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 …

Variance Shrinkage In Dunnett-Type Multiple Comparisons With Missing Data, Md Habibullah

UNF Graduate Theses and Dissertations

Dunnett’s procedure is widely used for comparing multiple treatments with a control, but its application becomes challenging in the presence of missing data and multiple com- parisons. An improved Dunnett-type procedure addresses this by using multiple imputation under Rubin’s framework and constructing unified confidence intervals based on a multi- variate t distribution, allowing valid simultaneous inference while controlling the family-wise error rate (FWER). This work further extends the method by incorporating shrinkage-based variance estimation. Specifically, individual group variances are shrunk toward a common value to improve stability. This approach is particularly effective when group variances are similar or moderately different, …

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 …

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 …

Leveraging Bayesian And Classical Techniques For Survival Analysis Using The Weibull-Rayleigh Distribution, Mahmoud Mansour, Rashad El-Sagheer, Nagwa Mohamed

Basic Science Engineering

This paper contributes to an extensive analysis of the Weibull-Rayleigh distribution (WRD), including Bayesian inference for randomly censored data. The WRD is a versatile model that fits various types of survival data, especially in situations including censoring, commonly found in biostatistics and engineering reliability research. The research investigates the derivation of the WRD’s probability density and cumulative distribution functions, employing maximum likelihood estimation (MLE) and Bayesian estimating techniques to accurately infer parameters. Gamma priors are utilized in Bayesian analysis, and approximate Bayesian estimates are derived by Gibbs sampling and Lindley’s approximation methods. An actual dataset that represents leukemia-free survival times …

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. …

Novel Nonparametric Testing Approaches For Multivariate Growth Curve Data: Finite-Sample, Resampling And Rank-Based Methods, Ting Zeng

Theses and Dissertations--Statistics

Multivariate growth curve data naturally arise in various fields, for example, biomedical science, public health, agriculture, social science and so on. For data of this type, the classical approach is to conduct multivariate analysis of variance (MANOVA) based on Wilks' Lambda and other multivariate statistics, which require the assumptions of multivariate normality and homogeneity of within-cell covariance matrices. However, data being analyzed nowadays show marked departure from multivariate normal distribution and homoscedasticity. In this dissertation, we investigate nonparametric testing approaches for multivariate growth curve data from three aspects, i.e., finite-sample, resampling and rank-based methods.

The first project proposes an approximate …

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 …

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 …

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 …

Minimizing The Perceived Financial Burden Due To Cancer, Hassan Azhar, Zoheb Allam, Gino Varghese, Daniel W. Engels, Sajiny John

SMU Data Science Review

In this paper, we present a regression model that predicts perceived financial burden that a cancer patient experiences in the treatment and management of the disease. Cancer patients do not fully understand the burden associated with the cost of cancer, and their lack of understanding can increase the difficulties associated with living with the disease, in particular coping with the cost. The relationship between demographic characteristics and financial burden were examined in order to better understand the characteristics of a cancer patient and their burden, while all subsets regression was used to determine the best predictors of financial burden. Age, …

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 …

Systematic Review And Meta-Analysis: Tuberculosis, Tnfα Inhibitors, And Crohn's Disease, Brent L. Cao

Honors Undergraduate Theses

Inflammation is often a protective reaction against harmful foreign agents. However, in many disease conditions, the mechanisms behind the inflammatory response are poorly understood. Often times, the inflammation causes adverse effects, such as joint pain, abdominal pain, fever, fatigue, and loss of appetite. Thus, many treatments aim to inhibit the inflammatory response in order to control adverse symptoms. Such treatments include TNFα inhibitors. However, a major risk associated with drugs inhibiting tumor necrosis factor alpha (TNFα) is serious infection, including tuberculosis (TB).

Anti-TNFα therapy is used to treat patients with Crohn’s disease, for which the risk of tuberculosis may be …

Novel Bayesian Adaptive Clinical Trial Designs In Early Phases, Haitao Pan

Dissertations and Theses (Open Access)

Early phase, or phase I and phase II, trials are the first step in testing new medicines that have been developed in the lab. The main goal of phase I clinical trials is to establish the recommended dose of new drugs for phase II trials. For the cytotoxic drugs, the goal is to find maximum tolerated dose (MTD). The guiding principle for dose escalation in phase I trials is to avoid exposing too many patients to subtherapeutic doses while preserving safety and maintaining rapid accrual. Therefore, dose escalation methods, especially Bayesian designs, are recommended to be used in phase I …

Denoising Tandem Mass Spectrometry Data, Felix Offei

Electronic Theses and Dissertations

Protein identification using tandem mass spectrometry (MS/MS) has proven to be an effective way to identify proteins in a biological sample. An observed spectrum is constructed from the data produced by the tandem mass spectrometer. A protein can be identified if the observed spectrum aligns with the theoretical spectrum. However, data generated by the tandem mass spectrometer are affected by errors thus making protein identification challenging in the field of proteomics. Some of these errors include wrong calibration of the instrument, instrument distortion and noise. In this thesis, we present a pre-processing method, which focuses on the removal of noisy …

Further Advances For The Sequential Multiple Assignment Randomized Trial (Smart), Tianjiao Dai

Dissertations and Theses (Open Access)

ABSTRACT

FURTHER ADVANCES FOR THE SEQUENTIAL MULTIPLE ASSIGNMENT RANDOMIZED TRIAL (SMART)

Tianjiao Dai, M.S.

