Joint frailty modeling of time-to-event data to elicit the evolution pathway of events: a generalized linear mixed model approach

Multimorbidity constitutes a serious challenge on the healthcare systems in the world, due to its association with poorer health-related outcomes, more complex clinical management, increases in health service utilization and costs, but a decrease in productivity. However, to date, most evidence on multimorbidity is derived from cross-sectional studies that have limited capacity to understand the pathway of multimorbid conditions. In this article, we present an innovative perspective on analyzing longitudinal data within a statistical framework of survival analysis of time-to-event recurrent data. The proposed methodology is based on a joint frailty modeling approach with multivariate random effects to account for the heterogeneous risk of failure and the presence of informative censoring due to a terminal event. We develop a generalized linear mixed model method for the efficient estimation of parameters. We demonstrate the capacity of our approach using a real cancer registry data set on the multimorbidity of melanoma patients and document the relative performance of the proposed joint frailty model to the natural competitor of a standard frailty model via extensive simulation studies. Our new approach is timely to advance evidence-based knowledge to address increasingly complex needs related to multimorbidity and develop interventions that are most effective and viable to better help a large number of individuals with multiple conditions.