{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:57:06Z","timestamp":1792173426426,"version":"4.4.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,12]],"date-time":"2023-01-12T00:00:00Z","timestamp":1673481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Biliary atresia (BA) is the most common form of severe neonatal obstructive jaundice. The etiology and pathogenesis of BA are multifactorial, and different factors may interact to produce heterogeneous pathological features and clinical outcomes. Despite different pathological features, all patients received the same treatment strategy. This study performed integrative clustering analysis based on multiple high-throughput datasets to identify the molecular subtypes of BA and provide a new treatment strategy for personalized treatment of the different subtypes of BA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The RNA sequence dataset GSE122340 in the Gene Expression Omnibus (GEO) database was downloaded; 31 BA and 20 control normal liver tissues were collected at our center for transcriptome sequencing, and clinical and follow-up data of BA patients were available. Molecular subtypes were identified using integrated unsupervised cluster analysis involving gene expression, biliary fibrosis, and immune enrichment scores based on the transcriptome dataset, and the results were validated using independent datasets.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Based on the results of the integrated unsupervised clustering analysis, four molecular subtypes were identified: autoimmune, inflammatory, virus infection-related, and oxidative stress. The autoimmune subtype with a moderate prognosis was dominated by autoimmune responses and morphogenesis, such as the Fc-gamma receptor and Wnt signaling pathway. The biological process of the inflammatory subtype was mainly the inflammatory response, with the best prognosis, youngest age at surgery, and lowest liver stiffness. The virus infection-related subtype had the worst prognosis and was enriched for a variety of biological processes such as viral infection, immunity, anatomical morphogenesis, and epithelial mesenchymal transition. The oxidative stress subtype was characterized by the activation of oxidative stress and various metabolic pathways and had a poor prognosis. The above results were verified independently in the validation sets.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study identified four molecular subtypes of BA with distinct prognosis and biological processes. According to the pathological characteristics of the different subtypes, individualized perioperative and preoperative treatment may be a new strategy to improve the prognosis of BA.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.1008246","type":"journal-article","created":{"date-parts":[[2023,1,12]],"date-time":"2023-01-12T07:05:43Z","timestamp":1673507143000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Identifying and validating molecular subtypes of biliary atresia using multiple high-throughput data integration analysis"],"prefix":"10.3389","volume":"13","author":[{"given":"Dingding","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shen","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiyun","family":"Hua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yichao","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangshuang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junmin","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawei","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinshi","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,1,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2015.74","article-title":"Pathogenesis of biliary atresia: Defining biology to understand clinical phenotypes","volume":"12","author":"Asai","year":"2015","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)32284-5","article-title":"Advances in paediatric gastroenterology","volume":"390","author":"Tam","year":"2017","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1007\/s00383-017-4172-6","article-title":"Update on investigations pertaining to the pathogenesis of biliary atresia","volume":"33","author":"Kilgore","year":"2017","journal-title":"Pediatr Surg Int"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s00383-018-4228-2","article-title":"Kasai Procedure improves nutritional status and decreases transplantation-associated complications","volume":"34","author":"Yang","year":"2018","journal-title":"Pediatr Surg Int"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29905","article-title":"Biliary atresia: Clinical and research challenges for the twenty-first century","volume":"68","author":"Bezerra","year":"2018","journal-title":"Hepatology"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29504","article-title":"Gene-disease associations identify a connectome with shared molecular pathways in human cholangiopathies","volume":"67","author":"Luo","year":"2018","journal-title":"Hepatology"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpedsurg.2013.08.007","article-title":"Factors influencing jaundice-free survival with the native liver in post-portoenterostomy biliary atresia patients: Results from a single institution","volume":"48","author":"Koga","year":"2013","journal-title":"J Pediatr Surg"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3122","article-title":"Stringtie