乙型或丙型肝炎的自然史由多个里程碑组成，如肝硬化和肝癌。为了完整地描述其自然过程，半竞争风险是一个常见问题，其中肝硬化和肝癌两者均具有兴趣，但只有前者可能被后者截尾。联合分布、脆弱性和多状态模型是半竞争风险的成熟分析方法。在这里，我们将半竞争风险转化为中介框架，以肝硬化为中介因素，以肝癌为结果。我们将间接效应和直接效应定义为暴露对肝癌发生的影响，分别通过肝硬化进行介导和非介导。通过将估计量推导为条件概率，我们在半竞争风险的联合分布、脆弱性和多状态模型下推导了相应的表达式。接下来，我们提出了基于非参数最大似然估计或U-统计的估计器，并建立了它们的渐近结果。数值研究表明，由于模型错误规范，联合分布模型的效率可能导致潜在偏差。此外，脆弱性模型的鲁棒性伴随着效率的损失，而多状态模型平衡了效率和鲁棒性。我们通过一项肝炎研究展示了所提方法的实用性，表明乙型和丙型肝炎通过增加肝硬化的发病率导致了肝癌的更高发生率。因此，中介模型提供了一个统一的框架，可以适应各种半竞争风险模型。© 2023 John Wiley & Sons Ltd.

Natural history of hepatitis B or C is comprised of multiple milestones such as liver cirrhosis and liver cancer. To fully characterize its natural course, semicompeting risks represent a common problem where liver cirrhosis and liver cancer are both of interest, but only the former may be censored by the latter. Copula, frailty and multistate models serve as well-established analytics for semicompeting risks. Here, we cast the semicompeting risks in a mediation framework, with liver cirrhosis as a mediator and liver cancer as an outcome. We define the indirect and direct effects as the effects of an exposure on the liver cancer incidence mediated and not mediated through liver cirrhosis, respectively. With the estimands derived as conditional probabilities, we derive respective expressions under the copula, frailty, and multistate models. Next, we propose estimators based on nonparametric maximum likelihood or U-statistics and establish their asymptotic results. Numerical studies demonstrate that the efficiency of copula models leads to potential bias due to model misspecification. Moreover, the robustness of frailty models is accompanied by a loss in efficiency, and multistate models balance the efficiency and robustness. We demonstrate the utility of the proposed methods by a hepatitis study, showing that hepatitis B and C lead to a higher incidence of liver cancer by increasing liver cirrhosis incidence. Thus, mediation modeling provides a unified framework that accommodates various semicompeting risks models.© 2023 John Wiley & Sons Ltd.