{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:12:05Z","timestamp":1790788325255,"version":"4.1.0"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"12","funder":[{"name":"Cooperative Studies Program","award":["CSP#2032"],"award-info":[{"award-number":["CSP#2032"]}]},{"name":"Million Veteran Program","award":["MVP#000, MVP#001"],"award-info":[{"award-number":["MVP#000, MVP#001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,12,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Mendelian randomization (MR) studies have been described as naturally occurring randomized trials. However, MR studies often deviate from appropriate trial design principles, and many use two-sample designs with strong assumptions not required in randomized trials. Using data from the Million Veteran Program, we empirically evaluated the impact of study design choices and two-sample approaches in an MR study of lipids and coronary artery disease. We designed an MR study of participants of European descent with no history of coronary artery disease and no contraindications to low-density lipoprotein cholesterol (LDL-C)\u2013related therapies to estimate 10-year odds ratios of coronary artery disease per 39\u00a0mg\/dL increase in LDL-C or 15.8\u00a0mg\/dL increase in high-density lipoprotein cholesterol (HDL-C). We then sequentially modified the design to reflect common decisions made in MR studies. For LDL-C, one-sample estimates ranged from 1.50 (95% CI, 1.34\u00a0\u2212\u00a01.68) to 2.23 (95% CI, 1.93\u00a0\u2212\u00a02.59) and two-sample estimates from 1.13 (95% CI, 1.01\u00a0\u2212\u00a01.26) to 1.30 (95% CI, 1.15\u00a0\u2212\u00a01.46). For HDL-C, estimates ranged from 0.76 (95% CI, 0.68\u00a0\u2212\u00a00.86) to 0.93 (95% CI, 0.65\u00a0\u2212\u00a01.34) across one- versus two-sample analyses. Estimates were most sensitive to the inclusion of prevalent outcomes. These results indicate the magnitude of MR estimates can vary with study design. We recommend future MR studies assess the sensitivity of estimates to different design decisions.<\/jats:p>","DOI":"10.1093\/aje\/kwaf190","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T11:40:20Z","timestamp":1755862820000},"page":"3581-3589","source":"Crossref","is-referenced-by-count":3,"title":["Mendelian randomization, lipids, and coronary artery disease: trade-offs between study designs and assumptions"],"prefix":"10.1093","volume":"194","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4234-7999","authenticated-orcid":false,"given":"Joy","family":"Shi","sequence":"first","affiliation":[{"name":"Division of Population Health and Data Sciences, Massachusetts Veterans Epidemiology Research and Information Collaborative (MAVERIC), VA Boston Healthcare System , Boston, MA ,","place":["United States"]},{"name":"CAUSALab, Harvard T.H. Chan School of Public Health , Boston, MA ,","place":["United States"]},{"name":"Department of Epidemiology, Harvard T.H. Chan School of Public Health , Boston, MA ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja A","family":"Swanson","sequence":"additional","affiliation":[{"name":"CAUSALab, Harvard T.H. Chan School of Public Health , Boston, MA ,","place":["United States"]},{"name":"Department of Epidemiology, Harvard T.H. Chan School of Public Health , Boston, MA ,","place":["United States"]},{"name":"Department of Epidemiology, University of Pittsburgh , Pittsburgh, PA ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth W","family":"Diemer","sequence":"additional","affiliation":[{"name":"CAUSALab, Harvard T.H. Chan School of Public Health , Boston, MA ,","place":["United States"]},{"name":"Department of Epidemiology, Harvard T.H. Chan School of Public Health , Boston, MA ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6700-2129","authenticated-orcid":false,"given":"Hanna","family":"Gerlovin","sequence":"additional","affiliation":[{"name":"Division of Population Health and Data Sciences, Massachusetts Veterans Epidemiology Research and Information Collaborative (MAVERIC), VA Boston Healthcare System , Boston, MA ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel C","family":"Posner","sequence":"additional","affiliation":[{"name":"Division of Population Health and Data Sciences, Massachusetts Veterans Epidemiology Research and Information Collaborative (MAVERIC), VA Boston Healthcare System , Boston, MA ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter W F","family":"Wilson","sequence":"additional","affiliation":[{"name":"Department of Medicine, Veteran Affairs Atlanta Healthcare System , Decatur, GA ,","place":["United States"]},{"name":"Division of Cardiology, Emory University School of Medicine , Atlanta, GA ,","place":["United States"]},{"name":"Department of Epidemiology, Rollins School of Public Health, Emory