Differential anchoring effects of vaccination comparator selection: characterizing a potential bias due to healthcare utilization in COVID-19 versus influenza

Abstract Introduction Observational data enables large-scale vaccine safety surveillance but requires careful evaluation of potential sources of bias. One potential source of bias is an index date selection procedure for the unvaccinated cohort or unvaccinated comparison time. Here, we evaluate different index date selection procedures for two vaccines: COVID-19 and influenza. Methods For each vaccine, we extracted patient baseline characteristics on the index date and up to 450 days prior and then compared them to the characteristics of the unvaccinated patients indexed on an arbitrary date or indexed on a date of a visit. Additionally, we compared vaccinated patients indexed on the date of vaccination and the same patients indexed on a prior date or visit. Results COVID-19 vaccination and influenza vaccination differ drastically from each other in terms of populations vaccinated and their status on the day of vaccination. When compared to indexing on a visit in unvaccinated population, influenza vaccination had markedly higher covariate proportions and COVID-19 vaccination had lower proportions of most covariates on the index date. In contrast, COVID-19 vaccination had similar covariate proportions when compared to an arbitrary date. These effects attenuated but were still present with a longer lookback period. The effect of day 0 was present even when patients served as their own controls. Conclusion Patient baseline characteristics are sensitive to the choice of the index date. In vaccine safety studies, unexposed index event should represent vaccination settings. Study designs previously used to assess influenza vaccination must be reassessed for COVID-19 to account for a potentially healthier population and lack of medical activity on the day of vaccination.