Biostatistics Commons^™

Novel R Shiny Tool For Survival Analysis With Time-Varying Covariate In Oncology Studies: Overcoming Biases And Enhancing Collaboration, Yimei Li, Yang Qiao, Fei Gao, Jordan Gauthier, Qiang Ed Zhang, Jenna Voutsinas, Wendy Leisenring, Ted Gooley, Corinne Summers, Alexandre Hirayama, Cameron Turtle, Rebecca Gardner, Jarcy Zee, Qian Vicky Wu

Wills Eye Hospital Papers

PURPOSE: Our study is motivated by evaluating the role of hematopoietic cell transplantation (HCT) after chimeric antigen receptor T-cell (CAR-T) therapy for ALL, a debated topic. Because patients may receive HCT at different times after CAR-T infusion or never, HCT post-CAR-T should be considered as a time-varying covariate (TVC).

METHODS: Standard Cox models and Kaplan-Meier (KM) curves (naïve method) assume that TVC status is known and fixed at baseline, which can yield biased estimates. Landmark analysis is a popular alternative but depends on a chosen landmark time. Time-dependent (TD) Cox model is better suited for TVC although visualizing survival curves …

Neighborhood Socioeconomic Status And Overall Survival Among Children With Acute Lymphoblastic Leukemia, Anna Hoppmann, Debroah M. Hurley, Stuart Cramer, Monique J. Brown Ph.D., Mph

Faculty Publications

A disadvantaged neighborhood, as represented by area-level socioeconomic status (SES) has been associated with adverse outcomes among children with acute lymphoblastic leukemia (ALL) in the US, but the duration of impact after ALL diagnosis is not well understood. This retrospective cohort study utilized the National Cancer Database (NCDB) to examine the impact of area-level SES on overall survival among children with ALL. Median income and education quartiles based on residential zip code were used to create a composite area-level SES variable. Individual-level variables included age, sex, race, year of diagnosis, primary payer, distance to care, rurality, time to treatment, and …

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 …

Highest Risk Density Region For The Communication Of The Impact Of A Treatment Covariate On The Time-To-Event Distribution, Giacomo Biganzoli, Giuseppe Marano Phd, Patrizia Boracchi Phd

COBRA Preprint Series

Analysis of time-to-event (TTE) data is central to clinical research, yet conventional summary measures like the hazard ratio (HR) and restricted mean survival time (RMST) present significant challenges. The HR is often misinterpreted, and its validity depends on the frequently violated proportional hazards assumption, while the RMST is highly sensitive to the choice of time horizon. This paper introduces two novel, assumption-free estimands to address these limitations: the Highest Risk Density Region (HRDR) and the Highest Net Risk Difference Region (HNRDR).

The HRDR identifies the narrowest time interval containing a pre-specified probability mass of events, directly answering the clinical question: …

Dynamic Prediction Of Disease Progression With Longitudinal Data, Wenhao Li

Dissertations and Theses (Open Access)

Dynamic prediction plays a pivotal role in clinical research, especially when forecasting time-to-event outcomes based on evolving longitudinal data. This process often leverages the integration of longitudinal and time-to-event data through joint modeling, a prevalent technique. Alongside joint modeling, landmark modeling stands as another key approach in the realm of longitudinal studies. These methodologies are instrumental in dynamically predicting clinical events by utilizing predictor variables measured over time, up until the moment predictions are made. Within this framework, Chapter 2 addresses the challenge of comparing joint modeling and landmark modeling for dynamic prediction in longitudinal studies, introducing a novel algorithm …

Mathematical Modeling Of Tumor Response Dynamics To Predict Progression-Free Survival In Patients With Recurrent High-Grade Glioma, Daniel James Glazar

USF Tampa Graduate Theses and Dissertations

In this dissertation, I aim to develop a mathematical model describing tumor volume response dynamics to perform individual dynamic predictions of progression-free survival (PFS) on patients with recurrent high-grade glioma (rHGG).

Patients with rHGG have a dismal prognosis with median overall survival (OS) of <12 months and median PFS of <7 months. However, there is a wide heterogeneity in treatment responses. Therefore, to aid clinicians with making decisions to alter therapeutic protocol, I would like to predict patient-specific PFS.

