{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,2]],"date-time":"2025-08-02T14:14:22Z","timestamp":1754144062461,"version":"3.41.2"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2025,4,18]],"date-time":"2025-04-18T00:00:00Z","timestamp":1744934400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Transformer-based neural networks excel in modelling high-dimensional, time-series data with complex dependencies. This proof-of-concept study applies a transformer-X-learner framework to estimate treatment effects using real-world data, using antihypertensive drug exposure and COVID-19 risk as an exemplar.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We conducted a case-control study of 303,220 NHS Greater Glasgow and Clyde patients aged\u2005\u2265\u200540 years during the first two COVID-19 pandemic waves. Using a transformer-X-learner framework that incorporated temporal patterns in medication usage and comorbidities, we controlled for confounding effects and estimated individual and average treatment effects ACEIs, beta-blockers (BBs), calcium channel blockers (CCBs), thiazides (THZs), and statins on 180-day SARS-CoV-2 infection risk.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The transformer-X-learner framework outperformed traditional approaches, achieving an F1 score of 0.82 and area under the precision-recall curve (AUPRC) of 0.78. ACEIs showed a negligible overall impact on COVID-19 risk (ATE: 0.97%\u00b15.5), while BBs (-8.3%\u00b17.3%) and CCBs (-9.7%\u00b18.1%) were protective. Statins (3.5%\u00b16.1%) and THZs (4.3%\u00b110.8%) showed slight increases in risk. Treatment effects were consistent across age, gender, and socioeconomic categories.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>ACEIs do not substantially increase the risk of COVID-19 infection while the protective effects of BBs and CCBs warrant further investigation. This study highlights the potential of transformer-based causal inference models as a powerful tool for evaluating treatment safety and efficacy in complex healthcare scenarios.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ajh\/hpaf055","type":"journal-article","created":{"date-parts":[[2025,4,18]],"date-time":"2025-04-18T01:11:32Z","timestamp":1744938692000},"page":"595-604","source":"Crossref","is-referenced-by-count":0,"title":["A Transformer-Based Framework for Counterfactual Estimation of Antihypertensive Treatment Effect on COVID-19 Infection Risk - A Proof-of-Concept Study"],"prefix":"10.1093","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6829-6432","authenticated-orcid":false,"given":"Tran Q B","family":"Tran","sequence":"first","affiliation":[{"name":"School of Cardiovascular and Metabolic Health, University of Glasgow , Glasgow ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefanie","family":"Lip","sequence":"additional","affiliation":[{"name":"School of Cardiovascular and Metabolic Health, University of Glasgow , Glasgow ,","place":["UK"]},{"name":"Queen Elizabeth University Hospital , Glasgow ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Honghan","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Health and Wellbeing, University of Glasgow , Glasgow ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2079-8684","authenticated-orcid":false,"given":"Shyam","family":"Visweswaran","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine , Pittsburgh, PA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jill P","family":"Pell","sequence":"additional","affiliation":[{"name":"School of Health and Wellbeing, University of Glasgow , Glasgow ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3869-5808","authenticated-orcid":false,"given":"Sandosh","family":"Padmanabhan","sequence":"additional","affiliation":[{"name":"School of Cardiovascular and Metabolic Health, University of Glasgow , Glasgow ,","place":["UK"]},{"name":"Queen Elizabeth University Hospital , Glasgow ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,4,18]]},"reference":[{"key":"2025071501515062300_CIT0001","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1056\/NEJMra2302038","article-title":"Artificial intelligence and machine learning in clinical medicine","volume":"388","author":"Haug","year":"2023","journal-title":"N Engl J Med"},{"key":"2025071501515062300_CIT0002","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1161\/CIRCRESAHA.121.318106","article-title":"Artificial intelligence in