Clinical Trials Commons^™

Using Covid-19 Vaccine Efficacy Data To Teach One-Sample Hypothesis Testing, Frank Wang

Numeracy

In late November 2020, there was a flurry of media coverage of two companies’ claims of 95% efficacy rates of newly developed COVID-19 vaccines, but information about the confidence interval was not reported. This paper presents a way of teaching the concept of hypothesis testing and the construction of confidence intervals using numbers announced by the drug makers Pfizer and Moderna publicized by the media. Instead of a two-sample test or more complicated statistical models, we use the elementary one-proportion z-test to analyze the data. The method is designed to be accessible for students who have only taken a …

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. …

Tricyclic Antidepressant Use And Risk Of Fractures: A Meta-Analysis Of Cohort Studies Through The Use Of Both Frequentist And Bayesian Approaches, Qing Wu, Yingke Xu, Yueyang Bao, Jovan Alvarez, Mikee Lianne Gonzales

School of Medicine Faculty Research

Background: Research findings regarding the association between tricyclic antidepressant (TCA) treatment and the risk of fracture are not consistent; we aimed to assess whether people who take TCAs are at an increased fracture risk. Methods: Relevant studies published through June 2020 were identified through database searches of MEDLINE, EMBASE, Scopus, PsycINFO, ISI Web of Science, WorldCat Dissertations and Theses from each database’s inception, as well as through manual searches of relevant reference lists. Two researchers independently performed literature searches, study selection, data abstraction and study appraisal by using a standardized protocol. Frequentist and Bayesian hierarchical random-effects models were used for …

Utility Of Inflammatory Markers To Predict Adverse Outcome In Acute Pancreatitis: A Retrospective Study In A Single Academic Center, Mohamad Mubder, Banreet Dhindsa, Danny Nguyen, Syed Saghir, Chad Cross, Ranjit Makar, Gordon Ohning

School of Medicine Faculty Research

Background/Aim: Acute pancreatitis (AP) is a commonly encountered emergency where early identification of complicated cases is important. Inflammatory markers like lymphocyte to monocyte ratio (LMR) and neutrophil to lymphocyte ratio (NLR) are simple and readily available markers. In this study, we evaluated the utility of these markers in the early identification of patients with complicated AP. Patients and Methods: All patients with a diagnosis of AP admitted to the University Medical Center in Las Vegas/Nevada between August 2015 and September 2018 were identified using ICD-10 codes. Medical records were reviewed retrospectively. Epidemiological measures and their associated confidence intervals were calculated …

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 …

Three Essays On Health Economics And Policy Evaluation, Shishir Shakya

Graduate Theses, Dissertations, and Problem Reports (ETD)

This dissertation consists of three essays on the U.S. Health care policy. Each paragraph below refers to the three abstracts for the three chapters in this dissertation, respectively. I provide quantitative evidence on how much Prescription Drug Monitoring Programs (PDMPs) affects the retail opioid prescribing behaviors. Using the American Community Survey (ACS), I retrieve county-level high dimensional panel data set from 2010 to 2017. I employ three separate identification strategies: difference-in-difference, double selection post-LASSO, and spatial difference-in-difference. I compare how the retail opioid prescribing behaviors of counties, that are mandatory for prescribers to check the PDMP before prescribing controlled substances …

A Two-Stage Design For Comparing Binomial Treatments With A Standard, Cecelia K. Schmidt

UNF Graduate Theses and Dissertations

We propose a method for comparing success rates of several populations among each other and against a desired standard success rate. This design is appropriate for a situation in which all experimental treatments have only two outcomes that can be considered “success”and “failure” respectively. The goal is to identify which treatment has the highest rate of success that is also higher than the desired standard. The design combines elements of both hypothesis testing and statistical selection. At the first stage, if none of the samples have a number of successes above the appropriate standard for the design, the experiment is …

Natural Lead-In Approaches To Response-Adaptive Allocation In Clinical Trials, Erin E. Donahue

Theses and Dissertations

Response-adaptive (RA) allocation designs can be implemented in clinical trials to skew the allocation of incoming subjects toward the better performing treatment group based on the previously accrued subjects' responses. These designs alleviate potential ethical concerns of equally allocating subjects in a trial when one treatment arm is inferior. The RA design can be generalized to include covariate information in the covariate-adjusted response-adaptive (CARA) design, which aims to maximize treatment successes conditional on a set of patient characteristics. While RA and CARA designs can improve the treatment of patients, they have unstable estimators and increased variability in early stages of …

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 …

Phase Iv Clinical Trials: Postmarketing Surveillance Of Prescription Drugs, Morgan Belling, Jacquline Nunner, Jessica Stemen

Pharmacy and Wellness Review

No abstract provided.

