Abstract
IMPORTANCE: In bilateral geographic atrophy (GA), enlargement rates in fellow eyes are often assumed to be highly correlated. On this basis, researchers have inferred treatment effects and proposed GA trials using the untreated fellow eye as an internal control. OBJECTIVE: To quantify the correlation in GA enlargement rates between fellow eyes. DESIGN, SETTING, AND PARTICIPANTS: This was a post hoc analysis of Age-Related Eye Disease Study 2 (AREDS2), a multicenter study of patients in retinal specialty clinics throughout the US. Included in the analysis were participants of the AREDS2 trial with bilateral GA. Study data were analyzed from May 2025 to January 2026. EXPOSURES: GA in the fellow eye. MAIN OUTCOMES AND MEASURES: Pearson correlation coefficient for 2-year GA enlargement rates in eye pairs. Rates were derived from planimetry of annual fundus photographs and expressed as untransformed, square root-transformed, and perimeter-adjusted rates. Correlation was analyzed overall and within clinically relevant strata. RESULTS: A total of 386 eyes of 193 AREDS2 participants (mean [SD] age, 75.5 [7.3] years; 118 female [61.1%]) with bilateral GA were included in this analysis. Correlations in enlargement rates varied substantially by transformation used as follows: moderate for untransformed (r = 0.51; 95% CI, 0.41-0.61), weak to moderate for square root-transformed (r = 0.38; 95% CI, 0.25-0.49), and very weak for perimeter-adjusted (r = 0.11; 95% CI, -0.03 to 0.25) rates. Correlation was consistently weaker in large vs small GA: 0.30 (95% CI, 0.07-0.50) vs 0.63 (95% CI, 0.41-0.78; untransformed), 0.38 (95% CI, 0.16-0.56) vs 0.46 (95% CI, 0.20-0.66; square root), and 0.03 (95% CI, -0.21 to 0.26) vs 0.22 (-0.08 to 0.49; perimeter), respectively. For GA location using untransformed rates, correlation was strongest for extrafoveal GA, intermediate for subfoveal GA, and weakest for discordant pairs. Square root rates showed a similar pattern. For focality using untransformed rates, correlation was similar for unifocal, multifocal, and discordant pairs. Using square root rates, it was strongest for unifocal GA, weakest for multifocal GA, and intermediate for discordant pairs. For reticular pseudodrusen (RPD) status, correlation was strongest for RPD absence, weakest for presence, and intermediate for discordant pairs. Differences were smaller using square root rates. CONCLUSIONS AND RELEVANCE: Results of this post hoc analysis of the AREDS2 trial reveal that correlation in GA enlargement rates between fellow eyes was modest. Key GA characteristics of area, location, focality, and RPD status, as well as the transformation used, were strongly associated with the correlation. Untransformed rates were inflated by a tendency for symmetry in baseline GA characteristics, whereas genuine biological correlation (best reflected by linear enlargement) was only weak to moderate. Researchers should be cautious of trials and analyses relying on assumptions of highly correlated enlargement rates.