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Assessing surrogate endpoints in vaccine trials with case-cohort sampling and the Cox model. (English) Zbl 1138.62082

Summary: 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 C. Frangakis and D. Rubin [Principal stratification in causal inference. Biometrics 58, 21–29 (2002)] and adapted by P. B. Gilbert and M. G. Hudgens [Evaluating causal effect predictiveness of candidate surrogate endpoints. Working Paper 291, UW Biostatistics (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 relationships 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.

MSC:

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

References:

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