hypertension","volume":"128","author":"Padmanabhan","year":"2021","journal-title":"Circ Res"},{"key":"2025071501515062300_CIT0003","doi-asserted-by":"crossref","first-page":"4156","DOI":"10.1073\/pnas.1804597116","article-title":"Metalearners for estimating heterogeneous treatment effects using machine learning","volume":"116","author":"K\u00fcnzel","year":"2019","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025071501515062300_CIT0004","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1016\/j.jacc.2018.01.058","article-title":"Angiotensin-converting enzyme inhibitors in hypertension: to use or not to use","volume":"71","author":"Messerli","year":"2018","journal-title":"J Am Coll Cardiol"},{"key":"2025071501515062300_CIT0005","doi-asserted-by":"crossref","first-page":"1874","DOI":"10.1097\/HJH.0000000000003480","article-title":"ESH guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension: endorsed by the International Society of Hypertension (ISH) and the European Renal Association (ERA)","volume":"41","author":"Mancia","year":"2023","journal-title":"J Hypertens"},{"key":"2025071501515062300_CIT0006","first-page":"60","article-title":"The use of ACE inhibitor in cardiovascular disease","volume":"38","author":"Nasution","year":"2006","journal-title":"Acta Med Indones"},{"key":"2025071501515062300_CIT0007","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1097\/MNH.0b013e328341164a","article-title":"Angiotensin-converting enzyme 2 is a key modulator of the renin-angiotensin system in cardiovascular and renal disease","volume":"20","author":"Tikellis","year":"2011","journal-title":"Curr Opin Nephrol Hypertens"},{"key":"2025071501515062300_CIT0008","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1007\/s10096-020-04138-6","article-title":"COVID-19: angiotensin-converting enzyme 2 (ACE2) expression and tissue susceptibility to SARS-CoV-2 infection","volume":"40","author":"Beyerstedt","year":"2021","journal-title":"Eur J Clin Microbiol Infect Dis"},{"key":"2025071501515062300_CIT0009","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1056\/NEJMsr2005760","article-title":"Renin\u2013angiotensin\u2013aldosterone system inhibitors in patients with Covid-19","volume":"382","author":"Vaduganathan","year":"2020","journal-title":"N Engl J Med"},{"key":"2025071501515062300_CIT0010","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1016\/S0140-6736(20)30937-5","article-title":"Endothelial cell infection and endotheliitis in COVID-19","volume":"395","author":"Varga","year":"2020","journal-title":"Lancet"},{"key":"2025071501515062300_CIT0011","doi-asserted-by":"crossref","first-page":"2605","DOI":"10.1161\/CIRCULATIONAHA.104.510461","article-title":"Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2","volume":"111","author":"Ferrario","year":"2005","journal-title":"Circulation"},{"key":"2025071501515062300_CIT0012","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1161\/HYPERTENSIONAHA.120.15289","article-title":"Clinical features of COVID-19 in patients with essential hypertension and the impacts of renin-angiotensin-aldosterone system inhibitors on the prognosis of COVID-19 patients","volume":"76","author":"Pan","year":"2020","journal-title":"Hypertension"},{"key":"2025071501515062300_CIT0013","doi-asserted-by":"crossref","first-page":"2058","DOI":"10.1093\/eurheartj\/ehaa433","article-title":"Association of hypertension and antihypertensive treatment with COVID-19 mortality: a retrospective observational study","volume":"41","author":"Gao","year":"2020","journal-title":"Eur Heart J"},{"key":"2025071501515062300_CIT0014","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/08037051.2021.1862483","article-title":"Potential protective effects of antihypertensive treatments during the Covid-19 pandemic: from inhibitors of the renin-angiotensin system to beta-adrenergic receptor blockers","volume":"30","author":"Kjeldsen","year":"2021","journal-title":"Blood Press"},{"key":"2025071501515062300_CIT0015","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1164\/rccm.200912-1840OC","article-title":"The angiotensin-converting enzyme 2\/angiogenesis-(1-7)\/Mas axis confers cardiopulmonary protection against lung fibrosis and pulmonary hypertension","volume":"182","author":"Shenoy","year":"2010","journal-title":"Am J Respir Crit Care Med"},{"key":"2025071501515062300_CIT0016","doi-asserted-by":"crossref","first-page":"S31","DOI":"10.4103\/sja.SJA_543_18","article-title":"The