  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.
