{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T06:04:00Z","timestamp":1780985040588,"version":"3.54.1"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100004339","name":"Sanofi Aventis","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100004339","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000092","name":"U.S. National Library of Medicine","doi-asserted-by":"publisher","award":["T15LM007092"],"award-info":[{"award-number":["T15LM007092"]}],"id":[{"id":"10.13039\/100000092","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NVIDIA Graduate Fellowship"},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["K99NS114850"],"award-info":[{"award-number":["K99NS114850"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Neurol"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Characterization of prediagnostic Parkinson\u2019s Disease (PD) and early prediction of subsequent development are critical for preventive interventions, risk stratification and understanding of disease pathology. This study aims to characterize the role of the prediagnostic period in PD and, using selected features from this period as novel interception points, construct a prediction model to accelerate the diagnosis in a real-world setting.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We constructed two sets of machine learning models: a retrospective approach highlighting exposures up to 5 years prior to PD diagnosis, and an alternative model that prospectively predicted future PD diagnosis from all individuals at their first diagnosis of a gait or tremor disorder, these being features that appeared to represent the initiation of a differential diagnostic window.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We found many novel features captured by the retrospective models; however, the high accuracy was primarily driven from surrogate diagnoses for PD, such as gait and tremor disorders, suggesting the presence of a distinctive differential diagnostic period when the clinician already suspected PD. The model utilizing a gait\/tremor diagnosis as the interception point, achieved a validation AUC of 0.874 with potential time compression to a future PD diagnosis of more than 300\u2009days. Comparisons of predictive diagnoses between the prospective and prediagnostic cohorts suggest the presence of distinctive trajectories of PD progression based on comorbidity profiles.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Overall, our machine learning approach allows for both guiding clinical decisions such as the initiation of neuroprotective interventions and importantly, the possibility of earlier diagnosis for clinical trials for disease modifying therapies.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12883-021-02226-4","type":"journal-article","created":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T05:03:31Z","timestamp":1621314211000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Accelerating diagnosis of Parkinson\u2019s disease through risk prediction"],"prefix":"10.1186","volume":"21","author":[{"given":"William","family":"Yuan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett","family":"Beaulieu-Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Krolewski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Palmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Veyrat-Follet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Frau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvie","family":"Bozzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meaghan","family":"Cogswell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinesh","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Coulouvrat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Leroy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanya Z.","family":"Fischer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. Pablo","family":"Sardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen J.","family":"Chandross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee L.","family":"Rubin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Marie","family":"Wills","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac","family":"Kohane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott L.","family":"Lipnick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,18]]},"reference":[{"key":"2226_CR1","doi-asserted-by":"publisher","first-page":"1583","DOI":"10.1002\/mds.25945","volume":"29","author":"T Pringsheim","year":"2014","unstructured":"Pringsheim T, Jette N, Frolkis A, Steeves TDL. The prevalence of Parkinson\u2019s disease: a systematic review and meta-analysis. Mov Disord. 