{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T09:05:50Z","timestamp":1768554350494,"version":"3.49.0"},"posted":{"date-parts":[[2022,4,16]]},"group-title":"Epidemiology","reference-count":169,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2022,5,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Mendelian Randomization (MR) uses genetic instrumental variables to make causal inferences. Whilst sometimes referred to as \u201cnature\u2019s randomized trial\u201d, it has distinct assumptions that make comparisons between the results of MR studies with those of actual randomized controlled trials (RCTs) invaluable. To scope the potential for (semi-)-automated triangulation of MR and RCT evidence, we mined\n                  <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/ClinicalTrials.Gov\">ClinicalTrials.Gov<\/jats:ext-link>\n                  , PubMed and EpigraphDB databases and carried out a series of 26 manual literature comparisons among 54 MR and 77 RCT publications. We found that only 11% of completed RCTs identified in\n                  <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/ClinicalTrials.Gov\">ClinicalTrials.Gov<\/jats:ext-link>\n                  submitted their results to the database. Similarly low coverage was revealed for Semantic Medline (SemMedDB) semantic triples derived from MR and RCT publications \u201325% and 12%, respectively. Among intervention types that can be mimicked by MR, only trials of pharmaceutical interventions could be automatically matched to MR results due to insufficient annotation with MeSH ontology. A manual survey of the literature highlighted the potential for triangulation across a number of exposure\/outcome pairs if these challenges can be addressed. We conclude that careful triangulation of MR with RCT evidence should involve consideration of similarity of phenotypes across study designs, intervention intensity and duration, study population demography and health status, comparator group, intervention goal and quality of evidence.\n                <\/jats:p>","DOI":"10.1101\/2022.04.11.22273633","type":"posted-content","created":{"date-parts":[[2022,4,16]],"date-time":"2022-04-16T15:50:10Z","timestamp":1650124210000},"source":"Crossref","is-referenced-by-count":3,"title":["Systematic comparison of Mendelian randomization studies and randomized controlled trials using electronic databases"],"prefix":"10.64898","author":[{"given":"Maria K.","family":"Sobczyk","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1407-8314","authenticated-orcid":false,"given":"George Davey","family":"Smith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0924-3247","authenticated-orcid":false,"given":"Tom R.","family":"Gaunt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2022050404050440000_2022.04.11.22273633v2.1","doi-asserted-by":"crossref","unstructured":"Ference, B. A. , Holmes, M.V & Smith, G. D. Using Mendelian Randomization to Improve the Design of Randomized Trials. Cold Spring Harb. Perspect. Med. 11, (2021).","DOI":"10.1101\/cshperspect.a040980"},{"key":"2022050404050440000_2022.04.11.22273633v2.2","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyg070"},{"key":"2022050404050440000_2022.04.11.22273633v2.3","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s43586-021-00092-5","article-title":"Mendelian randomization","volume":"2","year":"2022","journal-title":"Nat. Rev. Methods Prim"},{"key":"2022050404050440000_2022.04.11.22273633v2.4","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)67767-7"},{"key":"2022050404050440000_2022.04.11.22273633v2.5","doi-asserted-by":"publisher","DOI":"10.1007\/s10654-020-00622-7"},{"key":"2022050404050440000_2022.04.11.22273633v2.6","doi-asserted-by":"crossref","unstructured":"Davies, N. M. , Holmes, M. V. & Davey Smith, G. Reading Mendelian randomisation studies: A guide, glossary, and checklist for clinicians. BMJ 362, (2018).","DOI":"10.1136\/bmj.k601"},{"key":"2022050404050440000_2022.04.11.22273633v2.7","doi-asserted-by":"publisher","DOI":"10.1097\/EDE.0000000000000699"},{"key":"2022050404050440000_2022.04.11.22273633v2.8","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2017.21"},{"key":"2022050404050440000_2022.04.11.22273633v2.9","doi-asserted-by":"crossref","unstructured":"Egger, M. , Buitrago-Garcia, D. & Smith, G. D. Systematic Reviews of Epidemiological Studies of Etiology and Prevalence. in Systematic Reviews in Health Care: Meta-analyses in Context (eds. Egger, M. , Higgins, J.P.T. & Smith, G.D. ) Chapter 19 (Wiley-Blackwell, 2022).","DOI":"10.1002\/9781119099369.ch19"},{"key":"2022050404050440000_2022.04.11.22273633v2.10","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)60312-2"},{"key":"2022050404050440000_2022.04.11.22273633v2.11","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.numecd.2014.09.003","article-title":"Effects of HDL-modifiers on cardiovascular outcomes: A meta-analysis of randomized trials","volume":"25","year":"2015","journal-title":"Nutr. Metab. Cardiovasc. Dis"},{"key":"2022050404050440000_2022.04.11.22273633v2.12","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyaa016"},{"key":"2022050404050440000_2022.04.11.22273633v2.13","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djy081"},{"key":"2022050404050440000_2022.04.11.22273633v2.14","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2008.864"},{"key":"2022050404050440000_2022.04.11.22273633v2.