Bias due to differential and non-differential disease- and exposure misclassification in studies of vaccine effectiveness.

Background: Studies of vaccine effectiveness (VE) rely on accurate identification of vaccination and cases of vaccine-preventable disease. In practice, diagnostic tests, clinical case definitions and vaccination records often present inaccuracies, leading to biased VE estimates. Previous studies investigated the impact of non-differential disease misclassification on VE estimation.
Methods: We explored, through simulation, the impact of non-differential and differential disease- and exposure misclassification when estimating VE using cohort, case-control, test-negative case-control and case-cohort designs. The impact of misclassification on the estimated VE is demonstrated for VE studies on childhood seasonal influenza and pertussis vaccination. We additionally developed a web-application graphically presenting bias for user-selected parameters.
Results: Depending on the scenario, the misclassification parameters had differing impacts. Decreased exposure specificity had greatest impact for influenza VE estimation when vaccination coverage was low. Decreased exposure sensitivity had greatest impact for pertussis VE estimation for which high vaccination coverage is typically achieved. The impact of the exposure misclassification parameters was found to be more noticeable than that of the disease misclassification parameters. When misclassification is limited, all study designs perform equally. In case of substantial (differential) disease misclassification, the test-negative design performs worse.
Conclusions: Misclassification can lead to significant bias in VE estimates and its impact strongly depends on the scenario. We developed a web-application for assessing the potential (joint) impact of possibly differential disease- and exposure misclassification that can be modified by users to their own study scenario. Our results and the simulation tool may be used to guide better design, conduct and interpretation of future VE studies.
Competing Interests: At the time of the research, EM was employed by GSK and DM by Sanofi Pasteur. Both companies develop vaccines and support the IMI ADVANCE project. KB received consulting fees from vaccine producing companies (GSK, SPMSD, Pfizer, Takeda) not related to the research presented here. TDS received consulting fees from Pfizer and Takeda not related to this work. At the time of the research, SPV was employed by FISABIO and Erasmus MC. The authors have declared that no competing interests exist.