{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T11:46:16Z","timestamp":1791632776129,"version":"4.3.4"},"reference-count":31,"publisher":"European Respiratory Society (ERS)","issue":"2","license":[{"start":{"date-parts":[[2021,1,21]],"date-time":"2021-01-21T00:00:00Z","timestamp":1611187200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.ersjournals.com\/user-licence"}],"content-domain":{"domain":["publications.ersnet.org"],"crossmark-restriction":true},"short-container-title":["Eur Respir J"],"accepted":{"date-parts":[[2020,12,24]]},"published-print":{"date-parts":[[2021,8]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Primary ciliary dyskinesia (PCD) is a heterogeneous inherited disorder caused by mutations in approximately 50 cilia-related genes. PCD genotype\u2013phenotype relationships have mostly arisen from small case series because existing statistical approaches to investigating relationships have been unsuitable for rare diseases.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We applied a topological data analysis (TDA) approach to investigate genotype\u2013phenotype relationships in PCD. Data from separate training and validation cohorts included 396 genetically defined individuals carrying pathogenic variants in PCD genes. To develop the TDA models, 12 clinical and diagnostic variables were included. TDA-driven hypotheses were subsequently tested using traditional statistics.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Disease severity at diagnosis, measured by forced expiratory volume in 1\u2005s (FEV\n                      <jats:sub>1<\/jats:sub>\n                      ) z-score, was significantly worse in individuals with\n                      <jats:italic>CCDC39<\/jats:italic>\n                      mutations (compared to other gene mutations) and better in those with\n                      <jats:italic>DNAH11<\/jats:italic>\n                      mutations; the latter also reported less neonatal respiratory distress. Patients without neonatal respiratory distress had better preserved FEV\n                      <jats:sub>1<\/jats:sub>\n                      at diagnosis. Individuals with\n                      <jats:italic>DNAH5<\/jats:italic>\n                      mutations were phenotypically diverse. Cilia ultrastructure and beat pattern defects correlated closely to specific causative gene groups, confirming these tests can be used to support a genetic diagnosis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      This large scale, multi-national study presents PCD as a syndrome with overlapping symptoms and variations in phenotype according to genotype. TDA modelling confirmed genotype\u2013phenotype relationships reported by smaller studies (\n                      <jats:italic>e.g.<\/jats:italic>\n                      FEV\n                      <jats:sub>1<\/jats:sub>\n                      worse with\n                      <jats:italic>CCDC39<\/jats:italic>\n                      mutation) and identified new relationships, including FEV\n                      <jats:sub>1<\/jats:sub>\n                      preservation with\n                      <jats:italic>DNAH11<\/jats:italic>\n                      mutations and diversity of severity with\n                      <jats:italic>DNAH5<\/jats:italic>\n                      mutations.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1183\/13993003.02359-2020","type":"journal-article","created":{"date-parts":[[2021,1,21]],"date-time":"2021-01-21T10:59:16Z","timestamp":1611226756000},"page":"2002359","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":108,"title":["Topological data analysis reveals genotype\u2013phenotype relationships in primary ciliary dyskinesia"],"prefix":"10.1183","volume":"58","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7360-6060","authenticated-orcid":false,"given":"Amelia","family":"Shoemark","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1629-8601","authenticated-orcid":false,"given":"Bruna","family":"Rubbo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2178-0846","authenticated-orcid":false,"given":"Marie","family":"Legendre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud R.","family":"Fassad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric G.","family":"Haarman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunayna","family":"Best","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irma C.M.","family":"Bon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joost","family":"Brandsma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0903-9828","authenticated-orcid":false,"given":"Pierre-Regis","family":"Burgel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunnar","family":"Carlsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0580-2478","authenticated-orcid":false,"given":"Siobhan B.","family":"Carr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Carroll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt","family":"Edwards","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estelle","family":"Escudier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Honor\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Hunt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0188-2554","authenticated-orcid":false,"given":"Gregory","family":"Jouvion","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel R.","family":"Loebinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Maitre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Morris-Rosendahl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Francois","family":"Papon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille M.","family":"Parsons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitali P.","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N. Simon","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0528-5458","authenticated-orcid":false,"given":"Guillaume","family":"Thouvenin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woolf T.","family":"Walker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Hogg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah