The causal interpretation of “overall vaccine effectiveness” in test-negative studies

Abstract

Test-negative studies are commonly used to estimate influenza vaccine effectiveness (VE). In a typical study, an “overall VE” estimate may be reported based on data from the entire sample. However, there may be heterogeneity in VE, particularly by age. We therefore discuss the potential for a weighted average of age-specific VE estimates to provide a more meaningful measure of overall VE. We illustrate this perspective first using simulations to evaluate how overall VE would be biased when certain age groups are over-represented. We found unweighted overall VE estimates tended to be higher than weighted VE when children were over-represented and lower when elderly were over-represented. Then we extracted published estimates from the US Flu VE network, in which children are overrepresented, and some discrepancy between unweighted and weighted overall VE was observed. Differences in weighted versus unweighted overall VE could translate to substantial differences in the interpretation of individual risk reduction in vaccinated persons, and the total averted disease burden at the population level. Weighting overall estimates should be considered in VE studies in future.