How group structure impacts the numbers at risk for coronary artery disease: polygenic risk scores and non-genetic risk factors in the UK Biobank cohort

The UK Biobank is a large cohort study that recruited over 500,000 British participants aged 40-69 in 2006-2010 at 22 assessment centres from across the UK. Self-reported health outcomes and hospital admission data are two types of records that include participants’ disease status. Coronary artery disease (CAD) is the most common cause of death in the UK Biobank cohort. After distinguishing between prevalence and incidence CAD events for all UK Biobank participants, we identified geographical variations in age-standardised rates of CAD between assessment centres. Significant distributional differences were found between the pooled cohort equation scores of UK Biobank participants from England and Scotland using the Mann-Whitney test. Polygenic risk scores of UK Biobank participants from England and Scotland and from different assessment centres differed significantly using permutation tests. Our aim was to discriminate between assessment centres with different disease rates by collecting data on disease-related risk factors. However, relying solely on individual-level predictions and averaging them to obtain group-level predictions proved ineffective, particularly due to the presence of correlated covariates resulting from participation bias. By using the Mundlak model, which estimates a random effects regression by including the group means of the independent variables in the model, we effectively addressed these issues. In addition, we designed a simulation experiment to demonstrate the functionality of the Mundlak model. Our findings have applications in public health funding and strategy, as our approach can be used to predict case rates in the future, as both population structure and lifestyle changes are uncertain. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This publication has emanated from research conducted with funding from the Science Foundation Ireland under Grant number [SFI/12/RC/2289_P2]. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. ### 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 study uses data that has been published and used previously from 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