Health, socioeconomic and genetic predictors of COVID-19 vaccination uptake: a nationwide machine-learning study

Reduced participation in COVID-19 vaccination programs is a key societal concern. Understanding factors associated with vaccination uptake can help in planning effective immunization programs. We considered 2,890 health, socioeconomic, familial, and demographic factors measured on the entire Finnish population aged 30 to 80 (N=3,192,505) and genome-wide information for a subset of 273,765 individuals. Risk factors were further classified into 12 thematic categories and a machine learning model was trained for each category. The main outcome was uptaking the first COVID-19 vaccination dose by 31.10.2021, which has occurred for 90.3% of the individuals. The strongest predictor category was labor income in 2019 (AUC evaluated in a separate test set = 0.710, 95% CI: 0.708-0.712), while drug purchase history, including 376 drug classes, achieved a similar prediction performance (AUC = 0.706, 95% CI: 0.704-0.708). Higher relative risks of being unvaccinated were observed for some mental health diagnoses (e.g. dissocial personality disorder, OR=1.26, 95% CI : 1.24-1.27) and when considering vaccination status of first-degree relatives (OR=1.31, 95% CI:1.31-1.32 for unvaccinated mothers) We derived a prediction model for vaccination uptake by combining all the predictors and achieved good discrimination (AUC = 0.801, 95% CI: 0.799-0.803). The 1% of individuals with the highest risk of not vaccinating according to the model predictions had an average observed vaccination rate of only 18.8%. We identified 8 genetic loci associated with vaccination uptake and derived a polygenic score, which was a weak predictor of vaccination status in an independent subset (AUC=0.612, 95% CI: 0.601-0.623). Genetic effects were replicated in an additional 145,615 individuals from Estonia (genetic correlation=0.80, 95% CI: 0.66-0.95) and, similarly to data from Finland, correlated with mental health and propensity to participate in scientific studies. Individuals at higher genetic risk for severe COVID-19 were less likely to get vaccinated (OR=1.03, 95% CI: 1.02-1.05). Our results, while highlighting the importance of harmonized nationwide information, not limited to health, suggest that individuals at higher risk of suffering the worst consequences of COVID-19 are also those less likely to uptake COVID-19 vaccination. The results can support evidence-informed actions for COVID-19 and other areas of national immunization programs. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 101016775. The FinRegistry project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement No 945733), starting grant AI-Prevent. This Estonian Biobank study was funded by the European Union through the European Regional Development Fund Project No. 2014-2020.4.01.15-0012 GENTRANSMED. Data analysis was carried out in part in the High-Performance Computing Center of University of Tartu. The FinnGen project is funded by two grants from Business Finland (HUS 4685/31/2016 and UH 4386/31/2016) and the following industry partners: AbbVie Inc., AstraZeneca UK Ltd, Biogen MA Inc., Bristol Myers Squibb (and Celgene Corporation & Celgene International II Sarl), Genentech Inc., Merck Sharp & Dohme LCC, Pfizer Inc., GlaxoSmithKline Intellectual Property Development Ltd., Sanofi US Services Inc., Maze Therapeutics Inc., Janssen Biotech Inc, Novartis AG, and Boehringer Ingelheim International GmbH. ### 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: The FinRegistry project has received the following approvals for data access from the National Institute of Health and Welfare (THL/1776/6.02.00/2019 and subsequent amendments), DVV (Digi-, ja vaestotietovirasto) (VRK/5722/2019-2), Finnish Center for Pension (ETK/SUTI 22003) and Statistics Finland (TK-53-1451-19). The FinRegistry project has received IRB approval from the National Institute of Health and Welfare (Kokous 7/2019). Patients and control subjects in FinnGen provided informed consent for biobank research, based on the Finnish Biobank Act. Alternatively, separate research cohorts, collected prior the Finnish Biobank Act came into effect (in September 2013) and start of FinnGen (August 2017), were collected based on study-specific consents and later transferred to the Finnish biobanks after approval by Fimea (Finnish Medicines Agency), the National Supervisory Authority for Welfare and Health. Recruitment protocols followed the biobank protocols approved by Fimea. The Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa (HUS) statement number for the FinnGen study is Nr HUS/990/2017. The FinnGen study is approved by Finnish Institute for Health and Welfare (permit numbers: THL/2031/6.02.00/2017, THL/1101/5.05.00/2017, THL/341/6.02.00/2018, THL/2222/6.02.00/2018, THL/283/6.02.00/2019, THL/1721/5.05.00/2019 and THL/1524/5.05.00/2020), Digital and population data service agency (permit numbers: VRK43431/2017-3, VRK/6909/2018-3, VRK/4415/2019-3), the Social Insurance Institution (permit numbers: KELA 58/522/2017, KELA 131/522/2018, KELA 70/522/2019, KELA 98/522/2019, KELA 134/522/2019, KELA 138/522/2019, KELA 2/522/2020, KELA 16/522/2020), Findata permit numbers THL/2364/14.02/2020, THL/4055/14.06.00/2020,,THL/3433/14.06.00/2020, THL/4432/14.06/2020, THL/5189/14.06/2020, THL/5894/14.06.00/2020, THL/6619/14.06.00/2020, THL/209/14.06.00/2021, THL/688/14.06.00/2021, THL/1284/14.06.00/2021, THL/1965/14.06.00/2021, THL/5546/14.02.00/2020, THL/2658/14.06.00/2021, THL/4235/14.06.00/202, Statistics Finland (permit numbers: TK-53-1041-17 and TK/143/07.03.00/2020 (earlier TK-53-90-20) TK/1735/07.03.00/2021, TK/3112/07.03.00/2021) and Finnish Registry for Kidney Diseases permission/extract from the meeting minutes on 4th July 2019. The Biobank Access Decisions for FinnGen samples and data utilized in FinnGen Data Freeze 9 include: THL Biobank BB2017\_55, BB2017\_111, BB2018\_19, BB\_2018\_34, BB\_2018\_67, BB2018\_71, BB2019\_7, BB2019\_8, BB2019\_26, BB2020\_1, Finnish Red Cross Blood Service Biobank 7.12.2017, Helsinki Biobank HUS/359/2017, HUS/248/2020, Auria Biobank AB17-5154 and amendment #1 (August 17 2020), AB20-5926 and amendment #1 (April 23 2020) and its modification (Sep 22 2021), Biobank Borealis of Northern Finland\_2017\_1013, Biobank of Eastern Finland 1186/2018 and amendment 22/2020, Finnish Clinical Biobank Tampere MH0004 and amendments (21.02.2020 & 06.10.2020), Central Finland Biobank 1-2017, and Terveystalo Biobank STB 2018001 and amendment 25th Aug 2020. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data dictionaries for FinRegistry are publicly available on the FinRegistry website (www.finregistry.fi/finnish-registry-data). Access to FinRegistry data can be obtained by submitting a data permit application for individual-level data for the Finnish social and health data permit authority Findata (https://asiointi.findata.fi/). The application includes information on the purpose of data use; the requested data, including the variables, definitions for the target and control groups, and external datasets to be combined with FinRegistry data; the dates of the data needed; and a data utilization plan. The requests are evaluated on a case-by-case basis. Once approved, the data are sent to a secure computing environment Kapseli and can be accessed within the European Economic Area (EEA) and within countries with an adequacy decision from the European Commission. The Finnish biobank data can be accessed through the Fingenious services (https://site.fingenious.fi/en/) managed by FINBB. Summary statistics of the COVID-19 vaccination uptake GWAS will be made available at the GWAS Catalog upon publication.