The use of relative incidence ratios in self-controlled case series studies: an overview

Abstract

BackgroundThe self-controlled case series (SCCS) is a useful design for investigating associations between outcomes and transient exposures. The SCCS design controls for all fixed covariates, but effect modification can still occur. This can be evaluated by including interaction terms in the model which, when exponentiated, can be interpreted as a relative incidence ratio (RIR): the change in relative incidence (RI) for a unit change in an effect modifier.MethodsWe conducted a scoping review to investigate the use of RIRs in published primary SCCS studies, and conducted a case-study in one of our own primary SCCS studies to illustrate the use of RIRs within an SCCS analysis to investigate subgroup effects in the context of comparing whole cell (wcp) and acellular (acp) pertussis vaccines. Using this case study, we also illustrated the potential utility of RIRs in addressing the healthy vaccinee effect (HVE) in vaccine safety surveillance studies.ResultsOur scoping review identified 122 primary studies reporting an SCCS analysis. Of these, 24 described the use of interaction terms to test for effect modification. 21 of 24 studies reported stratum specific RIs, 22 of 24 reported the p-value for interaction, and less than half (10 of 24) reported the estimate of the interaction term/RIR, the stratum specific RIs and interaction p-values. Our case-study demonstrated that there was a nearly two-fold greater RI of ER visits and admissions following wcp vaccination relative to acp vaccination (RIR = 1.82, 95 % CI 1.64–2.01), where RI estimates in each subgroup were clearly impacted by a strong healthy vaccinee effect.ConclusionsWe demonstrated in our scoping review that calculating RIRs is not a widely utilized strategy. We showed that calculating RIRs across time periods is useful for the detection of relative changes in adverse event rates that might otherwise be missed due to the HVE. Many published studies of vaccine-associated adverse events could have missed/underestimated important safety signals masked by the HVE. With further development, our application of RIRs could be an important tool to address the HVE, particularly in the context of self-controlled study designs.

Effects of sex and birth weight on non-specific health services use following whole-cell pertussis vaccination: a self-controlled case series analysis

“…On the other hand, the use of RIRs can introduce other potential confounding as the resulting effect estimates are no longer within an individual. 28 We have taken steps to mediate this by adjusting for sex in the analysis of birth weight, and by adjusting for birth weight in the analysis of sex, but we cannot exclude the possibility of unmeasured confounding impacting our results. The use of all-cause health services utilization as an outcome represents both a strength and a weakness of our study.…”

“…Conversely, studies that report RIs without attempting to account for the healthy vaccinee effect have likely underestimated effect sizes. 28 A limitation of all self-controlled case series analyses is the possibility of coincident temporal exposures; however, to our knowledge there are no other routinelyadministered interventions at 2 months of age.…”

“…This RIR has the added benefit of allowing us to overcome the impact of the 'healthy vaccinee effect', the decision by parents and health care providers to forgo vaccination when a child is acutely ill resulting in the administration of vaccines to children who are in a comparatively healthy state. 28,31,32 Such an effect results in a marked reduction in events prior to vaccination and can mask any adverse effect in the immediate post-vaccination period. Using the ratio of relative incidence in two subgroups (e.g., males and females) can largely cancel out the healthy vaccinee effect where it is expected to behave similarly in the two subgroups.…”

T-cell receptor excision circle levels and safety of paediatric immunization: A population-based self-controlled case series analysis

“…Risk periods were based on the biologically expected impact of the vaccine and our previous work. 18 , 28 , 53 0–48 hours post-immunization was used as the risk period for non-live vaccines, and 4–12 days post-immunization for live-attenuated vaccines. The control periods were based on when the number of events post-vaccination had equilibrated, as determined through graphical examination.…”

Self-controlled Case Series Study (SCCSS): A Novel Research Method

“…Advantages [8,11,13,14,16,17] 1. It is based only on cases and provides consistent estimates of the relative incidence.…”