Inference in pseudo-observation-based regression using (biased) covariance estimation and naive bootstrapping

The pseudo-observation method is regularly applied to time-to-event data. However, to date such analyses have relied on not formally verified statements or ad-hoc methods regarding covariance estimation. This paper strives to close this gap in the literature. To begin with, we demonstrate that the usual Huber-White estimator is not consistent for the limiting covariance of parameter estimates in pseudo-observation regression approaches. By confirming that a plug-in estimator can be used instead, we obtain asymptotically exact and consistent tests for general linear hypotheses in the parameters of the model. Additionally, we confirm that naive bootstrapping can not be used for covariance estimation in the pseudo-observation model either. However, it can be used for hypothesis testing by applying a suitable studentization. Simulations illustrate the good performance of our proposed methods in many scenarios. Finally, we obtain a general uniform law of large numbers for U- and V-statistics, as such statistics are central in the mathematical analysis of the inference procedures developed in this work.