Evaluating the cost-effectiveness of polygenic risk score-stratified screening for abdominal aortic aneurysm

As the heritability of abdominal aortic aneurysm (AAA) is high and AAA partially shares genetic architecture with other cardiovascular diseases, there is interest in whether genetic information could inform AAA screening strategies. Exploiting pleiotropy and meta-analysing summary data from large AAA studies, we constructed a polygenic risk score (PRS) for AAA. Compared with the low PRS tertile, the intermediate and high PRS tertiles had hazard ratios for AAA of 2.13 (95%CI 1.61, 2.82) and 3.70 (95%CI 2.86, 4.80) respectively, after adjusting for known clinical risk factors. Using simulation modelling, we compared PRS- and smoking-stratified screening with inviting men at age 65 and not inviting women (current UK strategy). In a futuristic scenario where genomic information is available on the population, our modelling suggests inviting male current smokers with high PRS earlier than 65 and targeting screening in female smokers with high/intermediate PRS at 65 and 70 respectively, may improve cost-effectiveness. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement M.K. is funded by the BHF Cambridge CRE (RE/18/1/34212). L.G.K. was supported by the NIHR BTRU in Donor Health and Genomics (NIHR BTRU-2014-10024) and is supported by the NIHR BTRU in Donor Health and Behaviour (NIHR203337). M.I. was supported by the Munz Chair of Cardiovascular Prediction and Prevention and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014; NIHR203312)*. M.I. was also supported by the UK Economic and Social Research 878 Council (ES/T013192/1). L.P. is supported by a BHF Programme Grant (RG/18/13/33946). J.D. holds a British Heart Foundation Professorship and a NIHR Senior Investigator Award [*]. This work was supported by core funding from the British Heart Foundation (RG/13/13/30194; RG/18/13/33946), BHF Cambridge CRE (RE/18/1/34212) and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014; NIHR203312). *The views expressed are those of the authors and not necessarily those of the NIHR, NHSBT or the Department of Health and Social Care. This work was also supported by Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), and British Heart Foundation and Wellcome. ### 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: This research has been conducted using the UK Biobank Resource under Application Number 7439. Copyright (c) 2023, NHS England. Re-used with the permission of the NHS England [and/or UK Biobank]. All rights reserved. This research used data assets made available by National Safe Haven as part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (research which commenced between 1st October 2020 - 31st March 2021 grant ref MC\_PC\_20029; 1st April 2021 -30th September 2022 grant ref MC\_PC\_20058). For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission. 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 Code to perform all PRS development analyses reported in this manuscript is available at github.com/mkelcb/aaa-paper. The final AAA PRS file is available from the Supplementary data and from the PGS Catalog with score ID PGS003429. The full DES model is available at https://github.com/mikesweeting/AAA\_DES\_model.