Advisory Professor: Sanjay Shete, Ph.D.

Sequential multiple assignment randomized trial (SMART) designs have been developed these years for studying adaptive interventions. In my Ph.D. study, I mainly investigate how to further improve SMART designs and optimize the interventions for each individual in the trial. My dissertation has focused on two topics of SMART designs.

1) Developing a novel SMART design that can reduce the cost and side effects associated with the interventions and proposing the corresponding analytic methods. I have developed a time-varying SMART design in …

Variance Prior Specification For A Basket Trial Design Using Bayesian Hierarchical Modeling, Kristen Cunanan, Alexia Iasonos, Ronglai Shen, Mithat Gonen

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

Background: In the era of targeted therapies, clinical trials in oncology are rapidly evolving, wherein patients from multiple diseases are now enrolled and treated according to their genomic mutation(s). In such trials, known as basket trials, the different disease cohorts form the different baskets for inference. Several approaches have been proposed in the literature to efficiently use information from all baskets while simultaneously screening to find individual baskets where the drug works. Most proposed methods are developed in a Bayesian paradigm that requires specifying a prior distribution for a variance parameter, which controls the degree to which information is shared …

Models For Hsv Shedding Must Account For Two Levels Of Overdispersion, Amalia Magaret

UW Biostatistics Working Paper Series

We have frequently implemented crossover studies to evaluate new therapeutic interventions for genital herpes simplex virus infection. The outcome measured to assess the efficacy of interventions on herpes disease severity is the viral shedding rate, defined as the frequency of detection of HSV on the genital skin and mucosa. We performed a simulation study to ascertain whether our standard model, which we have used previously, was appropriately considering all the necessary features of the shedding data to provide correct inference. We simulated shedding data under our standard, validated assumptions and assessed the ability of 5 different models to reproduce the …

The Myth Of Making Inferences For An Overall Treatment Efficacy With Data From Multiple Comparative Studies Via Meta-Analysis, Takahiro Hasegawa, Brian Claggett, Lu Tian, Scott D. Solomon, Marc A. Pfeffer, Lee-Jen Wei

Harvard University Biostatistics Working Paper Series

Meta analysis techniques, if applied appropriately, can provide a summary of the totality of evidence regarding an overall difference between a new treatment and a control group using data from multiple comparative clinical studies. The standard meta analysis procedures, however, may not give a meaningful between-group difference summary measure or identify a meaningful patient population of interest, especially when the fixed effect model assumption is not met. Moreover, a single between-group comparison measure without a reference value obtained from patients in the control arm would likely not be informative enough for clinical decision making. In this paper, we propose a …

Missing Data In Clinical Trial: A Critical Look At The Proportionality Of Mnar And Mar Assumptions For Multiple Imputation, Theophile B. Dipita

College of Graduate Studies: Theses & Dissertations

Randomized control trial is a gold standard of research studies. Randomization helps reduce bias and infer causality. One constraint of these studies is that it depends on participants to obtain the desired data. Whatever the researcher can do, there is a possibility to end up with incomplete data. The problem is more relevant in clinical trials when missing data can be related to the condition under study. The benefits of randomization is compromised by missing data. Multiple imputation is a valid method of treating missing data under the assumption of MAR. Unfortunately this is an unverified assumptions. Current practice advise …

C-Learning: A New Classification Framework To Estimate Optimal Dynamic Treatment Regimes, Baqun Zhang, Min Zhang

The University of Michigan Department of Biostatistics Working Paper Series

Personalizing treatment to accommodate patient heterogeneity and the evolving nature of a disease over time has received considerable attention lately. A dynamic treatment regime is a set of decision rules, each corresponding to a decision point, that determine that next treatment based on each individual’s own available characteristics and treatment history up to that point. We show that identifying the optimal dynamic treatment regime can be recast as a sequential classification problem and is equivalent to sequentially minimizing a weighted expected misclassification error. This general classification perspective targets the exact goal of optimally individualizing treatments and is new and fundamentally …

Depicting Estimates Using The Intercept In Meta-Regression Models: The Moving Constant Technique, Blair T. Johnson Dr., Tania B. Huedo-Medina Dr.

CHIP Documents

In any scientific discipline, the ability to portray research patterns graphically often aids greatly in interpreting a phenomenon. In part to depict phenomena, the statistics and capabilities of meta-analytic models have grown increasingly sophisticated. Accordingly, this article details how to move the constant in weighted meta-analysis regression models (viz. “meta-regression”) to illuminate the patterns in such models across a range of complexities. Although it is commonly ignored in practice, the constant (or intercept) in such models can be indispensible when it is not relegated to its usual static role. The moving constant technique makes possible estimates and confidence intervals at …

Effectively Selecting A Target Population For A Future Comparative Study, Lihui Zhao, Lu Tian, Tianxi Cai, Brian Claggett, L. J. Wei

Harvard University Biostatistics Working Paper Series

When comparing a new treatment with a control in a randomized clinical study, the treatment effect is generally assessed by evaluating a summary measure over a specific study population. The success of the trial heavily depends on the choice of such a population. In this paper, we show a systematic, effective way to identify a promising population, for which the new treatment is expected to have a desired benefit, using the data from a current study involving similar comparator treatments. Specifically, with the existing data we first create a parametric scoring system using multiple covariates to estimate subject-specific treatment differences. …