{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T15:44:39Z","timestamp":1792338279466,"version":"4.4.0"},"reference-count":46,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T00:00:00Z","timestamp":1792281600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T00:00:00Z","timestamp":1792281600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["72301082"],"award-info":[{"award-number":["72301082"]}],"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":["82574958"],"award-info":[{"award-number":["82574958"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2025M773863"],"award-info":[{"award-number":["2025M773863"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The growing prevalence and complexity of multimorbidity pose significant challenges to healthcare systems worldwide. Here, we developed a heterogeneous graph neural network framework for multilabel multimorbidity prediction. The framework jointly encodes symptom and diagnostic information within a heterogeneous graph and incorporates biomedical knowledge subgraphs on both the disease and symptom sides. By integrating macro\u2010level clinical representations of symptoms and diseases with micro\u2010level molecular knowledge, the model generates multilabel probabilities across candidate disease categories. We evaluated the framework in two complementary tasks: Patient\u2010Level Symptom\u2013Disease Association (Task 1) and Visit\u2010Level Multimorbidity Completion (Task 2). In Task 1, symptoms recorded across all eligible visits within each patient's observation window were aggregated into a patient\u2010level symptom set to predict the disease categories recorded for that patient within the same observation window. In Task 2, symptoms and a subset of recorded positive diagnoses from the same visit were used to predict the remaining disease categories recorded for that visit. Together, these two tasks provide a unified framework for patient\u2010level symptom\u2013disease association and visit\u2010level multimorbidity completion. The framework characterized symptom\u2013disease\u2013biomedical knowledge associations and non\u2010random patterns of disease co\u2010occurrence, while supporting both patient\u2010level symptom\u2013disease association and visit\u2010level multimorbidity\u00a0completion.<\/jats:p>","DOI":"10.1002\/advs.78348","type":"journal-article","created":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T15:13:56Z","timestamp":1792336436000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Symptom\u2010Driven Prediction of Chronic Multimorbidity with a Macro\u2013Micro Heterogeneous Graph Neural Network"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9535-2634","authenticated-orcid":false,"given":"Yiheng","family":"Ye","sequence":"first","affiliation":[{"name":"State Key Laboratory of Traditional Chinese Medicine Syndrome \/ TCM Big Data Research Center The Second Clinical College of Guangzhou University of Chinese Medicine Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaoru","family":"Han","sequence":"additional","affiliation":[{"name":"The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine Shenzhen Traditional Chinese Medicine Hospital Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siqiao","family":"Tang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Traditional Chinese Medicine Syndrome \/ TCM Big Data Research Center The Second Clinical College of Guangzhou University of Chinese Medicine Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongxiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Business Administration, School of Management Jinan University Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haichen","family":"Shen","sequence":"additional","affiliation":[{"name":"School of Big Data and Artificial Intelligence Guangdong University of Finance &amp; Economics Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5105-8291","authenticated-orcid":false,"given":"Bingzhen","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Economics and Management Xidian University Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Statistics and Data Science Guangdong University of Finance &amp; Economics Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodong","family":"Chu","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Traditional Chinese Medicine Informatization, Institute of Traditional Chinese Medicine and Health, College of Traditional Chinese Medicine Jinan University Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5072-390X","authenticated-orcid":false,"given":"Lijuan","family":"Deng","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine Jinan University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoyang","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine The Second Affiliated Hospital of Guangzhou University of Chinese Medicine Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingchun","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology The Second Affiliated Hospital of Guangzhou University of Chinese Medicine Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2681-4611","authenticated-orcid":false,"given":"Kun","family":"Bao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Traditional Chinese Medicine Syndrome \/ TCM Big Data Research Center The Second Clinical College of Guangzhou University of Chinese Medicine Guangdong China"},{"name":"Guangdong\u2010Hong Kong\u2010Macau Joint Lab on Chinese Medicine and Immune Disease Research Guangzhou China"},{"name":"Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Disease the Second Affiliated Hospital of Guangzhou University of Chinese Medicine Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9667-3303","authenticated-orcid":false,"given":"Ronghua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Traditional Chinese Medicine Informatization, Institute of Traditional Chinese Medicine and Health, College of Traditional Chinese Medicine Jinan University Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery Linyi People's Hospital Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengwei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery Linyi People's Hospital Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3824-8215","authenticated-orcid":false,"given":"Xiaoli","family":"Chu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Traditional Chinese Medicine Syndrome \/ TCM Big Data Research Center The Second Clinical College of Guangzhou University of