2014;29:1583\u201390. https:\/\/doi.org\/10.1002\/mds.25945.","journal-title":"Mov Disord"},{"key":"2226_CR2","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1002\/mds.27360","volume":"33","author":"AE Lang","year":"2018","unstructured":"Lang AE, Espay AJ. Disease modification in Parkinson\u2019s disease: current approaches, challenges, and future considerations. Mov Disord. 2018;33:660\u201377.","journal-title":"Mov Disord"},{"key":"2226_CR3","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1016\/j.gde.2009.03.008","volume":"19","author":"J Hardy","year":"2009","unstructured":"Hardy J, Lewis P, Revesz T, Lees A, Paisan-Ruiz C. The genetics of Parkinson\u2019s syndromes: a critical review. Curr Opin Genet Dev. 2009;19:254\u201365. https:\/\/doi.org\/10.1016\/j.gde.2009.03.008.","journal-title":"Curr Opin Genet Dev"},{"key":"2226_CR4","doi-asserted-by":"publisher","first-page":"989","DOI":"10.1038\/ng.3043","volume":"46","author":"MA Nalls","year":"2014","unstructured":"Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, Saad M, et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson\u2019s disease. Nat Genet. 2014;46:989\u201393.","journal-title":"Nat Genet"},{"key":"2226_CR5","doi-asserted-by":"publisher","first-page":"1511","DOI":"10.1038\/ng.3955","volume":"49","author":"D Chang","year":"2017","unstructured":"Chang D, Nalls MA, Hallgr\u00edmsd\u00f3ttir IB, Hunkapiller J, van der Brug M, Cai F, et al. A meta-analysis of genome-wide association studies identifies 17 new Parkinson\u2019s disease risk loci. Nat Genet. 2017;49:1511\u20136.","journal-title":"Nat Genet"},{"key":"2226_CR6","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.arr.2017.12.007","volume":"42","author":"H Deng","year":"2018","unstructured":"Deng H, Wang P, Jankovic J. The genetics of Parkinson disease. Ageing Res Rev. 2018;42:72\u201385.","journal-title":"Ageing Res Rev"},{"key":"2226_CR7","doi-asserted-by":"publisher","first-page":"e348","DOI":"10.1212\/NXG.0000000000000348","volume":"5","author":"H Iwaki","year":"2019","unstructured":"Iwaki H, Blauwendraat C, Leonard HL, Liu G, Maple-Gr\u00f8dem J, Corvol J-C, et al. Genetic risk of Parkinson disease and progression:: An analysis of 13 longitudinal cohorts. Neurol Genet. 2019;5:e348.","journal-title":"Neurol Genet"},{"key":"2226_CR8","doi-asserted-by":"publisher","first-page":"1600","DOI":"10.1002\/mds.26431","volume":"30","author":"D Berg","year":"2015","unstructured":"Berg D, Postuma RB, Adler CH, Bloem BR, Chan P, Dubois B, et al. MDS research criteria for prodromal Parkinson\u2019s disease. Mov Disord. 2015;30:1600\u201311.","journal-title":"Mov Disord"},{"key":"2226_CR9","doi-asserted-by":"publisher","first-page":"681","DOI":"10.3233\/jpd-150685","volume":"5","author":"P Mahlknecht","year":"2015","unstructured":"Mahlknecht P, Seppi K, Poewe W. The Concept of Prodromal Parkinson\u2019s Disease. J Parkinsons Dis. 2015;5:681\u201397. https:\/\/doi.org\/10.3233\/jpd-150685.","journal-title":"J Parkinsons Dis"},{"key":"2226_CR10","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/S1474-4422(14)70287-X","volume":"14","author":"A Schrag","year":"2015","unstructured":"Schrag A, Horsfall L, Walters K, Noyce A, Petersen I. Prediagnostic presentations of Parkinson\u2019s disease in primary care: a case-control study. Lancet Neurol. 2015;14:57\u201364.","journal-title":"Lancet Neurol"},{"key":"2226_CR11","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1093\/brain\/aww291","volume":"140","author":"SKL Darweesh","year":"2017","unstructured":"Darweesh SKL, Verlinden VJA, Stricker BH, Hofman A, Koudstaal PJ, Ikram MA. Trajectories of prediagnostic functioning in Parkinson\u2019s disease. Brain. 2017;140:429\u201341.","journal-title":"Brain."},{"key":"2226_CR12","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1002\/mds.870120607","volume":"12","author":"EG Gonera","year":"1997","unstructured":"Gonera EG, van\u2019t Hof M, Berger HJ, van Weel C, Horstink MW. Symptoms and duration of the prodromal phase in Parkinson\u2019s disease. Mov Disord. 1997;12:871\u20136.","journal-title":"Mov Disord"},{"key":"2226_CR13","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1007\/s00415-013-7171-0","volume":"261","author":"S Lerche","year":"2014","unstructured":"Lerche S, Seppi K, Behnke S, Liepelt-Scarfone I, Godau J, Mahlknecht P, et al. Risk factors and prodromal markers and the development of Parkinson\u2019s disease. J Neurol. 2014;261:180\u20137.","journal-title":"J Neurol"},{"key":"2226_CR14","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1212\/WNL.57.3.456","volume":"57","author":"RD Abbott","year":"2001","unstructured":"Abbott RD, Petrovitch H, White LR, Masaki KH, Tanner CM, Curb JD, et al. Frequency of bowel movements and the future risk of Parkinson\u2019s disease. Neurology. 