PurposeTo evaluate the diagnostic accuracy of routinely used tests of visual function and retinal morphology compared with fundus fluorescein angiography (FFA) to detect onset of active macular neovascularization in unaffected fellow eyes of patients with unilateral neovascular age-related macular degeneration (nAMD).DesignProspective diagnostic accuracy cohort study conducted in 24 eye clinics in the United Kingdom over 3 years.ParticipantsOlder adults (>50 years) with recently diagnosed unilateral nAMD with a fellow (study) eye free of nAMD.MethodsSelf-reported vision, Amsler, clinic-measured visual acuity (VA), fundus assessment, and spectral domain OCT. The reference standard is FFA.Main Outcome MeasuresSensitivity and specificity of the 5 index tests.ResultsOf 552 participants monitored for up to 3 years, 145 (26.3%) developed active nAMD in the study eye, of whom 120 had an FFA at detection and constituted the primary analysis cohort. Index test positives at nAMD detection in those confirmed by FFA were self-reported vision much worse (5), distortion on Amsler (33), 10-letter decrease in acuity from baseline (36), fundus examination (64), and OCT (110). Percentage index test sensitivities were: self-reported vision 4.2 (95% confidence interval [CI], 1.6–9.8); Amsler 33.7 (95% CI, 25.1–43.5); VA 30.0 (95% CI, 22.5–38.7); fundus examination 53.8 (95% CI, 44.8–62.5); and OCT 91.7 (95% CI, 85.2–95.6). All 5 index test specificities were high at 97.0 (95% CI, 94.6–98.5), 81.4 (95% CI, 76.4–85.5), 66.3 (95% CI, 61.0–71.1), 97.6 (95% CI, 95.3–98.9), and 87.8 (95% CI, 83.8–90.9), respectively. The combination of OCT with one other index test that was a secondary outcome measure increased sensitivity marginally and decreased specificity for all combinations except fundus examination.ConclusionsTests of self-reported change in vision, unmasking of new distortion, measurements of acuity, and fundus checks to diagnose active nAMD performed poorly in contrast to OCT. Our findings support a change to guidelines in clinical practice to monitor for onset of nAMD.