{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T18:12:39Z","timestamp":1789150359713,"version":"build-2803163510"},"reference-count":48,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100001735","name":"Milton and Tamar Maltz Family Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001735","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001735","name":"Milton and Tamar Maltz Family Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001735","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001735","name":"Milton and Tamar Maltz Family Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001735","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Hypermobile Ehlers-Danlos Syndrome (hEDS) is a connective tissue disorder with variable symptom presentation across multiple organ systems and significant morbidity. Little is known about hEDS etiology and identifying patterns of symptom co-occurrence can reveal previously unidentified relationships between phenotypes and inform studies of underlying disease pathophysiology for symptoms that may share functional biological pathways. In this exploratory analysis, we specifically assessed the distribution of symptoms in case and controls to identify clusters of co-occurring symptoms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We have interrogated clinically relevant symptom areas in 47 females with hEDS, 36 age-matched female controls and 8 hypermobile patients without chronic pain. Studied symptoms include general health, mental health, body pain, vitality and energy, autonomic symptoms, bleeding, and gastrointestinal symptoms. We conducted hierarchal clustering on principle components (HCPC) to identify groups and compared the groups for the previously described symptoms. Radial plots were used to identify relationships between severe symptom categories.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our analysis reveals statistically significantly more severe symptoms in all categories in people with hEDS compared with age- and sex-matched controls and asymptomatic hypermobile patients. HCPC identified clearly separated Low, Moderate, and High symptom groups within participants. The Low dysfunction groups include nearly all controls and hypermobile patients without chronic pain. The High dysfunction group includes ~60% of people with hEDS, while around 40% are in the Moderate dysfunction cluster. Cluster solutions for all participants were stable with moderate fit (silhouette 0.64; Jaccard boot mean 0.91). Group level radial plots showed high bleeding severity across all symptom clusters, while disproportional severity of general health, physical function, limitation of role due to physical symptoms, pain, and social functioning deficits differentiates the High from Moderate and Low Dysfunction clusters.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Using this analysis at the group level has revealed patterns suggesting a progression of disease symptoms. People with hypermobility do not uniformly have severe symptoms but instead have some symptoms that differentiate from non-hypermobile individuals. While exploratory, using a radar multi-symptom analysis may be used to evaluate disproportionately severe symptoms contributing to the patterns of global symptom severity. These include pain but also ability to perform roles, suggesting strong utility of physical and occupational therapies to emphasize coping. This may also allow better targeting of etiological studies and may have additional utility at an individual level to develop symptom management strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0357565","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T17:58:06Z","timestamp":1789149486000},"page":"e0357565","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exploring cross-category relationships between symptoms in people with hypermobile EDS (hEDS) to identify disability patterns"],"prefix":"10.1371","volume":"21","author":[{"given":"Jennifer","family":"Andrews","sequence":"first","affiliation":[{"name":"ARID Lab","place":["Tucson, Arizona, United States of America"],"department":["Department of Pediatrics"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachery","family":"Harkey","sequence":"additional","affiliation":[{"name":"Stephens Family Clinical Research Institute, Carle Health","place":["Urbana, Illinois, United States of America"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Mathena","sequence":"additional","affiliation":[{"name":"ARID Lab","place":["Tucson, Arizona, United States of America"],"department":["Department of Pediatrics"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maureen","family":"Galindo","sequence":"additional","affiliation":[{"name":"Banner University of Arizona Medical Center","place":["Tucson, Arizona, United States of America"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0005-9083","authenticated-orcid":true,"given":"Sarrah","family":"Hannon","sequence":"additional","affiliation":[{"name":"ARID Lab","place":["Tucson, Arizona, United States of America"],"department":["Department of Pediatrics"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9481-2581","authenticated-orcid":true,"given":"Rohith","family":"Jesudas","sequence":"additional","affiliation":[{"name":"St. Jude