Analysis of composite endpoints with component-wise censoring in the presence of differential visit schedules

Composite endpoints are very common in clinical research, such as recurrence-free survival in oncology research, defined as the earliest of either death or disease recurrence. Because of the way data are collected in such studies, component-wise censoring is common, where, for example, recurrence is an interval-censored event and death is a right-censored event. However, a common way to analyze such component-wise censored composite endpoints is to treat them as right-censored, with the date at which the non-fatal event was detected serving as the date the event occurred. This approach is known to introduce upward bias when the Kaplan-Meier estimator is applied, but has more complex impact on semi-parametric regression approaches. In this article we compare the performance of the Cox model estimators for right-censored data and the Cox model estimators for interval-censored data in the context of component-wise censored data where the visit process differs across levels of a covariate of interest, a common scenario in observational data. We additionally examine estimators of the cause-specific hazard when applied to the individual components of such component-wise censored composite endpoints. We found that when visit schedules differed according to levels of a covariate of interest, the Cox model estimators for right-censored data and the estimators for cause-specific hazards were increasingly biased as the frequency of visits decreased. The Cox model estimator for interval-censored data with censoring at the last disease-free date is recommended for use in the presence of differential visit schedules.