{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T07:48:16Z","timestamp":1782805696048,"version":"3.54.5"},"reference-count":40,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"publisher","award":["2024YFC2510700"],"award-info":[{"award-number":["2024YFC2510700"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Science and Technology Special Project, Institute of Wenzhou, Zhejiang University","award":["XMGL-KJZX-202401"],"award-info":[{"award-number":["XMGL-KJZX-202401"]}]},{"name":"Exploration and Development Project of ZJUSS","award":["RD2024JCYL03"],"award-info":[{"award-number":["RD2024JCYL03"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Bioengineering"],"abstract":"<jats:p>Background: Network medicine has reshaped how systemic comorbidities are quantified, but the internal comorbidity structure of oral diseases remains undescribed at four-character ICD-10 granularity. Methods: A total of 2,863,671 outpatient visit records from 583,614 patients (2011\u20132025) were analyzed. Using ICD-10 four-character codes (75 disease nodes), comorbidity networks were constructed for five age strata, with edges selected by relative risk (RR) &gt; 1.5 and Bonferroni-corrected Fisher\u2019s exact tests. Patient-level longitudinal sequences were mined for progression trajectories, and quasi-causal analyses\u2014Cox regression, negative outcome controls, and Baron\u2013Kenny mediation\u2014were used to evaluate pathway directionality and specificity. Results: The all-age network contained 75 nodes and 167 edges (modularity = 0.53), forming eight communities. Network complexity peaked at 18\u201329 years and declined with age. Dental caries emerged as the strongest hub in the 60+ stratum (degree = 9). Cox regression adjusted for age, sex, and healthcare utilization confirmed pathway directionality (pulpitis \u2192 tooth defect: hazard ratio (HR) = 2.65; caries \u2192 pulpitis: HR = 2.25), and negative outcome controls confirmed biological specificity. Mediation analysis showed that pulpitis completely mediated the caries \u2192 tooth defect association (proportion mediated \u2248 100%; 95% confidence interval (CI), 90\u2013128%). An oral mucosal immune cluster (burning mouth syndrome, lichen planus, candidiasis, and xerostomia) emerged as a clinically actionable community. Conclusions: Oral diseases form biologically coherent, age-evolving comorbidity communities, and pulpitis is the critical mediating intervention point in the caries-to-tooth-defect cascade. The framework provides a reusable network-medicine substrate for age- and sex-specific risk-stratified oral disease management.<\/jats:p>","DOI":"10.3390\/bioengineering13070761","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T05:58:04Z","timestamp":1782799084000},"page":"761","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Network-Medicine Framework for Intra-Oral Comorbidity: Age-Stratified Clustering and Quasi-Causal Progression Modeling from Outpatient Electronic Health Records"],"prefix":"10.3390","volume":"13","author":[{"given":"Wei","family":"Chen","sequence":"first","affiliation":[{"name":"Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Zhejiang Key Laboratory of Oral Biomedical, Hangzhou 310000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8487-8522","authenticated-orcid":false,"given":"Peng","family":"Huang","sequence":"additional","affiliation":[{"name":"Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Zhejiang Key Laboratory of Oral Biomedical, Hangzhou 310000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijian","family":"Cheng","sequence":"additional","affiliation":[{"name":"Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Zhejiang Key Laboratory of Oral Biomedical, Hangzhou 310000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaowu","family":"Chen","sequence":"additional","affiliation":[{"name":"Zhejiang Provincial Key Laboratory of Internet Multimedia Technology, College of Biomedical Engineering & Instrument Science, Zhejiang University, Hangzhou 310027, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Tian","sequence":"additional","affiliation":[{"name":"Zhejiang Provincial Key Laboratory of Internet Multimedia Technology, College of Biomedical Engineering & Instrument Science, Zhejiang University, Hangzhou 310027, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumeng","family":"Song","sequence":"additional","affiliation":[{"name":"Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Zhejiang Key Laboratory of Oral Biomedical, Hangzhou 310000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Chen","sequence":"additional","affiliation":[{"name":"Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Zhejiang Key Laboratory of Oral Biomedical, Hangzhou 310000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianming","family":"Chen","sequence":"additional","affiliation":[{"name":"Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Zhejiang Key Laboratory of Oral Biomedical, Hangzhou 310000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4805-1279","authenticated-orcid":false,"given":"Rui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Zhejiang Key Laboratory of Oral Biomedical, Hangzhou 310000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Hidalgo, C.A., Blumm, N., Barab\u00e1si, A.L., and Christakis, N.A. (2009). A dynamic network approach for the study of human phenotypes. PLoS Comput. Biol., 5.","DOI":"10.1371\/journal.pcbi.1000353"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nrg2918","article-title":"Network medicine: A network-based approach to human disease","volume":"12","author":"Gulbahce","year":"2011","journal-title":"Nat. Rev. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/nrg3208","article-title":"Mining electronic health records: Towards better research applications and clinical care","volume":"13","author":"Jensen","year":"2012","journal-title":"Nat. Rev. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/s41746-024-01015-w","article-title":"Unraveling cradle-to-grave disease trajectories from multilayer comorbidity networks","volume":"7","author":"Dervic","year":"2024","journal-title":"npj Digit. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"115013","DOI":"10.1088\/1367-2630\/16\/11\/115013","article-title":"Spreading of diseases through comorbidity networks across life and gender","volume":"16","author":"Chmiel","year":"2014","journal-title":"New J. Phys."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1257601","DOI":"10.1126\/science.1257601","article-title":"Uncovering disease-disease relationships through the incomplete interactome","volume":"347","author":"Menche","year":"2015","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4212","DOI":"10.1038\/ncomms5212","article-title":"Human symptoms\u2013disease network","volume":"5","author":"Zhou","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/s41597-025-04508-9","article-title":"Comorbidity networks from population-wide health data: Aggregated data of 8.9M hospital patients (1997\u20132014)","volume":"12","author":"Dervic","year":"2025","journal-title":"Sci. Data"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1177\/00220345221098910","article-title":"Systemic multimorbidity clusters in people with periodontitis","volume":"101","author":"Larvin","year":"2022","journal-title":"J. Dent. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1177\/00220345251317487","article-title":"Caries is the hub of a complex network of chronic diseases across the life decades","volume":"104","author":"Rodrigues","year":"2025","journal-title":"J. Dent. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"7614","DOI":"10.1038\/s41467-022-35337-8","article-title":"An umbrella review of the evidence linking oral health and systemic noncommunicable diseases","volume":"13","author":"Botelho","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1111\/jcpe.13870","article-title":"Periodontitis is associated with multimorbidity in a large dental school population","volume":"50","author":"Beukers","year":"2023","journal-title":"J. Clin. Periodontol."},{"key":"ref_13","first-page":"13S","article-title":"Suboptimal oral health, multimorbidity, and access to dental care","volume":"9","author":"Limo","year":"2024","journal-title":"JDR Clin. Trans. Res."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Chen, I.D.S., Yang, C.M., Chen, M.J., Chen, M.C., Weng, R.M., and Yeh, C.H. (2023). Deep learning-based recognition of periodontitis and dental caries in dental X-ray images. Bioengineering, 10.","DOI":"10.3390\/bioengineering10080911"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Chuo, Y., Lin, W.M., Chen, T.Y., Chan, M.L., Chang, Y.S., Lin, Y.R., Lin, Y.J., Shao, Y.H., Chen, C.A., and Chen, S.L. (2022). A high-accuracy detection system: Based on transfer learning for apical lesions on periapical radiograph. Bioengineering, 9.","DOI":"10.3390\/bioengineering9120777"},{"key":"ref_16","unstructured":"GBD 2021 Oral Disorders Collaborators (2025). Trends in the global, regional, and national burden of oral conditions from 1990 to 2021: A systematic analysis for the Global Burden of Disease Study 2021. Lancet, 405, 897\u2013910."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1177\/0022034515602879","article-title":"Global economic impact of dental diseases","volume":"94","author":"Listl","year":"2015","journal-title":"J. Dent. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"15579883211016361","DOI":"10.1177\/15579883211016361","article-title":"Men and oral health: A review of sex and gender differences","volume":"15","author":"Lipsky","year":"2021","journal-title":"Am. J. Men\u2019s Health"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1902\/jop.2010.100045","article-title":"Sex differences in destructive periodontal disease: Exploring the biologic basis","volume":"81","author":"Shiau","year":"2010","journal-title":"J. Periodontol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"von Elm, E., Altman, D.G., Egger, M., Pocock, S.J., G\u00f8tzsche, P.C., and Vandenbroucke, J.P. (2007). The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies. PLoS Med., 4.","DOI":"10.1371\/journal.pmed.0040296"},{"key":"ref_21","unstructured":"World Health Organization (1995). Application of the International Classification of Diseases to Dentistry and Stomatology (ICD-DA), WHO. [3rd ed.]."