Research Hospital","place":["Memphis, Tennessee, United States of America"],"department":["Department of Hematology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1466-7941","authenticated-orcid":true,"given":"Christina M.","family":"Laukaitis","sequence":"additional","affiliation":[{"name":"Stephens Family Clinical Research Institute, Carle Health","place":["Urbana, Illinois, United States of America"]},{"name":"Carle Illinois College of Medicine, University of Illinois","place":["Urbana, Illinois, United States of America"]},{"name":"Carl R. Woese Institute for Genomic Biology, University of Illinois","place":["Urbana, Illinois, United States of America"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"issue":"4","key":"pone.0357565.ref001","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/j.ajhg.2018.02.018","article-title":"Bi-allelic alterations in AEBP1 lead to defective collagen assembly and connective tissue structure resulting in a variant of Ehlers-Danlos syndrome","volume":"102","author":"PR Blackburn","year":"2018","journal-title":"Am J Hum Genet"},{"issue":"1","key":"pone.0357565.ref002","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/ajmg.c.31552","article-title":"The 2017 international classification of the Ehlers-Danlos syndromes","volume":"175","author":"F Malfait","year":"2017","journal-title":"Am J Med Genet C Semin Med Genet"},{"issue":"4","key":"pone.0357565.ref003","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1002\/ajmg.c.31935","article-title":"Patients with Ehlers-Danlos syndrome on the diagnostic odyssey: rethinking complexity and difficulty as a hero\u2019s journey","volume":"187","author":"CME Halverson","year":"2021","journal-title":"Am J Med Genet C Semin Med Genet"},{"issue":"11","key":"pone.0357565.ref004","doi-asserted-by":"crossref","DOI":"10.1136\/bmjopen-2019-031365","article-title":"Diagnosed prevalence of Ehlers-Danlos syndrome and hypermobility spectrum disorder in Wales, UK: a national electronic cohort study and case-control comparison","volume":"9","author":"JC Demmler","year":"2019","journal-title":"BMJ Open"},{"issue":"1","key":"pone.0357565.ref005","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1002\/ajmg.c.31538","article-title":"Hypermobile Ehlers-Danlos syndrome (a.k.a. Ehlers-Danlos syndrome Type III and Ehlers-Danlos syndrome hypermobility type): Clinical description and natural history","volume":"175","author":"B Tinkle","year":"2017","journal-title":"Am J Med Genet C Semin Med Genet"},{"key":"pone.0357565.ref006","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1002\/(SICI)1096-8628(19980428)77:1<31::AID-AJMG8>3.0.CO;2-O","article-title":"Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997","volume":"77","author":"P Beighton","year":"1998","journal-title":"Am J Med Genet"},{"issue":"1","key":"pone.0357565.ref007","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1093\/bmb\/ldad013","article-title":"Placing joint hypermobility in context: traits, disorders and syndromes","volume":"147","author":"S Morlino","year":"2023","journal-title":"Br Med Bull"},{"issue":"1","key":"pone.0357565.ref008","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1002\/ajmg.c.31425","article-title":"Spectrum of mucocutaneous manifestations in 277 patients with joint hypermobility syndrome\/Ehlers-Danlos syndrome, hypermobility type","author":"M Castori","year":"2015","journal-title":"Am J Med Genet C Semin Med Genet"},{"issue":"7","key":"pone.0357565.ref009","doi-asserted-by":"crossref","first-page":"2012","DOI":"10.1002\/ajmg.a.62197","article-title":"Subtle differences in autonomic symptoms in people diagnosed with hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders","volume":"185","author":"KL Martinez","year":"2021","journal-title":"Am J Med Genet A"},{"issue":"2","key":"pone.0357565.ref010","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.jbi.2008.08.010","article-title":"Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support","volume":"42","author":"PA Harris","year":"2009","journal-title":"J Biomed Inform"},{"key":"pone.0357565.ref011","doi-asserted-by":"crossref","first-page":"3130","DOI":"10.1097\/00007632-200012150-00008","article-title":"SF-36 health survey update: spine","volume":"25","author":"JE Ware","year":"2000","journal-title":"Spine"},{"issue":"2","key":"pone.0357565.ref012","first-page":"100189","article-title":"Exercise and rehabilitation in people with Ehlers-Danlos syndrome: a systematic review","volume":"4","author":"S Buryk-Iggers","year":"2022","journal-title":"Arch Rehabil Res Clin Transl"},{"issue":"4","key":"pone.0357565.ref013","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1002\/ajmg.a.62640","article-title":"Longitudinal analysis of symptoms in the Ehlers-Danlos syndromes","volume":"188","author":"JR Schubart","year":"2022","journal-title":"Am J Med Genet A"},{"key":"pone.0357565.ref014","doi-asserted-by":"crossref","first-page":"103356","DOI":"10.1016\/j.autneu.2025.103356","article-title":"Autonomic symptom burden, comorbidities and quality of life in women with hypermobility spectrum disorders and hypermobile Ehlers-Danlos