enables improved reconstruction of a transcriptome from rna-seq reads","volume":"33","author":"Pertea","year":"2015","journal-title":"Nat Biotechnol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"Star: Ultrafast universal rna-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for rna-seq data with Deseq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1053\/j.gastro.2019.06.017","article-title":"Gene expression signatures associated with survival times of pediatric patients with biliary atresia identify potential therapeutic agents","volume":"157","author":"Luo","year":"2019","journal-title":"Gastroenterology"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27165","article-title":"Generation of functional cholangiocyte-like cells from human pluripotent stem cells and heparg cells","volume":"60","author":"Dianat","year":"2014","journal-title":"Hepatology"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2015-309655","article-title":"A hepatic stellate cell gene expression signature associated with outcomes in hepatitis c cirrhosis and hepatocellular carcinoma after curative resection","volume":"65","author":"Zhang","year":"2016","journal-title":"Gut"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1400062111","article-title":"Origin of myofibroblasts in the fibrotic liver in mice","volume":"111","author":"Iwaisako","year":"2014","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btx378","article-title":"Cancersubtypes: An R\/Bioconductor package for molecular cancer subtype identification, validation and visualization","volume":"33","author":"Xu","year":"2017","journal-title":"Bioinformatics"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-7","article-title":"Gsva: Gene set variation analysis for microarray and rna-seq data","volume":"14","author":"Hanzelmann","year":"2013","journal-title":"BMC Bioinf"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-9-559","article-title":"Wgcna: An r package for weighted correlation network analysis","volume":"9","author":"Langfelder","year":"2008","journal-title":"BMC Bioinf"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa1074","article-title":"The string database in 2021: Customizable protein-protein networks, and functional characterization of user-uploaded Gene\/Measurement sets","volume":"49","author":"Szklarczyk","year":"2021","journal-title":"Nucleic Acids Res"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-4-2","article-title":"An automated method for finding molecular complexes in Large protein interaction networks","volume":"4","author":"Bader","year":"2003","journal-title":"BMC Bioinf"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.11613\/bm.2013.018","article-title":"The chi-square test of independence","volume":"23","author":"McHugh","year":"2013","journal-title":"Biochem Med (Zagreb)"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyg.2013.00863","article-title":"Calculating and reporting effect sizes to facilitate cumulative science: A practical primer for T-tests and anovas","volume":"4","author":"Lakens","year":"2013","journal-title":"Front Psychol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1053\/j.sempedsurg.2012.05.003","article-title":"Biliary atresia: Cellular dynamics and immune dysregulation","volume":"21","author":"Feldman","year":"2012","journal-title":"Semin Pediatr Surg"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1053\/j.sempedsurg.2012.05.010","article-title":"Biliary atresia: Clinical aspects","volume":"21","author":"Davenport","year":"2012","journal-title":"Semin Pediatr Surg"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpedsurg.2007.12.058","article-title":"Cystic biliary atresia: An etiologic and prognostic subgroup","volume":"43","author":"Caponcelli","year":"2008","journal-title":"J Pediatr Surg"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpedsurg.2015.03.001","article-title":"Cytomegalovirus-associated biliary atresia: An aetiological and prognostic subgroup","volume":"50","author":"Zani","year":"2015","journal-title":"J Pediatr Surg"},{"key":"B27","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/gm154","article-title":"Staging of biliary atresia at diagnosis by molecular profiling of the liver","volume":"2","author":"Moyer","year":"2010","journal-title":"Genome Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.720841","article-title":"Unsupervised clustering reveals distinct subtypes of biliary atresia based on immune cell types and gene expression","volume":"12","author":"Pang","year":"2021","journal-title":"Front Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00252","article-title":"Importance of fc receptor gamma-chain itam tyrosines in neutrophil activation and in vivo autoimmune arthritis","volume":"10","author":"Nemeth","year":"2019","journal-title":"Front Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.08.050","article-title":"Foxo in the hole: Leveraging gwas for outcome and function","volume":"155","author":"Gregersen","year":"2013","journal-title":"Cell"},{"key":"B31","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1007\/5584_2021_640","article-title":"Eosinophils as major player in type 2 inflammation: Autoimmunity and beyond","volume":"1347","author":"Folci","year":"2021","journal-title":"Adv Exp Med Biol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01140","article-title":"The role of monocytes and macrophages in