{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:45:03Z","timestamp":1790675103891,"version":"4.1.0"},"reference-count":49,"publisher":"European Respiratory Society (ERS)","issue":"6","license":[{"start":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T00:00:00Z","timestamp":1608163200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["FS\/18\/52\/33808"],"award-info":[{"award-number":["FS\/18\/52\/33808"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["PG\/11\/116\/29288"],"award-info":[{"award-number":["PG\/11\/116\/29288"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Donald Heath Doctoral Training Fellowship"},{"DOI":"10.13039\/100005646","name":"Actelion Pharmaceuticals","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005646","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["publications.ersnet.org"],"crossmark-restriction":true},"short-container-title":["Eur Respir J"],"accepted":{"date-parts":[[2020,11,17]]},"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:p>Pulmonary arterial hypertension (PAH) is a devastating complication of systemic sclerosis (SSc). Screening for PAH in SSc has increased detection, allowed early treatment for PAH and improved patient outcomes. Blood-based biomarkers that reliably identify SSc patients at risk of PAH, or with early disease, would significantly improve screening, potentially leading to improved survival, and provide novel mechanistic insights into early disease. The main objective of this study was to identify a proteomic biomarker signature that could discriminate SSc patients with and without PAH using a machine learning approach and to validate the findings in an external cohort.<\/jats:p><jats:p>Serum samples from patients with SSc and PAH (n=77) and SSc without pulmonary hypertension (non-PH) (n=80) were randomly selected from the clinical DETECT study and underwent proteomic screening using the Myriad RBM Discovery platform consisting of 313 proteins. Samples from an independent validation SSc cohort (PAH n=22 and non-PH n=22) were obtained from the University of Sheffield (Sheffield, UK).<\/jats:p><jats:p>Random forest analysis identified a novel panel of eight proteins, comprising collagen IV, endostatin, insulin-like growth factor binding protein (IGFBP)-2, IGFBP-7, matrix metallopeptidase-2, neuropilin-1, N-terminal pro-brain natriuretic peptide and RAGE (receptor for advanced glycation end products), that discriminated PAH from non-PH in SSc patients in the DETECT Discovery Cohort (average area under the receiver operating characteristic curve 0.741, 65.1% sensitivity\/69.0% specificity), which was reproduced in the Sheffield Confirmatory Cohort (81.1% accuracy, 77.3% sensitivity\/86.5% specificity).<\/jats:p><jats:p>This novel eight-protein biomarker panel has the potential to improve early detection of PAH in SSc patients and may provide novel insights into the pathogenesis of PAH in the context of SSc.<\/jats:p>","DOI":"10.1183\/13993003.02591-2020","type":"journal-article","created":{"date-parts":[[2020,12,22]],"date-time":"2020-12-22T23:22:58Z","timestamp":1608679378000},"page":"2002591","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":79,"title":["Identifying early pulmonary arterial hypertension biomarkers in systemic sclerosis: machine learning on proteomics from the DETECT cohort"],"prefix":"10.1183","volume":"57","author":[{"given":"Yasmina","family":"Bauer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"de Bernard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4683-7696","authenticated-orcid":false,"given":"Peter","family":"Hickey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karri","family":"Ballard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Cruz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Cornelisse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harbajan","family":"Chadha-Boreham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Distler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Rosenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Doelberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastien","family":"Roux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Nayler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4192-9505","authenticated-orcid":false,"given":"Allan","family":"Lawrie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"81","published-online":{"date-parts":[[2020,12,17]]},"reference":[{"key":"2024102102102695000_57.6.2002591.1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.62.11.1088"},{"key":"2024102102102695000_57.6.2002591.2","doi-asserted-by":"publisher","DOI":"10.1002\/art.21433"},{"key":"2024102102102695000_57.6.2002591.3","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2009.114264"},{"key":"2024102102102695000_57.6.2002591.4","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200510-1668OC"},{"key":"2024102102102695000_57.6.2002591.5","doi-asserted-by":"publisher","DOI":"10.1002\/acr.22121"},{"key":"2024102102102695000_57.6.2002591.6","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00078411"},{"key":"2024102102102695000_57.6.2002591.7","doi-asserted-by":"crossref","first-page":"175","DOI":"10.3389\/fmed.2018.00175","article-title":"Circulating