To perform individual dynamic predictions, I employ the Claret tumor growth inhibition (TGI) model. I further develop this model by coupling it with two different survival models. Inter-patient heterogeneity is also taken into account through mixed effects, including covariate effects. Model PFS predictions were evaluated using receiver operating characteristic (ROC) curve analysis as well as Brier …

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 …

Detecting Gene-Gene Or Gene Environment Interactions In Association With Complex Disease Outcomes, Taiwo Adetunji Famuyiwa

Theses and Dissertations

Identifying gene–gene and gene–environment interaction is complicated and gainsaying most especially because of high multifactor dimensions involve in the analysis of such combination discrediting the functionality of parametric statistical method like Logistic Regression. [22] developed a multi-factor-dimensionality reduction (MDR) method for detecting and characterizing high-order gene-gene and gene-environment interactions in case-control and discordant-sib-pair studies with relatively small samples, which is inspired by the combinatorial partitioning method of [18]. [16] proposed Generalized MDR (GMDR) framework based on the score of a generalized linear model which allows adjustment of covariates, provides a unified framework for handling both dichotomous and quantitative phenotypes. However, …

Novel Feature Evaluation In Ultra-High Dimensional Right-Censored Data, With Applications To Head And Neck Cancer, Atika Farzana Urmi

Graduate Research Posters

Background: Head and neck cancer is the 6th most common cancer worldwide with an expected 1.08 million new cases each year. Such cancer data are ultra-high dimensional with thousands of clinical features and gene expressions, making it challenging for the traditional analytical tools to extract the potential biomarker for the cancer survival and control false discoveries. In addition, presence of heavy censoring can affect the screening procedures based on Kaplan-Meier (K-M) survival estimates.

Aim: To propose a model free, ultra-high dimensional feature screening method with two-dimensional survival outcome allowing false discovery rate (FDR) control.

Method: 516 primary tumor patients with …

Television Viewing Time And All-Cause Mortality: Interactions With Bmi, Physical Activity, Smoking, And Dietary Factors, Christopher T. Swain, Julie K. Bassett, Allison M. Hodge, David W. Dunstan, Neville Owen, Yi Yang, Harindra Jayasekara, James R. Hébert Scd, Nitin Shivappa Mbbs, Mph, Ph.D., Robert J. Macinnis, Roger L. Milne, Dallas R. English, Brigid M. Lynch

Faculty Publications

Background Higher levels of time spent sitting (sedentary behavior) contribute to adverse health outcomes, including earlier death. This effect may be modified by other lifestyle factors. We examined the association of television viewing (TV), a common leisure-time sedentary behavior, with all-cause mortality, and whether this is modified by body mass index (BMI), physical activity, smoking, alcohol intake, soft drink consumption, or diet-associated inflammation. Methods Using data from participants in the Melbourne Collaborative Cohort Study, flexible parametric survival models assessed the time-dependent association of self-reported TV time (three categories: < 2 h/day, 2-3 h/day, > 3 h/day) with all-cause mortality. Interaction terms were fitted to test whether …

Determinants Of Covid-19 Vaccinations Among A State-Wide Year-Long Surveillance Initiative In A Conservative Southern State, Lídia Gual-Gonzalez, Maggie S.J. Mccarter, Kyndall Dye-Braumuller, Stella Self, Connor H. Ross, Chloe Rodriguez-Ramos, Virginie G. Daguise, Melissa Nolan Ph.D., Mph

Faculty Publications

By the end of 2021, the COVID-19 pandemic resulted in over 54 million cases and more than 800,000 deaths in the United States, and over 350 million cases and more than 5 million deaths worldwide. The uniqueness and gravity of this pandemic have been reflected in the public health guidelines poorly received by a growing subset of the United States population. These poorly received guidelines, including vaccine receipt, are a highly complex psychosocial issue, and have impacted the successful prevention of disease spread. Given the intricate nature of this important barrier, any single statistical analysis methodologically fails to address all …

