting and a nonparametric method for data under a paired setting. The semiparametric method considers a two-part model, a logistic regression for …

Estimation Of The Treatment Effect With Bayesian Adjustment For Covariates, Li Xu

Theses and Dissertations--Statistics

The Bayesian adjustment for confounding (BAC) is a Bayesian model averaging method to select and adjust for confounding factors when evaluating the average causal effect of an exposure on a certain outcome. We extend the BAC method to time-to-event outcomes. Specifically, the posterior distribution of the exposure effect on a time-to-event outcome is calculated as a weighted average of posterior distributions from a number of candidate proportional hazards models, weighing each model by its ability to adjust for confounding factors. The Bayesian Information Criterion based on the partial likelihood is used to compare different models and approximate the Bayes factor. …

Enhancing Models And Measurements Of Traffic-Related Air Pollutants For Health Studies Using Dispersion Modeling And Bayesian Data Fusion, Stuart A. Batterman, Veronica J. Berrocal, Chad Milando, Owais Gilani, Saravanan Arunachalam, K. Max Zhang

Faculty Journal Articles

Research Report 202 describes a study led by Dr. Stuart Batterman at the University of Michigan, Ann Arbor and colleagues. The investigators evaluated the ability to predict traffic-related air pollution using a variety of methods and models, including a line source air pollution dispersion model and sophisticated spatiotemporal Bayesian data fusion methods. Exposure assessment for traffic-related air pollution is challenging because the pollutants are a complex mixture and vary greatly over space and time. Because extensive direct monitoring is difficult and expensive, a number of modeling approaches have been developed, but each model has its own limitations and errors.

Dr. …

Generalization Of Kullback-Leibler Divergence For Multi-Stage Diseases: Application To Diagnostic Test Accuracy And Optimal Cut-Points Selection Criterion, Chen Mo

College of Graduate Studies: Theses & Dissertations

The Kullback-Leibler divergence (KL), which captures the disparity between two distributions, has been considered as a measure for determining the diagnostic performance of an ordinal diagnostic test. This study applies KL and further generalizes it to comprehensively measure the diagnostic accuracy test for multi-stage (K > 2) diseases, named generalized total Kullback-Leibler divergence (GTKL). Also, GTKL is proposed as an optimal cut-points selection criterion for discriminating subjects among different disease stages. Moreover, the study investigates a variety of applications of GTKL on measuring the rule-in/out potentials in the single-stage and multi-stage levels. Intensive simulation studies are conducted to compare the performance …

Accounting For The Uncertainty Due To Chemicals Below The Detection Limit In Mixture Analysis, Paul M. Hargarten

Theses and Dissertations

Humans are exposed to multiple chemicals every day. Epidemiological studies have shown that chemical mixtures are associated with cancers, allergies, neurodevelopmental disorders, and other adverse health effects. To assess these associations, investigators are increasingly using chemical mixture approaches like weighted quantile sum (WQS) regression. In these studies, the research objectives are to determine whether a mixture of correlated chemicals is associated with an adverse health outcome and to identify the important chemicals. However, as experimental equipment measures each exposure to a chemical-specific detection limit, the exposures are unknown between zero and the detection limit. Indeed, the number of exposures below …

Distribution Of Human Exposure To Ozone During Commuting Hours In Connecticut Using The Cellular Device Network, Owais Gilani, Simon Urbanek, Michael J. Kane

Faculty Journal Articles

Epidemiologic studies have established associations between various air pollutants and adverse health outcomes for adults and children. Due to high costs of monitoring air pollutant concentrations for subjects enrolled in a study, statisticians predict exposure concentrations from spatial models that are developed using concentrations monitored at a few sites. In the absence of detailed information on when and where subjects move during the study window, researchers typically assume that the subjects spend their entire day at home, school, or work. This assumption can potentially lead to large exposure assignment bias. In this study, we aim to determine the distribution of …

Generalized Matrix Decomposition Regression: Estimation And Inference For Two-Way Structured Data, Yue Wang, Ali Shojaie, Tim Randolph, Jing Ma

UW Biostatistics Working Paper Series

Analysis of two-way structured data, i.e., data with structures among both variables and samples, is becoming increasingly common in ecology, biology and neuro-science. Classical dimension-reduction tools, such as the singular value decomposition (SVD), may perform poorly for two-way structured data. The generalized matrix decomposition (GMD, Allen et al., 2014) extends the SVD to two-way structured data and thus constructs singular vectors that account for both structures. While the GMD is a useful dimension-reduction tool for exploratory analysis of two-way structured data, it is unsupervised and cannot be used to assess the association between such data and an outcome of interest. …

Inference Of Heterogeneity In Meta-Analysis Of Rare Binary Events And Rss-Structured Cluster Randomized Studies, Chiyu Zhang

Statistical Science Theses and Dissertations

This dissertation contains two topics: (1) A Comparative Study of Statistical Methods for Quantifying and Testing Between-study Heterogeneity in Meta-analysis with Focus on Rare Binary Events; (2) Estimation of Variances in Cluster Randomized Designs Using Ranked Set Sampling.

