Biostatistics Commons^™

Novel Statistical Methods For Mediation Analysis With High-Dimensional Omics Mediators, Zhichao Xu

Dissertations and Theses (Open Access)

Mediation analysis is a widely used statistical method for examining how molecular traits, such as gene or protein expression, act as intermediaries linking an exposure to a health outcome. For example, it can help explain how smoking affects disease risk through molecular changes. The rapid progress in high-throughput omics profiling technologies and large-scale epidemiology consortia, such as the Trans-Omics for Precision Medicine (TOPMed) program from the National Heart, Lung and Blood Institute (NHLBI) and UK Biobank, now has resulted in an extensive accumulation of genomic data for biomedical research and analysis. At the same time, it poses significant methodological challenges, …

Using Causal Diagrams Within The Grading Of Recommendations, Assessment, Development And Evaluation Framework To Evaluate Confounding Adjustment In Observational Studies, Kevin Mcintyre, Karina N Tassiopoulos, Curtis Jeffrey, Saverio Stranges, Janet Martin

Epidemiology and Biostatistics Publications

BACKGROUND AND OBJECTIVES: The current Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system instructs appraisers to evaluate whether individual observational studies have sufficiently adjusted for confounding. However, it does not provide an explicit, transparent, or reproducible method for doing so. This article explores how implementing causal graphs into the GRADE framework can help appraisers and end-users of GRADE products to evaluate the adequacy of confounding control from observational studies.

METHODS: Using modern epidemiological theory, we propose a system for incorporating causal diagrams into the GRADE process to assess confounding control.

RESULTS: Integrating causal graphs into the GRADE framework enables …

Applications Of Causal Inference Methods For The Estimation Of Effects Of Bone Marrow Transplant And Prescription Drugs On Survival Of Aplastic Anemia Patients, Yesha M. Patel

Computational and Data Sciences (PhD) Dissertations

This dissertation provides an in-depth exploration into the treatment effectiveness for aplastic anemia using causal inference methods, structured around three pivotal research papers. Each paper contributes to a nuanced understanding of treatment impacts, specifically focusing on bone marrow transplantation (BMT) and prescription drugs, and the identification of optimal treatment strategies.

The first paper, "Causal Inference Analysis for Assessing the Effect of Bone Marrow Transplantation on the One-Year Survival of Adult and Pediatric Aplastic Anemia Patients," sets the foundation. It examines the short-term effectiveness of BMT in both adult and pediatric patients, providing crucial insights into how this treatment affects survival …

Bayesian Strategies For Propensity Score Estimation In Causal Inference., Uthpala I. Wanigasekara

Electronic Theses and Dissertations

Causal inference is a method used in various fields to draw causal conclusions based on data. It involves using assumptions, study designs, and estimation strategies to minimize the impact of confounding variables. Propensity scores are used to estimate outcome effects, through matching methods, stratification, weighting methods, and the Covariate Balancing Propensity Score method. However, they can be sensitive to estimation techniques and can lead to unstable findings. Researchers have proposed integrating weighing with regression adjustment in parametric models to improve causal inference validity. The first project focuses on Bayesian joint and two-stage methods for propensity score analysis. Propensity score modeling …

Statistical Approaches To Estimate Bidirectional And Time-Varying Causal Effects Using Mendelian Randomization, Jinhao Zou

Dissertations and Theses (Open Access)

Mendelian Randomization (MR) is an epidemiological framework using genetic variants as instrumental variables (IVs) to examine the causal effect of an exposure on an outcome. It is widely used to detect causal factors of diseases and provide insight into the biological pathway of diseases. Current methods under the MR framework are built to estimate the unidirectional causal effects of exposures on outcomes and neglect the potential bidirectional causal effects. However, a bidirectional causal effect creates a feedback loop that biases the casual inference in MR studies. Furthermore, current MR methods estimate the causal effect as a single value using cross-sectional …

Statistical Methods For Assessing Drug Interactions And Identifying Effect Modifiers Using Observational Data., Qian Xu

Electronic Theses and Dissertations

This dissertation consists of three projects related to causal inference based on observational data. In the first project, we propose a double robust to identify the effect modifiers and estimate optimal treatment. Observational studies differ from experimental studies in that assignment of subjects to treatments is not randomized but rather occurs due to natural mechanisms, which are usually hidden from the researchers. Many statistical methods to identify the treatment effect and select the optimal personalized treatment for experimental studies may not be suitable for observational studies any more. In this project, we propose a exible outcome model to select the …