Multivariate Statistical Modeling For Radio-Genomics Study, Tiantian Zeng

Theses and Dissertations--Statistics

Radiogenomics is a new direction in cancer research that focuses on the associations among radiomics, genomics and clinical outcome. Currently, the major challenge for Radiogenomics lies in the effective integration of genomics and imaging data for promising clinical outcome prediction. Herein, we propose a multivariate joint model that can integrate imaging and genomic data for better predicting the clinical outcome. Specifically, we jointly consider two multivariate group lasso models, one regresses imaging features on genomic features, and the other regresses patient’s clinical outcome on genomic features. An L1 penalty term is introduced for each variable, and weight in the penalty …

Dependent Censoring In Survival Analysis, Zhongcheng Lin

Dissertations

This dissertation mainly consists of two parts. In the first part, some properties of bivariate Archimedean Copulas formed by two time-to-event random variables are discussed under the setting of left censoring, where these two variables are subject to one left-censored independent variable respectively. Some distributional results for their joint cdf under different censoring patterns are presented. Those results are expected to be useful in both model fitting and checking procedures for Archimedean copula models with bivariate left-censored data. As an application of the theoretical results that are obtained, a moment estimator of the dependence parameter in Archimedean copula models is …

General Approach Of Causal Mediation Analysis With Causally Ordered Multiple Mediators And Survival Outcome, An-Shun Tai, Pei-Hsuan Lin, Yen-Tsung Huang, Sheng-Hsuan Lin

Harvard University Biostatistics Working Paper Series

Causal mediation analysis with multiple mediators (causal multi-mediation analysis) is critical in understanding why an intervention works, especially in medical research. Deriving the path-specific effects (PSEs) of exposure on the outcome through a certain set of mediators can detail the causal mechanism of interest. However, the existing models of causal multi-mediation analysis are usually restricted to partial decomposition, which can only evaluate the cumulative effect of several paths. Moreover, the general form of PSEs for an arbitrary number of mediators has not been proposed. In this study, we provide a generalized definition of PSE for partial decomposition (partPSE) and for …

Flowgraph Models For Clustered Multistate Time To Event Data, Kristin Hall

USF Tampa Graduate Theses and Dissertations

Healthcare systems have multistate processes. Such processes may be modeled using flowgraphs, which are directed graphs. Flowgraph models support a variety of transition time distributions, easily handle reversibility between states and allow alternate paths to the event or state of interest to be taken. However, estimation of flowgraph and first passage time distribution parameters can lead to incorrect inferences when interdependent data are treated as independent.

In this dissertation, we expand the flowgraph model to accommodate nested and correlated data structures. We develop a framework to incorporate random effects into transition probability and transition time components of a flowgraph model. …

Efficiency Of Two Sample Tests Via The T-Mean Survival Time For Analyzing Event Time Observations, Lu Tian, Haoda Fu, Stephen J. Ruberg, Hajime Uno, Lj Wei

Harvard University Biostatistics Working Paper Series

In comparing two treatments with the event time observations, the hazard ratio (HR) estimate is routinely used to quantify the treatment difference. However, this model dependent estimate may be difficult to interpret clinically especially when the proportional hazards (PH) assumption is violated. An alternative estimation procedure for treatment efficacy based on the restricted means survival time or t-year mean survival time (t-MST) has been discussed extensively in the statistical and clinical literature. On the other hand, a statistical test 1 via the HR or its asymptotically equivalent counterpart, the logrank test, is asymptotically distribution-free. In this paper, we assess the …

Finding The Cutpoint Of A Continuous Covariate In A Parametric Survival Analysis Model, Kabita Joshi

Theses and Dissertations

In many clinical studies, continuous variables such as age, blood pressure and cholesterol are measured and analyzed. Often clinicians prefer to categorize these continuous variables into different groups, such as low and high risk groups. The goal of this work is to find the cutpoint of a continuous variable where the transition occurs from low to high risk group. Different methods have been published in literature to find such a cutpoint. We extended the methods of Contal and O’Quigley (1999) which was based on the log-rank test and the methods of Klein and Wu (2004) which was based on the …

Cox Regression Models With Functional Covariates For Survival Data, Jonathan E. Gellar, Elizabeth Colantuoni, Dale M. Needham, Ciprian M. Crainiceanu

