Impact of pre-exposure time bias in self-controlled case series when the event conditions the exposure: Hip/femur fracture and use of benzodiazepines as a case study.

BACKGROUND: In self-controlled case series (SCCS), the event should not condition the probability of subsequent exposure. If this assumption is not met, an important bias could take place. The association of hip/femur fracture (HFF) and use of benzodiazepines (BDZ) has a bidirectional causal relationship and can serve as case study to investigate the impact of this methodological issue. OBJECTIVES: To assess the magnitude of bias introduced in a SCCS when HFF conditions the posterior exposure to BDZ and explore ways to correct it. METHODS: Four thousand four hundred fifty cases of HFF who had at least one BZD prescription were selected from the primary care health record database BIFAP. Exposure to BZD was divided into non-use, current, recent, and past use. Conditional Poisson regression was used to estimate incidence rate ratios (IRRs) of HFF among current vs non-use/past, adjusted for age. To investigate possible event-exposure dependence, a pre-exposure time of different lengths (15, 30, and 60 days) was excluded from the reference category to evaluate the IRR. RESULTS: IRR of HHF for current use was 0.79 (0.72-0.86); removing 30 days, IRR was 1.43 (1.31-1.57). Removing 15 days, IRR was 1.29 (1.18-1.41), and removing 60 days, IRR was 1.56 (1.42-1.72). A pre-exposure period up to 182 days was necessary to remove such effect giving an IRR of 1.64 (1.48-1.81). CONCLUSIONS: HFF remarkably conditioned the use of BDZs resulting in seriously biased IRRs when this association was studied through a SCCS design. The use of pre-exposure periods of different lengths helped to correct this error.