Multidimensional Clinical Phenotyping and Its Predictive Interaction with Structural–Functional Severity Endpoints in Diabetic Macular Edema: A Hospital-Based Systems-Biomarker Analysis

Background: To examine how multidimensional clinical phenotypes—spanning metabolic, vasculopathic, renal, inflammatory, and lifestyle domains—interact with structural and functional severity endpoints in diabetic macular edema (DME), using a hospital-based systems-biomarker model. Material and Methods: A cross-sectional analysis was conducted on patients with OCT-confirmed DME. Clinical phenotyping encompassed glyco-inflammatory load (HbA1c, CRP), metabolic–vascular indices (BP, lipid profile), renal microangiopathy (microalbuminuria, creatinine, eGFR), and lifestyle factors (BMI, smoking). Structural endpoints (central macular thickness, intraretinal cysts, DRIL, ELM/EZ integrity, choroidal thickness) and functional endpoints (best-corrected visual acuity, contrast sensitivity) were analyzed. Advanced multivariate interaction modeling and systems-biomarker scoring were performed. Results: A composite phenotype panel (HbA1c, microalbuminuria, LDL, systolic BP) explained 71.4% of structural severity variance. Glyco-inflammatory load highly correlated with DRIL and ELM/EZ disruption (r = 0.622, p < 0.001). Renal microangiopathy markers were independently tied to diffuse cystoid edema, and hypertension was a strong predictor of chronic edema. EZ disruption and DRIL extent were the most robust predictors of visual dysfunction. Conclusion: DME severity is orchestrated through synergistic, not isolated, systemic derangements. Systems-biomarker models offer powerful tools for predicting retinal injury and vision loss, underscoring the value of multidomain clinical profiling in precision management.

Keywords: DME, systems biomarkers, clinical phenotyping, DRIL, ELM/EZ integrity, metabolic dysregulation, retinal neurodegeneration.