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 …

Non Parametric Test For Testing Exponentiality Against Exponential Better Than Used In Laplace Transform Order, Mahmoud Mansour, M A W Mahmoud Prof.

Basic Science Engineering

In this paper, the test statistic for testing exponentiality against exponential better than used in Laplace transform order (EBUL) based on the Laplace transform technique is proposed. Pitman’s asymptotic efficiency of our test is calculated and compared with other tests. The percentiles of this test are tabulated. The powers of the test are estimated for famously used distributions in aging problems. In the case of censored data, our test is applied and the percentiles are also calculated and tabulated. Finally, real examples in different areas are utilized as practical applications for the proposed test.

Toxoplasma Gondii Igg Associations With Sleepwake Problems, Sleep Duration And Timing, Celine C. Corona, Ma Zhang, Abhishek Wadhawan, Melanie L. Daue, Maureen W. Groer, Aline Dagang, Christopher A. Lowry, Kathleen A. Ryan, Andrew J. Hoisington, John W. Stiller, Dietmar Fuchs, Braxton D. Mitchell, Teodor T. Postolache

Faculty Publications

Background: Evidence links Toxoplasma gondii (T. gondii), a neurotropic parasite, with schizophrenia, mood disorders and suicidal behavior, all of which are associated and exacerbated by disrupted sleep. Moreover, low-grade immune activation and dopaminergic overstimulation, which are consequences of T. gondii infection, could alter sleep patterns and duration. Methods: Sleep data on 833 Amish participants [mean age (SD) = 44.28 (16.99) years; 59.06% women] were obtained via self-reported questionnaires that assessed sleep problems, duration and timing. T. gondii IgG was measured with ELISA. Data were analyzed using multivariable logistic regressions and linear mixed models, with adjustment for age, sex and family …

A Parent-Led Intervention To Promote Recovery Following Pediatric Injury: Study Protocol For A Randomized Controlled Trial, Meghan L. Marsac, Ginny Sprang, Leila Guller, Kristen L. Kohser, John M. Draus Jr., Nancy Kassam-Adams

Pediatrics Faculty Publications

Background: Injury is one of the most prevalent potentially emotionally traumatic events that children experience and can lead to persistent impaired physical and emotional health. There is a need for interventions that promote full physical and emotional recovery and that can be easily accessed by all injured children. Based on research evidence regarding post-injury recovery, we created the Cellie Coping Kit for Children with Injury intervention to target key mechanisms of action and refined the intervention based on feedback from children, families, and experts in the field. The Cellie Coping Kit intervention is parent-guided and includes a toy (for engagement), …

The Potential Of Organ On Chip Technology For Replacing Animal Testing, Malcolm Wilkinson

Human Clinical Trials Collection

The term organ on a chip is used to describe the latest stage of development of in vitro cell culture technology. Figure 26.1 shows its steady development since the 1960s. Each step forward has improved our ability to model human-clinical response to new drugs or therapies and has enabled safety risk assessment of existing cosmetics, personal care products, or other chemicals in the environment. Scientific evidence that the predictive power of in vitro tests is superior to the use of animals will trigger a major shift in the way that medical research, in many areas, is carried out. In this …

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 …

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 …

A Programme For Risk Assessment And Minimisation Of Progressive Multifocal Leukoencephalopathy Developed For Vedolizumab Clinical Trials, Asit Parikh, Kristin Stephens, Eugene Major, Irving Fox, Catherine Milch, Serap Sankoh, Michael H. Lev, James M. Provenzale, Jesse Shick, Mark Patti, Megan Mcauliffe, Joseph R. Berger, David B. Clifford

Neurology Faculty Publications

Introduction Over the past decade, the potential for drug-associated progressive multifocal leukoencephalopathy (PML) has become an increasingly important consideration in certain drug development programmes, particularly those of immunomodulatory biologics. Whether the risk of PML with an investigational agent is proven (e.g. extrapolated from relevant experience, such as a class effect) or merely theoretical, the serious consequences of acquiring PML require careful risk minimisation and assessment. No single standard for such risk minimisation exists. Vedolizumab is a recently developed monoclonal antibody to α4β7 integrin. Its clinical development necessitated a dedicated PML risk minimisation assessment as part of a global preapproval regulatory …

