{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T23:04:25Z","timestamp":1788908665927,"version":"build-2803163510"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Sepsis biomarker research over the past 30\u202fyears has been plagued by the use of wrong animal models and inappropriate patient selections, leading to the failure of translating findings into precision medicine. Thousands of sepsis-related gene biomarkers have been published, but this excess hinders medical advancement because (1) an overwhelming number of genes make targeted drug development and precision medicine unfeasible; (2) many biomarkers lack cross-cohort validation, rendering them clinically unhelpful. Our goal is to identify a highly informative, single-digit set of sepsis biomarkers to advance precision medicine.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted large-scale research on heterogeneous populations, including patients with sepsis, severe sepsis, and septic shocks, and collected plasma samples from 32 sepsis patients and 18 healthy controls at Renmin Hospital of Wuhan University, China. RNA was isolated using the HYCEZMBIO Serum\/Plasma RNA Kit, and RT-qPCR was performed on the Roche Light Cycler 480 platform. An AI-based max-logistic competing classifier was applied across 11 cohorts with thousands of samples, using both self-designed and public datasets to identify the most critical sepsis biomarkers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our analysis highlights CKAP4, FCAR, and RNF4 as key genetic drivers in sepsis-related variations. In whole blood, NONO is crucial for immune response, while in plasma, PLEKHO1 and BMP6 reveal further genetic heterogeneities. Pediatric patients also exhibit significant contributions from RNASE2 and OGFOD3. These genes form the most effective miniature set of biomarkers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Achieving 99.42% accuracy across cohorts, this miniature set outperforms larger published gene sets. These findings provide critical insights for personalized risk assessment, targeted drug development, and tailored treatments for both adult and pediatric sepsis patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2025.1521827","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T01:28:28Z","timestamp":1751333308000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["AI-driven discovery of minimal sepsis biomarkers for disease detection and progression: precision medicine across diverse populations"],"prefix":"10.3389","volume":"12","author":[{"given":"Qiyuan","family":"Su","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingtao","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunlong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhou","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihua","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunming","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengxiu","family":"Ling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanwen","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liying","family":"Zhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengjun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,1]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/S0140-6736(19)32989-7","article-title":"Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the global burden of disease study","volume":"395","author":"Rudd","year":"2020","journal-title":"Lancet"},{"key":"ref2","article-title":"World Health Organization. Global report on the epidemiology and burden of sepsis: current evidence, identifying gaps and future directions","year":"2020"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/S0140-6736(18)30696-2","article-title":"Sepsis and septic shock","volume":"392","author":"Cecconi","year":"2018","journal-title":"Lancet"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1805","DOI":"10.1038\/s41564-022-01237-2","article-title":"Integrated host-microbe plasma metagenomics for sepsis diagnosis in a prospective cohort of critically ill adults","volume":"7","author":"Kalantar","year":"2022","journal-title":"Nat Microbiol"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"2450","DOI":"10.1016\/j.immuni.2021.10.012","article-title":"The immunology of sepsis","volume":"54","author":"van der 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Med"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"R149","DOI":"10.1186\/cc10274","article-title":"Development and validation of a novel molecular biomarker diagnostic test for the early detection of sepsis","volume":"15","author":"Sutherland","year":"2011","journal-title":"Crit Care"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"3091","DOI":"10.3389\/fimmu.2018.03091","article-title":"Endogenous retroviruses transcriptional modulation after severe infection, trauma and burn","volume":"9","author":"Tabone","year":"2018","journal-title":"Front Immunol"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"R127","DOI":"10.1186\/gb-2009-10-11-r127","article-title":"Genomic transcriptional profiling identifies a candidate blood biomarker signature for the diagnosis of septicemic melioidosis","volume":"10","author":"Pankla","year":"2009","journal-title":"Genome 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intent and causation","volume":"31","author":"Bathaee","year":"2018","journal-title":"Harvard