{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T08:58:11Z","timestamp":1793609891910,"version":"4.5.0"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T00:00:00Z","timestamp":1638316800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T00:00:00Z","timestamp":1639958400000},"content-version":"vor","delay-in-days":19,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Fabry disease (FD) is a rare genetic disorder characterized by glycosphingolipid accumulation and progressive damage across multiple organ systems. Due to its heterogeneous presentation, the condition is likely significantly underdiagnosed. Several approaches, including provider education efforts and newborn screening, have attempted to address underdiagnosis of FD across the age spectrum, with limited success. Artificial intelligence (AI) methods present another option for improving diagnosis. These methods isolate common health history patterns among patients using longitudinal real-world data, and can be particularly useful when patients experience nonspecific, heterogeneous symptoms over time. In this study, the performance of an AI tool in identifying patients with FD was analyzed. The tool was calibrated using de-identified health record data from a large cohort of nearly 5000 FD patients, and extracted phenotypic patterns from these records. The tool then used this FD pattern information to make individual-level estimates of FD in a testing dataset. Patterns were reviewed and confirmed with medical experts.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>The AI tool demonstrated strong analytic performance in identifying FD patients. In out-of-sample testing, it achieved an area under the receiver operating characteristic curve (AUROC) of 0.82. Strong performance was maintained when testing on male-only and female-only cohorts, with AUROCs of 0.83 and 0.82 respectively. The tool identified small segments of the population with greatly increased prevalence of FD: in the 1% of the population identified by the tool as at highest risk, FD was 23.9 times more prevalent than in the population overall. The AI algorithm used hundreds of phenotypic signals to make predictions and included both familiar symptoms associated with FD (e.g. renal manifestations) as well as less well-studied characteristics.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>The AI tool analyzed in this study performed very well in identifying Fabry disease patients using structured medical history data. Performance was maintained in all-male and all-female cohorts, and the phenotypic manifestations of FD highlighted by the tool were reviewed and confirmed by clinical experts in the condition. The platform\u2019s analytic performance, transparency, and ability to generate predictions based on existing real-world health data may allow it to contribute to reducing persistent underdiagnosis of Fabry disease.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13023-021-02150-3","type":"journal-article","created":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T10:03:12Z","timestamp":1639994592000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["A new approach to identifying patients with elevated risk for Fabry disease using a machine learning algorithm"],"prefix":"10.1186","volume":"16","author":[{"given":"John L.","family":"Jefferies","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison K.","family":"Spencer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather A.","family":"Lau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew W.","family":"Nelson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph D.","family":"Giuliano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3182-6983","authenticated-orcid":false,"given":"Joseph W.","family":"Zabinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Costas","family":"Boussios","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Curhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard E.","family":"Gliklich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David G.","family":"Warnock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,12,20]]},"reference":[{"key":"2150_CR1","doi-asserted-by":"publisher","first-page":"3148","DOI":"10.1016\/S0021-9258(18)51888-3","volume":"238","author":"CC Sweeley","year":"1963","unstructured":"Sweeley CC, Klionsky B. Fabry\u2019s disease: classification as a sphingolipidosis and partial characterization of a novel glycolipid. J Biol Chem. 1963;238:3148\u201350.","journal-title":"J Biol Chem"},{"key":"2150_CR2","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1056\/NEJM196705252762101","volume":"276","author":"RO Brady","year":"1967","unstructured":"Brady RO, Gal AE, et al. Enzymatic defect in Fabry\u2019s disease\u2014ceramidetrihexosidase deficiency. N Engl J Med. 1967;276:1163\u20137.","journal-title":"N Engl J Med"},{"issue":"5263","key":"2150_CR3","doi-asserted-by":"publisher","first-page":"1173","DOI":"10.1038\/2271173b0","volume":"227","author":"JA Kint","year":"1970","unstructured":"Kint JA. The enzyme defect in Fabry\u2019s disease. Nature. 