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2012.09.017"},{"key":"2022050404050440000_2022.04.11.22273633v2.16","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1604304"},{"key":"2022050404050440000_2022.04.11.22273633v2.17","doi-asserted-by":"crossref","unstructured":"Hegele, R. A. Editorial comment: when Mendelian randomization goes astray. Curr. Opin. Lipidol. 32, (2021).","DOI":"10.1097\/MOL.0000000000000735"},{"key":"2022050404050440000_2022.04.11.22273633v2.18","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1111\/j.1467-985X.2008.00547.x","article-title":"Bias modelling in evidence synthesis","volume":"172","year":"2009","journal-title":"J. R. Stat. Soc. Ser. A (Statistics Soc"},{"key":"2022050404050440000_2022.04.11.22273633v2.19","doi-asserted-by":"publisher","DOI":"10.1101\/2021.11.18.21266515"},{"key":"2022050404050440000_2022.04.11.22273633v2.20","doi-asserted-by":"publisher","DOI":"10.2105\/AJPH.94.3.400"},{"key":"2022050404050440000_2022.04.11.22273633v2.21","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1001\/jamapsychiatry.2018.3870","article-title":"A Mendelian Randomization Approach for Assessing the Relationship Between Physical Activity and Depression","volume":"76","year":"2019","journal-title":"JAMA Psychiatry"},{"key":"2022050404050440000_2022.04.11.22273633v2.22","doi-asserted-by":"crossref","first-page":"e1003725","DOI":"10.1371\/journal.pmed.1003725","article-title":"Long-term cost-effectiveness of interventions for obesity: A mendelian randomisation study","volume":"18","year":"2021","journal-title":"PLOS Med"},{"key":"2022050404050440000_2022.04.11.22273633v2.23","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-020-00493-1"},{"key":"2022050404050440000_2022.04.11.22273633v2.24","doi-asserted-by":"crossref","first-page":"2313","DOI":"10.1093\/eurheartj\/ehz962","article-title":"Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel","volume":"41","year":"2020","journal-title":"Eur. Heart J"},{"key":"2022050404050440000_2022.04.11.22273633v2.25","doi-asserted-by":"crossref","unstructured":"Munaf\u00f2, M. R. , Higgins, J. P. T. & Smith, G. D. Triangulating Evidence through the Inclusion of Genetically Informed Designs. Cold Spring Harb. Perspect. Med. 11, (2021).","DOI":"10.1101\/cshperspect.a040659"},{"key":"2022050404050440000_2022.04.11.22273633v2.26","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyw314"},{"key":"2022050404050440000_2022.04.11.22273633v2.27","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMsa1012065"},{"key":"2022050404050440000_2022.04.11.22273633v2.28","doi-asserted-by":"crossref","unstructured":"Liu, Y. et al. EpiGraphDB: a database and data mining platform for health data science. Bioinformatics 0\u20130 (2020).","DOI":"10.1101\/2020.08.01.230193"},{"key":"2022050404050440000_2022.04.11.22273633v2.29","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1038\/s41588-020-0682-6","article-title":"Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases","volume":"52","year":"2020","journal-title":"Nat. Genet"},{"key":"2022050404050440000_2022.04.11.22273633v2.30","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1517\/14740338.2014.932348","article-title":"Safety and tolerability of injectable lipid-lowering drugs: a review of available clinical data","volume":"13","year":"2014","journal-title":"Expert Opin. Drug Saf"},{"key":"2022050404050440000_2022.04.11.22273633v2.