Clinical Trials Commons^™

Efficacy Analysis In Clinical Trials: A Comprehensive Review Of Statistical And Machine Learning Approaches, Dhrubajyoti Ghosh, Samhita Pal

Faculty Articles

Efficacy testing is a cornerstone of clinical trials, ensuring that medical interventions achieve their intended therapeutic effects. Over the decades, a wide range of statistical methodologies have been developed to address the complexities of clinical trial data, including parametric, nonparametric, Bayesian, and machine learning approaches. Parametric methods, such as t-tests, ANOVA, and LMMs, have traditionally been the foundation of efficacy testing due to their efficiency under well-defined assumptions. Nonparametric techniques, including the Friedman test, Brunner-Munzel test, and modern extensions like nparLD, have emerged as robust alternatives, particularly for skewed, ordinal, or non-normal data. Bayesian methodologies have enabled the incorporation of …

Two-Stage Response-Adaptive Randomization Designs For Multi-Arm Trials With Normal Outcome, Tanjin Tamanna Happy

UNF Graduate Theses and Dissertations

This study focuses on improving how clinical trials compare new treatments with a standard treatment, when the response is quantitative (normally distributed). In a common two-stage design, several new treatments are first evaluated, and the best-performing one is selected if it appears better than the standard. In the second stage, this selected treatment is compared again with the standard using additional data to confirm its effectiveness. This approach is known to be efficient in terms of accuracy and sample size savings. We extend this design by introducing an adaptive method for assigning patients to treatments in the second stage. Instead …

Ridit-Based Adaptive Allocation In Two-Stage Clinical Trials With Binary Outcomes, Dewan Fahim

UNF Graduate Theses and Dissertations

This study explores better ways to assign patients to treatments in clinical trials with binary outcomes, such as success or failure. Adaptive methods are used to learn from early results and adjust treatment assignments during the trial, helping more patients receive better performing treatments while maintaining reliable conclusions. We focus on trials comparing multiple treatments using a two-stage design. In the first stage, several treatments are tested to identify the most promising one; in the second stage, that treatment is compared with a control. Unlike traditional equal assignment, we use adaptive allocation in the second stage to make better use …

Flexible Spatial Priors In Bayesian Neuroimaging: Gmrf, Nngp, And Deep Gmrf, Boyoung Hur

All Dissertations

Structural neuroimaging is essential for understanding neurological disorders such as Alzheimer’s disease, enabling accurate delineation of brain regions through image segmentation. Among various segmentation methods, multi-atlas-based approaches like label fusion have become leading techniques. In statistics, Bayesian hierarchical models for label fusion are increasingly favored for their ability to incorporate uncertainty and prior knowledge. Also, a key challenge in modeling neuroimaging data is spatial dependence among image voxels, making the choice of spatial prior critical—particularly in high-resolution settings where segmentation accuracy and computational efficiency are both essential.

This dissertation proposes fully Bayesian spatial hierarchical models that explore two flex- ible …

Evaluating Alpha Spending Functions Applied To Observational Time-To-Event Analysis, Moses Torgbenu

Electronic Theses and Dissertations

This thesis explores the theoretical foundation of the alpha spending approach and extends its application beyond the conventional setting of randomized controlled trials (RCTs) to observational studies with time to event analyses. In these less structured environments, key design parameters such as the total number of events are often unknown, posing challenges for the standard implementation of sequential analysis methods.

Through simulation studies, this research delivers several important contributions. First, it presents a modified approach that uses calendar time to define the timing of interim analyses while relying on event-based information to estimate the correlation among test statistics. This adjustment …

Innovative Methods For The Design And Analysis Of Phase Ii Clinical Trials, Feng Tian

Dissertations and Theses (Open Access)

Drug development has become increasingly time-consuming, costly, and risky in recent years. There is significant potential for improving clinical trial designs, particularly for phase II trials, which play a critical role in the drug development process. Innovative methods are especially necessary for addressing key challenges in phase II trials in terms of dose-ranging study, patient population selection, and decentralized clinical trials (DCTs). This dissertation presents a comprehensive set of methodologies that address these critical issues with three projects. The first project introduces a Bayesian adaptive dose-ranging design that integrates both efficacy and toxicity data to evaluate each dose comprehensively. The …

