A framework for joint assessment of a terminal event and a score existing only in the absence of the terminal event

TL;DR

This paper introduces a joint assessment framework for evaluating treatment effects on terminal events and disease scores in vulnerable populations, using semi-parametric methods and a novel testing procedure.

Contribution

It proposes a new statistical approach to simultaneously analyze terminal events and disease scores without the confounding effect of terminal events, applicable in clinical trial settings.

Findings

The method provides robust, efficient estimates of risks and scores at a landmark time.

A closed testing procedure enhances confirmatory assessment of treatment effects.

Simulation and real trial analysis demonstrate the approach's effectiveness.

Abstract

Analysis of data from randomized controlled trials in vulnerable populations requires special attention when assessing treatment effect by a score measuring, e.g., disease stage or activity together with onset of prevalent terminal events. In reality, it is impossible to disentangle a disease score from the terminal event, since the score is not clinically meaningful after this event. In this work, we propose to assess treatment interventions simultaneously on the terminal event and the disease score in the absence of a terminal event. Our proposal is based on a natural data-generating mechanism, respecting that a disease score does not exist beyond the terminal event. We use modern semi-parametric statistical methods to provide robust and efficient estimation of the risk of terminal event and expected disease score conditional on no terminal event at a pre-specified landmark time. We also use the simultaneous asymptotic behaviour of our estimators to develop a powerful closed testing procedure for confirmatory assessment of treatment effect on both onset of terminal event and level of disease score in the absence of a terminal event. A simulation study mimicking a large-scale outcome trial in chronic kidney patients as well as an analysis of that trial is provided to assess performance.