Reverse time-to-death as time-scale in time-to-event analysis for studies of advanced illness and palliative care

TL;DR

This paper introduces reverse time-to-death as a novel time-scale for time-to-event analysis, effectively reducing confounding in studies of advanced illness and palliative care by aligning patients at similar proximity to end-of-life.

Contribution

The study proposes and demonstrates the use of reverse time-to-death as a new analytical approach to mitigate time-varying confounding in end-of-life research.

Findings

rTTD analysis aligns patients by proximity to death, reducing confounding.

Using rTTD minimizes bias from unmeasured confounders in palliative care studies.

Traditional TOS analysis shows inflated hazard ratios due to confounding near end-of-life.

Abstract

Background: Incidence of adverse outcome events rises as patients with advanced illness approach end-of-life. Exposures that tend to occur near end-of-life, e.g., use of wheelchair, oxygen therapy and palliative care, may therefore be found associated with the incidence of the adverse outcomes. We propose a strategy for time-to-event analysis to mitigate the time-varying confounding. Methods: We propose a concept of reverse time-to-death (rTTD) and its use for the time-scale in time-to-event analysis. We used data on community-based palliative care uptake (exposure) and emergency department visits (outcome) among patients with advanced cancer in Singapore to illustrate. We compare the results against that of the common practice of using time-on-study (TOS) as time-scale. Results: Graphical analysis demonstrated that cancer patients receiving palliative care had higher rate of emergency department visits than non-recipients mainly because they were closer to end-of-life, and that rTTD analysis made comparison between patients at the same time-to-death. Analysis of emergency department visits in relation to palliative care using TOS time-scale showed significant increase in hazard ratio estimate when observed time-varying covariates were omitted from statistical adjustment (change-in-estimate=0.38; 95% CI 0.15 to 0.60). There was no such change in otherwise the same analysis using rTTD (change-in-estimate=0.04; 95% CI -0.02 to 0.11), demonstrating the ability of rTTD time-scale to mitigate confounding that intensifies in relation to time-to-death. Conclusion: Use of rTTD as time-scale in time-to-event analysis provides a simple and robust approach to control time-varying confounding in studies of advanced illness, even if the confounders are unmeasured.