Abstract
A common objective of cohort studies and clinical trials is to assess time-varying longitudinal continuous biomarkers as correlates of the instantaneous hazard of a study endpoint. We consider the setting where the biomarkers are measured in a designed sub-sample (i.e., case-cohort or two-phase sampling design), as is normative for prevention trials. We address this problem via joint models, with underlying biomarker trajectories characterized by a random effects model and their relationship with instantaneous risk characterized by a Cox model. For estimation and inference we extend the conditional score method of Tsiatis and Davidian (Biometrika 88(2):447–458, 2001) to accommodate the two-phase biomarker sampling design using augmented inverse probability weighting with nonparametric kernel regression. We present theoretical properties of the proposed estimators and finite-sample properties derived through simulations, and illustrate the methods with application to the AIDS Clinical Trials Group 175 antiretroviral therapy trial. We discuss how the methods are useful for evaluating a Prentice surrogate endpoint, mediation, and for generating hypotheses about biological mechanisms of treatment efficacy.
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Acknowledgments
This work was supported by the National Institute Of Allergy And Infectious Diseases of the National Institutes of Health [Award Numbers R37AI054165, UM1AI068635], and by the Bill and Melinda Gates Foundation [Award Number OPP1110049]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or BMGF. The authors thank Ching-Yun Wang for statistical input, the AIDS Clinical Trials Group (ACTG) operations, laboratory, and statistical data management centers for generating and providing the ACTG 175 data, and the ACTG 175 study participants and investigators, in particular protocol chair Scott Hammer who reviewed and approved this work.
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Fu, R., Gilbert, P.B. Joint modeling of longitudinal and survival data with the Cox model and two-phase sampling. Lifetime Data Anal 23, 136–159 (2017). https://doi.org/10.1007/s10985-016-9364-1
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DOI: https://doi.org/10.1007/s10985-016-9364-1