Meta-analysis, the statistical procedure for combining results from multiple studies, has been widely used in medical research to evaluate intervention efficacy and safety. In many practical situations, the variation of treatment effects among the collected studies, often measured by the heterogeneity parameter, may exist and can greatly affect the inference about effect sizes. Comparative studies have been done for only one or …

Statistical Inference For Networks Of High-Dimensional Point Processes, Xu Wang, Mladen Kolar, Ali Shojaie

UW Biostatistics Working Paper Series

Fueled in part by recent applications in neuroscience, high-dimensional Hawkes process have become a popular tool for modeling the network of interactions among multivariate point process data. While evaluating the uncertainty of the network estimates is critical in scientific applications, existing methodological and theoretical work have only focused on estimation. To bridge this gap, this paper proposes a high-dimensional statistical inference procedure with theoretical guarantees for multivariate Hawkes process. Key to this inference procedure is a new concentration inequality on the first- and second-order statistics for integrated stochastic processes, which summarizes the entire history of the process. We apply this …

Unified Methods For Feature Selection In Large-Scale Genomic Studies With Censored Survival Outcomes, Lauren Spirko-Burns, Karthik Devarajan

COBRA Preprint Series

One of the major goals in large-scale genomic studies is to identify genes with a prognostic impact on time-to-event outcomes which provide insight into the disease's process. With rapid developments in high-throughput genomic technologies in the past two decades, the scientific community is able to monitor the expression levels of tens of thousands of genes and proteins resulting in enormous data sets where the number of genomic features is far greater than the number of subjects. Methods based on univariate Cox regression are often used to select genomic features related to survival outcome; however, the Cox model assumes proportional hazards …

A Novel Pathway-Based Distance Score Enhances Assessment Of Disease Heterogeneity In Gene Expression, Yunqing Liu, Xiting Yan

Yale Day of Data

Distance-based unsupervised clustering of gene expression data is commonly used to identify heterogeneity in biologic samples. However, high noise levels in gene expression data and the relatively high correlation between genes are often encountered, so traditional distances such as Euclidean distance may not be effective at discriminating the biological differences between samples. In this study, we developed a novel computational method to assess the biological differences based on pathways by assuming that ontologically defined biological pathways in biologically similar samples have similar behavior. Application of this distance score results in more accurate, robust, and biologically meaningful clustering results in both …

Controlling For Confounding Via Propensity Score Methods Can Result In Biased Estimation Of The Conditional Auc: A Simulation Study, Hadiza I. Galadima, Donna K. Mcclish

Community & Environmental Health Faculty Publications

In the medical literature, there has been an increased interest in evaluating association between exposure and outcomes using nonrandomized observational studies. However, because assignments to exposure are not random in observational studies, comparisons of outcomes between exposed and nonexposed subjects must account for the effect of confounders. Propensity score methods have been widely used to control for confounding, when estimating exposure effect. Previous studies have shown that conditioning on the propensity score results in biased estimation of conditional odds ratio and hazard ratio. However, research is lacking on the performance of propensity score methods for covariate adjustment when estimating the …

Variable Selection In Accelerated Failure Time (Aft) Frailty Models: An Application Of Penalized Quasi-Likelihood, Sarbesh R. Pandeya

College of Graduate Studies: Theses & Dissertations

Variable selection is one of the standard ways of selecting models in large scale datasets. It has applications in many fields of research study, especially in large multi-center clinical trials. One of the prominent methods in variable selection is the penalized likelihood, which is both consistent and efficient. However, the penalized selection is significantly challenging under the influence of random (frailty) covariates. It is even more complicated when there is involvement of censoring as it may not have a closed-form solution for the marginal log-likelihood. Therefore, we applied the penalized quasi-likelihood (PQL) approach that approximates the solution for such a …

