{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T18:41:17Z","timestamp":1789065677169,"version":"build-2803163510"},"reference-count":50,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2023,11,9]],"date-time":"2023-11-09T00:00:00Z","timestamp":1699488000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFC2503300"],"award-info":[{"award-number":["2022YFC2503300"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFE0107600"],"award-info":[{"award-number":["2022YFE0107600"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32030053"],"award-info":[{"award-number":["32030053"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32150710522"],"award-info":[{"award-number":["32150710522"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32241017"],"award-info":[{"award-number":["32241017"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007567","name":"City University of Hong Kong","doi-asserted-by":"publisher","award":["9380154"],"award-info":[{"award-number":["9380154"]}],"id":[{"id":"10.13039\/100007567","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>The objective of this study was to discover differential metabolites and pathways underlying infrequent gout flares (InGF) and frequent gout flares (FrGF) using metabolomics and to establish a predictive model by machine learning (ML) algorithms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Serum samples from a discovery cohort of 163 patients with InGF and 239 patients with FrGF were analyzed by mass spectrometry\u2013based untargeted metabolomics to profile differential metabolites and explore dysregulated metabolic pathways using pathway enrichment analysis and network propagation\u2013based algorithms. ML algorithms were performed to establish a predictive model based on selected metabolites, which was further optimized by a quantitative targeted metabolomics method and validated in an independent validation cohort with 97 participants with InGF and 139 participants with FrGF.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 439 differential metabolites between InGF and FrGF groups were identified. Top dysregulated pathways included carbohydrates, amino acids, bile acids, and nucleotide metabolism. Subnetworks with maximum disturbances in the global metabolic networks featured cross\u2010talk between purine metabolism and caffeine metabolism, as well as interactions among pathways involving primary bile acid biosynthesis, taurine and hypotaurine metabolism, alanine, aspartate, and glutamate metabolism, suggesting epigenetic modifications and gut microbiome in metabolic alterations underlying InGF and FrGF. Potential metabolite biomarkers were identified using ML\u2010based multivariable selection and further validated by targeted metabolomics. Area under receiver operating characteristics curve for differentiating InGF and FrGF achieved 0.88 and 0.67 for the discovery and validation cohorts, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Systematic metabolic alterations underlie InGF and FrGF, and distinct profiles are associated with differences in gout flare frequencies. Predictive modeling based on selected metabolites from metabolomics can differentiate InGF and FrGF.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42635","type":"journal-article","created":{"date-parts":[[2023,6,30]],"date-time":"2023-06-30T15:54:00Z","timestamp":1688140440000},"page":"2252-2264","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Metabolomics and Machine Learning Identify Metabolic Differences and Potential Biomarkers for Frequent Versus Infrequent Gout Flares"],"prefix":"10.1002","volume":"75","author":[{"given":"Ming","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolism the Affiliated Hospital of Qingdao University, Qingdao, China and Shandong Provincial Clinical Research Center for Immune Diseases and Gout  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Li","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, ShanghaiTech University, Shanghai, China and Chinese Academy of Sciences (CAS) Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, CAS, Shanghai, China and Innovation Center for Intervention of Chronic Disease and Promotion of Health  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0720-2305","authenticated-orcid":false,"given":"Han","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism the Affiliated Hospital of Qingdao University, Qingdao, China and Shandong Provincial Clinical Research Center for Immune Diseases and Gout  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Pang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism the Affiliated Hospital of Qingdao University, Qingdao, China and Shandong Provincial Clinical Research Center for Immune Diseases and Gout  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingling","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism the Affiliated Hospital of Qingdao University, Qingdao, China and Shandong Provincial Key Laboratory of Metabolic Diseases, the Affiliated Hospital of Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism the Affiliated Hospital of Qingdao University, Qingdao, China and Shandong Provincial Key Laboratory of Metabolic Diseases, the Affiliated Hospital of Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2886-8285","authenticated-orcid":false,"given":"Jie","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism the Affiliated Hospital of Qingdao University, Qingdao, China and Shandong Provincial Key Laboratory of Metabolic Diseases, the Affiliated Hospital of Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism the Affiliated Hospital of Qingdao University, Qingdao, China and Shandong Provincial Clinical Research Center for Immune Diseases and Gout  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1277-4364","authenticated-orcid":false,"given":"Shuhui","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism the Affiliated Hospital of Qingdao University, Qingdao, China and Shandong Provincial Clinical Research Center for Immune Diseases and Gout  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningning","family":"Liang","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, CAS, Shanghai, China and Innovation Center for Intervention of Chronic Disease and Promotion of Health, Shanghai, China and University of Chinese Academy of Sciences, CAS  