{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T22:14:06Z","timestamp":1779315246752,"version":"3.51.4"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:00:00Z","timestamp":1761091200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:00:00Z","timestamp":1761091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["R61HD105619"],"award-info":[{"award-number":["R61HD105619"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"DOI":"10.1038\/s41598-025-20684-5","type":"journal-article","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T09:33:50Z","timestamp":1761125630000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Mass spectrometry combined with machine learning identifies novel protein signatures as demonstrated with multisystem inflammatory syndrome in children"],"prefix":"10.1038","volume":"15","author":[{"given":"Jeisac","family":"Guzm\u00e1n Rivera","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haiyan","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Richlin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Suarez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sunanda","family":"Gaur","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Ricciardi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Uzma N.","family":"Hasan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Cuddy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aalok R.","family":"Singh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hulya","family":"Bukulmez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David C.","family":"Kaelber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukiko","family":"Kimura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick W.","family":"Brady","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dawn","family":"Wahezi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evin","family":"Rothschild","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saquib A.","family":"Lakhani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine W.","family":"Herbst","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander H.","family":"Hogan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan C.","family":"Salazar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"Moroso-Fela","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason","family":"Roy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lawrence C.","family":"Kleinman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel B.","family":"Horton,","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dirk F.","family":"Moore","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Laura","family":"Gennaro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,10,22]]},"reference":[{"issue":"10237","key":"20684_CR1","doi-asserted-by":"publisher","first-page":"1607","DOI":"10.1016\/S0140-6736(20)31094-1","volume":"395","author":"S Riphagen","year":"2020","unstructured":"Riphagen, S., Gomez, X., Gonzalez-Martinez, C., Wilkinson, N. & Theocharis, P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet 395(10237), 1607\u20131608 (2020).","journal-title":"Lancet"},{"issue":"3","key":"20684_CR2","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1001\/jama.2020.10369","volume":"324","author":"E Whittaker","year":"2020","unstructured":"Whittaker, E. et al. Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2. JAMA 324(3), 259\u2013269 (2020).","journal-title":"JAMA"},{"key":"20684_CR3","unstructured":"Philadelphia TCsHo. Multisystem inflammatory syndrome (MIS-C) clinical pathway chop.edu (2021). Available from: https:\/\/pathways.chop.edu\/clinical-pathway\/multisystem-inflammatory-syndrome-mis-c-clinical-pathway."},{"issue":"20","key":"20684_CR4","doi-asserted-by":"publisher","DOI":"10.1172\/JCI151520","volume":"131","author":"RA Porritt","year":"2021","unstructured":"Porritt, R. A. et al. The autoimmune signature of hyperinflammatory multisystem inflammatory syndrome in children. J. Clin. Investig. 131(20), e151520 (2021).","journal-title":"J. Clin. Investig."},{"key":"20684_CR5","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2024.110237","volume":"264","author":"A Reiter","year":"2024","unstructured":"Reiter, A. et al. Proteomic mapping identifies serum marker signatures associated with MIS-C specific hyperinflammation and cardiovascular manifestation. Clin. Immunol. 264, 110237 (2024).","journal-title":"Clin. Immunol."},{"issue":"5","key":"20684_CR6","doi-asserted-by":"publisher","first-page":"1050","DOI":"10.1038\/s41591-022-01724-3","volume":"28","author":"K Sacco","year":"2022","unstructured":"Sacco, K. et al. Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19. Nat. Med. 28(5), 1050\u20131062 (2022).","journal-title":"Nat. Med."},{"issue":"1","key":"20684_CR7","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1038\/nmeth.3234","volume":"12","author":"A Doerr","year":"2015","unstructured":"Doerr, A. DIA mass spectrometry. Nat. Methods 12(1), 35 (2015).","journal-title":"Nat. Methods"},{"key":"20684_CR8","doi-asserted-by":"publisher","DOI":"10.1142\/7922","volume-title":"A Gentle Introduction to Support Vector Machines in Biomedicine","author":"A Statnikov","year":"2011","unstructured":"Statnikov, A., Aliferis, C. F., Hardin, D. P. & Guyon, I. A Gentle Introduction to Support Vector Machines in Biomedicine (World Scientific Publishing Co, 2011)."