autoimmune diseases: A comprehensive review","volume":"10","author":"Ma","year":"2019","journal-title":"Front Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2016.71","article-title":"The role of neutrophils and netosis in autoimmune and renal diseases","volume":"12","author":"Gupta","year":"2016","journal-title":"Nat Rev Nephrol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1002\/hep.32107","article-title":"Biliary organoids uncover delayed epithelial development and barrier function in biliary atresia","volume":"75","author":"Amarachintha","year":"2022","journal-title":"Hepatology"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00329","article-title":"Innate immunity and pathogenesis of biliary atresia","volume":"11","author":"Ortiz-Perez","year":"2020","journal-title":"Front Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28947","article-title":"The srl peptide of rhesus rotavirus Vp4 protein governs cholangiocyte infection and the murine model of biliary atresia","volume":"65","author":"Mohanty","year":"2017","journal-title":"Hepatology"},{"key":"B37","doi-asserted-by":"publisher","first-page":"e00510","DOI":"10.1128\/JVI.00510-17","article-title":"A point mutation in the rhesus rotavirus Vp4 protein generated through a rotavirus reverse genetics system attenuates biliary atresia in the murine model","volume":"91","author":"Mohanty","year":"2017","journal-title":"J Virol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00079.2015","article-title":"Rhesus rotavirus Vp4 sequence-specific activation of mononuclear cells is associated with cholangiopathy in murine biliary atresia","volume":"309","author":"Walther","year":"2015","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2021.710450","article-title":"Prognosis of biliary atresia associated with cytomegalovirus: A meta-analysis","volume":"9","author":"Zhao","year":"2021","journal-title":"Front Pediatr"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/pr.2014.181","article-title":"The expression of epithelial-mesenchymal transition-related proteins in biliary epithelial cells is associated with liver fibrosis in biliary atresia","volume":"77","author":"Xiao","year":"2015","journal-title":"Pediatr Res"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1007\/s12519-018-0203-1","article-title":"Liver fibrosis in biliary atresia","volume":"15","author":"Shen","year":"2019","journal-title":"World J Pediatr"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1007\/s00383-017-4154-8","article-title":"Sclerosing and obstructive cholangiopathy in biliary atresia: Mechanisms and association with biliary innate immunity","volume":"33","author":"Harada","year":"2017","journal-title":"Pediatr Surg Int"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1867","DOI":"10.1016\/j.cell.2020.10.048","article-title":"Liver immune profiling reveals pathogenesis and therapeutics for biliary atresia","volume":"183","author":"Wang","year":"2020","journal-title":"Cell"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.4103\/1319-3767.61234","article-title":"Antioxidant enzyme activities in hepatic tissue from children with chronic cholestatic liver disease","volume":"16","author":"Ismail","year":"2010","journal-title":"Saudi J Gastroenterol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/srep26969","article-title":"Global methylation, oxidative stress, and relative telomere length in biliary atresia patients","volume":"6","author":"Udomsinprasert","year":"2016","journal-title":"Sci Rep"},{"key":"B46","doi-asserted-by":"publisher","first-page":"894","DOI":"10.1002\/hep.28603","article-title":"Glutathione antioxidant pathway activity and reserve determine toxicity and specificity of the biliary toxin biliatresone in zebrafish","volume":"64","author":"Zhao","year":"2016","journal-title":"Hepatology"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28599","article-title":"The toxin biliatresone causes mouse extrahepatic cholangiocyte damage and fibrosis through decreased glutathione and Sox17","volume":"64","author":"Waisbourd-Zinman","year":"2016","journal-title":"Hepatology"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1002\/prca.201000049","article-title":"Hepatitis c virus-induced oxidative stress and mitochondrial dysfunction: A focus on recent advances in proteomics","volume":"4","author":"Simula","year":"2010","journal-title":"Proteomics Clin Appl"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.micinf.2017.08.008","article-title":"The role of oxidative stress in influenza virus infection","volume":"19","author":"Liu","year":"2017","journal-title":"Microbes Infect"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/6208067","article-title":"Therapeutic modulation of virus-induced oxidative stress Via the Nrf2-dependent antioxidative pathway","volume":"2018","author":"Lee","year":"2018","journal-title":"Oxid Med Cell Longev"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1008246\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,12]],"date-time":"2023-01-12T07:05:48Z","timestamp":1673507148000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1008246\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,12]]},"references-count":50,"alternative-id":["10.3389\/fimmu.2022.1008246"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.1008246","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,12]]},"article-number":"1008246"}}