Unsupervised Learning In Phylogenomic Analysis Over The Space Of Phylogenetic Trees, Qiwen Kang

Theses and Dissertations--Statistics

A phylogenetic tree is a tree to represent an evolutionary history between species or other entities. Phylogenomics is a new field intersecting phylogenetics and genomics and it is well-known that we need statistical learning methods to handle and analyze a large amount of data which can be generated relatively cheaply with new technologies. Based on the existing Markov models, we introduce a new method, CURatio, to identify outliers in a given gene data set. This method, intrinsically an unsupervised method, can find outliers from thousands or even more genes. This ability to analyze large amounts of genes (even with missing …

Statistical Methods For Joint Analysis Of Multiple Phenotypes And Their Applications For Phewas, Xueling Li

Dissertations, Master's Theses and Master's Reports

Genome-wide association studies (GWAS) have successfully detected tens of thousands of robust SNP-trait associations. Earlier researches have primarily focused on association studies of genetic variants and some well-defined functions or phenotypic traits. Emerging evidence suggests that pleiotropy, the phenomenon of one genetic variant affects multiple phenotypes, is widespread, especially in complex human diseases. Therefore, individual phenotype analyses may lose statistical power to identify the underlying genetic mechanism. Contrasting with single phenotype analyses, joint analysis of multiple phenotypes exploits the correlations between phenotypes and aggregates multiple weak marginal effects and is therefore likely to provide new insights into the functional consequences …

Statistical Modeling Of Influenza-Like-Illness In Montana Using Spatial And Temporal Methods, Benjamin A. Stark

Graduate Student Theses, Dissertations, & Professional Papers

Studying air pollution and public health has been a historically important question in science. It has long been hypothesized that severe air pollution conditions lead to negative implications in basic human health. Primarily, areas thats are prone to severe degrees of human pollution are the focus of such studies. Such research relating to less populated areas are scarce, and this scarcity raises the question of how such pollution dynamics (human-made and natural) influence human health in more rural areas.

The aim of this study is to explore this hole in research; in particular we explore possible links between air pollution …

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 …

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 …

Bayesian Analytical Approaches For Metabolomics : A Novel Method For Molecular Structure-Informed Metabolite Interaction Modeling, A Novel Diagnostic Model For Differentiating Myocardial Infarction Type, And Approaches For Compound Identification Given Mass Spectrometry Data., Patrick J. Trainor

Electronic Theses and Dissertations

Metabolomics, the study of small molecules in biological systems, has enjoyed great success in enabling researchers to examine disease-associated metabolic dysregulation and has been utilized for the discovery biomarkers of disease and phenotypic states. In spite of recent technological advances in the analytical platforms utilized in metabolomics and the proliferation of tools for the analysis of metabolomics data, significant challenges in metabolomics data analyses remain. In this dissertation, we present three of these challenges and Bayesian methodological solutions for each. In the first part we develop a new methodology to serve a basis for making higher order inferences in metabolomics, …

Generalized Spatiotemporal Modeling And Causal Inference For Assessing Treatment Effects For Multiple Groups For Ordinal Outcome., Soutik Ghosal

Electronic Theses and Dissertations

This dissertation consists of three projects and can be categorized in two broad research areas: generalized spatiotemporal modeling and causal inference based on observational data. In the first project, I introduce a Bayesian hierarchical mixed effect hurdle model with a nested random effect structure to model the count for primary care providers and understand their spatial and temporal variation. This study further enables us to identify the health professional shortage areas and the possible impacting factors. In the second project, I have unified popular parametric and nonparametric propensity score-based methods to assess the treatment effect of multiple groups for ordinal …

Developing Statistical Methods For Data From Platforms Measuring Gene Expression, Gaoxiang Jia

Statistical Science Theses and Dissertations

This research contains two topics: (1) PBNPA: a permutation-based non-parametric analysis of CRISPR screen data; (2) RCRnorm: an integrated system of random-coefficient hierarchical regression models for normalizing NanoString nCounter data from FFPE samples.

Clustered regularly-interspaced short palindromic repeats (CRISPR) screens are usually implemented in cultured cells to identify genes with critical functions. Although several methods have been developed or adapted to analyze CRISPR screening data, no single spe- cific algorithm has gained popularity. Thus, rigorous procedures are needed to overcome the shortcomings of existing algorithms. We developed a Permutation-Based Non-Parametric Analysis (PBNPA) algorithm, which computes p-values at the gene level …

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 …