Investigating confounding in network‐based test‐negative design influenza vaccine effectiveness studies—Experience from the DRIVE project

• Published in: Influenza and other respiratory viruses Vol. 17; no. 1; pp. e13087 - n/a
• Main Authors: Stuurman, Anke L., Levi, Miriam, Beutels, Philippe, Bricout, Hélène, Descamps, Alexandre, Dos Santos, Gaël, McGovern, Ian, Mira‐Iglesias, Ainara, Nauta, Jos, Torcel‐Pagnon, Laurence, Biccler, Jorne
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.01.2023; John Wiley and Sons Inc
• Subjects: adjustment; Age; Aged; Case-Control Studies; Comorbidity; confounders; covariate; Effectiveness; Health care; Hospitals; Humans; Infections; Influenza; Influenza A Virus, H3N2 Subtype; influenza vaccine effectiveness; Influenza Vaccines; Influenza, Human - epidemiology; Influenza, Human - prevention & control; Lung diseases; Observational studies; Original; Primary care; Respiratory diseases; Seasons; Systematic review; test‐negative design; Treatment Outcome; Vaccination; Vaccine Efficacy; Vaccines; Viruses; Italy; Europe; Spain; covariate; influenza vaccine effectiveness; adjustment; test-negative design; confounders
• ISSN: 1750-2640; 1750-2659; 1750-2659
• DOI: 10.1111/irv.13087

Background: Establishing a large study network to conduct influenza vaccine effectiveness (IVE) studies while collecting appropriate variables to account for potential bias is important; the most relevant variables should be prioritized. We explored the impact of potential confounders on IVE in the DRIVE multi‐country network of sites conducting test‐negative design (TND) studies. Methods: We constructed a directed acyclic graph (DAG) to map the relationship between influenza vaccination, medically attended influenza infection, confounders, and other variables. Additionally, we used the Development of Robust and Innovative Vaccines Effectiveness (DRIVE) data from the 2018/2019 and 2019/2020 seasons to explore the effect of covariate adjustment on IVE estimates. The reference model was adjusted for age, sex, calendar time, and season. The covariates studied were presence of at least one, two, or three chronic diseases; presence of six specific chronic diseases; and prior healthcare use. Analyses were conducted by site and subsequently pooled. Results: The following variables were included in the DAG: age, sex, time within influenza season and year, health status and comorbidities, study site, health‐care‐seeking behavior, contact patterns and social precautionary behavior, socioeconomic status, and pre‐existing immunity. Across all age groups and settings, only adjustment for lung disease in older adults in the primary care setting resulted in a relative change of the IVE point estimate >10%. Conclusion: Our study supports a parsimonious approach to confounder adjustment in TND studies, limited to adjusting for age, sex, and calendar time. Practical implications are that necessitating fewer variables lowers the threshold for enrollment of sites in IVE studies and simplifies the pooling of data from different IVE studies or study networks.