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.

翻译：背景：随着晚期疾病患者接近生命终点，不良结局事件的发生率会上升。因此，那些倾向于在生命终点附近发生的暴露（例如使用轮椅、氧疗和姑息治疗）可能会被发现与不良结局的发生相关。我们提出一种时间-事件分析策略，以减轻时变混杂效应。方法：我们提出了反向死亡时间（rTTD）的概念，并将其用作时间-事件分析中的时间尺度。我们使用新加坡晚期癌症患者接受社区姑息治疗（暴露）与急诊就诊（结局）的数据进行说明。我们将结果与使用研究时间（TOS）作为时间尺度的常见做法进行比较。结果：图示分析表明，接受姑息治疗的癌症患者比未接受者有更高的急诊就诊率，主要是因为他们更接近生命终点，而rTTD分析则比较了处于相同死亡时间点的患者。使用TOS时间尺度分析急诊就诊与姑息治疗的关系时发现，当从统计调整中忽略观察到的时变协变量时，风险比估计值显著增加（估计值变化=0.38；95% CI 0.15 至 0.60）。而在使用rTTD的相同分析中则没有这种变化（估计值变化=0.04；95% CI -0.02 至 0.11），这证明了rTTD时间尺度能够减轻与死亡时间相关的、日益增强的混杂效应。结论：在时间-事件分析中使用rTTD作为时间尺度，为控制晚期疾病研究中的时变混杂效应提供了一种简单而稳健的方法，即使混杂因素未被测量。