},{"issue":"17","key":"20684_CR9","doi-asserted-by":"publisher","first-page":"e927","DOI":"10.1161\/CIR.0000000000000484","volume":"135","author":"BW McCrindle","year":"2017","unstructured":"McCrindle, B. W. et al. Diagnosis, treatment, and long-term management of Kawasaki disease: A scientific statement for health professionals from the American Heart Association. Circulation 135(17), e927\u2013e999 (2017).","journal-title":"Circulation"},{"issue":"1","key":"20684_CR10","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1038\/s41596-018-0082-x","volume":"14","author":"CS Hughes","year":"2019","unstructured":"Hughes, C. S. et al. Single-pot, solid-phase-enhanced sample preparation for proteomics experiments. Nat. Protoc. 14(1), 68\u201385 (2019).","journal-title":"Nat. Protoc."},{"issue":"1","key":"20684_CR11","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/s41592-019-0638-x","volume":"17","author":"V Demichev","year":"2020","unstructured":"Demichev, V., Messner, C. B., Vernardis, S. I., Lilley, K. S. & Ralser, M. DIA-NN: Neural networks and interference correction enable deep proteome coverage in high throughput. Nat. Methods 17(1), 41\u201344 (2020).","journal-title":"Nat. Methods"},{"issue":"9","key":"20684_CR12","doi-asserted-by":"publisher","first-page":"2513","DOI":"10.1074\/mcp.M113.031591","volume":"13","author":"J Cox","year":"2014","unstructured":"Cox, J. et al. Accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction, termed MaxLFQ. Mol. Cell. Proteom. 13(9), 2513\u20132526 (2014).","journal-title":"Mol. Cell. Proteom."},{"issue":"6","key":"20684_CR13","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0245824","volume":"16","author":"O Menyhart","year":"2021","unstructured":"Menyhart, O., Weltz, B. & Gy\u0151rffy, B. MultipleTesting.com: A tool for life science researchers for multiple hypothesis testing correction. PLoS ONE 16(6), e0245824 (2021).","journal-title":"PLoS ONE"},{"issue":"1","key":"20684_CR14","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1111\/j.1541-0420.2005.00420.x","volume":"62","author":"MS Pepe","year":"2006","unstructured":"Pepe, M. S., Cai, T. & Longton, G. Combining predictors for classification using the area under the receiver operating characteristic curve. Biometrics 62(1), 221\u2013229 (2006).","journal-title":"Biometrics"},{"issue":"W1","key":"20684_CR15","doi-asserted-by":"publisher","first-page":"W90","DOI":"10.1093\/nar\/gkw377","volume":"44","author":"MV Kuleshov","year":"2016","unstructured":"Kuleshov, M. V. et al. Enrichr: A comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 44(W1), W90\u2013W97 (2016).","journal-title":"Nucleic Acids Res."},{"issue":"1","key":"20684_CR16","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1038\/s42003-024-06370-8","volume":"7","author":"U Nygaard","year":"2024","unstructured":"Nygaard, U. et al. Proteomic profiling reveals diagnostic signatures and pathogenic insights in multisystem inflammatory syndrome in children. Commun. Biol. 7(1), 688 (2024).","journal-title":"Commun. Biol."},{"issue":"5","key":"20684_CR17","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1097\/INF.0000000000004267","volume":"43","author":"S Yeoh","year":"2024","unstructured":"Yeoh, S. et al. Plasma protein biomarkers distinguish multisystem inflammatory syndrome in children from other pediatric infectious and inflammatory diseases. Pediatr. Infect. Dis. J. 43(5), 444\u2013453 (2024).","journal-title":"Pediatr. Infect. Dis. J."},{"issue":"5","key":"20684_CR18","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2022.188760","volume":"1877","author":"A Soman","year":"2022","unstructured":"Soman, A. & Asha, N. S. Unfolding the cascade of SERPINA3: Inflammation to cancer. Biochim. Biophys. Acta Rev. Cancer 1877(5), 188760 (2022).","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"issue":"1","key":"20684_CR19","doi-asserted-by":"publisher","first-page":"156","DOI":"10.3390\/biomedicines11010156","volume":"11","author":"M de Mezer","year":"2023","unstructured":"de Mezer, M. et al. SERPINA3: Stimulator or inhibitor of pathological changes. Biomedicines 11(1), 156 (2023).","journal-title":"Biomedicines"},{"key":"20684_CR20","doi-asserted-by":"publisher","DOI":"10.1016\/j.virusres.2021.198408","volume":"300","author":"S Abbasi","year":"2021","unstructured":"Abbasi, S. et al. Impact of human rhinoviruses on gene expression in pediatric patients with severe acute respiratory infection. Virus Res. 300, 198408 (2021).","journal-title":"Virus Res."},{"key":"20684_CR21","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.652799","volume":"12","author":"K Suvarna","year":"2021","unstructured":"Suvarna, K. et al. Proteomics and machine learning approaches reveal a set of prognostic markers for COVID-19 severity with drug repurposing potential. Front. Physiol. 12, 652799 (2021).","journal-title":"Front. Physiol."