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2010.07.046"},{"key":"2022050404050440000_2022.04.11.22273633v2.32","first-page":"211","article-title":"Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer\u2019s disease: a systematic review and meta-analysis","volume":"3","year":"2008","journal-title":"Clin. Interv. Aging"},{"key":"2022050404050440000_2022.04.11.22273633v2.33","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2017.11467"},{"key":"2022050404050440000_2022.04.11.22273633v2.34","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1093\/ajhp\/57.suppl_1.S3","article-title":"Overview of the angiotensin-converting-enzyme inhibitors","volume":"57","year":"2000","journal-title":"Am. J. Heal. Pharm"},{"key":"2022050404050440000_2022.04.11.22273633v2.35","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts591"},{"key":"2022050404050440000_2022.04.11.22273633v2.36","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.1093\/jamia\/ocaa163","article-title":"Trialstreamer: A living, automatically updated database of clinical trial reports","volume":"27","year":"2020","journal-title":"J. Am. Med. Informatics Assoc"},{"key":"2022050404050440000_2022.04.11.22273633v2.37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001866"},{"key":"2022050404050440000_2022.04.11.22273633v2.38","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1177\/1352458513489756","article-title":"The effect of vitamin D-related interventions on multiple sclerosis relapses: a meta-analysis","volume":"19","year":"2013","journal-title":"Mult. Scler. J"},{"key":"2022050404050440000_2022.04.11.22273633v2.39","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1177\/1352458517690271","article-title":"A systematic review of the effects of modifiable risk factor interventions on the progression of multiple sclerosis","volume":"23","year":"2017","journal-title":"Mult. Scler. J"},{"key":"2022050404050440000_2022.04.11.22273633v2.40","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/s12944-020-01257-z","article-title":"Association of physical activity, sedentary behaviours and sleep duration with cardiovascular diseases and lipid profiles: a Mendelian randomization analysis","volume":"19","year":"2020","journal-title":"Lipids Health Dis"},{"key":"2022050404050440000_2022.04.11.22273633v2.41","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1007\/s00198-020-05786-2","article-title":"Estimates of the effects of physical activity on osteoporosis using multivariable Mendelian randomization analysis","volume":"32","year":"2021","journal-title":"Osteoporos. Int"},{"key":"2022050404050440000_2022.04.11.22273633v2.42","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/j.ypmed.2003.12.012","article-title":"Walking, lipids, and lipoproteins: a meta-analysis of randomized controlled trials","volume":"38","year":"2004","journal-title":"Prev. Med. (Baltim)"},{"key":"2022050404050440000_2022.04.11.22273633v2.43","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.jmhg.2005.09.003","article-title":"Aerobic exercise and lipids and lipoproteins in men: a meta-analysis of randomized controlled trials","volume":"3","year":"2006","journal-title":"J. Men\u2019s Heal. Gend"},{"key":"2022050404050440000_2022.04.11.22273633v2.44","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1089\/jwh.2004.13.1148","article-title":"Aerobic Exercise and Lipids and Lipoproteins in Women: A Meta-Analysis of Randomized Controlled Trials","volume":"13","year":"2004","journal-title":"J. Women\u2019s Heal"},{"key":"2022050404050440000_2022.04.11.22273633v2.45","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ypmed.2008.10.010","article-title":"Impact of progressive resistance training on lipids and lipoproteins in adults: A meta-analysis of randomized controlled trials","volume":"48","year":"2009","journal-title":"Prev. Med. (Baltim)"},{"key":"2022050404050440000_2022.04.11.22273633v2.46","doi-asserted-by":"crossref","unstructured":"Mosti, M. P. et al. Maximal Strength Training Improves Bone Mineral Density and Neuromuscular Performance in Young Adult Women. J. Strength Cond. Res. 28, (2014).","DOI":"10.1519\/JSC.0000000000000493"},{"key":"2022050404050440000_2022.04.11.22273633v2.47","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2012.12.045"},{"key":"2022050404050440000_2022.04.11.22273633v2.48","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1995.03530240025035"},{"key":"2022050404050440000_2022.04.11.22273633v2.49","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1093\/clinchem\/hvaa049","article-title":"25-Hydroxyvitamin D and Risk of Osteoporotic Fractures: Mendelian Randomization Analysis in 2 Large Population-Based Cohorts","volume":"66","year":"2020","journal-title":"Clin. Chem"},{"key":"2022050404050440000_2022.04.11.22273633v2.50","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1109617"},{"key":"2022050404050440000_2022.04.11.22273633v2.51","doi-asserted-by":"publisher","DOI":"10.1001\/archinternmed.2008.600"},{"key":"2022050404050440000_2022.04.11.22273633v2.52","doi-asserted-by":"publisher","DOI":"10.1001\/jama.293.18.2257"},{"key":"2022050404050440000_2022.04.11.22273633v2.53","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1001\/jamapsychiatry.2020.3946","article-title":"Association Between Physical Activity and Schizophrenia: Results of a 2-Sample Mendelian Randomization