{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T08:37:28Z","timestamp":1783067848575,"version":"3.54.6"},"reference-count":37,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,7,28]],"date-time":"2021-07-28T00:00:00Z","timestamp":1627430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000092","name":"U.S. National Library of Medicine","doi-asserted-by":"publisher","award":["LM012895"],"award-info":[{"award-number":["LM012895"]}],"id":[{"id":"10.13039\/100000092","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM132713"],"award-info":[{"award-number":["GM132713"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006458","name":"Children's Hospital of Philadelphia","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100006458","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Human genetic disorders, such as Down syndrome, have a wide variety of clinical phenotypic presentations, and characterizing each nuanced phenotype and subtype can be difficult. In this study, we examined the electronic health records of 4095 individuals with Down syndrome at the Children\u2019s Hospital of Philadelphia to create a method to characterize the phenotypic spectrum digitally. We extracted Human Phenotype Ontology (HPO) terms from quality-filtered patient notes using a natural language processing (NLP) approach MetaMap. We catalogued the most common HPO terms related to Down syndrome patients and compared the terms with those from a baseline population. We characterized the top 100 HPO terms by their frequencies at different ages of clinical visits and highlighted selected terms that have time-dependent distributions. We also discovered phenotypic terms that have not been significantly associated with Down syndrome, such as \u201cProptosis\u201d, \u201cDownslanted palpebral fissures\u201d, and \u201cMicrotia\u201d. In summary, our study demonstrated that the clinical phenotypic spectrum of individual with Mendelian diseases can be characterized through NLP-based digital phenotyping on population-scale electronic health records (EHRs).<\/jats:p>","DOI":"10.3390\/genes12081159","type":"journal-article","created":{"date-parts":[[2021,7,28]],"date-time":"2021-07-28T11:12:52Z","timestamp":1627470772000},"page":"1159","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Clinical Phenotypic Spectrum of 4095 Individuals with Down Syndrome from Text Mining of Electronic Health Records"],"prefix":"10.3390","volume":"12","author":[{"given":"James Margolin","family":"Havrilla","sequence":"first","affiliation":[{"name":"Center for Cellular and Molecular Therapeutics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengge","family":"Zhao","sequence":"additional","affiliation":[{"name":"Center for Cellular and Molecular Therapeutics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunhua","family":"Weng","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingo","family":"Helbig","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Health Informatics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"},{"name":"Division of Neurology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"},{"name":"The Epilepsy NeuroGenetics Initiative (ENGIN), Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"},{"name":"Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Bhoj","sequence":"additional","affiliation":[{"name":"Division of Human Genetics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"},{"name":"Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Cellular and Molecular Therapeutics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"},{"name":"Department of Biomedical and Health Informatics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"},{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/s41572-019-0143-7","article-title":"Down Syndrome","volume":"6","author":"Antonarakis","year":"2020","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1089\/gtmb.2011.0066","article-title":"Down Syndrome: Parental Origin, Recombination, and Maternal Age","volume":"16","author":"Wagner","year":"2012","journal-title":"Genet. Test. Mol. Biomark."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1002\/ajmg.a.35248","article-title":"Cytogenetic and Epidemiological Findings in Down Syndrome: England and Wales 1989\u20132009","volume":"158A","author":"Morris","year":"2012","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1006\/geno.1998.5335","article-title":"10 Years ofGenomics, Chromosome 21, and Down Syndrome","volume":"51","author":"Antonarakis","year":"1998","journal-title":"Genomics"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1136\/adc.2003.031765","article-title":"Mosaic Down\u2019s Syndrome Prevalence in a Complete Population Study","volume":"89","author":"Devlin","year":"2004","journal-title":"Arch. Dis. Child."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1242\/dmm.008078","article-title":"Down Syndrome: Searching for the Genetic Culprits","volume":"4","author":"Fisher","year":"2011","journal-title":"Dis. Model. Mech."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"287","DOI":"10.5830\/CVJA-2016-019","article-title":"Congenital Heart Disease and Down Syndrome: Various Aspects of a Confirmed Association","volume":"27","author":"Benhaourech","year":"2016","journal-title":"Cardiovasc. J. Afr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1002\/(SICI)1096-8628(19981116)80:3<213::AID-AJMG6>3.0.CO;2-8","article-title":"Population-Based Study of Congenital Heart Defects in Down Syndrome","volume":"80","author":"Freeman","year":"1998","journal-title":"Am. J. Med. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1111\/j.1365-2788.2007.01013.x","article-title":"Hospitalizations of Infants and Young Children with Down Syndrome: Evidence from Inpatient Person-Records from a Statewide Administrative Database","volume":"51","author":"So","year":"2007","journal-title":"J. Intellect. Disabil. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1542\/peds.2011-1605","article-title":"Committee on Genetics Health Supervision for Children with Down Syndrome","volume":"128","author":"Bull","year":"2011","journal-title":"Pediatrics"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"57","DOI":"10.3389\/fgene.2013.00057","article-title":"Down Syndrome Related Muscle Hypotonia: Association with COL6A3 Functional SNP rs2270669","volume":"4","author":"Dey","year":"2013","journal-title":"Front. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"287","DOI":"10.2147\/NSS.S154723","article-title":"Obstructive Sleep Apnea in Patients with Down Syndrome: Current Perspectives","volume":"10","author":"Simpson","year":"2018","journal-title":"Nat. Sci. Sleep"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1904","DOI":"10.12659\/MSM.893377","article-title":"Delays in Motor Development in Children with Down Syndrome","volume":"21","author":"Malak","year":"2015","journal-title":"Med. Sci. Monit."},{"key":"ref_14","unstructured":"Madhok, S.S., and Shabbir, N. (2020). Hypotonia. StatPearls, StatPearls Publishing."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1513\/pats.200709-155MG","article-title":"The Epidemiology of Adult Obstructive Sleep Apnea","volume":"5","author":"Punjabi","year":"2008","journal-title":"Proc. Am. Thorac. Soc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"D1207","DOI":"10.1093\/nar\/gkaa1043","article-title":"The Human Phenotype Ontology in 2021","volume":"49","author":"Gargano","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"D1038","DOI":"10.1093\/nar\/gky1151","article-title":"OMIM.org: Leveraging Knowledge across Phenotype-Gene Relationships","volume":"47","author":"Amberger","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"D993","DOI":"10.1093\/nar\/gkt937","article-title":"DECIPHER: Database for the Interpretation of Phenotype-Linked Plausibly Pathogenic Sequence and Copy-Number Variation","volume":"42","author":"Bragin","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_19","first-page":"518","article-title":"Orphanet: A European Database for Rare Diseases","volume":"152","author":"Weinreich","year":"2008","journal-title":"Ned. Tijdschr. Geneeskd."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1080\/02763869.2020.1726152","article-title":"MedGen: NCBI\u2019s Portal to Information on Medical Conditions with a Genetic Component","volume":"39","author":"Louden","year":"2020","journal-title":"Med. Ref. Serv. Q."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"D980","DOI":"10.1093\/nar\/gkt1113","article-title":"ClinVar: Public Archive of Relationships among Sequence Variation and Human Phenotype","volume":"42","author":"Landrum","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"D925","DOI":"10.1093\/nar\/gks1173","article-title":"The NIH Genetic Testing Registry: A New, Centralized Database of Genetic Tests to Enable Access to Comprehensive Information and Improve Transparency","volume":"41","author":"Rubinstein","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/gm530","article-title":"International Ethics Harmonization and the Global Alliance for Genomics and Health","volume":"6","author":"Knoppers","year":"2014","journal-title":"Genome Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.ajhg.2018.05.010","article-title":"Deep Phenotyping on Electronic Health Records Facilitates Genetic Diagnosis by Clinical Exomes","volume":"103","author":"Son","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"W566","DOI":"10.1093\/nar\/gkz386","article-title":"Doc2Hpo: A Web Application for Efficient and Accurate HPO Concept Curation","volume":"47","author":"Liu","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"lqaa032","DOI":"10.1093\/nargab\/lqaa032","article-title":"Phen2Gene: Rapid Phenotype-Driven Gene Prioritization for Rare Diseases","volume":"2","author":"Zhao","year":"2020","journal-title":"NAR Genom. Bioinform."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/s13073-021-00909-8","article-title":"PhenCards: A Data Resource Linking Human Phenotype Information to Biomedical Knowledge","volume":"13","author":"Havrilla","year":"2021","journal-title":"Genome Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"252ra123","DOI":"10.1126\/scitranslmed.3009262","article-title":"Effective Diagnosis of Genetic Disease by Computational Phenotype Analysis of the Disease-Associated Genome","volume":"6","author":"Zemojtel","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1016\/S0140-6736(14)61705-0","article-title":"Genetic Diagnosis of Developmental Disorders in the DDD Study: A Scalable Analysis of Genome-Wide Research Data","volume":"385","author":"Wright","year":"2015","journal-title":"Lancet"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"265ra168","DOI":"10.1126\/scitranslmed.3010076","article-title":"Effectiveness of Exome and Genome Sequencing Guided by Acuity of Illness for Diagnosis of Neurodevelopmental Disorders","volume":"6","author":"Soden","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_31","unstructured":"Aronson, A.R. (2001, January 3\u20137). Effective Mapping of Biomedical Text to the UMLS Metathesaurus: The MetaMap Program. Proceedings of the AMIA Symposium, Washington, DC, USA."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"D267","DOI":"10.1093\/nar\/gkh061","article-title":"The Unified Medical Language System (UMLS): Integrating Biomedical Terminology","volume":"32","author":"Bodenreider","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1197\/jamia.M1552","article-title":"Automated Encoding of Clinical Documents Based on Natural Language Processing","volume":"11","author":"Friedman","year":"2004","journal-title":"J. Am. Med. Inform. Assoc."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2060","DOI":"10.1038\/s41436-020-0923-1","article-title":"A Longitudinal Footprint of Genetic Epilepsies Using Automated Electronic Medical Record Interpretation","volume":"22","author":"Ganesan","year":"2020","journal-title":"Genet. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/S0002-9394(00)00459-1","article-title":"Acute Megakaryoblastic Leukemia in Down Syndrome: Orbital Infiltration","volume":"130","author":"Olson","year":"2000","journal-title":"Am. J. Ophthalmol."},{"key":"ref_36","first-page":"4","article-title":"Accuracy of the Clinical Diagnosis of Down Syndrome","volume":"73","author":"Devlin","year":"2004","journal-title":"Ulster Med. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1642","DOI":"10.4103\/jfmpc.jfmpc_162_19","article-title":"Speech and Language Delay in Children: Prevalence and Risk Factors","volume":"8","author":"Sunderajan","year":"2019","journal-title":"J. Family Med. Prim. Care"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/8\/1159\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:36:15Z","timestamp":1760164575000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/8\/1159"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,28]]},"references-count":37,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["genes12081159"],"URL":"https:\/\/doi.org\/10.3390\/genes12081159","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,28]]}}}