To describe the system for grading age-related macular degeneration from fundus photographs in the Age-Related Eye Disease Study. This is a prospective multicenter cohort study of the course of age-related macular degeneration and a placebo-controlled clinical trial of the effect of high-dose vitamin and mineral supplements on development of advanced age-related macular degeneration. Standardized stereoscopic 30-degree color fundus photographs are taken at 11 clinical centers and evaluated by graders at a reading center for quality and age-related macular degeneration abnormalities. Macular subfields are defined by a grid, and presence and severity of various age-related macular degeneration abnormalities are graded using standard/example photographs and measuring circles. Advanced age-related macular degeneration abnormalities (presence/absence) include retinal pigment epithelial detachment, serous (or hemorrhagic) sensory retinal detachment, hard exudates, subretinal/subretinal pigment epithelial hemorrhage, subretinal fibrous tissue, and photocoagulation scars. Other abnormalities (multistep scales) include retinal pigment epithelial abnormalities (geographic atrophy, depigmentation, and increased pigment), and drusen (size, type [hard versus soft distinct or indistinct], and total area). Contemporaneous variability is tested by having different graders evaluate samples of photographs, and temporal variability by annual regrading of a dedicated subset. In a cumulative sample of 1230 eyes for contemporaneous reproducibility, agreement on advanced age-related macular degeneration was 96% (kappa = 0.88) and for four-step age-related macular degeneration level was 83% (kappa = 0.77). Agreement was moderate for pigment epithelial detachment (kappa = 0.54) and substantial for serous sensory retinal detachment, hard exudates, subretinal/subretinal pigment epithelial hemorrhage, subretinal fibrous tissue, and central geographic atrophy (kappa = 0.73-0.82). For pigment abnormalities, agreement was substantial for geographic atrophy (kappa = 0.63; kappa(weighted) = 0.71, 0.75 weight for one-step disagreements), and moderate for depigmentation (kappa = 0.41, kappa(weighted) = 0.51) and increased pigment (kappa = 0.54, kappa(weighted) = 0.71). For drusen, agreement was moderate to substantial for presence/maximum size (kappa = 0.50, kappa(weighted) = 0.68), type (kappa = 0.61, kappa(weighted) = 0.69), and area (kappa = 0.56, kappa(weighted) = 0.77). Six annual regrades of 119 eyes showed little temporal drift in grading of various age-related macular degeneration abnormalities, except for drusen type. The Age-Related Eye Disease Study has demonstrated satisfactory reliability for detecting onset of advanced age-related macular degeneration in a cohort, and moderate to substantial agreement on various abnormalities across the age-related macular degeneration spectrum. The Age-Related Eye Disease Study system for classification of age-related macular degeneration is suitable for longitudinal multicenter studies.