M.","family":"Mitchison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8701-9975","authenticated-orcid":false,"given":"Jane S.","family":"Lucas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"81","published-online":{"date-parts":[[2021,1,21]]},"reference":[{"key":"2024102102171086000_58.2.2002359.1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00736-2016"},{"key":"2024102102171086000_58.2.2002359.2","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/S2213-2600(19)30374-1","article-title":"Primary ciliary dyskinesia in the genomics age","volume":"8","author":"Lucas","year":"2020","journal-title":"Lancet Respir Med"},{"key":"2024102102171086000_58.2.2002359.3","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/s41572-020-0209-6","article-title":"Motile ciliopathies","volume":"6","author":"Wallmeier","year":"2020","journal-title":"Nat Rev Dis Primers"},{"key":"2024102102171086000_58.2.2002359.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.08.016"},{"key":"2024102102171086000_58.2.2002359.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2009.01.011"},{"key":"2024102102171086000_58.2.2002359.6","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5418"},{"key":"2024102102171086000_58.2.2002359.7","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2018-212104"},{"key":"2024102102171086000_58.2.2002359.8","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201409-1672OC"},{"key":"2024102102171086000_58.2.2002359.9","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1164\/rccm.201803-0548OC","article-title":"Primary ciliary dyskinesia: longitudinal study of lung disease by ultrastructure defect and genotype","volume":"199","author":"Davis","year":"2019","journal-title":"Am J Respir Crit Care Med"},{"key":"2024102102171086000_58.2.2002359.10","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1038\/srep01236","article-title":"Extracting insights from the shape of complex data using topology","volume":"3","author":"Lum","year":"2013","journal-title":"Sci Rep"},{"key":"2024102102171086000_58.2.2002359.11","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms9581"},{"key":"2024102102171086000_58.2.2002359.12","doi-asserted-by":"publisher","DOI":"10.1038\/nature25171"},{"key":"2024102102171086000_58.2.2002359.13","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1620994114"},{"key":"2024102102171086000_58.2.2002359.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.aca.2015.12.037"},{"key":"2024102102171086000_58.2.2002359.15","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1102826108"},{"key":"2024102102171086000_58.2.2002359.16","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaa9364"},{"key":"2024102102171086000_58.2.2002359.17","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1016\/j.jaci.2017.12.982","article-title":"Airway pathological heterogeneity in asthma: visualization of disease microclusters using topological data analysis","volume":"142","author":"Siddiqui","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"2024102102171086000_58.2.2002359.18","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01090-2016"},{"key":"2024102102171086000_58.2.2002359.19","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"2024102102171086000_58.2.2002359.20","unstructured":"Singh G , M\u00e9moli F , Carlsson F , et al. Topological methods for the analysis of high dimensional data sets and 3D object recognition. In: Botsch M , Pajarola R , Chen B , Zwicker M , eds. Eurographics symposium on point based graphics. The Eurographics Association, 2007; pp. 91\u2013100."},{"key":"2024102102171086000_58.2.2002359.21","unstructured":"Glushakov S , Kotenko I , Rekalo A . Paper ML07: handling missing data in clinical trials using topological data analysis. Pharmaceutical Users Software Exchange 2018 (PHUSE 2018). November 4\u20137, 2018, Frankfurt, Germany. www.lexjansen.com\/phuse\/2018\/ml\/ML07.pdf"},{"key":"2024102102171086000_58.2.2002359.22","doi-asserted-by":"publisher","DOI":"10.1001\/archoto.2010.183"},{"key":"2024102102171086000_58.2.2002359.23","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2961"},{"key":"2024102102171086000_58.2.2002359.24","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201409-1672OC"},{"key":"2024102102171086000_58.2.2002359.25","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00209-2016"},{"key":"2024102102171086000_58.2.2002359.26","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/s00408-018-0086-x","article-title":"Primary ciliary dyskinesia due to microtubular defects is associated with worse lung clearance index","volume":"196","author":"Irving","year":"2018","journal-title":"Lung"},{"key":"2024102102171086000_58.2.2002359.27","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201311-2047OC"},{"key":"2024102102171086000_58.2.2002359.28","doi-asserted-by":"publisher","DOI":"10.1007\/s00431-013-1996-5"},{"key":"2024102102171086000_58.2.2002359.29","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1153"},{"key":"2024102102171086000_58.2.2002359.30","doi-asserted-by":"publisher","DOI":"10.1136\/thorax.58.6.552"},{"key":"2024102102171086000_58.2.2002359.31","doi-asserted-by":"publisher","DOI":"10.7326\/M14-0698"}],"container-title":["European Respiratory Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1183\/13993003.02359-2020","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T02:46:54Z","timestamp":1740365214000},"score":1,"resource":{"primary":{"URL":"https:\/\/publications.ersnet.org\/lookup\/doi\/10.1183\/13993003.02359-2020"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,21]]},"references-count":31,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,8,5]]},"published-print":{"date-parts":[[2021,8]]}},"alternative-id":["10.1183\/13993003.02359-2020"],"URL":"https:\/\/doi.org\/10.1183\/13993003.02359-2020","relation":{},"ISSN":["0903-1936","1399-3003"],"issn-type":[{"value":"0903-1936","type":"print"},{"value":"1399-3003","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,21]]}}}