Estimating Treatment Effect On Medical Cost And Examining Medical Cost Trajectory Using Splines And Change Point Techniques., Indranil Ghosh

Electronic Theses and Dissertations

In the world of growing medical needs, other than the clinical outcomes, the cost of healthcare is one of the important aspects to evaluate. The cost of treatment could act as a decisive factor on which one to choose from two equally likely effective treatment options. In literature, the most used quantity for the cost of treatment is cumulative lifetime cost since the diagnosis of a disease. While it provides a bird' eye view of the treatment cost, it fails to capture the underlying pattern of the treatment cost trajectory. We developed a marginal structural functional model (MSFM) using an …

Observational Studies In Group Testing And Potential Applications., Alexander Christopher Noll

Electronic Theses and Dissertations

The use of group testing to identify individuals with targeted outcomes in a population can greatly improve the efficiency, speed, and cost effectiveness of testing a population for an outcome, or at least for identifying the prevalence of an outcome in a population. The implementation of causal inference techniques can provide the basis for an observational study that would allow an investigator to gather estimates for treatment effectiveness if group testing was conducted on the population in a certain way. This thesis examines a simulation of the above outlined principles in order to demonstrate a potential application for determining treatment …

Causal Mediation Analysis For Difference-In-Difference Design And Panel Data, Pei-Hsuan Hsia, An-Shun Tai, Chu-Lan Michael Kao, Yu-Hsuan Lin, Sheng-Hsuan Lin

Harvard University Biostatistics Working Paper Series

Advantages of panel data, i.e., difference in difference (DID) design data, are a large sample size and easy availability. Therefore, panel data are widely used in epidemiology and in all social science fields. The literatures on causal inferences of panel data setting or DID design are growing, but no theory or mediation analysis method has been proposed for such settings. In this study, we propose a methodology for conducting causal mediation analysis in DID design and panel data setting. We provide formal counterfactual definitions for controlled direct effect and natural direct and indirect effect in panel data setting and DID …

Modified-Half-Normal Distribution And Different Methods To Estimate Average Treatment Effect., Jingchao Sun

Electronic Theses and Dissertations

This dissertation consists of three projects related to Modified-Half-Normal distribution and causal inference. In my first project, a new distribution called Modified-Half-Normal distribution was introduced. I explored a few of its distributional properties, the procedures for generating random samples based on Bayesian approaches, and the parameter estimation based on the method of moments. The second project deals with the problem of selection bias of average treatment effect (ATE) if we use the observational data. I combined the propensity score based inverse probability of treatment weighting (IPTW) method and the directed acyclic graph (DAG) to solve this problem. The third project …

Statistical Methods For Estimating And Testing Treatment Effect For Multiple Treatment Groups In Observational Studies., Xiaofang Yan

Electronic Theses and Dissertations

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Bayesian Approach On Short Time-Course Data Of Protein Phosphorylation, Casual Inference For Ordinal Outcome And Causal Analysis Of Dietary And Physical Activity In T2dm Using Nhanes Data., You Wu

Electronic Theses and Dissertations

This dissertation contains three different projects in proteomics and causal inferences. In the first project, I apply a Bayesian hierarchical model to assess the stability of phosphorylated proteins under short-time cold ischemia. This study provides inference on the stability of these phosphorylated proteins, which is valuable when using these proteins as biomarkers for a disease. in the second project, I perform a comparative study of different confounding-adjusted to estimate the treatment effect when the outcome variable is ordinal using observational data. The adjusted U-statistics method is compared with other methods such as ordinal logistic regression, propensity score based stratification and …

Tmle For Marginal Structural Models Based On An Instrument, Boriska Toth, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

We consider estimation of a causal effect of a possibly continuous treatment when treatment assignment is potentially subject to unmeasured confounding, but an instrumental variable is available. Our focus is on estimating heterogeneous treatment effects, so that the treatment effect can be a function of an arbitrary subset of the observed covariates. One setting where this framework is especially useful is with clinical outcomes. Allowing the causal dose-response curve to depend on a subset of the covariates, we define our parameter of interest to be the projection of the true dose-response curve onto a user-supplied working marginal structural model. We …

Propensity Score Methods : A Simulation And Case Study Involving Breast Cancer Patients., John Craycroft

