Quantifying and adjusting for confounding from health-seeking behaviour and healthcare access in observational research.

Objective: To assess the feasibility and effect of using proxy markers of health-seeking behaviour and healthcare access to quantify and adjust for confounding in observational studies of influenza and COVID-19 vaccine effectiveness (VE). Design: Cohort study for influenza VE in the 2019/2020 influenza season and for early COVID-19 VE (December 2020 to March 2021). Setting: Primary care data pre-linked to secondary care and death data in England. Participants: Individuals aged ≥66 years on 1 September 2019. Interventions: Vaccination with any influenza vaccination in the 2019/2020 season or with either a BNT162b2 or ChAdOx1-S vaccination from 08/12/2020 to 31/03/2021. Main outcome measures: Influenza or COVID-19 specific infections, hospitalisation and death. VE was estimated with sequential adjustment for demographics, underlying health conditions, and 14 markers reflecting uptake of public health interventions (screenings, vaccinations and NHS health checks), active healthcare access/use (prostate antigen testing, bone density scans, GP practice visits, low value procedures and blood pressure measurements) and lack of access/underuse (hospital visits for ambulatory care sensitive conditions and did not attend primary care visits). Influenza vaccination in the 2019/2020 season was also considered as a negative exposure intervention against the first wave of COVID-19. Results: We included 1,991,284, 1,796,667, and 1,946,943 individuals in the influenza, COVID-19 and negative exposure VE populations, respectively. Vaccinated individuals were more likely to display active health-seeking behaviour, including participation in UK national screening programmes, compared with unvaccinated individuals. In the 2019/2020 influenza season, adjusting for health-seeking markers increased VE against infection from -1.5% (95%CI: -3.2,0.1) to 7.1% (95%CI: 5.4,8.7), but this trend was less apparent for more severe outcomes. For COVID-19 during early vaccine roll out, adjusting for health-seeking markers in addition to demographics and underlying health conditions did not change VE estimates against infection or severe disease (e.g., two doses of BNT162b2 against infection: from 82.8% [95%CI: 78.4,86.3] to 83.1% [95%CI: 78.7,86.5]). Adjusting for health-seeking markers removed bias in the negative exposure analysis of influenza vaccination against SARS-CoV-2 infection (-7.5% [95%CI: -10.6,-4.5] vs -2.1% [95%CI: -6.0,1.7] before vs after adjusting for health-seeking markers). Conclusions: Markers of health-seeking behaviour and healthcare access can be identified in electronic health records, are associated with vaccination uptake, and can be used to quantify and account for confounding in observational studies. ### Competing Interest Statement Competing interests: SG is also a part-time salaried employee of Evidera, which is a business unit of Pharmaceutical Product Development (PPD), part of Thermo Fisher Scientific. ### Funding Statement Funding: SG, EPKP, NA, JLW and HIM are funded by the National Institute of Health and Care Research (NIHR) Health Protection Research Unit in Vaccines and Immunisation (grant reference: NIHR200929), a partnership between UK Health Security Agency (UKHSA) and London School of Hygiene and Tropical Medicine. The views expressed are those of the author(s) and not necessarily those of the NIHR, UKHSA or the Department of Health and Social Care. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Our study was approved by CPRDs (#21_000737) and LSHTMs (#28169) independent ethics review committees. To meet CPRD patient confidentiality requirements we redacted counts relating to less than 5 individuals and conducted secondary suppression where necessary. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All the analyses were conducted using R versions 4.2.2 to 4.2.4. All programming code from this project can be found in the Github repository: https://github.com/grahams99/Health-seeking-behaviour. The code lists and related search terms can be found on LSHTM Data Compass (https://doi.org/10.17037/DATA.00003684).