Analysis","volume":"78","year":"2021","journal-title":"JAMA Psychiatry"},{"key":"2022050404050440000_2022.04.11.22273633v2.54","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.jad.2019.11.034","article-title":"The causal relationships of device-measured physical activity with bipolar disorder and schizophrenia in adults: A 2-Sample mendelian randomization study","volume":"263","year":"2020","journal-title":"J. Affect. Disord"},{"key":"2022050404050440000_2022.04.11.22273633v2.55","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.13r08765"},{"key":"2022050404050440000_2022.04.11.22273633v2.56","doi-asserted-by":"publisher","DOI":"10.1017\/S0033291714003110"},{"key":"2022050404050440000_2022.04.11.22273633v2.57","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.genhosppsych.2019.11.002","article-title":"Physical exercise for negative symptoms of schizophrenia: Systematic review of randomized controlled trials and meta-analysis","volume":"62","year":"2020","journal-title":"Gen. Hosp. Psychiatry"},{"key":"2022050404050440000_2022.04.11.22273633v2.58","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2016.7050"},{"key":"2022050404050440000_2022.04.11.22273633v2.59","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1001\/jamainternmed.2017.6015","article-title":"Association of Blood Pressure Lowering With Mortality and Cardiovascular Disease Across Blood Pressure Levels: A Systematic Review and Meta-analysis","volume":"178","year":"2018","journal-title":"JAMA Intern. Med"},{"key":"2022050404050440000_2022.04.11.22273633v2.60","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1016\/S0140-6736(21)01921-8","article-title":"Age-stratified and blood-pressure-stratified effects of blood-pressure-lowering pharmacotherapy for the prevention of cardiovascular disease and death: an individual participant-level data meta-analysis","volume":"398","year":"2021","journal-title":"Lancet"},{"key":"2022050404050440000_2022.04.11.22273633v2.61","doi-asserted-by":"crossref","first-page":"e016773","DOI":"10.1161\/JAHA.120.016773","article-title":"Genetically Predicted Midlife Blood Pressure and Coronary Artery Disease Risk: Mendelian Randomization Analysis","volume":"9","year":"2020","journal-title":"J. Am. Heart Assoc"},{"key":"2022050404050440000_2022.04.11.22273633v2.62","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.1161\/HYPERTENSIONAHA.120.16534","article-title":"Relationship Between Blood Pressure and Incident Cardiovascular Disease: Linear and Nonlinear Mendelian Randomization Analyses","volume":"77","year":"2021","journal-title":"Hypertension"},{"key":"2022050404050440000_2022.04.11.22273633v2.63","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1161\/HYPERTENSIONAHA.120.16138","article-title":"Blood Pressure and Risk of Cardiovascular Disease in UK Biobank","volume":"77","year":"2021","journal-title":"Hypertension"},{"key":"2022050404050440000_2022.04.11.22273633v2.64","doi-asserted-by":"crossref","first-page":"e183788","DOI":"10.1001\/jamanetworkopen.2018.3788","article-title":"Association Between Obesity and Cardiovascular Outcomes: A Systematic Review and Meta-analysis of Mendelian Randomization Studies","volume":"1","year":"2018","journal-title":"JAMA Netw. Open"},{"key":"2022050404050440000_2022.04.11.22273633v2.65","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehz388"},{"key":"2022050404050440000_2022.04.11.22273633v2.66","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1212914"},{"key":"2022050404050440000_2022.04.11.22273633v2.67","doi-asserted-by":"publisher","DOI":"10.1192\/bjp.180.5.411"},{"key":"2022050404050440000_2022.04.11.22273633v2.68","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1001\/jamapsychiatry.2018.4175","article-title":"Assessment of Bidirectional Relationships Between Physical Activity and Depression Among Adults: A 2-Sample Mendelian Randomization Study","volume":"76","year":"2019","journal-title":"JAMA Psychiatry"},{"key":"2022050404050440000_2022.04.11.22273633v2.69","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1176\/appi.ajp.2020.19111158","article-title":"An Exposure-Wide and Mendelian Randomization Approach to Identifying Modifiable Factors for the Prevention of Depression","volume":"177","year":"2020","journal-title":"Am. J. Psychiatry"},{"key":"2022050404050440000_2022.04.11.22273633v2.70","doi-asserted-by":"publisher","DOI":"10.1177\/014107689208500910"},{"key":"2022050404050440000_2022.04.11.22273633v2.71","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpsychires.2016.02.023"},{"key":"2022050404050440000_2022.04.11.22273633v2.72","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.jad.2016.03.063","article-title":"Exercise as a treatment for depression: A