Multivariate frailty models for two types of recurrent events with a dependent terminal event: application to breast cancer data.

Individuals may experience more than one type of recurrent event and a terminal event during the life course of a disease. Follow-up may be interrupted for several reasons, including the end of a study, or patients lost to follow-up, which are non informative censoring events. Death could also stop the follow-up, hence, it is considered as a dependent terminal event. We propose a multivariate frailty model that jointly analyzes two types of recurrent events with a dependent terminal event. Two estimation methods are proposed: a semiparametrical approach using penalized likelihood estimation where baseline hazard functions are approximated by M-s plines, and another one with piecewise constant baseline hazard functions. Finally, we derived martingale residuals to check the goodness-of-fit. We illustrate our proposals with a real dataset on breast cancer. The main objective was to model the dependency between the two types of recurrent events (locoregional and metastatic) and the terminal event (death) after a breast cancer.