Clinical Trials Commons^™

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 …

Burden Of Atopic Dermatitis In The United States: Analysis Of Healthcare Claims Data In The Commercial, Medicare, And Medi-Cal Databases, Sulena Shrestha, Raymond Miao, Li Wang, Jingdong Chao, Huseyin Yuce, Wenhui Wei

Publications and Research

Comparative data on the burden of atopic dermatitis (AD) in adults relative to the general population are limited. We performed a large-scale evaluation of the burden of disease among US adults with AD relative to matched non-AD controls, encompassing comorbidities, healthcare resource utilization (HCRU), and costs, using healthcare claims data. The impact of AD disease severity on these outcomes was also evaluated.

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 …

Studying The Optimal Scheduling For Controlling Prostate Cancer Under Intermittent Androgen Suppression, Sunil K. Dhar, Hans R. Chaudhry, Bruce G. Bukiet, Zhiming Ji, Nan Gao, Thomas W. Findley

Harvard University Biostatistics Working Paper Series

This retrospective study shows that the majority of patients’ correlations between PSA and Testosterone during the on-treatment period is at least 0.90. Model-based duration calculations to control PSA levels during off-treatment are provided. There are two pairs of models. In one pair, the Generalized Linear Model and Mixed Model are both used to analyze the variability of PSA at the individual patient level by using the variable “Patient ID” as a repeated measure. In the second pair, Patient ID is not used as a repeated measure but additional baseline variables are included to analyze the variability of PSA.

A Predictive Probability Interim Design For Phase Ii Clinical Trials With Continuous Endpoints, Meng Liu

Theses and Dissertations--Epidemiology and Biostatistics

Phase II clinical trials aim to potentially screen out ineffective and identify effective therapies to move forward to randomized phase III trials. Single-arm studies remain the most utilized design in phase II oncology trials, especially in scenarios where a randomized design is simply not practical. Due to concerns regarding excessive toxicity or ineffective new treatment strategies, interim analyses are typically incorporated in the trial, and the choice of statistical methods mainly depends on the type of primary endpoints. For oncology trials, the most common primary objectives in phase II trials include tumor response rate (binary endpoint) and progression disease-free survival …

Analysis Of Data From A Study To Identify Potential Biomarkers To Indicate Renal Injury, Mitchell D. Tahtinen

Dissertations, Master's Theses and Master's Reports

Ureteropelvic junction obstruction is a disease in which flow from the kidney to the bladder is obstructed for extended periods of time causing irreversible damage to the kidney. Current tests to detect kidney damage caused by obstruction are not effective until significant damage occurs. The purpose of this report is to identify a panel of biomarkers in urine to detect kidney damage earlier by analyzing data collected from a two-part study. Currently, two established urinary biomarkers to indicate kidney damage are NGAL and KIM-1. Biomarkers of interest in this study are CD13, CD10, and CD26. Results from the linear mixed …

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 …

Genetic Predictors Of Metabolic Side Effects Of Diuretic Therapy, Jorge L. Del Aguila

Dissertations and Theses (Open Access)

Thiazide diuretics are a recommended first-line monotherapy for hypertension (i.e.SBP>140 mmHg or DBP>90 mmHg). Even so, diuretics are associated with adverse metabolic side effects, such as hyperlipidemia, hyperglycemia and hypokalemia which increase the risk of developing type II diabetes. This thesis used three analytical strategies to identify and quantify genetic factors that contribute to the development of adverse metabolic effects due to thiazide diuretic treatment. I performed a genome-wide association study (GWAS) and meta-analysis of the change in fasting plasma glucose and triglycerides in response to HCTZ from two different clinical trials: the Pharmacogenomic Evaluation of Antihypertensive Responses …

A Study Of Joinpoint Models For Longitudinal Data, Libo Zhou

UNLV Theses, Dissertations, Professional Papers, and Capstones

In many medical studies, data are collected simultaneously on multiple biomarkers from each individual. Levels of these biomarkers are measured periodically over certain time duration, giving rise to longitudinal trajectories. The subjects under study may also be subject to dropout due to several competing causes, the likelihood of which may be affected by the levels of these biomarkers. In this dissertation, we investigate flexible Bayesian modeling of such data, taking into account any available covariate information as well as possible censoring of the drop-out times. We propose joint models for multiple biomarkers with multiple causes of dropout. Our proposed models …

Bayesian Adaptive Designs For Early Phase Clinical Trials, Chunyan Cai

Dissertations and Theses (Open Access)

My dissertation focuses mainly on Bayesian adaptive designs for phase I and phase II clinical trials. It includes three specific topics: (1) proposing a novel two-dimensional dose-finding algorithm for biological agents, (2) developing Bayesian adaptive screening designs to provide more efficient and ethical clinical trials, and (3) incorporating missing late-onset responses to make an early stopping decision.