University , Atlanta, GA ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J Michael","family":"Gaziano","sequence":"additional","affiliation":[{"name":"Division of Population Health and Data Sciences, Massachusetts Veterans Epidemiology Research and Information Collaborative (MAVERIC), VA Boston Healthcare System , Boston, MA ,","place":["United States"]},{"name":"Department of Medicine, Harvard Medical School , Boston, MA ,","place":["United States"]},{"name":"Department of Medicine, Division of Aging, Brigham and Women\u2019s Hospital , Boston, MA ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1727-7076","authenticated-orcid":false,"given":"Kelly","family":"Cho","sequence":"additional","affiliation":[{"name":"Division of Population Health and Data Sciences, Massachusetts Veterans Epidemiology Research and Information Collaborative (MAVERIC), VA Boston Healthcare System , Boston, MA ,","place":["United States"]},{"name":"Department of Medicine, Harvard Medical School , Boston, MA ,","place":["United States"]},{"name":"Department of Medicine, Division of Aging, Brigham and Women\u2019s Hospital , Boston, MA ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1619-8456","authenticated-orcid":false,"given":"Miguel A","family":"Hern\u00e1n","sequence":"additional","affiliation":[{"name":"CAUSALab, Harvard T.H. Chan School of Public Health , Boston, MA ,","place":["United States"]},{"name":"Department of Epidemiology, Harvard T.H. Chan School of Public Health , Boston, MA ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"On behalf of the VA Million Veteran Program","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,8,29]]},"reference":[{"issue":"9","key":"2025120218123518600_ref1","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1093\/eurheartj\/eht571","article-title":"Mendelian randomization of blood lipids for coronary heart disease","volume":"36","author":"Holmes","year":"2015","journal-title":"Eur Heart J."},{"issue":"12","key":"2025120218123518600_ref2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.119.002711","article-title":"Genetic determinants of lipids and cardiovascular disease outcomes: a wide-angled Mendelian randomization investigation","volume":"12","author":"Allara","year":"2019","journal-title":"Circ: Genom Precis Med."},{"issue":"14","key":"2025120218123518600_ref3","doi-asserted-by":"publisher","first-page":"1381","DOI":"10.1001\/jama.2019.14120","article-title":"Association of genetic variants related to combined exposure to lower low-density lipoproteins and lower systolic blood pressure with lifetime risk of cardiovascular disease","volume":"322","author":"Ference","year":"2019","journal-title":"JAMA."},{"issue":"4","key":"2025120218123518600_ref4","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1016\/j.jjcc.2018.04.007","article-title":"Mendelian randomization: its impact on cardiovascular disease","volume":"72","author":"Kawashiri","year":"2018","journal-title":"J Cardiol."},{"issue":"47","key":"2025120218123518600_ref5","doi-asserted-by":"publisher","first-page":"4913","DOI":"10.1093\/eurheartj\/ehad736","article-title":"Mendelian randomization for cardiovascular diseases: principles and applications","volume":"44","author":"Larsson","year":"2023","journal-title":"Eur Heart J."},{"issue":"9841","key":"2025120218123518600_ref6","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1016\/S0140-6736(12)60367-5","article-title":"The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials","volume":"380","author":"Cholesterol Treatment Trialists\u2019 (Ctt) Collaborators","year":"2012","journal-title":"Lancet."},{"issue":"9753","key":"2025120218123518600_ref7","doi-asserted-by":"publisher","first-page":"1670","DOI":"10.1016\/S0140-6736(10)61350-5","article-title":"Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials","volume":"376","author":"Cholesterol Treatment Trialists\u2019 (Ctt) Collaboration","year":"2010","journal-title":"Lancet."},{"issue":"21","key":"2025120218123518600_ref8","doi-asserted-by":"publisher","first-page":"2109","DOI":"10.1056\/NEJMoa0706628","article-title":"Effects of torcetrapib in patients at high risk for coronary events","volume":"357","author":"Barter","year":"2007","journal-title":"N Engl J Med."},{"issue":"24","key":"2025120218123518600_ref9","doi-asserted-by":"publisher","first-page":"2255","DOI":"10.1056\/NEJMoa1107579","article-title":"Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy","volume":"365","author":"The AIM-HIGH Investigators","year":"2011","journal-title":"N Engl J Med."},{"issue":"3","key":"2025120218123518600_ref10","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1056\/NEJMoa1300955","article-title":"The HPS2-THRIVE collaborative group. 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