title: Joint modeling of longitudinal and survival data with the Cox model and two-phase sampling.
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.
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA, 98195, USA. rongf@uw.edu.
authors.forename: Rong
authors.identifier: 0000-0002-6961-986X
authors.initials: R
authors.lastname: Fu
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA, 98195, USA.|Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Gilbert
mesh_terms: D015415:Biomarkers; D015331:Cohort Studies; D023381:Endpoint Determination; D006801:Humans; D016016:Proportional Hazards Models
chemical_list: D015415:Biomarkers
keywords: Case-cohort; Measurement error; Prentice surrogate endpoint evaluation; Proportional hazards model; Random effects model