Treating patients with novel biological agents is becoming a leading trend in oncology. Unlike cytotoxic agents, for which toxicity and efficacy monotonically increase with dose, biological agents may exhibit non-monotonic patterns in their dose-response relationships. Using a trial with two biological agents as …

Adaptive Randomization Designs, Jenna Colavincenzo

Statistics

Adaptive design methodologies use prior information to develop a clinical trial design. The goal of an adaptive design is to maintain the integrity and validity of the study while giving the researcher flexibility in identifying the optimal treatment. An example of an adaptive design can be seen in a basic pharmaceutical trial. There are three phases of the overall trial to compare treatments and experimenters use the information from the previous phase to make changes to the subsequent phase before it begins.

Adaptive design methods have been in practice since the 1970s, but have become increasingly complex ever since. One …

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. …

Bayesian Phase I Dose Finding In Cancer Trials, Lin Yang

Dissertations and Theses (Open Access)

This dissertation explores phase I dose-finding designs in cancer trials from three perspectives: the alternative Bayesian dose-escalation rules, a design based on a time-to-dose-limiting toxicity (DLT) model, and a design based on a discrete-time multi-state (DTMS) model.

We list alternative Bayesian dose-escalation rules and perform a simulation study for the intra-rule and inter-rule comparisons based on two statistical models to identify the most appropriate rule under certain scenarios. We provide evidence that all the Bayesian rules outperform the traditional ``3+3'' design in the allocation of patients and selection of the maximum tolerated dose.

The design based on a time-to-DLT model …

On The Covariate-Adjusted Estimation For An Overall Treatment Difference With Data From A Randomized Comparative Clinical Trial, Lu Tian, Tianxi Cai, Lihui Zhao, L. J. Wei

Harvard University Biostatistics Working Paper Series

No abstract provided.

Stratifying Subjects For Treatment Selection With Censored Event Time Data From A Comparative Study, Lihui Zhao, Tianxi Cai, Lu Tian, Hajime Uno, Scott D. Solomon, L. J. Wei

Harvard University Biostatistics Working Paper Series

No abstract provided.

Estimating Causal Effects In Trials Involving Multi-Treatment Arms Subject To Non-Compliance: A Bayesian Frame-Work, Qi Long, Roderick J. Little, Xihong Lin

Harvard University Biostatistics Working Paper Series

No abstract provided.

Assessing Noninferiority In A Three-Arm Trial Using The Bayesian Approach, Pulak Ghosh, Farouk S. Nathoo, Mithat Gonen, Ram C. Tiwari

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

Non-inferiority trials, which aim to demonstrate that a test product is not worse than a competitor by more than a pre-specified small amount, are of great importance to the pharmaceutical community. As a result, methodology for designing and analyzing such trials is required, and developing new methods for such analysis is an important area of statistical research. The three-arm clinical trial is usually recommended for non-inferiority trials by the Food and Drug Administration (FDA). The three-arm trial consists of a placebo, a reference, and an experimental treatment, and simultaneously tests the superiority of the reference over the placebo along with …

Nonparametric Regression With Missing Outcomes Using Weighted Kernel Estimating Equations, Lu Wang, Andrea Rotnitzky, Xihong Lin

Harvard University Biostatistics Working Paper Series

No abstract provided.

Utilizing The Integrated Difference Of Two Survival Functions To Quantify The Treatment Contrast For Designing, Monitoring And Analyzing A Comparative Clinical Study, Lihui Zhao, Lu Tian, Hajime Uno, Scott D. Solomon, Marc A. Pfeffer, J. S. Schindler, L. J. Wei

Harvard University Biostatistics Working Paper Series

No abstract provided.

Graphical Procedures For Evaluating Overall And Subject-Specific Incremental Values From New Predictors With Censored Event Time Data, Hajime Uno, Tianxi Cai, Lu Tian, L. J. Wei

Harvard University Biostatistics Working Paper Series

No abstract provided.

A Comparison Of Methods For Estimating The Causal Effect Of A Treatment In Randomized Clinical Trials Subject To Noncompliance, Rod Little, Qi Long, Xihong Lin

Harvard University Biostatistics Working Paper Series

No abstract provided.

Nonparametric Inference Procedure For Percentiles Of The Random Effect Distribution In Meta Analysis, Rui Wang, Lu Tian, Tianxi Cai, L. J. Wei

Harvard University Biostatistics Working Paper Series

No abstract provided.

Targeted Methods For Biomarker Discovery, The Search For A Standard, Catherine Tuglus, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

More often than not biomarker studies analyze large quantities of variables with complicated and generally unknown correlation structure. There are numerous statistical methods which attempt to unravel these variables and determine the underlying mechanism through identification of causally related biomarkers. Results from these methods are generally difficult to interpret and nearly impossible to compare across studies. The FDA has currently called for a standardization of methods and protocol for biomarker detection. In response, we propose targeted variable importance (tVIM) as a standardized method for biomarker discovery. Through the use of targeted Maximum Likelihood, tVIM provides double robust estimates of variable …

Effectively Combining Independent 2 X 2 Tables For Valid Inferences In Meta Analysis With All Available Data But No Artificial Continuity Corrections For Studies With Zero Events And Its Application To The Analysis Of Rosiglitazone's Cardiovascular Disease Related Event Data, Lu Tian, Tianxi Cai, Nikita Piankov, Pierre-Yves Cremieux, L. J. Wei

Harvard University Biostatistics Working Paper Series

No abstract provided.