STROBE guidelines","volume":"13","author":"Cuschieri","year":"2019","journal-title":"Saudi J Anaesth"},{"key":"2025071501515062300_CIT0017","doi-asserted-by":"crossref","first-page":"e657","DOI":"10.1016\/S2589-7500(23)00128-0","article-title":"Illness severity assessment of older adults in critical illness using machine learning (ELDER-ICU): an international multicentre study with subgroup bias evaluation","volume":"5","author":"Liu","year":"2023","journal-title":"The Lancet Digital Health"},{"key":"2025071501515062300_CIT0018","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1186\/s12871-022-01827-x","article-title":"Machine learning prediction of postoperative major adverse cardiovascular events in geriatric patients: a prospective cohort study","volume":"22","author":"Peng","year":"2022","journal-title":"BMC Anesthesiology"},{"key":"2025071501515062300_CIT0019","first-page":"977","article-title":"Applying machine learning to predict real-world individual treatment effects: insights from a virtual patient cohort","volume":"26","author":"Fang","year":"2019","journal-title":"JAMIA"},{"key":"2025071501515062300_CIT0020","doi-asserted-by":"crossref","first-page":"e040644","DOI":"10.1136\/bmjopen-2020-040644","article-title":"Currently prescribed drugs in the UK that could upregulate or downregulate ACE2 in COVID-19 disease: a systematic review","volume":"10","author":"Dambha-Miller","year":"2020","journal-title":"BMJ Open"},{"key":"2025071501515062300_CIT0021","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.ahj.2022.04.001","article-title":"Discontinuing vs continuing ACEIs and ARBs in hospitalized patients with COVID-19 according to disease severity: insights from the BRACE CORONA trial","volume":"249","author":"Macedo","year":"2022","journal-title":"Am Heart J"},{"key":"2025071501515062300_CIT0022","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1002\/ejhf.2060","article-title":"Association between renin-angiotensin-aldosterone system inhibitor use and COVID-19 hospitalization and death: a 1.4 million patient nationwide registry analysis","volume":"23","author":"Savarese","year":"2021","journal-title":"Eur J Heart Fail"},{"key":"2025071501515062300_CIT0023","doi-asserted-by":"crossref","first-page":"2431","DOI":"10.1056\/NEJMoa2006923","article-title":"Renin-angiotensin-aldosterone system blockers and the risk of Covid-19","volume":"382","author":"Mancia","year":"2020","journal-title":"N Engl J Med"},{"key":"2025071501515062300_CIT0024","doi-asserted-by":"crossref","first-page":"e044010","DOI":"10.1136\/bmjopen-2020-044010","article-title":"Association of outpatient ACE inhibitors and angiotensin receptor blockers and outcomes of acute respiratory illness: a retrospective cohort study","volume":"11","author":"Jeffery","year":"2021","journal-title":"BMJ Open"},{"key":"2025071501515062300_CIT0025","doi-asserted-by":"crossref","first-page":"749291","DOI":"10.3389\/fimmu.2021.749291","article-title":"Effects of \u03b2-blockers on the sympathetic and cytokines storms in Covid-19","volume":"12","author":"Al-kuraishy","year":"2021","journal-title":"Front Immunol"},{"key":"2025071501515062300_CIT0026","doi-asserted-by":"crossref","first-page":"109809","DOI":"10.1016\/j.mehy.2020.109809","article-title":"Can beta-adrenergic blockers be used in the treatment of COVID-19","volume":"142","author":"Vasanthakumar","year":"2020","journal-title":"Med Hypotheses"},{"key":"2025071501515062300_CIT0027","doi-asserted-by":"crossref","first-page":"2807","DOI":"10.1021\/acsinfecdis.1c00023","article-title":"Inhibitors of L-type calcium channels show therapeutic potential for treating SARS-CoV-2 Infections by preventing virus entry and spread","volume":"7","author":"Straus","year":"2021","journal-title":"ACS Infect Dis"},{"key":"2025071501515062300_CIT0028","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/s41421-020-00235-0","article-title":"Calcium channel blocker amlodipine besylate therapy is associated with reduced case fatality rate of COVID-19 patients with hypertension","volume":"6","author":"Zhang","year":"2020","journal-title":"Cell Discovery"},{"key":"2025071501515062300_CIT0029","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/s41421-020-00221-6","article-title":"Antihypertensive drugs are associated with reduced fatal outcomes and improved clinical characteristics in elderly COVID-19 patients","volume":"6","author":"Yan","year":"2020","journal-title":"Cell