meta-analysis","volume":"202","year":"2016","journal-title":"J. Affect. Disord"},{"key":"2022050404050440000_2022.04.11.22273633v2.73","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1001\/jamapsychiatry.2018.0572","article-title":"Association of Efficacy of Resistance Exercise Training With Depressive Symptoms: Meta-analysis and Meta-regression Analysis of Randomized Clinical Trials","volume":"75","year":"2018","journal-title":"JAMA Psychiatry"},{"key":"2022050404050440000_2022.04.11.22273633v2.74","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1002456"},{"key":"2022050404050440000_2022.04.11.22273633v2.75","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1016\/j.jid.2020.09.013","article-title":"Causal Analysis Shows Evidence of Atopic Dermatitis Leading to an Increase in Vitamin D Levels","volume":"141","year":"2021","journal-title":"J. Invest. Dermatol"},{"key":"2022050404050440000_2022.04.11.22273633v2.76","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2014.08.002"},{"key":"2022050404050440000_2022.04.11.22273633v2.77","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2133.2008.08601.x"},{"key":"2022050404050440000_2022.04.11.22273633v2.78","unstructured":"Amestejani, M. et al. Vitamin D supplementation in the treatment of atopic dermatitis: a clinical trial study. J. Drugs Dermatology 11, (2012)."},{"key":"2022050404050440000_2022.04.11.22273633v2.79","doi-asserted-by":"publisher","DOI":"10.3109\/09546630903578566"},{"key":"2022050404050440000_2022.04.11.22273633v2.80","doi-asserted-by":"crossref","unstructured":"Meisinger, C. , Linseisen, J. , Leitzmann, M. , Baurecht, H. & Baumeister, S. E. Association of physical activity and sedentary behavior with type 2 diabetes and glycemic traits: a two-sample Mendelian randomization study. BMJ Open Diabetes Res. Care 8, (2020).","DOI":"10.1136\/bmjdrc-2020-001896"},{"key":"2022050404050440000_2022.04.11.22273633v2.81","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1007\/s13300-021-01005-1","article-title":"Movement is Improvement: The Therapeutic Effects of Exercise and General Physical Activity on Glycemic Control in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Controlled Trials","volume":"12","year":"2021","journal-title":"Diabetes Ther"},{"key":"2022050404050440000_2022.04.11.22273633v2.82","doi-asserted-by":"publisher","DOI":"10.2337\/db16-0418"},{"key":"2022050404050440000_2022.04.11.22273633v2.83","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.116.026560"},{"key":"2022050404050440000_2022.04.11.22273633v2.84","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2019.00094"},{"key":"2022050404050440000_2022.04.11.22273633v2.85","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1002982"},{"key":"2022050404050440000_2022.04.11.22273633v2.86","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2020.00603"},{"key":"2022050404050440000_2022.04.11.22273633v2.87","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.20.4.537"},{"key":"2022050404050440000_2022.04.11.22273633v2.88","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200105033441801"},{"key":"2022050404050440000_2022.04.11.22273633v2.89","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa012512"},{"key":"2022050404050440000_2022.04.11.22273633v2.90","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1500858"},{"key":"2022050404050440000_2022.04.11.22273633v2.91","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1615664"},{"key":"2022050404050440000_2022.04.11.22273633v2.92","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.35.2.544"},{"key":"2022050404050440000_2022.04.11.22273633v2.93","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-134-1-200101020-00007"},{"key":"2022050404050440000_2022.04.11.22273633v2.94","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.7.5.707"},{"key":"2022050404050440000_2022.04.11.22273633v2.95","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/S0140-6736(87)90413-2","article-title":"REGULAR ALCOHOL USE RAISES BLOOD PRESSURE IN TREATED HYPERTENSIVE SUBJECTS: A Randomised Controlled Trial","volume":"329","year":"1987","journal-title":"Lancet"},{"key":"2022050404050440000_2022.04.11.22273633v2.96","doi-asserted-by":"publisher","DOI":"10.1161\/hy1101.093424"},{"key":"2022050404050440000_2022.04.11.22273633v2.97","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.20.4.533"},{"key":"2022050404050440000_2022.04.11.22273633v2.98","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.ypmed.2016.08.011","article-title":"Training fast or slow? Exercise for depression: A randomized controlled trial","volume":"91","year":"2016","journal-title":"Prev. Med. (Baltim)"},{"key":"2022050404050440000_2022.04.11.22273633v2.99","doi-asserted-by":"crossref","unstructured":"Ma, C. et al. Effects of weight