Dual-Criterion Dose Finding Designs For Phase I Clinical Trials, Yunlong Yang

Dissertations and Theses (Open Access)

The primary objective of Phase I oncology trials is to assess the safety and tolerability of novel therapeutics. Conventional dose escalation methods identify the maximum tolerated dose (MTD) based on dose-limiting toxicity (DLT). However, as cancer therapies have evolved from chemotherapy to targeted therapies, these traditional methods have become problematic. Many targeted therapies rarely produce DLT and are administered over multiple cycles, potentially resulting in the accumulation of lower-grade toxicities, which can lead to intolerance, such as dose reduction or interruption. To address this issue, we proposed dual-criterion designs that find the MTD based on both DLT and non-DLT-caused intolerance. …

Discounting Effect Size When Borrowing External Data In Clinical Studies, Zhuanzhuan Ma, Chul Ahn, Bin Wang, Xuefeng Li

Research Symposium

Background: When borrowing information from external data to augment a current trial, many available methods discount the sample size but retain the effect size from previous studies. Discounting the sample size is just one way to discount the prior information. It may not be appropriate if the underlying assumption of unbiased treatment effect does not hold, for example, when the treatment effect in the historical study is likely higher than the one expected in the current trial.

Methods: To tackle this potential issue, we study some methods to shrink the effect size from previous studies assuming that the prior effect …

A Two-Stage Design For Choosing Among Several Normal Treatments In Comparison With A Control: The Case Of Common, Known Variance, Samarasuriyage Sayura Sankalpa Senaratne

UNF Graduate Theses and Dissertations

A two-stage design is developed for comparing the means of multiple normally distributed treatment groups under a known common variance, with the aim of identifying the treatment with the highest mean while minimizing the expected sample size, a crucial consideration in clinical trials. The proposed methodology integrates elements of both hypothesis testing and selection procedures to achieve greater efficiency and decision-making power. In the initial stage, if no treatment exhibits a mean surpassing a predefined efficacy threshold, the trial is terminated early, conserving resources. If one or more treatments exceed the threshold, the procedure advances to a second stage, where …

An Improved Bayesian Pick-The-Winner (Ibpw) Design For Randomized Phase Ii Clinical Trials, Wanni Lei, Maosen Peng, Xi K. Zhou

COBRA Preprint Series

Phase II clinical trials play a pivotal role in drug development by screening a large number of drug candidates to identify those with promising preliminary efficacy for phase III testing. Trial designs that enable efficient decision-making with small sample sizes and early futility stopping while controlling for type I and II errors in hypothesis testing, such as Simon’s two-stage design, are preferred. Randomized multi-arm trials are increasingly used in phase II settings to overcome the limitations associated with using historical controls as the reference. However, how to effectively balance efficiency and accurate decision-making continues to be an important research topic. …

Causal Inference For The Effect Of Continuous Treatment On Time-To-Event Outcomes And Mediation Analysis On Health Disparities In Observational Studies., Triparna Poddar

Electronic Theses and Dissertations

The dissertation comprises two projects related to causal inference based on observational data. In healthcare research, where abundant observational data such as claims data and electronic records are available, researchers often aim to study the treatment effect and the pathway of that effect. However, estimating treatment effects in observational data presents challenges due to confounding factors. The first project focuses on estimating continuous treatment effects for survival outcomes, while the second concentrates on mediation analysis, allowing the exploration of the pathway of the causal effect. Both projects involve addressing confounding variables. In the first project, I investigate estimation of the …

Addressing The Analytical And Computational Challenges Using Machine Learning In Biomedical Research, Yizhuo Wang

Dissertations and Theses (Open Access)

In the contemporary healthcare field, professionals are confronted with an ever-growing volume of clinical data stored in electronic health records, alongside the genomic data stemming from laboratory experiments. As a response to this deluge of data, the application of machine learning (ML) techniques is gaining popularity since ML techniques have demonstrated an exceptional proficiency in processing big data and deciphering complex nonlinear patterns that are intrinsic to biomedical research.