1970;227(5263):1173.","journal-title":"Nature"},{"issue":"4","key":"2150_CR4","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1016\/j.ymgme.2018.02.014","volume":"123","author":"A Ortiz","year":"2018","unstructured":"Ortiz A, Germain DP, Desnick RJ, Politei J, Mauer M, Burlina A, et al. Fabry disease revisited: management and treatment recommendations for adult patients. Mol Genet Metab. 2018;123(4):416\u201327.","journal-title":"Mol Genet Metab"},{"issue":"33","key":"2150_CR5","doi-asserted-by":"publisher","first-page":"5974","DOI":"10.2174\/13816128113199990352","volume":"19","author":"A Tuttolomondo","year":"2013","unstructured":"Tuttolomondo A, Pecoraro R, Simonetta I, Miceli S, Pinto A, Licata G. Anderson-Fabry disease: a multiorgan disease. Curr Pharm Des. 2013;19(33):5974\u201396.","journal-title":"Curr Pharm Des"},{"issue":"2","key":"2150_CR6","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1016\/j.kint.2016.10.004","volume":"91","author":"R Schiffmann","year":"2017","unstructured":"Schiffmann R, Hughes DA, Linthorst GE, Ortiz A, Svarstad E, Warnock DG, et al. Screening, diagnosis, and management of patients with Fabry disease: conclusions from a \u201ckidney disease: improving global outcomes\u201d (KDIGO) controversies conference. Kidney Int. 2017;91(2):284\u201393.","journal-title":"Kidney Int"},{"issue":"5","key":"2150_CR7","doi-asserted-by":"publisher","first-page":"1631","DOI":"10.1681\/ASN.2016090964","volume":"28","author":"M Arends","year":"2017","unstructured":"Arends M, Wanner C, Hughes D, Mehta A, Oder D, Watkinson OT, et al. Characterization of classical and nonclassical fabry disease: a multicenter study. J Am Soc Nephrol. 2017;28(5):1631\u201341.","journal-title":"J Am Soc Nephrol"},{"issue":"9","key":"2150_CR8","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1093\/qjmed\/hcq117","volume":"103","author":"A Mehta","year":"2010","unstructured":"Mehta A, Beck M, Eyskens F, Feliciani C, Kantola I, Ramaswami U, et al. Fabry disease: a review of current management strategies. QJM. 2010;103(9):641\u201359.","journal-title":"QJM"},{"issue":"7","key":"2150_CR9","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1007\/s11940-016-0414-5","volume":"18","author":"M Ranieri","year":"2016","unstructured":"Ranieri M, Bedini G, Parati EA, Bersano A. Fabry disease: recognition, diagnosis, and treatment of neurological features. Curr Treat Options Neurol. 2016;18(7):33.","journal-title":"Curr Treat Options Neurol"},{"key":"2150_CR10","doi-asserted-by":"publisher","first-page":"232640981668573","DOI":"10.1177\/2326409816685735","volume":"5","author":"MA Curiati","year":"2017","unstructured":"Curiati MA, Aranda CS, Kyosen SO, Varela P, Pereira VG, D\u2019Almeida V, et al. The challenge of diagnosis and indication for treatment in fabry disease. J Inborn Errors Metab Screen. 2017;5:232640981668573.","journal-title":"J Inborn Errors Metab Screen"},{"issue":"2","key":"2150_CR11","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1007\/s10545-007-0521-2","volume":"30","author":"CM Eng","year":"2007","unstructured":"Eng CM, Fletcher J, Wilcox WR, Waldek S, Scott CR, Sillence DO, et al. Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry registry. J Inherit Metab Dis. 2007;30(2):184\u201392.","journal-title":"J Inherit Metab Dis"},{"issue":"1","key":"2150_CR12","doi-asserted-by":"publisher","first-page":"e000567","DOI":"10.1136\/openhrt-2016-000567","volume":"4","author":"A-L Savary","year":"2017","unstructured":"Savary A-L, Morello R, Brasse-Lagnel C, Milliez P, Bekri S, Labombarda F. Enhancing the diagnosis of Fabry disease in cardiology with a targeted information: a before\u2013after control\u2013impact study. Open Heart. 2017;4(1):e000567.","journal-title":"Open Heart."