loss interventions for adults who are obese on mortality, cardiovascular disease, and cancer: systematic review and meta-analysis. BMJ 359, (2017).","DOI":"10.1136\/bmj.j4849"},{"key":"2022050404050440000_2022.04.11.22273633v2.100","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.109.130005"},{"key":"2022050404050440000_2022.04.11.22273633v2.101","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1001\/jamacardio.2016.5804","article-title":"Association of Body Mass Index With Cardiometabolic Disease in the UK Biobank: A Mendelian Randomization Study","volume":"2","year":"2017","journal-title":"JAMA Cardiol"},{"key":"2022050404050440000_2022.04.11.22273633v2.102","doi-asserted-by":"crossref","first-page":"e11252","DOI":"10.1097\/MD.0000000000011252","article-title":"Causal association of body mass index with hypertension using a Mendelian randomization design","volume":"97","year":"2018","journal-title":"Medicine (Baltimore)"},{"key":"2022050404050440000_2022.04.11.22273633v2.103","doi-asserted-by":"crossref","first-page":"1971","DOI":"10.1161\/HYPERTENSIONAHA.120.15761","article-title":"Association of Cardiovascular Risk Factors and Lifestyle Behaviors With Hypertension","volume":"76","year":"2020","journal-title":"Hypertension"},{"key":"2022050404050440000_2022.04.11.22273633v2.104","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.09.011"},{"key":"2022050404050440000_2022.04.11.22273633v2.105","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1007\/s00394-019-01990-x","article-title":"Vitamin D, prediabetes and type 2 diabetes: bidirectional Mendelian randomization analysis","volume":"59","year":"2020","journal-title":"Eur. J. Nutr"},{"key":"2022050404050440000_2022.04.11.22273633v2.106","doi-asserted-by":"publisher","DOI":"10.1111\/dme.12273"},{"key":"2022050404050440000_2022.04.11.22273633v2.107","doi-asserted-by":"publisher","DOI":"10.2337\/dc14-0218"},{"key":"2022050404050440000_2022.04.11.22273633v2.108","doi-asserted-by":"crossref","first-page":"e0154215","DOI":"10.1371\/journal.pone.0154215","article-title":"Effect of Vitamin D3 Supplementation on Inflammatory Markers and Glycemic Measures among Overweight or Obese Adults: A Systematic Review of Randomized Controlled Trials","volume":"11","year":"2016","journal-title":"PLoS One"},{"key":"2022050404050440000_2022.04.11.22273633v2.109","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-2343"},{"key":"2022050404050440000_2022.04.11.22273633v2.110","doi-asserted-by":"crossref","first-page":"110870","DOI":"10.1016\/j.nut.2020.110870","article-title":"Are vitamins relevant to cancer risks? A Mendelian randomization investigation","volume":"78","year":"2020","journal-title":"Nutrition"},{"key":"2022050404050440000_2022.04.11.22273633v2.111","doi-asserted-by":"publisher","DOI":"10.1080\/01635581.2010.494335"},{"key":"2022050404050440000_2022.04.11.22273633v2.112","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2008.862"},{"key":"2022050404050440000_2022.04.11.22273633v2.113","doi-asserted-by":"publisher","DOI":"10.3945\/ajcn.114.085480"},{"key":"2022050404050440000_2022.04.11.22273633v2.114","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/90.6.440"},{"key":"2022050404050440000_2022.04.11.22273633v2.115","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2891-3-8"},{"key":"2022050404050440000_2022.04.11.22273633v2.116","doi-asserted-by":"crossref","unstructured":"Micha\u00eblsson, K. , Melhus, H. & Larsson, S. C. Serum 25-Hydroxyvitamin D Concentrations and Major Depression: A Mendelian Randomization Study. Nutrients 10, (2018).","DOI":"10.3390\/nu10121987"},{"key":"2022050404050440000_2022.04.11.22273633v2.117","doi-asserted-by":"crossref","unstructured":"Libuda, L. et al. Vitamin D and the Risk of Depression: A Causal Relationship? Findings from a Mendelian Randomization Study. Nutrients 11, (2019).","DOI":"10.3390\/nu11051085"},{"key":"2022050404050440000_2022.04.11.22273633v2.118","doi-asserted-by":"crossref","unstructured":"Mulugeta, A. , Lumsden, A. & Hypp\u00f6nen, E. Relationship between Serum 25(OH)D and Depression: Causal Evidence from a Bi-Directional Mendelian Randomization Study. Nutrients 13, (2021).","DOI":"10.3390\/nu13010109"},{"key":"2022050404050440000_2022.04.11.22273633v2.119","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/s41398-019-0554-y","article-title":"A role for vitamin D and omega-3 fatty acids in major depression? An exploration using