Abstract
PURPOSE: To determine if a family history of age-related macular degeneration (AMD) and genetic variants identify eyes at higher risk for progression to advanced AMD (AAMD), after controlling for baseline demographics, behavioral factors, and macular status. DESIGN: Prospective, longitudinal cohort study. METHODS: Eyes were classified using the Age-Related Eye Disease Study severity scale. Non-genetic and genetic predictors for progression to AAMD, geographic atrophy, and neovascular disease were evaluated. Cox proportional hazards models using the eye as the unit of analysis were used to calculate hazard ratios (HRs), accounting for correlated data. Discrimination between progressing and non-progressing eyes was assessed using C-statistics and net reclassification improvement (NRI). RESULTS: Among 4910 eyes, 863 progressed to AAMD over 12 years. Baseline AMD severity scale and status of the fellow eye were important predictors; genes provided additional discrimination. A family history of AMD also independently predicted progression after accounting for genetic and other covariates: 1 family member versus none (HR 1.21 [95% confidence interval {CI} 1.02-1.43]; P = 0.03); ≥2 family members versus none (HR 1.55 [95% CI 1.26-1.90]; P < 0.001). A composite risk score calculated using β estimates of both non-genetic and significant genetic factors predicted progression to AAMD (HR 5.57; 90(th) vs 10(th) percentile; area under the receiver operating characteristic curve [AUC] = 0.92), providing superior fit compared with other models, including one with only ocular variables (NRI = 0.34; P < 0.001; AUC = 0.87, ΔAUC 0.05 ± 0.005; P < 0.001). CONCLUSION: Genetic variants and family history provided additional discrimination for predicting progression to AAMD, after accounting for baseline macular status and other covariates.