Chinese Medicine Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,18]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen\u20102017\u2010017264"},{"key":"e_1_2_10_3_1","volume-title":"Multimorbidity: Technical Series on Safer Primary Care","author":"World Health Organization","year":"2016"},{"key":"e_1_2_10_4_1","first-page":"29","article-title":"ICARE4EU: Improving Care for People with Multiple Chronic Conditions in Europe","volume":"19","author":"Rijken M.","year":"2013","journal-title":"Eurohealth"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/ageing\/afx201"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572\u2010022\u201000376\u20104"},{"key":"e_1_2_10_7_1","volume-title":"Ageing: Debate the Issues","author":"Love P. G.","year":"2015"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2023.101860"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1004205"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12916\u2010017\u20100978\u20102"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjmed\u20102026\u2010002605"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010023\u201002420\u20106"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1177\/17423953221087647"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eswa.2022.117761"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010020\u201017419\u20107"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010025\u201008869\u20104"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2589\u20107500(21)00275\u20102"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010020\u20100916\u20102"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41746\u2010025\u201001749\u20101"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/d41586\u2010020\u201000837\u20104"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2014.04.011"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/ipd.12274"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010025\u201009529\u20103"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010021\u201001292\u2010y"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2589\u20107500(24)00147\u2010X"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(05)66702\u20105"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2589\u20107500(23)00147\u20104"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202404671"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010021\u201001964\u20102"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eswa.2020.113918"},{"key":"e_1_2_10_31_1","unstructured":"S.Bhoi M. L.Lee andW.Hsu \u201cPREMIER: Personalized Recommendation for Medical Prescriptions from Electronic Records \u201darXiv(2020): arXiv:2008.13569."},{"key":"e_1_2_10_32_1","doi-asserted-by":"crossref","unstructured":"A.Li E.Casiraghi andJ.Rousu \u201cFedMed: Federated Learning\u2010Based Personalized and Safe Medication Recommendation \u201d inProceedings of the 32nd ACM SIGKDD Conference on Knowledge Discovery and Data Mining V.2(Association for Computing Machinery 2026) 11319\u201311327.","DOI":"10.1145\/3770855.3818934"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neunet.2026.109168"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010024\u201003074\u20108"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02783-w"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43856\u2010024\u201000529\u20104"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010025\u201067372\u20106"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41746\u2010025\u201002290\u2010x"},{"key":"e_1_2_10_39_1","first-page":"2071","article-title":"Complex Embeddings for Simple Link Prediction","volume":"48","author":"Trouillon T.","year":"2016","journal-title":"Proceedings of Machine Learning Research"},{"key":"e_1_2_10_40_1","first-page":"2787","article-title":"Translating Embeddings for Modeling Multi\u2010Relational Data","volume":"26","author":"Bordes A.","year":"2013","journal-title":"Advances in Neural Information Processing Systems"},{"key":"e_1_2_10_41_1","unstructured":"T. N.KipfandM.Welling \u201cSemi\u2010Supervised Classification with Graph Convolutional Networks \u201d inProceedings of the 5th International Conference on Learning Representations(OpenReview 2017)."},{"key":"e_1_2_10_42_1","unstructured":"P.Veli\u010dkovi\u0107 G.Cucurull A.Casanova A.Romero P.Li\u00f2 andY.Bengio \u201cGraph Attention Networks \u201d inProceedings of the 6th International Conference on Learning Representations(OpenReview 2018)."},{"key":"e_1_2_10_43_1","doi-asserted-by":"crossref","unstructured":"X.Ge A.Satpathy R. D.Williams J.Stankovic andH.Alemzadeh \u201cDKEC: Domain Knowledge Enhanced Multi\u2010Label Classification for Diagnosis Prediction \u201d inProceedings of the 2024 Conference on Empirical Methods in Natural Language Processing(Association for Computational Linguistics 2024) 12798\u201312813.","DOI":"10.18653\/v1\/2024.emnlp-main.712"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbac255"},{"key":"e_1_2_10_45_1","doi-asserted-by":"crossref","unstructured":"Z.Hu Y.Dong K.Wang andY.Sun \u201cHeterogeneous Graph Transformer \u201d inProceedings of The Web Conference 2020(Association for Computing Machinery 2020) 2704\u20132710.","DOI":"10.1145\/3366423.3380027"},{"key":"e_1_2_10_46_1","doi-asserted-by":"crossref","unstructured":"T.\u2010Y.Lin P.Goyal R.Girshick K.He andP.Doll\u00e1r \u201cFocal Loss for Dense Object Detection \u201d inProceedings of the 2017 IEEE International Conference on Computer Vision(IEEE 2017) 2999\u20133007.","DOI":"10.1109\/ICCV.2017.324"},{"key":"e_1_2_10_47_1","doi-asserted-by":"crossref","unstructured":"X.Wang H.Ji C.Shi et\u00a0al. \u201cHeterogeneous Graph Attention Network \u201d inProceedings of the World Wide Web Conference(Association for Computing Machinery 2019) 2022\u20132032.","DOI":"10.1145\/3308558.3313562"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.78348","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.78348","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.78348","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T15:14:04Z","timestamp":1792336444000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.78348"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,18]]},"references-count":46,"alternative-id":["10.1002\/advs.78348"],"URL":"https:\/\/doi.org\/10.1002\/advs.78348","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,18]]},"assertion":[{"value":"2026-07-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e78348"}}