Discovery"},{"key":"2025071501515062300_CIT0030","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1016\/j.jacc.2021.07.003","article-title":"Metoprolol in critically Ill patients with COVID-19","volume":"78","author":"Clemente-Morag\u00f3n","year":"2021","journal-title":"J Am Coll Cardiol"},{"key":"2025071501515062300_CIT0031","first-page":"e8069","article-title":"Nifedipine and amlodipine are associated with improved mortality and decreased risk for intubation and mechanical ventilation in elderly patients hospitalized for COVID-19","volume":"12","author":"Solaimanzadeh","year":"2020","journal-title":"Cureus"},{"key":"2025071501515062300_CIT0032","first-page":"e15573","article-title":"Does baseline diuretics use affect prognosis in patients with COVID-19","volume":"13","author":"Guragai","year":"2021","journal-title":"Cureus"},{"key":"2025071501515062300_CIT0033","doi-asserted-by":"crossref","first-page":"1252556","DOI":"10.3389\/fmed.2023.1252556","article-title":"Retrospective cohort study to evaluate the continuous use of anticholesterolemics and diuretics in patients with COVID-19","volume":"10","author":"Oliveira","year":"2024","journal-title":"Frontiers in Medicine"},{"key":"2025071501515062300_CIT0034","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1097\/HJH.0000000000002450","article-title":"Can angiotensin receptor-blocking drugs perhaps be harmful in the COVID-19 pandemic","volume":"38","author":"Esler","year":"2020","journal-title":"J Hypertens"},{"key":"2025071501515062300_CIT0035","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1007\/s00228-024-03709-2","article-title":"Use of drugs for hypertension or heart failure and the risk of death in COVID-19: association with loop-diuretics","volume":"80","author":"Fastbom","year":"2024","journal-title":"Eur J Clin Pharmacol"},{"key":"2025071501515062300_CIT0036","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.amjcard.2020.09.012","article-title":"Relation of Statin use prior to admission to severity and recovery among COVID-19 inpatients","volume":"136","author":"Daniels","year":"2020","journal-title":"Am J Cardiol"},{"key":"2025071501515062300_CIT0037","doi-asserted-by":"crossref","first-page":"e001674","DOI":"10.1136\/bmjresp-2023-001674","article-title":"Repurposed drug studies on the primary prevention of SARS-CoV-2 infection during the pandemic: systematic review and meta-analysis","volume":"10","author":"Zhou","year":"2023","journal-title":"BMJ Open Respir Res"},{"key":"2025071501515062300_CIT0038","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1111\/imm.12902","article-title":"Immune modulatory effects of statins","volume":"154","author":"Zeiser","year":"2018","journal-title":"Immunology"},{"key":"2025071501515062300_CIT0039","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41746-020-00372-6","article-title":"Machine learning-based prediction of COVID-19 diagnosis based on symptoms","volume":"4","author":"Zoabi","year":"2021","journal-title":"NPJ Digit Med"},{"key":"2025071501515062300_CIT0040","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1186\/s12879-024-09298-w","article-title":"The predictive power of data: machine learning analysis for Covid-19 mortality based on personal, clinical, preclinical, and laboratory variables in a case-control study","volume":"24","author":"Seyedtabib","year":"2024","journal-title":"BMC Infect Dis"}],"container-title":["American Journal of Hypertension"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajh\/advance-article-pdf\/doi\/10.1093\/ajh\/hpaf055\/62951515\/hpaf055.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajh\/article-pdf\/38\/8\/595\/62951515\/hpaf055.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajh\/article-pdf\/38\/8\/595\/62951515\/hpaf055.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T05:52:02Z","timestamp":1752558722000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajh\/article\/38\/8\/595\/8115801"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,18]]},"references-count":40,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,4,18]]},"published-print":{"date-parts":[[2025,7,15]]}},"URL":"https:\/\/doi.org\/10.1093\/ajh\/hpaf055","relation":{},"ISSN":["0895-7061","1941-7225"],"issn-type":[{"type":"print","value":"0895-7061"},{"type":"electronic","value":"1941-7225"}],"subject":[],"published-other":{"date-parts":[[2025,8]]},"published":{"date-parts":[[2025,4,18]]}}}