arXiv subjects

Denise Esserman

Publications and source records attributed to Denise Esserman.

9 recordsLinked to original sources

arXiv2025

Correlation Matters! Streamlining the Sample Size Procedure with Composite Time-to-event Endpoints

Composite endpoints are widely used in cardiovascular clinical trials to improve statistical efficiency while preserving clinical relevance. The Win Ratio (WR) measure and more general frameworks of Win Statistics have emerged as increasingly popular alternatives to traditional time-to-first-event analyses. Although analytic sample size formulas for WR have been developed, they rely on design parameters that are often not straightforward to specify. Consequently, sample size determination in clinical trials with WR as the primary analysis is most often based on simulations, which can be computationally intensive. Moreover, these simulations commonly assume independence among component endpoints, an assumption that may not hold in practice and can lead to misleading power estimates. To address this challenge, we derive refined formulas to calculate the proportions of wins, losses, and ties for multiple prioritized time-to-event endpoints. These formulas rely on familiar design inputs and become directly applicable when integrated with existing sample size methods. We conduct a comprehensive assessment of how correlation among endpoints affects sample size requirements across varying design features. We further demonstrate the role of correlations through two case studies based on the landmark SPRINT and STICH clinical trials to generate further insights.

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arXiv2024

Misclassification of Vaccination Status in Electronic Health Records: A Bayesian Approach in Cluster Randomized Trials

Misclassification in binary outcomes is not uncommon and statistical methods to investigate its impact on policy-driving study results are lacking. While misclassifying binary outcomes is a statistically ubiquitous phenomena, we focus on misclassification in a public health application: vaccinations. One such study design in public health that addresses policy is the cluster controlled randomized trial (CCRT). A CCRT that measures the impact of a novel behavioral intervention on increasing vaccine uptake can be severely biased when the supporting data are incomplete vaccination records. In particular, these vaccine records more often may be prone to negative misclassification, that is, a clinic's record of an individual patient's vaccination status may be unvaccinated when, in reality, this patient was vaccinated outside of the clinic. With large nation-wide endeavors to encourage vaccinations without a gold-standard vaccine record system, sensitivity analyses that incorporate misclassification rates are promising for robust inference. In this work we introduce a novel extension of Bayesian logistic regression where we perturb the clinic size and vaccination count with random draws from expert-elicited prior distributions. These prior distributions represent the misclassification rates for each clinic that stochastically add unvaccinated counts to the observed vaccinated counts. These prior distributions are assigned for each clinic (the first level in a group-level randomized trial). We demonstrate this method with a data application from a CCRT evaluating the influence of a behavioral intervention on vaccination uptake among U.S. veterans. A simulation study is carried out demonstrating its estimation properties.

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arXiv2023

Power calculation for cross-sectional stepped wedge cluster randomized trials with a time-to-event endpoint

Stepped wedge cluster randomized trials (SW-CRTs) are a form of randomized trial whereby clusters are progressively transitioned from control to intervention, with the timing of transition randomized for each cluster. An important task at the design stage is to ensure that the planned trial has sufficient power. While methods for determining power have been well-developed for SW-CRTs with continuous and binary outcomes, limited methods for power calculation are available for SW-CRTs with censored time-to-event outcomes. In this article, we propose a stratified marginal Cox model to analyze cross-sectional SW-CRTs and then derive an explicit expression of the robust sandwich variance to facilitate power calculations without the need for computationally intensive simulations. Power formulas based on both the Wald and robust score tests are developed, assuming constant within-period and between-period correlation parameters, and are further validated via simulation under different finite-sample scenarios. Finally, we illustrate our methods in the context of a SW-CRT testing the effect of a new electronic reminder system on time to catheter removal in hospital settings. We also offer an R Shiny application to facilitate sample size and power calculations using our proposed methods.

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arXiv2023

Group sequential two-stage preference designs

The two-stage preference design (TSPD) enables the inference for treatment efficacy while allowing for incorporation of patient preference to treatment. It can provide unbiased estimates for selection and preference effects, where a selection effect occurs when patients who prefer one treatment respond differently than those who prefer another, and a preference effect is the difference in response caused by an interaction between the patient's preference and the actual treatment they receive. One potential barrier to adopting TSPD in practice, however, is the relatively large sample size required to estimate selection and preference effects with sufficient power. To address this concern, we propose a group sequential two-stage preference design (GS-TSPD), which combines TSPD with sequential monitoring for early stopping. In the GS-TSPD, pre-planned sequential monitoring allows investigators to conduct repeated hypothesis tests on accumulated data prior to full enrollment to assess study eligibility for early trial termination without inflating type I error rates. Thus, the procedure allows investigators to terminate the study when there is sufficient evidence of treatment, selection, or preference effects during an interim analysis, thereby reducing the design resource in expectation. To formalize such a procedure, we verify the independent increments assumption for testing the selection and preference effects and apply group sequential stopping boundaries from the approximate sequential density functions. Simulations are then conducted to investigate the operating characteristics of our proposed GS-TSPD compared to the traditional TSPD. We demonstrate the applicability of the design using a study of Hepatitis C treatment modality.