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1007\/s41109-018-0101-4","article-title":"Statistical methods for constructing disease comorbidity networks from longitudinal inpatient data","volume":"3","author":"Fotouhi","year":"2018","journal-title":"Appl. Netw. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Newman, M.E.J. (2010). Networks: An Introduction, Oxford University Press.","DOI":"10.1093\/acprof:oso\/9780199206650.003.0001"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"P10008","DOI":"10.1088\/1742-5468\/2008\/10\/P10008","article-title":"Fast unfolding of communities in large networks","volume":"2008","author":"Blondel","year":"2008","journal-title":"J. Stat. Mech."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7821","DOI":"10.1073\/pnas.122653799","article-title":"Community structure in social and biological networks","volume":"99","author":"Girvan","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1037\/0022-3514.51.6.1173","article-title":"The moderator-mediator variable distinction in social psychological research: Conceptual, strategic, and statistical considerations","volume":"51","author":"Baron","year":"1986","journal-title":"J. Pers. Soc. Psychol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Spirtes, P., Glymour, C., and Scheines, R. (2000). Causation, Prediction, and Search, MIT Press. [2nd ed.].","DOI":"10.7551\/mitpress\/1754.001.0001"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3133","DOI":"10.1214\/09-AOS685","article-title":"Estimating high-dimensional intervention effects from observational data","volume":"37","author":"Maathuis","year":"2009","journal-title":"Ann. Stat."},{"key":"ref_29","first-page":"S159","article-title":"Staging and grading of periodontitis: Framework and proposal of a new classification and case definition","volume":"89","author":"Tonetti","year":"2018","journal-title":"J. Periodontol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1111\/odi.13868","article-title":"Worldwide prevalence estimates of burning mouth syndrome: A systematic review and meta-analysis","volume":"28","author":"Wu","year":"2022","journal-title":"Oral Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1862","DOI":"10.1111\/odi.13704","article-title":"Oral potentially malignant disorders: A consensus report from an international seminar on nomenclature and classification","volume":"27","author":"Warnakulasuriya","year":"2021","journal-title":"Oral Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"102364","DOI":"10.1016\/j.jaut.2019.102364","article-title":"Sj\u00f6gren\u2019s syndrome: Old and new therapeutic targets","volume":"110","author":"Mavragani","year":"2020","journal-title":"J. Autoimmun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.clim.2019.04.009","article-title":"Sj\u00f6gren\u2019s syndrome: An update on disease pathogenesis, clinical manifestations and treatment","volume":"203","author":"Vivino","year":"2019","journal-title":"Clin. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1111\/odi.14127","article-title":"Autoimmune disorders in oral lichen planus: A systematic review and meta-analysis","volume":"29","author":"Warnakulasuriya","year":"2023","journal-title":"Oral Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1111\/odi.13572","article-title":"Association between oral lichen planus and systemic conditions and medications: Case-control study","volume":"27","author":"Dave","year":"2021","journal-title":"Oral Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3155","DOI":"10.1111\/odi.14798","article-title":"A multi-center cross-sectional study of 1495 Chinese oral lichen planus patients","volume":"30","author":"Liu","year":"2024","journal-title":"Oral Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1111\/ger.12085","article-title":"Epidemiology of oral health conditions in older people","volume":"31","author":"Thomson","year":"2014","journal-title":"Gerodontology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"411","DOI":"10.2105\/AJPH.2011.300362","article-title":"Burden of oral disease among older adults and implications for public health priorities","volume":"102","author":"Griffin","year":"2012","journal-title":"Am. J. Public Health"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1177\/0022034520908533","article-title":"Global, regional, and national levels and trends in burden of oral conditions from 1990 to 2017: A systematic analysis for the Global Burden of Disease 2017 Study","volume":"99","author":"Bernabe","year":"2020","journal-title":"J. Dent. Res."},{"key":"ref_40","unstructured":"Rothman, K.J., Greenland, S., and Lash, T.L. (2008). Modern Epidemiology, Lippincott Williams & Wilkins. [3rd ed.]."}],"container-title":["Bioengineering"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2306-5354\/13\/7\/761\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T07:34:58Z","timestamp":1782804898000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2306-5354\/13\/7\/761"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,29]]},"references-count":40,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["bioengineering13070761"],"URL":"https:\/\/doi.org\/10.3390\/bioengineering13070761","relation":{},"ISSN":["2306-5354"],"issn-type":[{"value":"2306-5354","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,29]]}}}