},{"issue":"1","key":"20684_CR22","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1038\/s42003-021-02095-0","volume":"4","author":"MG Ferrarini","year":"2021","unstructured":"Ferrarini, M. G. et al. Genome-wide bioinformatic analyses predict key host and viral factors in SARS-CoV-2 pathogenesis. Commun. Biol. 4(1), 590 (2021).","journal-title":"Commun. Biol."},{"key":"20684_CR23","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1158951","volume":"14","author":"R Gong","year":"2023","unstructured":"Gong, R. et al. Integrative proteomic profiling of lung tissues and blood in acute respiratory distress syndrome. Front. Immunol. 14, 1158951 (2023).","journal-title":"Front. Immunol."},{"issue":"6","key":"20684_CR24","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1177\/17534259211043159","volume":"27","author":"K Kobayashi","year":"2021","unstructured":"Kobayashi, K., Tachibana, M. & Tsutsumi, Y. Neglected roles of IgG Fc-binding protein secreted from airway mucin-producing cells in protecting against SARS-CoV-2 infection. Innate Immun. 27(6), 423\u2013436 (2021).","journal-title":"Innate Immun."},{"issue":"3","key":"20684_CR25","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1093\/jimmun\/vkaf006","volume":"214","author":"R Khan","year":"2025","unstructured":"Khan, R. et al. A genetically modulated Toll-like receptor-tolerant phenotype in peripheral blood cells of children with multisystem inflammatory syndrome. J. Immunol. 214(3), 373\u2013383 (2025).","journal-title":"J. Immunol."},{"issue":"14","key":"20684_CR26","doi-asserted-by":"publisher","DOI":"10.1172\/JCI149633","volume":"131","author":"LM Yonker","year":"2021","unstructured":"Yonker, L. M. et al. Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier. J. Clin. Investig. 131(14), e149633 (2021).","journal-title":"J. Clin. Investig."},{"issue":"23","key":"20684_CR27","doi-asserted-by":"publisher","first-page":"6051","DOI":"10.1182\/bloodadvances.2020003471","volume":"4","author":"C Diorio","year":"2020","unstructured":"Diorio, C. et al. Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations. Blood Adv. 4(23), 6051\u20136063 (2020).","journal-title":"Blood Adv."},{"issue":"1","key":"20684_CR28","doi-asserted-by":"publisher","first-page":"7222","DOI":"10.1038\/s41467-021-27544-6","volume":"12","author":"C Diorio","year":"2021","unstructured":"Diorio, C. et al. Proteomic profiling of MIS-C patients indicates heterogeneity relating to interferon gamma dysregulation and vascular endothelial dysfunction. Nat. Commun. 12(1), 7222 (2021).","journal-title":"Nat. Commun."},{"issue":"4","key":"20684_CR29","doi-asserted-by":"publisher","first-page":"e427","DOI":"10.1097\/MPH.0000000000002583","volume":"45","author":"AA Boucher","year":"2023","unstructured":"Boucher, A. A. et al. Prolonged elevations of factor VIII and von willebrand factor antigen after multisystem inflammatory syndrome in children. J. Pediatr. Hematol. Oncol. 45(4), e427\u2013e432 (2023).","journal-title":"J. Pediatr. Hematol. Oncol."},{"key":"20684_CR30","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.cca.2021.02.011","volume":"517","author":"Y Li","year":"2021","unstructured":"Li, Y. et al. Lipid metabolism changes in patients with severe COVID-19. Clin. Chim. Acta 517, 66\u201373 (2021).","journal-title":"Clin. Chim. Acta"},{"key":"20684_CR31","doi-asserted-by":"publisher","first-page":"1033660","DOI":"10.3389\/fcvm.2022.1033660","volume":"9","author":"M Mietus-Snyder","year":"2022","unstructured":"Mietus-Snyder, M. et al. Changes in HDL cholesterol, particles, and function associate with pediatric COVID-19 severity. Front. Cardiovasc. Med. 9, 1033660 (2022).","journal-title":"Front. Cardiovasc. Med."},{"issue":"1","key":"20684_CR32","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1515\/dx-2023-0109","volume":"12","author":"N Stehouwer","year":"2025","unstructured":"Stehouwer, N., Rowland-Seymour, A., Gruppen, L., Albert, J. M. & Qua, K. Validity and reliability of Brier scoring for assessment of probabilistic diagnostic reasoning. Diagnosis (Berlin) 12(1), 53\u201360 (2025).","journal-title":"Diagnosis (Berlin)"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-20684-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-20684-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-20684-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T09:33:52Z","timestamp":1761125632000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-20684-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,22]]},"references-count":32,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["20684"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-20684-5","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,22]]},"assertion":[{"value":"20 June 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 September 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 October 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All study activities were approved by the Rutgers Institutional Review Board (Pro2020002961) and all methods were performed in accordance with the relevant guidelines. All participants, including parents and\/or legal guardians, provided informed consent prior to engaging in study activities.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Study approval"}}],"article-number":"36843"}}