2001;57:456\u201362.","journal-title":"Neurology."},{"key":"2226_CR15","doi-asserted-by":"publisher","first-page":"1442","DOI":"10.1212\/01.wnl.0000183056.89590.0d","volume":"65","author":"RD Abbott","year":"2005","unstructured":"Abbott RD, Ross GW, White LR, Tanner CM, Masaki KH, Nelson JS, et al. Excessive daytime sleepiness and subsequent development of Parkinson disease. Neurology. 2005;65:1442\u20136.","journal-title":"Neurology."},{"key":"2226_CR16","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1002\/ana.21291","volume":"63","author":"GW Ross","year":"2008","unstructured":"Ross GW, Petrovitch H, Abbott RD, Tanner CM, Popper J, Masaki K, et al. Association of olfactory dysfunction with risk for future Parkinson\u2019s disease. Ann Neurol. 2008;63:167\u201373.","journal-title":"Ann Neurol"},{"key":"2226_CR17","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1002\/mds.24996","volume":"27","author":"RB Postuma","year":"2012","unstructured":"Postuma RB, Aarsland D, Barone P, Burn DJ, Hawkes CH, Oertel W, et al. Identifying prodromal Parkinson\u2019s disease: pre-motor disorders in Parkinson's disease. Mov Disord. 2012;27:617\u201326.","journal-title":"Mov Disord"},{"key":"2226_CR18","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1002\/mds.27616","volume":"34","author":"A Schrag","year":"2019","unstructured":"Schrag A, Anastasiou Z, Ambler G, Noyce A, Walters K. Predicting diagnosis of Parkinson\u2019s disease: A risk algorithm based on primary care presentations. Mov Disord. 2019;34:480\u20136.","journal-title":"Mov Disord"},{"key":"2226_CR19","doi-asserted-by":"publisher","first-page":"1978","DOI":"10.1007\/s00415-013-6905-3","volume":"260","author":"DP Breen","year":"2013","unstructured":"Breen DP, Evans JR, Farrell K, Brayne C, Barker RA. Determinants of delayed diagnosis in Parkinson\u2019s disease. J Neurol. 2013;260:1978\u201381. https:\/\/doi.org\/10.1007\/s00415-013-6905-3.","journal-title":"J Neurol"},{"key":"2226_CR20","doi-asserted-by":"publisher","first-page":"1107","DOI":"10.1038\/s41467-021-21390-2","volume":"12","author":"W Yuan","year":"2021","unstructured":"Yuan W, Beaulieu-Jones BK, Yu K-H, Lipnick SL, Palmer N, Loscalzo J, et al. Temporal bias in case-control design: preventing reliable predictions of the future. Nat Commun. 2021;12:1107.","journal-title":"Nat Commun"},{"key":"2226_CR21","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1097\/PRS.0b013e318219c171","volume":"128","author":"PB Burns","year":"2011","unstructured":"Burns PB, Rohrich RJ, Chung KC. The levels of evidence and their role in evidence-based medicine. Plast Reconstr Surg. 2011;128:305\u201310.","journal-title":"Plast Reconstr Surg"},{"key":"2226_CR22","doi-asserted-by":"publisher","first-page":"1696","DOI":"10.1212\/01.wnl.0000279518.10072.df","volume":"69","author":"A Alonso","year":"2007","unstructured":"Alonso A, Rodr\u00edguez LAG, Logroscino G, Hern\u00e1n MA. Gout and risk of Parkinson disease: a prospective study. Neurology. 2007;69:1696\u2013700.","journal-title":"Neurology."},{"key":"2226_CR23","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1002\/pds.1115","volume":"14","author":"JD Lewis","year":"2005","unstructured":"Lewis JD, Bilker WB, Weinstein RB, Strom BL. The relationship between time since registration and measured incidence rates in the general practice research database. Pharmacoepidemiol Drug Saf. 2005;14:443\u201351.","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"2226_CR24","doi-asserted-by":"publisher","first-page":"1205","DOI":"10.1093\/bioinformatics\/btq126","volume":"26","author":"JC Denny","year":"2010","unstructured":"Denny JC, Ritchie MD, Basford MA, Pulley JM, Bastarache L, Brown-Gentry K, et al. PheWAS: demonstrating the feasibility of a phenome-wide scan to discover gene-disease associations. Bioinformatics. 2010;26:1205\u201310.","journal-title":"Bioinformatics."},{"key":"2226_CR25","first-page":"295","volume":"25","author":"AL Beam","year":"2020","unstructured":"Beam AL, Kompa B, Schmaltz A, Fried I, Weber G, Palmer N, et al. Clinical concept embeddings learned from massive sources of multimodal medical data. Pac Symp Biocomput. 2020;25:295\u2013306.","journal-title":"Pac Symp Biocomput"},{"key":"2226_CR26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/nrdp.2017.13","volume":"3","author":"W Poewe","year":"2017","unstructured":"Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, et al. Parkinson disease. Nat Rev Dis Primers. 2017;3:1\u201321.","journal-title":"Nat Rev Dis Primers"},{"key":"2226_CR27","doi-asserted-by":"publisher","unstructured":"Faustino PR, Duarte GS, Chendo I, Castro Caldas A, Reim\u00e3o S, Fernandes RM, et al. Risk of developing Parkinson disease in bipolar disorder: a systematic review and meta-analysis. JAMA Neurol. 