Assessing surrogate endpoints in vaccine trials with case-cohort sampling and the Cox model

DOI10.1214/07-AOAS132zbMATH Open1138.62082arXiv0803.3919WikidataQ37012786 ScholiaQ37012786MaRDI QIDQ2482986FDOQ2482986

Li Qin, Dongfeng Li, Dean A. Follmann, Peter B. Gilbert

Publication date: 30 April 2008

Published in: The Annals of Applied Statistics (Search for Journal in Brave)

Abstract: Assessing immune responses to study vaccines as surrogates of protection plays a central role in vaccine clinical trials. Motivated by three ongoing or pending HIV vaccine efficacy trials, we consider such surrogate endpoint assessment in a randomized placebo-controlled trial with case-cohort sampling of immune responses and a time to event endpoint. Based on the principal surrogate definition under the principal stratification framework proposed by Frangakis and Rubin [Biometrics 58 (2002) 21--29] and adapted by Gilbert and Hudgens (2006), we introduce estimands that measure the value of an immune response as a surrogate of protection in the context of the Cox proportional hazards model. The estimands are not identified because the immune response to vaccine is not measured in placebo recipients. We formulate the problem as a Cox model with missing covariates, and employ novel trial designs for predicting the missing immune responses and thereby identifying the estimands. The first design utilizes information from baseline predictors of the immune response, and bridges their relationship in the vaccine recipients to the placebo recipients. The second design provides a validation set for the unmeasured immune responses of uninfected placebo recipients by immunizing them with the study vaccine after trial closeout. A maximum estimated likelihood approach is proposed for estimation of the parameters. Simulated data examples are given to evaluate the proposed designs and study their properties.

Full work available at URL: https://arxiv.org/abs/0803.3919

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zbMATH Keywords

missing datapotential outcomesprincipal stratificationclinical trialsurrogate markerdiscrete failure time model

Mathematics Subject Classification ID

Estimation in survival analysis and censored data (62N02) Applications of statistics to biology and medical sciences; meta analysis (62P10)

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Cited In (12)

• Design and estimation for evaluating principal surrogate markers in vaccine trials
• Predicting overall vaccine efficacy in a new setting by re-calibrating baseline covariate and intermediate response endpoint effect modifiers of type-specific vaccine efficacy
• A Multiple Imputation Approach for the Evaluation of Surrogate Markers in the Principal Stratification Causal Inference Framework
• A Bayesian Approach to Improved Estimation of Causal Effect Predictiveness for a Principal Surrogate Endpoint
• Solutions for Surrogacy Validation with Longitudinal Outcomes for a Gene Therapy
• Surrogacy validation for time-to-event outcomes with illness-death frailty models
• Simultaneous inference of treatment effect modification by intermediate response endpoint principal strata with application to vaccine trials
• Efficient nonparametric inference on the effects of stochastic interventions under two‐phase sampling, with applications to vaccine efficacy trials
• Identification of causal effects within principal strata using auxiliary variables
• Evaluating principal surrogate markers in vaccine trials in the presence of multiphase sampling
• Augmented Designs to Assess Principal Strata Direct Effects
• A unified evaluation of differential vaccine efficacy

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