PURPOSE: The self-controlled risk interval design is commonly used to assess the association between an acute exposure and an adverse event of interest, implicitly adjusting for fixed, non-time-varying covariates. Explicit adjustment needs to be made for time-varying covariates, for example, age in young children. It can be performed via either a fixed or random adjustment. The random-adjustment approach can provide valid point and interval estimates but requires access to individual-level data for an unexposed baseline sample. The fixed-adjustment approach does not have this requirement and will provide a valid point estimate but may underestimate the variance. We conducted a comprehensive simulation study to evaluate their performance.
METHODS: We designed the simulation study using empirical data from the Food and Drug Administration-sponsored Mini-Sentinel Post-licensure Rapid Immunization Safety Monitoring Rotavirus Vaccines and Intussusception study in children 5-36.9 weeks of age. The time-varying confounder is age. We considered a variety of design parameters including sample size, relative risk, time-varying baseline risks, and risk interval length.
RESULTS: The random-adjustment approach has very good performance in almost all considered settings. The fixed-adjustment approach can be used as a good alternative when the number of events used to estimate the time-varying baseline risks is at least the number of events used to estimate the relative risk, which is almost always the case.
CONCLUSIONS: We successfully identified settings in which the fixed-adjustment approach can be used as a good alternative and provided guidelines on the selection and implementation of appropriate analyses for the self-controlled risk interval design.
