An improved method for the effect estimation of the intermediate event on the outcome based on the susceptible pre-identification

BACKGROUND: In follow-up studies, the occurrence of the intermediate event may influence the risk of the outcome of interest. Existing methods estimate the effect of the intermediate event by including a time-varying covariate in the outcome model. However, the insusceptible fraction to the intermediate event in the study population has not been considered in the literature, leading to effect estimation bias due to the inaccurate dataset. METHODS: In this paper, we propose a new effect estimation method, in which the susceptible subpopulation is identified firstly so that the estimation could be conducted in the right population. Then, the effect is estimated via the extended Cox regression and landmark methods in the identified susceptible subpopulation. For susceptibility identification, patients with observed intermediate event time are classified as susceptible. Based on the mixture cure model fitted the incidence and time of the intermediate event, the susceptibility of the patient with censored intermediate event time is predicted by the residual intermediate event time imputation. The effect estimation performance of the new method was investigated in various scenarios via Monte-Carlo simulations with the performance of existing methods serving as the comparison. The application of the proposed method to mycosis fungoides data has been reported as an example. RESULTS: The simulation results show that the estimation bias of the proposed method is smaller than that of the existing methods, especially in the case of a large insusceptible fraction. The results hold for small sample sizes. Besides, the estimation bias of the new method decreases with the increase of the covariates, especially continuous covariates, in the mixture cure model. The heterogeneity of the effect of covariates on the outcome in the insusceptible and susceptible subpopulation, as well as the landmark time, does not affect the estimation performance of the new method. CONCLUSIONS: Based on the pre-identification of the susceptible, the proposed new method could improve the effect estimation accuracy of the intermediate event on the outcome when there is an insusceptible fraction to the intermediate event in the study population. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12874-021-01378-8.