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Causal Mediation Analysis of Survival Outcome with Multiple Mediators.

ABSTRACT: Mediation analyses have been a popular approach to investigate the effect of an exposure on an outcome through a mediator. Mediation models with multiple mediators have been proposed for continuous and dichotomous outcomes. However, development of multimediator models for survival outcomes is still limited.We present methods for multimediator analyses using three survival models: Aalen additive hazard models, Cox proportional hazard models, and semiparametric probit models. Effects through mediators can be characterized by path-specific effects, for which definitions and identifiability assumptions are provided. We derive closed-form expressions for path-specific effects for the three models, which are intuitively interpreted using a causal diagram.Mediation analyses using Cox models under the rare-outcome assumption and Aalen additive hazard models consider effects on log hazard ratio and hazard difference, respectively; analyses using semiparametric probit models consider effects on difference in transformed survival time and survival probability. The three models were applied to a hepatitis study where we investigated effects of hepatitis C on liver cancer incidence mediated through baseline and/or follow-up hepatitis B viral load. The three methods show consistent results on respective effect scales, which suggest an adverse estimated effect of hepatitis C on liver cancer not mediated through hepatitis B, and a protective estimated effect mediated through the baseline (and possibly follow-up) of hepatitis B viral load.Causal mediation analyses of survival outcome with multiple mediators are developed for additive hazard and proportional hazard and probit models with utility demonstrated in a hepatitis study.

SUBMITTER: Huang YT

PROVIDER: S-EPMC5408128 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Causal Mediation Analysis of Survival Outcome with Multiple Mediators.

Huang Yen-Tsung YT Yang Hwai-I HI

Epidemiology (Cambridge, Mass.) 20170501 3

<h4>Background</h4>Mediation analyses have been a popular approach to investigate the effect of an exposure on an outcome through a mediator. Mediation models with multiple mediators have been proposed for continuous and dichotomous outcomes. However, development of multimediator models for survival outcomes is still limited.<h4>Methods</h4>We present methods for multimediator analyses using three survival models: Aalen additive hazard models, Cox proportional hazard models, and semiparametric p ...[more]

PMID: 28296661

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Project description:BackgroundMapping expression quantitative trait loci (eQTLs) has provided insight into gene regulation. Compared to cis-eQTLs, the regulatory mechanisms of trans-eQTLs are less known. Previous studies suggest that trans-eQTLs may regulate expression of remote genes by altering the expression of nearby genes. Trans-association has been studied in the mediation analysis with a single mediator. However, prior applications with one mediator are prone to model misspecification due to correlations between genes. Motivated from the observation that trans-eQTLs are more likely to associate with more than one cis-gene than randomly selected SNPs in the GTEx dataset, we developed a computational method to identify trans-eQTLs that are mediated by multiple mediators.ResultsWe proposed two hypothesis tests for testing the total mediation effect (TME) and the component-wise mediation effects (CME), respectively. We demonstrated in simulation studies that the type I error rates were controlled in both tests despite model misspecification. The TME test was more powerful than the CME test when the two mediation effects are in the same direction, while the CME test was more powerful than the TME test when the two mediation effects are in opposite direction. Multiple mediator analysis had increased power to detect mediated trans-eQTLs, especially in large samples. In the HapMap3 data, we identified 11 mediated trans-eQTLs that were not detected by the single mediator analysis in the combined samples of African populations. Moreover, the mediated trans-eQTLs in the HapMap3 samples are more likely to be trait-associated SNPs. In terms of computation, although there is no limit in the number of mediators in our model, analysis takes more time when adding additional mediators. In the analysis of the HapMap3 samples, we included at most 5 cis-gene mediators. Majority of the trios we considered have one or two mediators.ConclusionsTrans-eQTLs are more likely to associate with multiple cis-genes than randomly selected SNPs. Mediation analysis with multiple mediators improves power of identification of mediated trans-eQTLs, especially in large samples.

Dataset Information

Causal Mediation Analysis of Survival Outcome with Multiple Mediators.

Publications

Causal Mediation Analysis of Survival Outcome with Multiple Mediators.

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