syndrome","volume":"262","author":"ML Collins Hutchinson","year":"2025","journal-title":"Auton Neurosci"},{"issue":"12","key":"pone.0357565.ref015","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1016\/j.mayocp.2012.10.013","article-title":"COMPASS 31: a refined and abbreviated composite autonomic symptom score","volume":"87","author":"DM Sletten","year":"2012","journal-title":"Mayo Clin Proc"},{"key":"pone.0357565.ref016","doi-asserted-by":"crossref","DOI":"10.2174\/011573403X271096231203164216","article-title":"Cardiovascular symptoms, dysautonomia, and quality of life in adult and pediatric patients with hypermobile Ehlers-Danlos syndrome: a brief review","volume":"20","author":"A Hertel","year":"2024","journal-title":"Curr Cardiol Rev"},{"key":"pone.0357565.ref017","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/1471-230X-8-30","article-title":"Evaluation of the Birmingham IBS symptom questionnaire","volume":"8","author":"AK Roalfe","year":"2008","journal-title":"BMC Gastroenterol"},{"issue":"11","key":"pone.0357565.ref018","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.3390\/nu9111208","article-title":"Symptom severity following rifaximin and the probiotic VSL#3 in patients with chronic pelvic pain syndrome (due to inflammatory prostatitis) plus Irritable Bowel Syndrome","volume":"9","author":"E Vicari","year":"2017","journal-title":"Nutrients"},{"issue":"2","key":"pone.0357565.ref019","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.juro.2011.10.036","article-title":"Association of neuropathic pain with bladder, bowel and catastrophizing symptoms in women with bladder pain syndrome","volume":"187","author":"L Cory","year":"2012","journal-title":"J Urol"},{"issue":"2","key":"pone.0357565.ref020","doi-asserted-by":"crossref","first-page":"235","DOI":"10.3748\/wjg.v19.i2.235","article-title":"Partially hydrolyzed guar gum in pediatric functional abdominal pain","volume":"19","author":"C Romano","year":"2013","journal-title":"World J Gastroenterol"},{"issue":"5","key":"pone.0357565.ref021","doi-asserted-by":"crossref","DOI":"10.1111\/hae.12747","article-title":"Generation and optimization of the self-administered bleeding assessment tool and its validation as a screening test for von Willebrand disease","volume":"21","author":"M Deforest","year":"2015","journal-title":"Haemophilia"},{"issue":"1","key":"pone.0357565.ref022","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1111\/hae.70174","article-title":"Distressing bleeding symptoms in interviews of patients with hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder","volume":"32","author":"R Jesudas","year":"2026","journal-title":"Haemophilia"},{"issue":"7","key":"pone.0357565.ref023","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1016\/j.jtha.2023.04.004","article-title":"Characterization of bleeding symptoms in Ehlers-Danlos syndrome","volume":"21","author":"M Kumskova","year":"2023","journal-title":"J Thromb Haemost"},{"key":"pone.0357565.ref024","volume-title":"R: A language and environment for statistical computing","author":"R Core Team","year":"2021"},{"key":"pone.0357565.ref025","article-title":"FactoMineR: An R Package for Multivariate Analysis","volume":"25","author":"S L\u00ea","year":"2008","journal-title":"J Stat Soft"},{"key":"pone.0357565.ref026","volume-title":"Principal component methods-hierarchical clustering-partitional clustering: why would we need to choose for visualizing data?","author":"F Husson","year":"2010"},{"key":"pone.0357565.ref027","article-title":"Practical Guide to Principal Component Methods in R. STHDA","author":"A Kassambra","year":"2017"},{"key":"pone.0357565.ref028","unstructured":"Holbert C. Clustering on Principal Component Analysis. In: Blog [Internet]. 2023. Available from: https:\/\/www.cfholbert.com\/blog\/cluster-pca\/"},{"issue":"1","key":"pone.0357565.ref029","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1186\/s12859-022-04675-1","article-title":"Statistical power for cluster analysis","volume":"23","author":"ES Dalmaijer","year":"2022","journal-title":"BMC Bioinformatics"},{"key":"pone.0357565.ref030","doi-asserted-by":"crossref","DOI":"10.18637\/jss.v070.i01","article-title":"missMDA: A package for handling missing values in multivariate data analysis","volume":"70","author":"J Josse","year":"2016","journal-title":"J Stat Soft"},{"key":"pone.0357565.ref031","doi-asserted-by":"crossref","DOI":"10.18637\/jss.v057.i12","article-title":"Building bivariate tables: The compareGroups package for R","volume":"57","author":"I Subirana","year":"2014","journal-title":"J Stat Soft"},{"issue":"1","key":"pone.0357565.ref032","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Y Benjamini","year":"1995","journal-title":"J R Stat Soc Series B: Stat Methodol"},{"key":"pone.0357565.ref033","article-title":"Exploratory multivariate analysis by example using R","author":"F Husson","year":"2017","journal-title":"Chapman and Hall\/CRC"},{"issue":"1","key":"pone.0357565.ref034","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.csda.2006.11.025","article-title":"Cluster-wise assessment of cluster stability","volume":"52","author":"C Hennig","year":"2007","journal-title":"Comput Stat Data