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongzhen","family":"Tao","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, CAS, Shanghai, China and Innovation Center for Intervention of Chronic Disease and Promotion of Health  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4632-4476","authenticated-orcid":false,"given":"Nicola","family":"Dalbeth","sequence":"additional","affiliation":[{"name":"Department of Medicine Faculty of Medical and Health Sciences, University of Auckland  Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0844-8726","authenticated-orcid":false,"given":"Tony R.","family":"Merriman","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Otago, Dunedin, New Zealand and Division of Clinical Immunology and Rheumatology University of Alabama at Birmingham"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Terkeltaub","sequence":"additional","affiliation":[{"name":"VA San Diego Healthcare System, San Diego, California and University of California San Diego, La Jolla  California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7049-1560","authenticated-orcid":false,"given":"Huiyong","family":"Yin","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, ShanghaiTech University, Shanghai, China and CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, CAS, Shanghai, China and Innovation Center for Intervention of Chronic Disease and Promotion of Health, Shanghai, China and Department of Biomedical Sciences, City University of Hong Kong  Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4622-3731","authenticated-orcid":false,"given":"Changgui","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism the Affiliated Hospital of Qingdao University, Qingdao, China and Shandong Provincial Key Laboratory of Metabolic Diseases, the Affiliated Hospital of Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,11,9]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2016.08.006"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10389-017-0812-5"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00569-9"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/acr.24180"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2016-209707"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00296-015-3284-3"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-022-02772-3"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keq363"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2020.04.008"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1785-z"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-nutr-082018-124344"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1080\/004982599238047"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2016.1"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2017.5"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-018-1600-5"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01980-3"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.41733"},{"issue":"10","key":"e_1_2_7_19_1","first-page":"2557","article-title":"2015 Gout classification criteria: an American College of Rheumatology\/European League Against Rheumatism collaborative initiative","volume":"67","author":"Neogi T","year":"2015","journal-title":"Ann Rheum Dis"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.3760\/cma.j.issn.1000-6699.2020.01.001"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2396-4"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.analchem.5b04491"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13668-3"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2020-217342"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM196910022811405"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keaa018"},{"issue":"9","key":"e_1_2_7_27_1","article-title":"A genome\u2010wide association analysis of 2,622,830 individuals reveals new pathogenic pathways in gout [abstract]","volume":"74","author":"Merriman T","year":"2022","journal-title":"Arthritis Rheumatol"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1080\/10409238.2020.1832438"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2014-206564"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbspin.2022.105364"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12833"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2014.1"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21242-z"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keac507"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2021.670593"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20225753"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-018-2487-5"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.6202607"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.22762"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.22712"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11306-013-0565-2"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/acr2.11425"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-018-1629-5"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.berh.2021.101723"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1570-0232(03)00065-5"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1097\/FPC.0b013e3283505d5e"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/bmc.736"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2020.12.028"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M117.791285"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2019-216374"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-022-02852-4"}],"container-title":["Arthritis &amp; Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.42635","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T19:33:12Z","timestamp":1759951992000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.42635"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,9]]},"references-count":50,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2023,12]]}},"alternative-id":["10.1002\/art.42635"],"URL":"https:\/\/doi.org\/10.1002\/art.42635","archive":["Portico"],"relation":{},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"value":"2326-5191","type":"print"},{"value":"2326-5205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,9]]},"assertion":[{"value":"2022-12-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-06-20","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-11-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}