My research leverages ML's capabilities to address the computational challenges spanning diverse areas, including adaptive clinical trial designs, survival analysis, and high-dimensional genetic data analysis. Specifically, Chapter 2 focused on the …

Predicting Hiv Vaccine-Mediated Protection Level To Identify Immune Correlates Using Positive Unlabeled Learning, Shiwei Xu

Dartmouth College Ph.D Dissertations

The development of a vaccine for Human Immunodeficiency Virus type 1 (HIV-1) is a crucial step in preventing the global spread of AIDS. To ensure the progress and effectiveness of this vaccine, it is essential to establish efficient biotechnology platforms and data mining methods. These methods would help identify immune characteristics that distinguish individuals with varying levels of vaccine-induced protection and determine the underlying factors that contribute to protection against HIV acquisition. While previous studies have focused on identifying immune markers associated with infection outcomes among vaccinated patients, it is important to acknowledge the limitations of traditional case-control analytical protocols …

Bayesian Semi-Mechanistic Dose-Finding Designs For Phase I Oncology Trials, Chao Yang

Dissertations and Theses (Open Access)

Bayesian adaptive designs are getting more popular in research and in practice because they are flexible and efficient in evaluating an experimental drug. In oncology, despite the great advances in novel dose-finding designs, the high failure rates of clinical cancer drug development from phase I to III trials call for further improvements on novel designs, in addition to the need to promote and adopt novel designs in practice. Because anticancer agents often have a narrow therapeutic index, an accurate identification of the maximum tolerated dose (MTD) in a phase I trial is crucial for identifying a tolerable and efficacious dose …

Bayesian Adaptive Clinical Trial Design, Mengyi Lu

Dissertations and Theses (Open Access)

The landscape of drug development in oncology has changed from conventional chemotherapies to molecular targeted therapies and immunotherapies, which provide innovative therapeutic modalities for treating cancers. These novel therapeutic agents work through mechanisms that fundamentally differ from standard chemotherapeutic agents, making the conventional trial design paradigm inefficient and dysfunctional. Specifically, the focus of dose-finding trials has shifted from finding the maximum tolerated dose (MTD) to the optimal biological dose (OBD), defined as the dose that optimizes the risk–benefit tradeoff. How to accurately identify the OBD and its dosing schedule is of great importance to maximize efficacy and safety of targeted …

Factors Affecting Time To Recovery: A Covid-19 Survival Analysis, Fernanda Montoya

Honors Capstones

This project is focused on the recovery rates of patients diagnosed with COVID-19 after different clinical trial drug treatments. Data for the clinical trial studied was obtained from the National Institute of Allergy and Infectious Diseases for the primary purpose of a survival analysis on patient time to recovery under a placebo and therapeutic drug treatment. Specifically, patients in this clinical trial were randomly selected to receive remdesivir, an antiviral drug, in combination with a placebo or baricitinib, a janus kinase inhibitor drug. Cox PH models were used to identify how the different treatment drugs affect time to recovery and …

Non-Inferiority Testing: Kernel Estimation And Overlap Measure, Larie C. Ward

College of Graduate Studies: Theses & Dissertations

In non-inferiority testing, the decision of whether a proposed treatment is non-inferior to a reference treatment depends on model assumptions and choices of acceptable tolerance limits. Here, we consider a method that employs kernels to estimate the probability density functions of both the experimental and reference populations from two independent samples. Based on these densities, we introduce a quantity called the overlap coefficient or overlap measure. A bootstrap technique is helpful in exploring the distribution and variance empirically. We derive the distribution of this measure and define a hypothesis test that can be applied to the non-inferiority setting under some …

Optimal Two-Stage Designs Based On Restricted Mean Survival Time For A Single-Arm Study, Guogen Shan

School of Public Health Faculty Research

© 2021 The Author(s) Restricted mean survival time is an alternative measure of treatment effect to hazard ratio in clinical trials with time-to-event outcome. The current methods have been focused on one-stage designs. In this article, we propose optimal two-stage designs for a single-arm study with the smallest expected sample size. We compare the performance of the new optimal two-stage designs with the existing one-stage design with regards to the expected sample size and the expected total study length. The simulation results indicate that the new two-stage designs can save the expected sample size substantially as compared to the one-stage …