Anal"},{"issue":"3","key":"pone.0357565.ref035","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.ridd.2012.11.018","article-title":"Clinical heterogeneity in patients with the hypermobility type of Ehlers-Danlos syndrome","volume":"34","author":"I De Wandele","year":"2013","journal-title":"Res Dev Disabil"},{"issue":"3","key":"pone.0357565.ref036","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.jpainsymman.2019.05.013","article-title":"Use of cluster analysis to delineate symptom profiles in an Ehlers-Danlos syndrome patient population","volume":"58","author":"JR Schubart","year":"2019","journal-title":"J Pain Symptom Manage"},{"issue":"3","key":"pone.0357565.ref037","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.mayocpiqo.2024.04.001","article-title":"Phenotypic clusters and multimorbidity in hypermobile Ehlers-Danlos syndrome","volume":"8","author":"T Petrucci","year":"2024","journal-title":"Mayo Clin Proc Innov Qual Outcomes"},{"issue":"10","key":"pone.0357565.ref038","first-page":"1722","article-title":"Severity classes in adults with hypermobile Ehlers-Danlos syndrome\/hypermobility spectrum disorders: a pilot study of 105 Italian patients","volume":"58","author":"M Copetti","year":"2019","journal-title":"Rheumatology (Oxford)"},{"issue":"2","key":"pone.0357565.ref039","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.cgh.2020.02.034","article-title":"Rome IV functional gastrointestinal disorders and health impairment in subjects with hypermobility spectrum disorders or hypermobile Ehlers-Danlos syndrome","volume":"19","author":"CY Lam","year":"2021","journal-title":"Clin Gastroenterol Hepatol"},{"issue":"9","key":"pone.0357565.ref040","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1111\/jgh.15927","article-title":"Hypermobile Ehlers-Danlos syndrome and disorders of the gastrointestinal tract: what the gastroenterologist needs to know","volume":"37","author":"PA Thwaites","year":"2022","journal-title":"J Gastroenterol Hepatol"},{"issue":"5","key":"pone.0357565.ref041","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1111\/j.1365-2141.2004.05220.x","article-title":"Bleeding and bruising in patients with Ehlers-Danlos syndrome and other collagen vascular disorders","volume":"127","author":"A De Paepe","year":"2004","journal-title":"Br J Haematol"},{"issue":"5","key":"pone.0357565.ref042","doi-asserted-by":"crossref","DOI":"10.1111\/hae.13063","article-title":"Epidemiology of bleeding symptoms and hypermobile Ehlers-Danlos syndrome in paediatrics","volume":"22","author":"SE Hickey","year":"2016","journal-title":"Haemophilia"},{"issue":"12","key":"pone.0357565.ref043","doi-asserted-by":"crossref","first-page":"2425","DOI":"10.1111\/jth.14310","article-title":"Hemostatic abnormalities in patients with Ehlers-Danlos syndrome","volume":"16","author":"A Artoni","year":"2018","journal-title":"J Thromb Haemost"},{"issue":"4","key":"pone.0357565.ref044","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1111\/hae.13800","article-title":"An update on the new classification of Ehlers-Danlos syndrome and review of the causes of bleeding in this population","volume":"25","author":"R Jesudas","year":"2019","journal-title":"Haemophilia"},{"key":"pone.0357565.ref045","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/B978-0-323-95082-4.00069-4","article-title":"Bruising and bleeding","author":"CM Laukaitis","year":"2024","journal-title":"The Symptom-Based Handbook for Ehlers-Danlos Syndromes and Hypermobility Spectrum Disorders. Elsevier"},{"issue":"20","key":"pone.0357565.ref046","doi-asserted-by":"crossref","first-page":"6957","DOI":"10.3390\/ijerph20206957","article-title":"Childbearing with hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders: a large international survey of outcomes and complications","volume":"20","author":"G Pearce","year":"2023","journal-title":"Int J Environ Res Public Health"},{"issue":"5","key":"pone.0357565.ref047","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0302401","article-title":"Management of childbearing with hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders: a scoping review and expert co-creation of evidence-based clinical guidelines","volume":"19","author":"S Pezaro","year":"2024","journal-title":"PLoS One"},{"key":"pone.0357565.ref048","doi-asserted-by":"crossref","first-page":"1085950","DOI":"10.3389\/fendo.2023.1085950","article-title":"Understanding the relationships between physiological and psychosocial stress, cortisol and cognition","volume":"14","author":"KA James","year":"2023","journal-title":"Front Endocrinol (Lausanne)"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0357565","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T17:58:15Z","timestamp":1789149495000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0357565"}},"subtitle":[],"editor":[{"given":"Martin E.","family":"Matsumura","sequence":"first","affiliation":[{"name":"Geisinger Health System","place":["UNITED STATES OF AMERICA"]}],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,9,11]]},"references-count":48,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9,11]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0357565","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,11]]}}}