},{"issue":"5","key":"2150_CR13","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1007\/s10897-013-9613-3","volume":"22","author":"DA Laney","year":"2013","unstructured":"Laney DA, Bennett RL, Clarke V, Fox A, Hopkin RJ, Johnson J, et al. Fabry disease practice guidelines: recommendations of the national society of genetic counselors. J Genet Couns. 2013;22(5):555\u201364.","journal-title":"J Genet Couns"},{"issue":"1","key":"2150_CR14","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1086\/504601","volume":"79","author":"M Spada","year":"2006","unstructured":"Spada M, Pagliardini S, Yasuda M, Tukel T, Thiagarajan G, Sakuraba H, et al. High incidence of later-onset Fabry disease revealed by newborn screening. Am J Hum Genet. 2006;79(1):31\u201340.","journal-title":"Am J Hum Genet"},{"issue":"25","key":"2150_CR15","doi-asserted-by":"publisher","first-page":"2399","DOI":"10.1016\/j.jacc.2007.06.062","volume":"50","author":"L Monserrat","year":"2007","unstructured":"Monserrat L, Gimeno-Blanes JR, Mar\u00edn F, Hermida-Prieto M, Garc\u00eda-Honrubia A, P\u00e9rez I, et al. Prevalence of Fabry disease in a cohort of 508 unrelated patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2007;50(25):2399\u2013403.","journal-title":"J Am Coll Cardiol"},{"issue":"4","key":"2150_CR16","doi-asserted-by":"publisher","first-page":"629","DOI":"10.2215\/CJN.08780812","volume":"8","author":"H Maruyama","year":"2013","unstructured":"Maruyama H, Takata T, Tsubata Y, Tazawa R, Goto K, Tohyama J, et al. Screening of male dialysis patients for Fabry disease by plasma globotriaosylsphingosine. Clin J Am Soc Nephrol. 2013;8(4):629\u201336.","journal-title":"Clin J Am Soc Nephrol"},{"key":"2150_CR17","doi-asserted-by":"publisher","first-page":"104272","DOI":"10.1016\/j.ijmedinf.2020.104272","volume":"143","author":"DS Lindberg","year":"2020","unstructured":"Lindberg DS, Prosperi M, Bjarnadottir RI, Thomas J, Crane M, Chen Z, et al. Identification of important factors in an inpatient fall risk prediction model to improve the quality of care using EHR and electronic administrative data: a machine-learning approach. Int J Med Inf. 2020;143:104272.","journal-title":"Int J Med Inf"},{"issue":"1","key":"2150_CR18","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1186\/s13073-019-0689-8","volume":"11","author":"R Dias","year":"2019","unstructured":"Dias R, Torkamani A. Artificial intelligence in clinical and genomic diagnostics. Genome Med. 2019;11(1):70.","journal-title":"Genome Med"},{"issue":"2","key":"2150_CR19","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1167\/tvst.9.2.13","volume":"9","author":"W-C Lin","year":"2020","unstructured":"Lin W-C, Chen JS, Chiang MF, Hribar MR. Applications of artificial intelligence to electronic health record data in ophthalmology. Transl Vis Sci Technol. 2020;9(2):13.","journal-title":"Transl Vis Sci Technol"},{"issue":"8","key":"2150_CR20","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1038\/s41582-020-0377-8","volume":"16","author":"MA Myszczynska","year":"2020","unstructured":"Myszczynska MA, Ojamies PN, Lacoste AMB, Neil D, Saffari A, Mead R, et al. Applications of machine learning to diagnosis and treatment of neurodegenerative diseases. Nat Rev Neurol. 2020;16(8):440\u201356.","journal-title":"Nat Rev Neurol"},{"issue":"21","key":"2150_CR21","doi-asserted-by":"publisher","first-page":"2657","DOI":"10.1016\/j.jacc.2017.03.571","volume":"69","author":"C Krittanawong","year":"2017","unstructured":"Krittanawong C, Zhang H, Wang Z, Aydar M, Kitai T. Artificial intelligence in precision cardiovascular medicine. J Am Coll Cardiol. 2017;69(21):2657\u201364.","journal-title":"J Am Coll Cardiol"},{"issue":"1","key":"2150_CR22","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1053\/j.gastro.2019.08.058","volume":"158","author":"C Le Berre","year":"2020","unstructured":"Le Berre C, Sandborn WJ, Aridhi S, Devignes M-D, Fournier L, Sma\u00efl-Tabbone M, et al. Application of artificial intelligence to gastroenterology and Hepatology. Gastroenterology. 2020;158(1):76-94.e2.","journal-title":"Gastroenterology"},{"key":"2150_CR23","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.neuroimage.2019.02.057","volume":"193","author":"D Scheinost","year":"2019","unstructured":"Scheinost D, Noble S, Horien C, Greene AS, Lake EMR, Salehi M, et al. Ten simple rules for predictive modeling of individual differences in neuroimaging. Neuroimage. 