Potential Bias in Self‐Controlled Case Series Design: Impact of Incident Versus Prevalent Scenarios of Exposure and Outcome

Purpose To assess changes in study results in self‐controlled case series (SCCS) studies and explore potential biases when applying incident and prevalent exposure and outcome scenarios. Methods We used the National Health Insurance Service database in South Korea to conduct two SCCS studies: (1) the risk of retinal detachment following fluoroquinolone use (expected elevated risk), and (2) the risk of acute cardiovascular disease following ranibizumab use (expected null association). Exposure and outcome scenarios were classified based on a washout period of 2 and 1 year, respectively, before the observation period: incident exposure‐incident outcome, incident exposure‐prevalent outcome, prevalent exposure‐incident outcome, and prevalent exposure‐prevalent outcome. For each scenario, conditional Poisson regression models, adjusted for time‐varying age, estimated incidence rate ratios (IRRs) with 95% confidence intervals (CIs). Results In the fluoroquinolone study, IRRs of retinal detachment were as follows: 1.83 (95% CI 1.72–1.96) for incident exposure‐incident outcome, 1.83 (1.71–1.95) for incident exposure‐prevalent outcome, 1.71 (1.62–1.80) for prevalent exposure‐incident outcome, and 1.70 (1.62–1.79) for prevalent exposure‐prevalent outcome scenario. In the ranibizumab study, IRRs of acute cardiovascular disease were 0.91 (0.84–0.99), 0.89 (0.82–0.97), 1.02 (0.94–1.10), and 1.00 (0.93–1.08), respectively. Conclusions In prevalent exposure scenarios, IRRs in both studies were attenuated, consistent with prevalent user bias. In prevalent outcome scenarios, where survivor bias was anticipated, no notable shifts in IRRs were observed, possibly due to the high severity and low recurrence of the outcomes associated with the respective exposures. Further consideration of prevalent user and survivor bias is important when interpreting SCCS results. Additional research is needed to quantify the impact of varying exposure and outcome definitions on SCCS estimates.