Marginal Structural Illness-Death Models for Semi-Competing Risks Data

The three-state illness death model has been established as a general approach for regression analysis of semi-competing risks data. For observational data the marginal structural models (MSM) are a useful tool, under the potential outcomes framework to define and estimate parameters with causal interpretations. In this paper we introduce a class of marginal structural illness death models for the analysis of observational semi competing risks data. We consider two specific such models, the usual Markov illness death MSM and the general Markov illness death MSM where the latter incorporates a frailty term. For interpretation purposes, risk contrasts under the MSMs are defined. Inference under the usual Markov MSM can be carried out using estimating equations with inverse probability weighting, while inference under the general Markov MSM requires a weighted EM algorithm. We study the inference procedures under both MSMs using extensive simulations, and apply them to the analysis of mid-life alcohol exposure on late life cognitive impairment as well as mortality using the Honolulu-Asia Aging Study data set. The R codes developed in this work have been implemented in the R package semicmprskcoxmsm that is publicly available on CRAN

On Defense of the Hazard Ratio

There has been debate on whether the hazard function should be used for causal inference in time-to-event studies. The main criticism is that there is selection bias because the risk sets beyond the first event time are comprised of subsets of survivors who are no longer balanced in the risk factors, even in the absence of unmeasured confounding, measurement error, and model misspecification. In this short communication we use the potential outcomes framework and the single-world intervention graph to show that there is indeed no selection bias when estimating the average treatment effect, and that the hazard ratio over time can provide a useful interpretation in practical settings

Doubly Robust Estimation under Covariate-Induced Dependent Left Truncation

In prevalent cohort studies with follow-up, the time-to-event outcome is subject to left truncation leading to selection bias. For estimation of the distribution of time-to-event, conventional methods adjusting for left truncation tend to rely on the (quasi-)independence assumption that the truncation time and the event time are "independent" on the observed region. This assumption is violated when there is dependence between the truncation time and the event time possibly induced by measured covariates. Inverse probability of truncation weighting leveraging covariate information can be used in this case, but it is sensitive to misspecification of the truncation model. In this work, we apply the semiparametric theory to find the efficient influence curve of an expected (arbitrarily transformed) survival time in the presence of covariate-induced dependent left truncation. We then use it to construct estimators that are shown to enjoy double-robustness properties. Our work represents the first attempt to construct doubly robust estimators in the presence of left truncation, which does not fall under the established framework of coarsened data where doubly robust approaches are developed. We provide technical conditions for the asymptotic properties that appear to not have been carefully examined in the literature for time-to-event data, and study the estimators via extensive simulation. We apply the estimators to two data sets from practice, with different right-censoring patterns

Semiparametrically Efficient Score for the Survival Odds Ratio

We consider a general proportional odds model for survival data under binary treatment, where the functional form of the covariates is left unspecified. We derive the efficient score for the conditional survival odds ratio given the covariates using modern semiparametric theory. The efficient score may be useful in the development of doubly robust estimators, although computational challenges remain