Variations In Institutional Review Board Processes And Consent Requirements For Trauma Research: An East Multicenter Survey, Jeffry Nahmias, Areg Grigorian, Scott Brakenridge, Randeep S. Jawa, Daniel N. Holena, John Varujan Agapian, Brandon Bruns, Paul J. Chestovich, Bruce Chung, Jonathan Nguyen, Carl I. Schulman, Kristan Staudenmayer, Rachel Dixon, Jason W. Smith, Andrew C. Bernard, Jose L. Pascual

School of Medicine Faculty Research

Oversight of human subject research has evolved considerably since its inception. However, previous studies identified a lack of consistency of institutional review board (IRB) determination for the type of review required and whether informed consent is necessary, especially for prospective observational studies, which pose minimal risk of harm. We hypothesized that there is significant inter-institution variation in IRB requirements for the type of review and necessity of informed consent, especially for prospective observational trials without blood/tissue utilization. We also sought to describe investigators’ and IRB members’ attitudes toward the type of review and need for consent. Eastern Association for the …

Low-Fat Abiraterone Food Effect Is Of Little Consequence, Jill M. Kolesar, Glenn X. Liu

Pharmacy Practice and Science Faculty Publications

No abstract provided.

Quality Of Life During Treatment With Chemohormonal Therapy: Analysis Of E3805 Chemohormonal Androgen Ablation Randomized Trial In Prostate Cancer, Alicia K. Morgans, Yu-Hui Chen, Christopher J. Sweeney, David F. Jarrard, Elizabeth R. Plimack, Benjamin A. Gartrell, Michael A. Carducci, Maha Hussain, Jorge A. Garcia, David Cella, Robert S. Dipaola, Linda J. Patrick-Miller

Internal Medicine Faculty Publications

Purpose

Chemohormonal therapy with docetaxel and androgen deprivation therapy (ADT+D) for metastatic hormone-sensitive prostate cancer improves overall survival as compared with androgen deprivation therapy (ADT) alone. We compared the quality of life (QOL) between patients with metastatic hormone-sensitive prostate cancer who were treated with ADT+D and those who were treated with ADT alone.

Methods

Men were randomly assigned to ADT+ D (six cycles) or to ADT alone. QOL was assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P), FACT-Taxane, Functional Assessment of Chronic Illness Therapy-Fatigue, and the Brief Pain Inventory at baseline and at 3, 6, 9, and 12 months. The …

Telotristat Ethyl In Carcinoid Syndrome: Safety And Efficacy In The Telecast Phase 3 Trial, Marianne Pavel, David J. Gross, Marta Benavent, Petros Perros, Raj Srirajaskanthan, Richard R. P. Warner, Matthew H. Kulke, Lowell B. Anthony, Pamela L. Kunz, Dieter Hörsch, Martin O Weickert, Pablo Lapuerta, Wenjun Jiang, Kenneth Kassler-Taub, Suman Wason, Rosanna Fleming, Douglas Fleming, Rocio Garcia-Carbonero

Internal Medicine Faculty Publications

Telotristat ethyl, a tryptophan hydroxylase inhibitor, was efficacious and well tolerated in the phase 3 TELESTAR study in patients with carcinoid syndrome (CS) experiencing ≥ 4 bowel movements per day (BMs/day) while on somatostatin analogs (SSAs). TELECAST, a phase 3 companion study, assessed the safety and efficacy of telotristat ethyl in patients with CS (diarrhea, flushing, abdominal pain, nausea or elevated urinary 5-hydroxyindoleacetic acid (u5-HIAA)) with < 4 BMs/day on SSAs (or ≥ 1 symptom or ≥ 4 BMs/day if not on SSAs) during a 12-week double-blind treatment period followed by a 36-week open-label extension (OLE). The primary safety and efficacy endpoints were incidence of treatment-emergent adverse events (TEAEs) and percent change from baseline in 24-h u5-HIAA at week 12. Patients (N = 76) were randomly assigned (1:1:1) to receive placebo or telotristat ethyl 250 mg or 500 mg 3 times per day (tid); 67 continued receiving telotristat ethyl 500 mg tid during the OLE. …