Estimation of Marginal Interventional Effects for a Time-to-Event Mediator in a Multi-State Model Framework and Its Application

The method was further applied to the Henan HIV/AIDS Antiretroviral Therapy Cohort to analyze the mediating effect of CD4 recovery in the association between timing of ART initiation and all-cause mortality.Results Simulation studies showed that MIMS-TEM had low bias and stable confidence interval coverage across different truncation levels and effect scenarios, and generally outperformed simplified approaches that excluded pre-mediator death, treated pre-mediator death as censoring, or coarsened the mediator into a binary variable.

Compared with the CMAverse method, MIMS-TEM showed more stable performance in estimating population-level marginal effects. In the application study, compared with ART initiation >30 days after diagnosis, ART initiation within 7 days reduced the 9-year cumulative mortality risk, with a total effect of -0.046 (95% CI: -0.070 to -0.029), a direct effect of -0.043 (95% CI: -0.069 to -0.028), and an indirect effect of -0.002 (95% CI: -0.005 to -0.001).

ART initiation within 8–30 days also showed a protective effect.Conclusion MIMS-TEM can estimate population-level marginal interventional effects for a time-to-event mediator under a semi-competing risk structure, providing methodological support for evaluating public health intervention effects and investigating underlying mechanisms. The application results support the continued implementation of rapid ART initiation strategies in HIV/AIDS prevention and control, and suggest that the protective effect of timely ART initiation may be mainly achieved through pathways other than CD4 recovery.