protein biomarkers in systemic sclerosis related pulmonary arterial hypertension: a review of published data","volume":"5","author":"Hickey","year":"2018","journal-title":"Front Med"},{"key":"2024102102102695000_57.6.2002591.8","doi-asserted-by":"crossref","first-page":"2045894018798613","DOI":"10.1177\/2045894018798613","article-title":"High levels of healthcare utilization prior to diagnosis in idiopathic pulmonary arterial hypertension support the feasibility of an early diagnosis algorithm: the SPHInX project","volume":"8","author":"Bergemann","year":"2018","journal-title":"Pulm Circ"},{"key":"2024102102102695000_57.6.2002591.9","doi-asserted-by":"crossref","first-page":"2045894019890549","DOI":"10.1177\/2045894019890549","article-title":"Utilising artificial intelligence to determine patients at risk of a rare disease: idiopathic pulmonary arterial hypertension","volume":"9","author":"Kiely","year":"2019","journal-title":"Pulm Circ"},{"key":"2024102102102695000_57.6.2002591.10","doi-asserted-by":"crossref","first-page":"K9","DOI":"10.1093\/eurheartj\/suz204","article-title":"Screening strategies for pulmonary arterial hypertension","volume":"21","author":"Kiely","year":"2019","journal-title":"Eur Heart J Suppl"},{"key":"2024102102102695000_57.6.2002591.11","doi-asserted-by":"publisher","DOI":"10.1002\/art.30541"},{"key":"2024102102102695000_57.6.2002591.12","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-203301"},{"key":"2024102102102695000_57.6.2002591.13","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13075-015-0517-5","article-title":"A comparison of the predictive accuracy of three screening models for pulmonary arterial hypertension in systemic sclerosis","volume":"17","author":"Hao","year":"2015","journal-title":"Arthritis Res Ther"},{"key":"2024102102102695000_57.6.2002591.14","doi-asserted-by":"crossref","unstructured":"Gali\u00e8 N, Humbert M, Vachiery JL, et al. 2015 ESC\/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J 2015; 46: 903\u2013975. doi:10.1183\/13993003.01032-2015.","DOI":"10.1183\/13993003.01032-2015"},{"key":"2024102102102695000_57.6.2002591.15","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.mvr.2016.03.007","article-title":"Serum uric acid as a marker of microvascular damage in systemic sclerosis patients","volume":"106","author":"Gigante","year":"2016","journal-title":"Microvasc Res"},{"key":"2024102102102695000_57.6.2002591.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2015.08.109"},{"key":"2024102102102695000_57.6.2002591.17","doi-asserted-by":"crossref","first-page":"587","DOI":"10.3389\/fphys.2018.00587","article-title":"Biomarkers for pulmonary vascular remodeling in systemic sclerosis: a pathophysiological approach","volume":"9","author":"Odler","year":"2018","journal-title":"Front Physiol"},{"key":"2024102102102695000_57.6.2002591.18","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200317115"},{"key":"2024102102102695000_57.6.2002591.19","doi-asserted-by":"crossref","first-page":"577S","DOI":"10.1378\/chest.128.6_suppl.577S-a","article-title":"Mts1\/S100A4 stimulates human pulmonary artery smooth muscle cell migration through multiple signaling pathways","volume":"128","author":"Spiekerkoetter","year":"2005","journal-title":"Chest"},{"key":"2024102102102695000_57.6.2002591.20","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.205120"},{"key":"2024102102102695000_57.6.2002591.21","doi-asserted-by":"crossref","first-page":"e0203046","DOI":"10.1371\/journal.pone.0203046","article-title":"Crucial role of RAGE in inappropriate increase of smooth muscle cells from patients with pulmonary arterial hypertension","volume":"13","author":"Nakamura","year":"2018","journal-title":"PLoS One"},{"key":"2024102102102695000_57.6.2002591.22","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1093\/cvr\/cvx051","article-title":"RAGE-mediated extracellular matrix proteins accumulation exacerbates HySu-induced pulmonary hypertension","volume":"113","author":"Jia","year":"2017","journal-title":"Cardiovasc Res"},{"key":"2024102102102695000_57.6.2002591.23","first-page":"459","article-title":"Signal diversity of receptor for advanced glycation end products","volume":"71","author":"Sakaguchi","year":"2017","journal-title":"Acta Med Okayama"},{"key":"2024102102102695000_57.6.2002591.24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0106440"},{"key":"2024102102102695000_57.6.2002591.25","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1536\/ihj.15-188","article-title":"Plasma levels of receptor for advanced glycation end-products and high-mobility group box 1 in patients with pulmonary hypertension","volume":"57","author":"Suzuki","year":"2016","journal-title":"Int Heart J"},{"key":"2024102102102695000_57.6.2002591.26","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000176025.57706.1e"},{"key":"2024102102102695000_57.6.2002591.27","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00368.2010"},{"key":"2024102102102695000_57.6.2002591.28","doi-asserted-by":"publisher","DOI":"10.1203\/PDR.0b013e31815b690d"},{"key":"2024102102102695000_57.6.2002591.29","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.yjmcc.2018.06.006","article-title":"MMP-2 