Johns Hopkins University, Dept. of Biostatistics Working Papers

We extend the Cox proportional hazards model to cases when the exposure is a densely sampled functional process, measured at baseline. The fundamental idea is to combine penalized signal regression with methods developed for mixed effects proportional hazards models. The model is fit by maximizing the penalized partial likelihood, with smoothing parameters estimated by a likelihood-based criterion such as AIC or EPIC. The model may be extended to allow for multiple functional predictors, time varying coefficients, and missing or unequally-spaced data. Methods were inspired by and applied to a study of the association between time to death after hospital discharge …

A Predictive Enrichment Procedure To Identify Potential Responders To A New Therapy For Randomized, Comparative, Controlled Clinical Studies, Junlong Li, Lihui Zhao, Lu Tian, Tianxi Cai, Brian Claggett, Andrea Callegaro, Benjamin Dizier, Bart Spiessens, Fernando Ulloa-Montoya, L. J. Wei

Harvard University Biostatistics Working Paper Series

No abstract provided.

Penalized Smoothed Partial Rank Estimator For The Nonparametric Transformation Survival Model With High-Dimensional Covariates, Wei Dai, Yi Li

The University of Michigan Department of Biostatistics Working Paper Series

Microarray technology has the potential to lead to a better understanding of biological processes and diseases such as cancer. When failure time outcomes are also available, one might be interested in relating gene expression profiles to the survival outcome such as time to cancer recurrence or time to death. This is statistically challenging because the number of covariates greatly exceeds the number of observations. While the majority of work has focused on regularized Cox regression model and accelerated failure time model, they may be restrictive in practice. We relax the model assumption and and consider a nonparametric transformation model that …

A Frailty Approach For Survival Analysis With Error-Prone Covariate, Sehee Kim, Yi Li, Donna Spiegelman

The University of Michigan Department of Biostatistics Working Paper Series

This paper discovers an inherent relationship between the survival model with covariate measurement error and the frailty model. The discovery motivates our using a frailty-based estimating equation to draw inference for the proportional hazards model with error-prone covariates. Our established framework accommodates general distributional structures for the error-prone covariates, not restricted to a linear additive measurement error model or Gaussian measurement error. When the conditional distribution of the frailty given the surrogate is unknown, it is estimated through a semiparametric copula function. The proposed copula-based approach enables us to fit flexible measurement error models without the curse of dimensionality as …

Non-Likelihood Based Model Evaluation And Comparison With Application To Genetic And Clinical Hiv-1 Outcomes, Ashley Elise Giambrone

Legacy Theses & Dissertations (2009 - 2024)

Although treatment for human immunodeficiency virus type-1 (HIV-1) has undergone drastic change and morbidity and mortality has decreased over time, the development of drug-resistant HIV-1 is of concern for the long-term antiretroviral treatment of infected individuals. Drug-resistant virus is known to manifest with potentially complex mutational patterns in the HIV-1 genotype sequence and is associated with decreased response to therapy. Resistance occurs either as a result of development of mutations in the viral genome under selective drug pressure or as a result of naturally occurring polymorphisms. The most effective treatment methods are still debated at this time; however, current treatment …

A Monte Carlo Approach To Change Point Detection In A Liver Transplant, Alexia Melissa Makris

USF Tampa Graduate Theses and Dissertations

Patient survival post liver transplant (LT) is important to both the patient and the center's accreditation, but over the years physicians have noticed that distant patients struggle with post LT care. I hypothesized that patient's distance from the transplant center had a detrimental effect on post LT survival. I suspected Hepatitis C (HCV) and Hepatocellular Carcinoma (HCC) patients would deteriorate due to their recurrent disease and there is a need for close monitoring post LT. From the current literature it was not clear if patients' distance from a transplant center affects outcomes post LT. Firozvi et al. (Firozvi AA, 2008) …

Survival Prediction For Brain Tumor Patients Using Gene Expression Data, Vinicius Bonato

Dissertations and Theses (Open Access)

Brain tumor is one of the most aggressive types of cancer in humans, with an estimated median survival time of 12 months and only 4% of the patients surviving more than 5 years after disease diagnosis. Until recently, brain tumor prognosis has been based only on clinical information such as tumor grade and patient age, but there are reports indicating that molecular profiling of gliomas can reveal subgroups of patients with distinct survival rates. We hypothesize that coupling molecular profiling of brain tumors with clinical information might improve predictions of patient survival time and, consequently, better guide future treatment decisions. …