J Law Technol"},{"key":"ref19","doi-asserted-by":"publisher","DOI":"10.1038\/d41586-022-00858-1","article-title":"Breaking into the black box of artificial intelligence","author":"Savage","year":"2022","journal-title":"Nature"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1016\/j.gim.2021.09.021","article-title":"The difficulties of broad data sharing in genomic medicine: empirical evidence from diverse participants in prenatal and pediatric clinical genomics research","volume":"24","author":"Norstad","year":"2022","journal-title":"Genet Med"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1080\/07350015.2015.1137761","article-title":"Max-linear competing factor models","volume":"36","author":"Cui","year":"2018","journal-title":"J Bus Econ 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models with regularization","volume":"222","author":"Cui","year":"2021","journal-title":"J Econ"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1136\/eb-2012-100645","article-title":"Principles for high-quality, high-value testing","volume":"18","author":"Power","year":"2013","journal-title":"Evid Based Med"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.ygeno.2017.08.007","article-title":"How many differentially expressed genes: a perspective from the comparison of genotypic and phenotypic distances","volume":"110","author":"Zhao","year":"2018","journal-title":"Genomics"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1042\/bj2710285","article-title":"The structure and function of human IgA","volume":"271","author":"Kerr","year":"1990","journal-title":"Biochem J"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1146\/annurev.immunol.21.120601.141011","article-title":"IgA Fc receptors","volume":"21","author":"Monteiro","year":"2003","journal-title":"Annu Rev Immunol"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1002\/path.1877","article-title":"The function of immunoglobulin a in immunity","volume":"208","author":"Woof","year":"2006","journal-title":"J Pathol"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"612","DOI":"10.1038\/mi.2011.36","article-title":"The human immunoglobulin a fc receptor Fc\u03b1RI: a multifaceted regulator of mucosal immunity","volume":"4","author":"Bakema","year":"2011","journal-title":"Mucosal Immunol"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1097\/00024382-200116050-00004","article-title":"Enhanced expression of fc alpha receptor I on blood phagocytes of patients with gram-negative bacteremia is associated with tyrosine phosphorylation of the FcR-gamma subunit","volume":"16","author":"Chiamolera","year":"2001","journal-title":"Shock"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"4080","DOI":"10.4049\/jimmunol.152.8.4080","article-title":"Lipopolysaccharide and cytokine augmentation of human monocyte IgA receptor expression and function","volume":"152","author":"Shen","year":"1994","journal-title":"J Immunol"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1016\/j.autrev.2012.10.011","article-title":"Anti-inflammatory role of the IgA fc receptor (CD89): from autoimmunity to therapeutic perspectives","volume":"12","author":"Ben Mkaddem","year":"2013","journal-title":"Autoimmun Rev"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"1766","DOI":"10.1002\/art.39142","article-title":"Reversal of arthritis by human monomeric IgA through the receptor-mediated SH2 domain-containing phosphatase 1 inhibitory pathway","volume":"67","author":"Rossato","year":"2015","journal-title":"Arthritis Rheumatol"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"5649","DOI":"10.4049\/jimmunol.1400028","article-title":"Human IgA fc receptor Fc\u03b1RI (CD89) triggers different forms of neutrophil death depending on the inflammatory microenvironment","volume":"193","author":"Wehrli","year":"2014","journal-title":"J Immunol"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1056\/nejm200103083441001","article-title":"Efficacy and safety of recombinant human activated protein C for severe sepsis","volume":"344","author":"Bernard","year":"2001","journal-title":"N Engl J Med"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"e1900185","DOI":"10.1002\/pmic.201900185","article-title":"RNF4-a paradigm for SUMOylation-mediated ubiquitination","volume":"19","author":"Kumar","year":"2019","journal-title":"Proteomics"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"1827","DOI":"10.2147\/jir.S300679","article-title":"PARP inhibitors: an innovative approach to the treatment of inflammation and metabolic disorders in Sepsis","volume":"14","author":"Wasyluk","year":"2021","journal-title":"J Inflamm Res"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"828","DOI":"10.1016\/j.kint.2022.05.026","article-title":"Insulin-like growth factor binding protein 7 promotes acute kidney injury by alleviating poly ADP ribose polymerase 1 degradation","volume":"102","author":"Yu","year":"2022","journal-title":"Kidney Int"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1038\/s41556-021-00807-6","article-title":"The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from chromatin","volume":"24","author":"Krastev","year":"2022","journal-title":"Nat Cell Biol"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"2689","DOI":"10.1172\/jci84658","article-title":"CKAP4 is a Dickkopf1 receptor and is involved in tumor 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