Fitting a shared frailty illness-death model to left-truncated semi-competing risks data to examine the impact of education level on incident dementia

Abstract

Background: Semi-competing risks arise when interest lies in the time-to-event for some non-terminal event, the observation of which is subject to some terminal event. One approach to assessing the impact of covariates on semi-competing risks data is through the illness-death model with shared frailty, where hazard regression models are used to model the effect of covariates on the endpoints. The shared frailty term, which can be viewed as an individual-specific random effect, acknowledges dependence between the events that is not accounted for by covariates. Although methods exist for fitting such a model to right-censored semi-competing risks data, there is currently a gap in the literature for fitting such models when a flexible baseline hazard specification is desired and the data are left-truncated, for example when time is on the age scale. We provide a modeling framework and openly available code for implementation. Methods: We specified the model and the likelihood function that accounts for left-truncated data, and provided an approach to estimation and inference via maximum likelihood. Our model was fully parametric, specifying baseline hazards via Weibull or B-splines. Using simulated data we examined the operating characteristics of the implementation in terms of bias and coverage. We applied our methods to a dataset of 33,117 Kaiser Permanente Northern California members aged 65 or older examining the relationship between educational level (categorized as: high school or less; trade school, some college or college graduate; post-graduate) and incident dementia and death. Results: A simulation study showed that our implementation provided regression parameter estimates with negligible bias and good coverage. In our data application, we found higher levels of education are associated with a lower risk of incident dementia, after adjusting for sex and race/ethnicity. Conclusions: As illustrated by our analysis of Kaiser data, our proposed modeling framework allows the analyst to assess the impact of covariates on semi-competing risks data, such as incident dementia and death, while accounting for dependence between the outcomes when data are left-truncated, as is common in studies of aging and dementia.