Semiparametric Marginal Regression for Clustered Competing Risks Data with Missing Cause of Failure

TL;DR

This paper introduces a novel semiparametric method for analyzing clustered competing risks data with missing causes, accounting for informative cluster size and missingness, and demonstrates its effectiveness through simulations and real data application.

Contribution

It develops the first population-averaged analysis approach for clustered competing risks data with missing causes and informative cluster size, using a maximum partial pseudolikelihood estimator.

Findings

Method performs well in simulations.

Ignoring within-cluster dependence leads to invalid inferences.

Applied successfully to HIV study data.

Abstract

Clustered competing risks data are commonly encountered in multicenter studies. The analysis of such data is often complicated due to informative cluster size, a situation where the outcomes under study are associated with the size of the cluster. In addition, cause of failure is frequently incompletely observed in real-world settings. To the best of our knowledge, there is no methodology for population-averaged analysis with clustered competing risks data with informative cluster size and missing causes of failure. To address this problem, we consider the semiparametric marginal proportional cause-specific hazards model and propose a maximum partial pseudolikelihood estimator under a missing at random assumption. To make the latter assumption more plausible in practice, we allow for auxiliary variables that may be related to the probability of missingness. The proposed method does not impose assumptions regarding the within-cluster dependence and allows for informative cluster size. The asymptotic properties of the proposed estimators for both regression coefficients and infinite-dimensional parameters, such as the marginal cumulative incidence functions, are rigorously established. Simulation studies show that the proposed method performs well and that methods that ignore the within-cluster dependence and the informative cluster size lead to invalid inferences. The proposed method is applied to competing risks data from a large multicenter HIV study in sub-Saharan Africa where a significant portion of causes of failure is missing.