Electronic Theses and Dissertations

Observational data presents unique challenges for analysis that are not encountered with experimental data resulting from carefully designed randomized controlled trials. Selection bias and unbalanced treatment assignments can obscure estimations of treatment effects, making the process of causal inference from observational data highly problematic. In 1983, Paul Rosenbaum and Donald Rubin formalized an approach for analyzing observational data that adjusts treatment effect estimates for the set of non-treatment variables that are measured at baseline. The propensity score is the conditional probability of assignment to a treatment group given the covariates. Using this score, one may balance the covariates across treatment …

A Weighted Instrumental Variable Estimator To Control For Instrument-Outcome Confounders, Douglas Lehmann, Yun Li, Rajiv Saran, Yi Li

The University of Michigan Department of Biostatistics Working Paper Series

No abstract provided.

Semi-Parametric Estimation And Inference For The Mean Outcome Of The Single Time-Point Intervention In A Causally Connected Population, Oleg Sofrygin, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

We study the framework for semi-parametric estimation and statistical inference for the sample average treatment-specific mean effects in observational settings where data are collected on a single network of connected units (e.g., in the presence of interference or spillover). Despite recent advances, many of the current statistical methods rely on estimation techniques that assume a particular parametric model for the outcome, even though some of the most important statistical assumptions required by these models are most likely violated in the observational network settings, often resulting in invalid and anti-conservative statistical inference. In this manuscript, we rely on the recent methodological …

A General Framework For Diagnosing Confounding Of Time-Varying And Other Joint Exposures, John W. Jackson

Harvard University Biostatistics Working Paper Series

No abstract provided.

Adaptive Pre-Specification In Randomized Trials With And Without Pair-Matching, Laura B. Balzer, Mark J. Van Der Laan, Maya L. Petersen

U.C. Berkeley Division of Biostatistics Working Paper Series

In randomized trials, adjustment for measured covariates during the analysis can reduce variance and increase power. To avoid misleading inference, the analysis plan must be pre-specified. However, it is unclear a priori which baseline covariates (if any) should be included in the analysis. Consider, for example, the Sustainable East Africa Research in Community Health (SEARCH) trial for HIV prevention and treatment. There are 16 matched pairs of communities and many potential adjustment variables, including region, HIV prevalence, male circumcision coverage and measures of community-level viral load. In this paper, we propose a rigorous procedure to data-adaptively select the adjustment set …

Applying Multiple Imputation For External Calibration To Propensty Score Analysis, Yenny Webb-Vargas, Kara E. Rudolph, D. Lenis, Peter Murakami, Elizabeth A. Stuart

Johns Hopkins University, Dept. of Biostatistics Working Papers

Although covariate measurement error is likely the norm rather than the exception, methods for handling covariate measurement error in propensity score methods have not been widely investigated. We consider a multiple imputation-based approach that uses an external calibration sample with information on the true and mismeasured covariates, Multiple Imputation for External Calibration (MI-EC), to correct for the measurement error, and investigate its performance using simulation studies. As expected, using the covariate measured with error leads to bias in the treatment effect estimate. In contrast, the MI-EC method can eliminate almost all the bias. We confirm that the outcome must be …

Super-Learning Of An Optimal Dynamic Treatment Rule, Alexander R. Luedtke, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

We consider the estimation of an optimal dynamic two time-point treatment rule defined as the rule that maximizes the mean outcome under the dynamic treatment, where the candidate rules are restricted to depend only on a user-supplied subset of the baseline and intermediate covariates. This estimation problem is addressed in a statistical model for the data distribution that is nonparametric, beyond possible knowledge about the treatment and censoring mechanisms. We propose data adaptive estimators of this optimal dynamic regime which are defined by sequential loss-based learning under both the blip function and weighted classification frameworks. Rather than \textit{a priori} selecting …

Targeted Learning Of The Mean Outcome Under An Optimal Dynamic Treatment Rule, Mark J. Van Der Laan, Alexander R. Luedtke

U.C. Berkeley Division of Biostatistics Working Paper Series

We consider estimation of and inference for the mean outcome under the optimal dynamic two time-point treatment rule defined as the rule that maximizes the mean outcome under the dynamic treatment, where the candidate rules are restricted to depend only on a user-supplied subset of the baseline and intermediate covariates. This estimation problem is addressed in a statistical model for the data distribution that is nonparametric beyond possible knowledge about the treatment and censoring mechanism. This contrasts from the current literature that relies on parametric assumptions. We establish that the mean of the counterfactual outcome under the optimal dynamic treatment …