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arXiv2023

Bayesian pathway analysis over brain network mediators for survival data

Technological advancements in noninvasive imaging facilitate the construction of whole brain interconnected networks, known as brain connectivity. Existing approaches to analyze brain connectivity frequently disaggregate the entire network into a vector of unique edges or summary measures, leading to a substantial loss of information. Motivated by the need to explore the effect mechanism among genetic exposure, brain connectivity and time to disease onset, we propose an integrative Bayesian framework to model the effect pathway between each of these components while quantifying the mediating role of brain networks. To accommodate the biological architectures of brain connectivity constructed along white matter fiber tracts, we develop a structural modeling framework that includes a symmetric matrix-variate accelerated failure time model and a symmetric matrix response regression to characterize the effect paths. We further impose within-graph sparsity and between-graph shrinkage to identify informative network configurations and eliminate the interference of noisy components. Extensive simulations confirm the superiority of our method compared with existing alternatives. By applying the proposed method to the landmark Alzheimer's Disease Neuroimaging Initiative study, we obtain neurobiologically plausible insights that may inform future intervention strategies.

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arXiv2023

Maximin optimal cluster randomized designs for assessing treatment effect heterogeneity

Cluster randomized trials (CRTs) are studies where treatment is randomized at the cluster level but outcomes are typically collected at the individual level. When CRTs are employed in pragmatic settings, baseline population characteristics may moderate treatment effects, leading to what is known as heterogeneous treatment effects (HTEs). Pre-specified, hypothesis-driven HTE analyses in CRTs can enable an understanding of how interventions may impact subpopulation outcomes. While closed-form sample size formulas have recently been proposed, assuming known intracluster correlation coefficients (ICCs) for both the covariate and outcome, guidance on optimal cluster randomized designs to ensure maximum power with pre-specified HTE analyses has not yet been developed. We derive new design formulas to determine the cluster size and number of clusters to achieve the locally optimal design (LOD) that minimizes variance for estimating the HTE parameter given a budget constraint. Given the LODs are based on covariate and outcome-ICC values that are usually unknown, we further develop the maximin design for assessing HTE, identifying the combination of design resources that maximize the relative efficiency of the HTE analysis in the worst case scenario. In addition, given the analysis of the average treatment effect is often of primary interest, we also establish optimal designs to accommodate multiple objectives by combining considerations for studying both the average and heterogeneous treatment effects. We illustrate our methods using the context of the Kerala Diabetes Prevention Program CRT, and provide an R Shiny app to facilitate calculation of optimal designs under a wide range of design parameters.

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arXiv2022

Bayesian semi-parametric inference for clustered recurrent events with zero-inflation and a terminal event/4163305

Recurrent event data are common in clinical studies when participants are followed longitudinally, and are often subject to a terminal event. With the increasing popularity of large pragmatic trials with a heterogeneous source population, participants are often nested in clinics and can be either susceptible or structurally unsusceptible to the recurrent process. These complications require new modeling strategies to accommodate potential zero-event inflation as well as hierarchical data structures in both the terminal and non-terminal event processes. In this paper, we develop a Bayesian semi-parametric model to jointly characterize the zero-inflated recurrent event process and the terminal event process. We use a point mass mixture of non-homogeneous Poisson processes to describe the recurrent intensity and introduce shared random effects from different sources to bridge the non-terminal and terminal event processes. To achieve robustness, we consider nonparametric Dirichlet processes to model the residual of the accelerated failure time model for the survival process as well as the cluster-specific frailty distribution, and develop a Markov Chain Monte Carlo algorithm for posterior inference. We demonstrate the superiority of our proposed model compared with competing models via simulations and apply our method to a pragmatic cluster randomized trial for fall injury prevention among the elderly.

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arXiv2021

Competing risks regression for clustered survival data via the marginal additive subdistribution hazards model

A population-averaged additive subdistribution hazards model is proposed to assess the marginal effects of covariates on the cumulative incidence function and to analyze correlated failure time data subject to competing risks. This approach extends the population-averaged additive hazards model by accommodating potentially dependent censoring due to competing events other than the event of interest. Assuming an independent working correlation structure, an estimating equations approach is outlined to estimate the regression coefficients and a new sandwich variance estimator is proposed. The proposed sandwich variance estimator accounts for both the correlations between failure times and between the censoring times, and is robust to misspecification of the unknown dependency structure within each cluster. We further develop goodness-of-fit tests to assess the adequacy of the additive structure of the subdistribution hazards for the overall model and each covariate. Simulation studies are conducted to investigate the performance of the proposed methods in finite samples. We illustrate our methods using data from the STrategies to Reduce Injuries and Develop confidence in Elders (STRIDE) trial.

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arXiv2021

Bayesian local exchangeability design for phase II basket trials

We propose an information borrowing strategy for the design and monitoring of phase II basket trials based on the local multisource exchangeability assumption between baskets (disease types). In our proposed local-MEM framework, information borrowing is only allowed to occur locally, i.e., among baskets with similar response rate and the amount of information borrowing is determined by the level of similarity in response rate, whereas baskets not considered similar are not allowed to share information. We construct a two-stage design for phase II basket trials using the proposed strategy. The proposed method is compared to competing Bayesian methods and Simon's two-stage design in a variety of simulation scenarios. We demonstrate the proposed method is able to maintain the family-wise type I error rate at a reasonable level and has desirable basket-wise power compared to Simon's two-stage design. In addition, our method is computationally efficient compared to existing Bayesian methods in that the posterior profiles of interest can be derived explicitly without the need for sampling algorithms.

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