Using Frailty Models to Identify the Longitudinal Biomarkers in Survival Analysis

We introduce a score test to identify longitudinal biomarkers or surrogates for a time to event outcome. This method is an extension of Henderson et al. (2000 Henderson , R. , Diggle , P. , Dobson , A. ( 2000 ). Joint modelling of longitudinal measurements and event time data . Biostatistics 1 ( 4 ): 465 – 480 .[Crossref], [PubMed] , [Google Scholar], 2002 Henderson , R. , Diggle , P. , Dobson , A. ( 2002 ). Identification and efficacy of longitudinal markers for survival . Biostatistics 3 ( 1 ): 33 – 50 .[Crossref], [PubMed], [Web of Science ®] , [Google Scholar]). In this article, a score test is based on a joint likelihood function which combines the likelihood functions of the longitudinal biomarkers and the survival times. Henderson et al. (2000 Henderson , R. , Diggle , P. , Dobson , A. ( 2000 ). Joint modelling of longitudinal measurements and event time data . Biostatistics 1 ( 4 ): 465 – 480 .[Crossref], [PubMed] , [Google Scholar], 2002 Henderson , R. , Diggle , P. , Dobson , A. ( 2002 ). Identification and efficacy of longitudinal markers for survival . Biostatistics 3 ( 1 ): 33 – 50 .[Crossref], [PubMed], [Web of Science ®] , [Google Scholar]) assumed that the same random effect exists in the longitudinal component and in the Cox model and then they can derive a score test to determine if a longitudinal biomarker is associated with time to an event. We extend this work and our score test is based on a joint likelihood function which allows other random effects to be present in the survival function.

Considering heterogeneous baseline hazards in individuals, we use simulations to explore how the factors can influence the power of a score test to detect the association of a longitudinal biomarker and the survival time. These factors include the functional form of the random effects from the longitudinal biomarkers, in the different number of individuals, and time points per individual. We illustrate our method using a prothrombin index as a predictor of survival in liver cirrhosis patients.