genomics","volume":"9","year":"2019","journal-title":"Transl. Psychiatry"},{"key":"2022050404050440000_2022.04.11.22273633v2.120","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwr482"},{"key":"2022050404050440000_2022.04.11.22273633v2.121","doi-asserted-by":"publisher","DOI":"10.1192\/bjp.bp.111.104349"},{"key":"2022050404050440000_2022.04.11.22273633v2.122","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0057647"},{"key":"2022050404050440000_2022.04.11.22273633v2.123","doi-asserted-by":"publisher","DOI":"10.1007\/s10654-013-9874-z"},{"key":"2022050404050440000_2022.04.11.22273633v2.124","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/S2213-8587(14)70113-5","article-title":"Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study","volume":"2","year":"2014","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2022050404050440000_2022.04.11.22273633v2.125","doi-asserted-by":"crossref","first-page":"e1003410","DOI":"10.1371\/journal.pmed.1003410","article-title":"Evaluating the relationship between alcohol consumption, tobacco use, and cardiovascular disease: A multivariable Mendelian randomization study","volume":"17","year":"2020","journal-title":"PLOS Med"},{"key":"2022050404050440000_2022.04.11.22273633v2.126","doi-asserted-by":"publisher","DOI":"10.1016\/j.ahj.2010.09.023"},{"key":"2022050404050440000_2022.04.11.22273633v2.127","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/S0091-7435(03)00110-5","article-title":"The effects of cessation from cigarette smoking on the lipid and lipoprotein profiles: a meta-analysis","volume":"37","year":"2003","journal-title":"Prev. Med. (Baltim)"},{"key":"2022050404050440000_2022.04.11.22273633v2.128","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyu113"},{"key":"2022050404050440000_2022.04.11.22273633v2.129","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/153.4.353"},{"key":"2022050404050440000_2022.04.11.22273633v2.130","doi-asserted-by":"publisher","DOI":"10.1038\/ejcn.2012.68"},{"key":"2022050404050440000_2022.04.11.22273633v2.131","doi-asserted-by":"crossref","first-page":"2159","DOI":"10.1016\/j.numecd.2020.08.017","article-title":"Effect of coffee consumption on dyslipidemia: A meta-analysis of randomized controlled trials","volume":"30","year":"2020","journal-title":"Nutr. Metab. Cardiovasc. Dis"},{"key":"2022050404050440000_2022.04.11.22273633v2.132","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.nutr.17.1.305"},{"key":"2022050404050440000_2022.04.11.22273633v2.133","doi-asserted-by":"crossref","first-page":"4404","DOI":"10.1016\/j.clnu.2020.12.042","article-title":"Habitual coffee intake and plasma lipid profile: Evidence from UK Biobank","volume":"40","year":"2021","journal-title":"Clin. Nutr"},{"key":"2022050404050440000_2022.04.11.22273633v2.134","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1038\/s41467-022-28240-9","article-title":"Caffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance","volume":"13","year":"2022","journal-title":"Nat. Commun"},{"key":"2022050404050440000_2022.04.11.22273633v2.135","doi-asserted-by":"crossref","first-page":"36500","DOI":"10.1038\/srep36500","article-title":"Habitual coffee consumption and risk of type 2 diabetes, ischemic heart disease, depression and Alzheimer\u2019s disease: a Mendelian randomization study","volume":"6","year":"2016","journal-title":"Sci. Rep"},{"key":"2022050404050440000_2022.04.11.22273633v2.136","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyv083"},{"key":"2022050404050440000_2022.04.11.22273633v2.137","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMsr1611785"},{"key":"2022050404050440000_2022.04.11.22273633v2.138","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMsa1409364"},{"key":"2022050404050440000_2022.04.11.22273633v2.139","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)33220-9"},{"key":"2022050404050440000_2022.04.11.22273633v2.140","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1001\/jamainternmed.2016.6008","article-title":"Failure of Investigational Drugs in Late-Stage Clinical Development and Publication of Trial Results","volume":"176","year":"2016","journal-title":"JAMA Intern. Med"},{"key":"2022050404050440000_2022.04.11.22273633v2.141","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0303-9"},{"key":"2022050404050440000_2022.04.11.22273633v2.142","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2013.06.044"},{"key":"2022050404050440000_2022.04.11.22273633v2.143","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2010.06.015"},{"key":"2022050404050440000_2022.04.11.22273633v2.144","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.282836"},{"key":"2022050404050440000_2022.04.11.22273633v2.145","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.03.014"},{"key":"2022050404050440000_2022.04.11.22273633v2.146","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0099-7"},{"key":"2022050404050440000_2022.04.11.22273633v2.147","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1811263115"},{"key":"2022050404050440000_2022.04.11.22273633v2.148","unstructured":"Cupido, A. J. et al. Dissecting the IL-6 pathway in cardiometabolic disease: A Mendelian randomization study on both IL6 and IL6R. Br. J. Clin. Pharmacol. n\/a,."