2019;193:35\u201345.","journal-title":"Neuroimage"},{"issue":"1","key":"2150_CR24","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1186\/s13023-015-0296-8","volume":"10","author":"M Arends","year":"2015","unstructured":"Arends M, Hollak CEM, Biegstraaten M. Quality of life in patients with Fabry disease: a systematic review of the literature. Orphanet J Rare Dis. 2015;10(1):77.","journal-title":"Orphanet J Rare Dis"},{"issue":"10","key":"2150_CR25","doi-asserted-by":"publisher","first-page":"103702","DOI":"10.1016\/j.ejmg.2019.103702","volume":"62","author":"PM Elliott","year":"2019","unstructured":"Elliott PM, Germain DP, Hilz MJ, Spada M, Wanner C, Falissard B. Why systematic literature reviews in Fabry disease should include all published evidence. Eur J Med Genet. 2019;62(10):103702.","journal-title":"Eur J Med Genet"},{"issue":"11","key":"2150_CR26","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1097\/GIM.0b013e3181bb05bb","volume":"11","author":"S Waldek","year":"2009","unstructured":"Waldek S, Patel MR, Banikazemi M, Lemay R, Lee P. Life expectancy and cause of death in males and females with Fabry disease: findings from the Fabry registry. Genet Med. 2009;11(11):790\u20136.","journal-title":"Genet Med"}],"container-title":["Orphanet Journal of Rare Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-021-02150-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13023-021-02150-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-021-02150-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T10:27:56Z","timestamp":1639996076000},"score":1,"resource":{"primary":{"URL":"https:\/\/ojrd.biomedcentral.com\/articles\/10.1186\/s13023-021-02150-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12]]},"references-count":26,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["2150"],"URL":"https:\/\/doi.org\/10.1186\/s13023-021-02150-3","relation":{},"ISSN":["1750-1172"],"issn-type":[{"value":"1750-1172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12]]},"assertion":[{"value":"21 July 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 December 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 December 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":"Use of the de-identified data examined in this initiative to study patient characteristics and outcomes in retrospective, non-interventional, secondary analyses has been determined to be exempt from institutional review board (IRB) oversight by an independent IRB.","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":"JJ reports honoria from Sanofi Genzyme, Chiesi Pharma, Amicus, Abbott, CHFSolutions, Audentes, AstraZeneca, and IPS Heart. AS reports employment and stock options at OM1, Inc. HL reports grant\/research support and advisory board membership with grant, honoraria, and reimbursed travel\/food for Amicus and Biomarin, advisory board membership with honoria, reimbursed travel\/food for Chieisi and Actellion, grant\/research support, consultant, advisory board membership, fellowship grant with research support, honoraria, and reimbursed travel\/food from Sanofi, grant\/research support, advisory board membership with honoria, reimbursed travel\/food from Takeda, grant\/research support, consultant, advisory board membership, employment with honoria, reimbursed travel\/food, and salary at Ultragenyx, grant\/research support from Mallinckrodt, Intrabio, Pfizer, Protalix, Ovid Therapeutics, and Denali, grant research support, consultant at Prevail Therapeutics and Aspa Therapeutics. Advisory board membership with honoria for Taysha, Advisory board membership and lecturer with honoria at National Gaucher Foundation and National Fabry Disease Foundation, advisory board member, lecturer, and grant support from National Tay Sachs and Allied Diseases, lecturer with honoraria for FSIG, advisory board member, researcher for Adult Polyglucosan Body Disorders Research Foundation. MN reports salary, stock, and benefits from Amicus Therapeutics, Inc. JG reports salary, stock, and stock options at Amicus Therapeutics, Inc. JZ reports employment and stock options at OM1, Inc. CB reports employment and stock options at OM1, Inc. GC reports stock options from OM1, Inc., employment at Brigham and Women\u2019s Hospital, consultant activities at and stock options from Allena Pharmaceuticals, holding a grant from Decibel Therapeutics and GSK, and consultant activities for Dicerna, Shire-Takeda, and AstraZeneca. RG reports employment and stock options at OM1, Inc. DW reports stock ownership in Reata Pharma, advisory-board membership at Chiesi Pharma, and consultant activities for Amicus Biotherapeutics and Protalix Biotherapuetics.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"518"}}