and MMP-9 contribute to the angiogenic effect produced by hypoxia\/15-HETE in pulmonary endothelial cells","volume":"121","author":"Liu","year":"2018","journal-title":"J Mol Cell Cardiol"},{"key":"2024102102102695000_57.6.2002591.30","doi-asserted-by":"crossref","first-page":"e005133","DOI":"10.1161\/CIRCHEARTFAILURE.118.005133","article-title":"IGFBP7 (insulin-like growth factor-binding protein-7) and neprilysin inhibition in patients with heart failure","volume":"11","author":"Januzzi","year":"2018","journal-title":"Circ Heart Fail"},{"key":"2024102102102695000_57.6.2002591.31","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1097\/HCO.0000000000000594","article-title":"Update on the diagnosis and management of acute heart failure","volume":"34","author":"Gouda","year":"2019","journal-title":"Curr Opin Cardiol"},{"key":"2024102102102695000_57.6.2002591.32","doi-asserted-by":"crossref","unstructured":"Gandhi PU , Gaggin HK , Redfield MM , et al. Insulin-like growth factor-binding protein-7 as a biomarker of diastolic dysfunction and functional capacity in heart failure with preserved ejection fraction: results from the RELAX trial. JACC Heart Fail 2016: 860\u2013869. doi:10.1016\/j.jchf.2016.08.002","DOI":"10.1016\/j.jchf.2016.08.002"},{"key":"2024102102102695000_57.6.2002591.33","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1186\/s12872-016-0376-2","article-title":"Serum insulin-like growth factor-1 and its binding protein-7: potential novel biomarkers for heart failure with preserved ejection fraction","volume":"16","author":"Barroso","year":"2016","journal-title":"BMC Cardiovasc Disord"},{"key":"2024102102102695000_57.6.2002591.34","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa031994"},{"key":"2024102102102695000_57.6.2002591.35","doi-asserted-by":"publisher","DOI":"10.1247\/csf.27.9"},{"key":"2024102102102695000_57.6.2002591.36","doi-asserted-by":"crossref","unstructured":"Ortega N . New functional roles for non-collagenous domains of basement membrane collagens. J Cell Sci 2002: 4201\u20134214. doi:10.1242\/jcs.00106","DOI":"10.1242\/jcs.00106"},{"key":"2024102102102695000_57.6.2002591.37","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.semcdb.2018.08.007","article-title":"Extracellular matrix scaffolding in angiogenesis and capillary homeostasis","volume":"89","author":"Marchand","year":"2019","journal-title":"Semin Cell Dev Biol"},{"key":"2024102102102695000_57.6.2002591.38","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201409-1742OC"},{"key":"2024102102102695000_57.6.2002591.39","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.3389\/fphys.2018.01311","article-title":"Guidance molecules in vascular smooth muscle","volume":"9","author":"Finney","year":"2018","journal-title":"Front Physiol"},{"key":"2024102102102695000_57.6.2002591.40","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M310047200"},{"key":"2024102102102695000_57.6.2002591.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2011.03.040"},{"key":"2024102102102695000_57.6.2002591.42","doi-asserted-by":"publisher","DOI":"10.1002\/path.953"},{"key":"2024102102102695000_57.6.2002591.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2007.09.006"},{"key":"2024102102102695000_57.6.2002591.44","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra040291"},{"key":"2024102102102695000_57.6.2002591.45","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000243584.45145.3f"},{"key":"2024102102102695000_57.6.2002591.46","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01913-2018"},{"key":"2024102102102695000_57.6.2002591.47","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-014-0493-1"},{"key":"2024102102102695000_57.6.2002591.48","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00038-2019"},{"key":"2024102102102695000_57.6.2002591.49","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1186\/s13075-018-1679-8","article-title":"Serum biomarker for diagnostic evaluation of pulmonary arterial hypertension in systemic sclerosis","volume":"20","author":"Rice","year":"2018","journal-title":"Arthritis Res Ther"}],"container-title":["European Respiratory Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1183\/13993003.02591-2020","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T07:43:13Z","timestamp":1740382993000},"score":1,"resource":{"primary":{"URL":"https:\/\/publications.ersnet.org\/lookup\/doi\/10.1183\/13993003.02591-2020"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,17]]},"references-count":49,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6,24]]},"published-print":{"date-parts":[[2021,6]]}},"alternative-id":["10.1183\/13993003.02591-2020"],"URL":"https:\/\/doi.org\/10.1183\/13993003.02591-2020","relation":{},"ISSN":["0903-1936","1399-3003"],"issn-type":[{"value":"0903-1936","type":"print"},{"value":"1399-3003","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,17]]}}}