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.
Highlights
The self-controlled case series (SCCS) is a useful design for investigating associations between outcomes and transient exposures
These interaction terms can be interpreted as relative incidence ratios (RIR)
We have previously conducted a study of emergency room (ER) visits and admissions following diphtheriatetanus-acellular pertussis vaccine (DTaP)-IPV-Hib vaccine recommended at ages 2, 4 and 6 months in which we found no evidence of increased risk of events in the first 72 h following vaccination, but we observed a strong healthy vaccinee effect (HVE), which is described by Fig. 1 [22]
Summary
The self-controlled case series (SCCS) is a useful design for investigating associations between outcomes and transient exposures. The self-controlled case series design (SCCS) was developed to address a number of challenges associated with studying the association between adverse health outcomes and transient exposures, such as vaccination, in observational data. The SCCS has important advantages: 1) it addresses confounding resulting from differences between the vaccinated and unvaccinated individuals in non-randomized study settings; 2) traditional cohort and case-control designs may not be feasible for studying vaccines with coverage approaching 100 % as it would be difficult to recruit unvaccinated controls; and 3) safety surveillance systems typically only collect data for individuals who reported an adverse event thought to be related to vaccination
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