2019. https:\/\/doi.org\/10.1001\/jamaneurol.2019.3446.","DOI":"10.1001\/jamaneurol.2019.3446"},{"key":"2226_CR28","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1176\/jnp.8.1.20","volume":"8","author":"SA Cole","year":"1996","unstructured":"Cole SA, Woodard JL, Juncos JL, Kogos JL, Youngstrom EA, Watts RL. Depression and disability in Parkinson\u2019s disease. J Neuropsychiatr Clin Neurosci. 1996;8:20\u20135.","journal-title":"J Neuropsychiatr Clin Neurosci"},{"key":"2226_CR29","first-page":"389195","volume":"2013","author":"S Skodda","year":"2013","unstructured":"Skodda S, Gr\u00f6nheit W, Mancinelli N, Schlegel U. Progression of voice and speech impairment in the course of Parkinson\u2019s disease: a longitudinal study. Parkinsons Dis. 2013;2013:389195.","journal-title":"Parkinsons Dis"},{"issue":"Suppl 3","key":"2226_CR30","first-page":"III\/40","volume":"249","author":"G Becker","year":"2002","unstructured":"Becker G, M\u00fcller A, Braune S, B\u00fcttner T, Benecke R, Greulich W, et al. Early diagnosis of Parkinson\u2019s disease. J Neurol. 2002;249(Suppl 3):III\/40\u20138.","journal-title":"J Neurol"},{"key":"2226_CR31","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1136\/jnnp.51.6.745","volume":"51","author":"WR Gibb","year":"1988","unstructured":"Gibb WR, Lees AJ. The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson\u2019s disease. J Neurol Neurosurg Psychiatry. 1988;51:745\u201352.","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"2226_CR32","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1002\/mds.25383","volume":"28","author":"GT Stebbins","year":"2013","unstructured":"Stebbins GT, Goetz CG, Burn DJ, Jankovic J, Khoo TK, Tilley BC. How to identify tremor dominant and postural instability\/gait difficulty groups with the movement disorder society unified Parkinson\u2019s disease rating scale: comparison with the unified Parkinson's disease rating scale. Mov Disord. 2013;28:668\u201370.","journal-title":"Mov Disord"},{"key":"2226_CR33","doi-asserted-by":"publisher","first-page":"1655","DOI":"10.1002\/mds.27135","volume":"32","author":"S Fengler","year":"2017","unstructured":"Fengler S, Liepelt-Scarfone I, Brockmann K, Sch\u00e4ffer E, Berg D, Kalbe E. Cognitive changes in prodromal Parkinson\u2019s disease: A review. Mov Disord. 2017;32:1655\u201366.","journal-title":"Mov Disord"},{"key":"2226_CR34","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1002\/mds.27670","volume":"34","author":"RB Postuma","year":"2019","unstructured":"Postuma RB, Berg D. Prodromal Parkinson\u2019s disease: the decade past, the decade to come. Mov Disord. 2019;34:665\u201375.","journal-title":"Mov Disord"},{"key":"2226_CR35","doi-asserted-by":"publisher","unstructured":"Shah NH, Milstein A, Bagley PhD SC. Making machine learning models clinically useful. JAMA. 2019. https:\/\/doi.org\/10.1001\/jama.2019.10306.","DOI":"10.1001\/jama.2019.10306"}],"container-title":["BMC Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12883-021-02226-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12883-021-02226-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12883-021-02226-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T05:04:24Z","timestamp":1621314264000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcneurol.biomedcentral.com\/articles\/10.1186\/s12883-021-02226-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,18]]},"references-count":35,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["2226"],"URL":"https:\/\/doi.org\/10.1186\/s12883-021-02226-4","relation":{},"ISSN":["1471-2377"],"issn-type":[{"value":"1471-2377","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,18]]},"assertion":[{"value":"22 August 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 May 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 May 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Ethics approval and consent to participate has granted for all aspects of the study. For the administrative claims data, the Harvard Medical School Institutional Review Board approved the research using regularly collected deidentified data by waiving the requirement for patient consent for analysis of this database as it was deemed to not be human subjects research. The use of identifiable data from the Partners Healthcare system was approved under by the Institutional Review Board (Protocol #: 2017P002452).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"CVF, FF, CC, SB, MC, DK, CC, BL, TF, SPS, and KJC are Sanofi employees.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"201"}}