A Unification Of Mediation And Interaction: A Four-Way Decomposition, Tyler J. Vanderweele

Harvard University Biostatistics Working Paper Series

It is shown that the overall effect of an exposure on an outcome, in the presence of a mediator with which the exposure may interact, can be decomposed into four components: (i) the effect of the exposure in the absence of the mediator, (ii) the interactive effect when the mediator is left to what it would be in the absence of exposure, (iii) a mediated interaction, and (iv) a pure mediated effect. These four components, respectively, correspond to the portion of the effect that is due to neither mediation nor interaction, to just interaction (but not mediation), to both mediation …

Estimating Population Treatment Effects From A Survey Sub-Sample, Kara E. Rudolph, Ivan Diaz, Michael Rosenblum, Elizabeth A. Stuart

Johns Hopkins University, Dept. of Biostatistics Working Papers

We consider the problem of estimating an average treatment effect for a target population from a survey sub-sample. Our motivating example is generalizing a treatment effect estimated in a sub-sample of the National Comorbidity Survey Replication Adolescent Supplement to the population of U.S. adolescents. To address this problem, we evaluate easy-to-implement methods that account for both non-random treatment assignment and a non-random two-stage selection mechanism. We compare the performance of a Horvitz-Thompson estimator using inverse probability weighting (IPW) and two double robust estimators in a variety of scenarios. We demonstrate that the two double robust estimators generally outperform IPW in …

A Unification Of Mediation And Interaction, Tyler J. Vanderweele

Harvard University Biostatistics Working Paper Series

We show that the overall effect of an exposure on an outcome, in the presence of a mediator with which the exposure may interact, can be decomposed into four components: (i) the effect of the exposure in the absence of the mediator, (ii) the interactive effect when the mediator is left to what is would be in the absence of exposure, (iii) a mediated interaction and (iv) a pure mediated effect. These four components respectively correspond to the portion of the effect that is due to neither mediation nor interaction, to just interaction (but not mediation), to both mediation and …

Targeted Learning Of An Optimal Dynamic Treatment, And Statistical Inference For Its Mean Outcome, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

Suppose we observe n independent and identically distributed observations of a time-dependent random variable consisting of baseline covariates, initial treatment and censoring indicator, intermediate covariates, subsequent treatment and censoring indicator, and a final outcome. For example, this could be data generated by a sequentially randomized controlled trial, where subjects are sequentially randomized to a first line and second line treatment, possibly assigned in response to an intermediate biomarker, and are subject to right-censoring. In this article we consider estimation of an optimal dynamic multiple time-point treatment rule defined as the rule that maximizes the mean outcome under the dynamic treatment, …

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 …

In Praise Of Simplicity Not Mathematistry! Ten Simple Powerful Ideas For The Statistical Scientist, Roderick J. Little

The University of Michigan Department of Biostatistics Working Paper Series

Ronald Fisher was by all accounts a first-rate mathematician, but he saw himself as a scientist, not a mathematician, and he railed against what George Box called (in his Fisher lecture) "mathematistry". Mathematics is the indispensable foundation for statistics, but our subject is constantly under assault by people who want to turn statistics into a branch of mathematics, making the subject as impenetrable to non-mathematicians as possible. Valuing simplicity, I describe ten simple and powerful ideas that have influenced my thinking about statistics, in my areas of research interest: missing data, causal inference, survey sampling, and statistical modeling in general. …

Causal Inference In Longitudinal Studies With History-Restricted Marginal Structural Models, Romain Neugebauer, Mark J. Van Der Laan, Ira B. Tager

U.C. Berkeley Division of Biostatistics Working Paper Series

Causal Inference based on Marginal Structural Models (MSMs) is particularly attractive to subject-matter investigators because MSM parameters provide explicit representations of causal effects. We introduce History-Restricted Marginal Structural Models (HRMSMs) for longitudinal data for the purpose of defining causal parameters which may often be better suited for Public Health research. This new class of MSMs allows investigators to analyze the causal effect of a treatment on an outcome based on a fixed, shorter and user-specified history of exposure compared to MSMs. By default, the latter represents the treatment causal effect of interest based on a treatment history defined by the …