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Statistics in Medicine
Article . 2012 . Peer-reviewed
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Estimation of treatment effect under non‐proportional hazards and conditionally independent censoring

Authors: Adam P. Boyd; John Kittelson; Daniel L. Gillen;

Estimation of treatment effect under non‐proportional hazards and conditionally independent censoring

Abstract

In clinical trials with time‐to‐event outcomes, it is common to estimate the marginal hazard ratio from the proportional hazards model, even when the proportional hazards assumption is not valid. This is unavoidable from the perspective that the estimator must be specified a priori if probability statements about treatment effect estimates are desired. Marginal hazard ratio estimates under non‐proportional hazards are still useful, as they can be considered to be average treatment effect estimates over the support of the data. However, as many have shown, under non‐proportional hazard, the ‘usual’ unweighted marginal hazard ratio estimate is a function of the censoring distribution, which is not normally considered to be scientifically relevant when describing the treatment effect. In addition, in many practical settings, the censoring distribution is only conditionally independent (e.g., differing across treatment arms), which further complicates the interpretation. In this paper, we investigate an estimator of the hazard ratio that removes the influence of censoring and propose a consistent robust variance estimator. We compare the coverage probability of the estimator to both the usual Cox model estimator and an estimator proposed by Xu and O'Quigley (2000) when censoring is independent of the covariate. The new estimator should be used for inference that does not depend on the censoring distribution. It is particularly relevant to adaptive clinical trials where, by design, censoring distributions differ across treatment arms. Copyright © 2012 John Wiley & Sons, Ltd.

Keywords

Analysis of Variance, Time Factors, Treatment Outcome, Bias, Brain Neoplasms, Sample Size, Humans, Computer Simulation, Neoplasm Metastasis, Proportional Hazards Models, Randomized Controlled Trials as Topic

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    Top 10%
    influence
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citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
23
Top 10%
Top 10%
Average
bronze