Innovative Statistical Models In Cancer Immunotherapy Trial Design, Jing Wei

Theses and Dissertations--Statistics

A challenge arising in cancer immunotherapy trial design is the presence of non-proportional hazards (NPH) patterns in survival curves. We considered three different NPH patterns caused by delayed treatment effect, cure rate and responder rate of treatment group in this dissertation. These three NPH patterns would violate the proportional hazard model assumption and ignoring any of them in an immunotherapy trial design will result in substantial loss of statistical power.

In this dissertation, four models to deal with NPH patterns are discussed. First, a piecewise proportional hazards model is proposed to incorporate delayed treatment effect into the trial design consideration. …

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 …

A Modular Framework For Early-Phase Seamless Oncology Trials, Philip S. Boonstra, Thomas M. Braun, Elizabeth C. Chase

The University of Michigan Department of Biostatistics Working Paper Series

Background: As our understanding of the etiology and mechanisms of cancer becomes more sophisticated and the number of therapeutic options increases, phase I oncology trials today have multiple primary objectives. Many such designs are now 'seamless', meaning that the trial estimates both the maximum tolerated dose and the efficacy at this dose level. Sponsors often proceed with further study only with this additional efficacy evidence. However, with this increasing complexity in trial design, it becomes challenging to articulate fundamental operating characteristics of these trials, such as (i) what is the probability that the design will identify an acceptable, i.e. safe …

Integrated Multiple Adaptive Design Involving Sample Size Re-Estimation And (Covariate-Adjusted) Response-Adaptive Randomization For Continuous And Binary Outcomes, Christine M. Orndahl

Theses and Dissertations

Historically, clinical trials have been performed based on decisions made prior to the start of the trial. Adaptive designs have been developed to provide increased flexibility, allowing pre-specified changes to occur based on interim data. Each adaptive design addresses a unique pitfall of a non-adaptive design, such as minimizing the chance of an under- or over-powered study by utilizing interim data to update the sample size estimate (sample size re-estimation) or increasing the ethical benefit of a trial by allocating more participants to the better performing treatment group ([covariate-adjusted] response-adaptive randomization). Additional benefit is attainable by combining more than one …

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. …

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 …

A Signature Enrichment Design With Bayesian Adaptive Randomization For Cancer Clinical Trials, Fang Xia

Dissertations and Theses (Open Access)

Clinical trials in the era of precision medicine demand more flexible and efficient trial designs. Adaptive clinical trial designs allow pre-specified modifications of an on-going clinical trial and could shorten the trial duration. We reviewed five common types of adaptive clinical trials based on adaptation methods. In particular, outcome-randomization becomes more popular as it can assign more patients to the promising treatments based on the accumulated trial data. This data-driven allocation allows more patients to benefit from the trial, which is especially important for cancer patients. We compared different Bayesian outcome-adaptive randomization methods and discussed them from both methodological and …

Sample Size Calculation Of Clinical Trials With Correlated Outcomes, Dateng Li

Statistical Science Theses and Dissertations

In this thesis, we investigate sample size calculation for three kinds of clinical trials: (1). Randomized controlled trials (RCTs) with longitudinal count outcomes; (2). Cluster randomized trials (CRTs) with count outcomes; (3). CRTs with multiple binary co-primary endpoints.

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 …

Safety Constraint Optimization Of Combination Drug Therapy In Hypertension Clinical Trials, Victor Chukwu

College of Graduate Studies: Theses & Dissertations

In Clinical Practice, combination drug therapy has become common in treating many disease conditions. The purpose of these combinations is often to ensure optimal efficacy and to reduce adverse effects that may arise from monotherapy. Clinical trials have also been conducted to ensure efficacy and safety of these combinations before they are introduced into the market. However, adverse effects still occur with combination therapies. The objective of this study is to (1) To determine a region of optimum doses of Drug A and Drug B in combination while focusing on efficacy alone (2) To determine a region of optimum doses …

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 …