To determine predictive factors and risk scores for conversion to overall advanced age-related macular degeneration (AMD), geographic atrophy (GA), neovascular disease (NV), and loss of vision, and to validate the model for AMD in an external cohort.

Progression to advanced AMD was evaluated using stepwise survival analysis. Risk scores including genetic, demographic, behavioral, and ocular factors were derived for 3 AMD endpoints and were validated and calibrated in a large independent cohort. Vision loss of 15 or more letters was evaluated as a new endpoint in genetic analyses.

Eight common and rare variants in genes CFH, C3, ARMS2, COL8A1, and HSPH1/B3GALTL conferred a significantly higher risk of transition to advanced AMD. Three loci (C2, CFB, RAD51B) were associated with lower rate of progression. A protective effect was suggested for CTRB1 and PELI3. The age-adjusted area under the curve (AUC) for the composite model including 13 loci model was 0.900 over 12 years (0.896 in the validation cohort). Generally, progressors had a higher risk category and nonprogressors had a lower risk category when genetic factors were considered. Furthermore, there was heterogeneity between models for GA and NV. The model was calibrated in the validation cohort. Determinants of visual loss included age, education, body mass index, smoking, and several common and rare genetic variants.

Eyes with the same baseline macular grade had a wide range of estimated probability of subsequent progression and visual loss based on the validated risk score. Identifying high-risk individuals at an earlier stage using predictive modeling could lead to improved preventive and therapeutic strategies in the era of precision medicine.