TABLE 2.

Rationale for inclusion of confounders in the DAG

Confounder	Rationale for inclusion in the DAG
Healthcare‐seeking behavior	In TND studies, there is less bias because of healthcare‐seeking behavior, defined as a person's propensity to seek care when ill, than in cohort studies, as the study population is restricted to persons who seek medical care for ILI or SARI [45]. However, as described by Sullivan et al., “someone's propensity to seek care, […] is based on many factors” and is therefore “unlikely to be completely captured by a single binary indicator of whether or not a person presents himself/herself to a physician when experiencing influenza symptoms, so healthcare‐seeking would remain partially unobserved and the TND design is unlikely to completely block the effects of this confounder” [46]. Healthcare‐seeking behavior, in general, may also be associated with increased opportunities to be offered influenza vaccine. Healthcare‐seeking behavior bias is likely more pronounced for mild disease than for severe disease. Healthcare‐seeking behavior is not straightforward to operationalize, but proxies could include sex (with females being generally more prone to seek care than males 25 ), the number of recent GP visits, or up‐to‐date pneumococcal vaccination (for adult age groups). 19
Pre‐existing immunity from infection or vaccination	Depending on the circulating influenza strains and the degree and duration of residual immunity, persons having recently experienced an influenza infection may be (partially) protected from influenza [47, 48]. At the same time, a recent prior influenza infection has been reported by GPs as a factor that increases influenza vaccine acceptance [49]. Confounding because of immunizing infections may be expected to vary across seasons, as population‐level intensity, severity of recent influenza seasons and changes in influenza vaccine composition could impact the perceived necessity of vaccination. Prior influenza vaccination may be a confounder of IVE when influenza vaccination in the current season is associated with vaccination history and when vaccination modifies the risk of natural infection because of lower previous risk of infection or persisting immunity [50]. However, prior influenza vaccination is highly predictive of influenza vaccination in the current season 29 ; this collinearity may lead to overadjustment if this variable is included in statistical models.
Social contact patterns and precautionary social behavior	Social contact patterns affect the risk of exposure to influenza virus. Social contact patterns may be related to occupation; healthcare workers with direct patient contact may be more likely to have occupational exposure to influenza, and this group is typically targeted for influenza vaccination [51]. Contact patterns have been highly associated with age and household size, whereas the average number of contacts varies between countries [52–54]. Persons working with young children may be more willing to accept vaccination if they have an additional risk factor (e.g., a medical condition). Among older adults, social inclusion into family or informal social networks—which may increase their number of contacts—was found to positively affect vaccine uptake. 11 In a study conducted among older adults in three European countries, exposure to children under the age of five living outside of the household explained 10% of all acute respiratory tract infections [55]. Precautionary social behavior affects the risk of exposure to influenza virus and may impact motivation to be vaccinated. Although precautionary behavior is always relevant in the prevention of influenza, preventive measures such as face mask wearing, physical distancing, and handwashing have become widespread since 2020 with the COVID‐19 pandemic. These measures against SARS‐COV‐2 virus transmission also impact the circulation of other respiratory viruses such as influenza, as illustrated by the strong reductions in influenza circulation in Europe in the 2020/2021 Northern Hemisphere winter [56]. In addition, precautionary behavior such as mask wearing and distancing likely lead to a smaller dose of the initial inoculum if exposed despite the measures taken, thereby reducing the chance of developing severe disease [57]. The relevance of precautionary social behavior in IVE studies will likely depend on future COVID‐19 containment measures.
Socioeconomic status and ethnicity	Higher socioeconomic status or educational level may support increased vaccine uptake (in older adults), 11 and uptake has been found to be lower in certain ethnic groups (migration background, religion) [58–61]. At the same time, it may impact healthcare‐seeking behavior (including accessibility of healthcare) and other social aspects such as contact patterns and health beliefs leading to precautionary behavior, and health status.

Note: GP: General Practitioner; DAG, directed acyclic graph; TND, test‐negative design; ILI, influenza‐like illness; SARI, severe acute respiratory infection; IVE, influenza vaccine effectiveness.