A Network-Medicine Framework for Intra-Oral Comorbidity: Age-Stratified Clustering and Quasi-Causal Progression Modeling from Outpatient Electronic Health Records.

backgroundNetwork medicine has reshaped how systemic comorbidities are quantified, but the internal comorbidity structure of oral diseases remains undescribed at four-character ICD-10 granularity.

methodsA total of 2,863,671 outpatient visit records from 583,614 patients (2011-2025) 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) > 1.5 and Bonferroni-corrected Fisher's exact tests. Patient-level longitudinal sequences were mined for progression trajectories, and quasi-causal analyses-Cox regression, negative outcome controls, and Baron-Kenny mediation-were used to evaluate pathway directionality and specificity.

resultsThe all-age network contained 75 nodes and 167 edges (modularity = 0.53), forming eight communities. Network complexity peaked at 18-29 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 → tooth defect: hazard ratio (HR) = 2.65; caries → pulpitis: HR = 2.25), and negative outcome controls confirmed biological specificity. Mediation analysis showed that pulpitis completely mediated the caries → tooth defect association (proportion mediated ≈ 100%; 95% confidence interval (CI), 90-128%). An oral mucosal immune cluster (burning mouth syndrome, lichen planus, candidiasis, and xerostomia) emerged as a clinically actionable community.

conclusionsOral 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.