},{"key":"2022050404050440000_2022.04.11.22273633v2.149","unstructured":"Gallo, M. A. & Kaufman, D. Antagonistic and agonistic effects of tamoxifen: significance in human cancer. Semin. Oncol. 24, S1\u201471\u2014S1\u201480 (1997)."},{"key":"2022050404050440000_2022.04.11.22273633v2.150","first-page":"360","article-title":"How to use Mendelian randomization to anticipate the results of randomized trials","volume":"39","year":"2017","journal-title":"Eur. Heart J"},{"key":"2022050404050440000_2022.04.11.22273633v2.151","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2017.156"},{"key":"2022050404050440000_2022.04.11.22273633v2.152","doi-asserted-by":"publisher","DOI":"10.1007\/s00520-009-0655-x"},{"key":"2022050404050440000_2022.04.11.22273633v2.153","doi-asserted-by":"crossref","first-page":"2645","DOI":"10.1093\/eurheartj\/ehaa209","article-title":"The Mediterranean diet, plasma metabolome, and cardiovascular disease risk","volume":"41","year":"2020","journal-title":"Eur. Heart J"},{"key":"2022050404050440000_2022.04.11.22273633v2.154","doi-asserted-by":"publisher","DOI":"10.1136\/bmj-2021-065805"},{"key":"2022050404050440000_2022.04.11.22273633v2.155"},{"key":"2022050404050440000_2022.04.11.22273633v2.156","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.eurpsy.2018.07.004","article-title":"EPA guidance on physical activity as a treatment for severe mental illness: a meta-review of the evidence and Position Statement from the European Psychiatric Association (EPA), supported by the International Organization of Physical Therapists in Mental","volume":"54","year":"2018","journal-title":"Eur. Psychiatry"},{"key":"2022050404050440000_2022.04.11.22273633v2.157","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kws344"},{"key":"2022050404050440000_2022.04.11.22273633v2.158","doi-asserted-by":"crossref","first-page":"101577","DOI":"10.1016\/j.canep.2019.101577","article-title":"Reporting and guidelines for mendelian randomization analysis: A systematic review of oncological studies","volume":"62","year":"2019","journal-title":"Cancer Epidemiol"},{"key":"2022050404050440000_2022.04.11.22273633v2.159","doi-asserted-by":"crossref","unstructured":"Poole, R. et al. Coffee consumption and health: umbrella review of meta-analyses of multiple health outcomes. BMJ 359, (2017).","DOI":"10.1136\/bmj.j5024"},{"key":"2022050404050440000_2022.04.11.22273633v2.160","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.311.7003.485"},{"key":"2022050404050440000_2022.04.11.22273633v2.161","doi-asserted-by":"publisher","DOI":"10.1093\/ptj\/81.8.1464"},{"key":"2022050404050440000_2022.04.11.22273633v2.162","first-page":"485","article-title":"Understanding Clinical Trial Reports: Extracting Medical Entities and Their Relations","volume":"2021","year":"2021","journal-title":"AMIA Jt. Summits Transl. Sci. proceedings. AMIA Jt. Summits Transl. Sci"},{"key":"2022050404050440000_2022.04.11.22273633v2.163","unstructured":"Whitton, J. & Hunter, A. Automated tabulation of clinical trial results: A joint entity and relation extraction approach with transformer-based language representations. (2021)."},{"key":"2022050404050440000_2022.04.11.22273633v2.164","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0033677"},{"key":"2022050404050440000_2022.04.11.22273633v2.165","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4442"},{"key":"2022050404050440000_2022.04.11.22273633v2.166","first-page":"D1302","article-title":"Open Targets Platform: supporting systematic drug\u2013target identification and prioritisation","volume":"49","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"2022050404050440000_2022.04.11.22273633v2.167","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1037"},{"key":"2022050404050440000_2022.04.11.22273633v2.168","first-page":"583","article-title":"MELODI Presto: a fast and agile tool to explore semantic triples derived from biomedical literature","volume":"37","year":"2020","journal-title":"Bioinformatics"},{"key":"2022050404050440000_2022.04.11.22273633v2.169","doi-asserted-by":"publisher","DOI":"10.1016\/j.amepre.2004.04.017"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2022.04.11.22273633","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T14:41:13Z","timestamp":1768488073000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2022.04.11.22273633"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,16]]},"references-count":169,"URL":"https:\/\/doi.org\/10.1101\/2022.04.11.22273633","relation":{},"subject":[],"published":{"date-parts":[[2022,4,16]]},"subtype":"preprint"}}