Describing Candidate Geographic Atrophy Phenotypes and Their Different Growth Parameters

Describe distinct candidate geographic atrophy (GA) phenotypes in age-related macular degeneration (AMD) and their different growth parameters.

Prospective cohort study.

Patients with GA enrolled in the University of Colorado AMD Registry from 9/2014-9/2022, with follow-up through 4/2023 were included. Patients with ≥five fundus autofluorescence (FAF) time points were included. Longitudinal FAFs for each patient's eye were reviewed by two graders for candidate GA phenotype: (1) unifocal foveal-involving, (2) large coalescing multifocal, (3) small numerous multifocal, as well as presence of a concomitant peripapillary component. Each FAF image was processed using an artificial intelligence (AI) based segmentation model to automatically delineate GA lesions and calculate lesion area, with manual review and adjustment performed by a vitreoretinal specialist. Square-root transformed (SQRT) growth rate was calculated per eye. Gompertz modelling of GA growth was performed to estimate each eye's maximum GA growth rate and maximum projected GA size. Linear regression using generalized estimating equations was used to estimate associations between phenotypes and measures of GA growth rate.

81 eyes with GA from 48 patients were included. Average subject age was 80 years (SD: 8). Average baseline GA size was 6.4 mm² (SD:7.5). Eyes with a peripapillary component had faster modeled maximum GA growth rates (Beta 0.37; 95%CI:0.16,0.59; p<0.001) and higher predicted maximum GA size (Beta 0.24; 95%CI:0.10,0.38; p<0.001) in univariate analysis. After adjusting for presence of a peripapillary component, the large coalescing multifocal and small numerous multifocal phenotypes had larger predicted maximum GA sizes than the unifocal foveal-involving phenotype (Beta 0.10; 95%CI:0.03,0.18; p=0.009 and Beta 0.10; 95%CI:-0.00,0.21; p=0.059, respectively). The small numerous multifocal phenotype had faster SQRT and modeled maximum GA growth rates compared to the unifocal foveal-involving phenotype (Beta 0.09; 95%CI:0.03,0.16; p=0.005 and Beta 0.29; 95%CI:0.13,0.44; p<0.001, respectively), and the large coalescing multifocal phenotype had borderline faster SQRT growth rates than the unifocal foveal-involving phenotype (p=0.05). Further, the small numerous multifocal phenotype had marginally higher modeled maximum GA growth rates than the large coalescing multifocal phenotype (estimated marginal mean difference 0.200mm/yr; 95%CI:-0.00,0.40; p=0.054).

We describe three candidate GA phenotypes and their different growth parameters. The large coalescing multifocal and small numerous multifocal phenotypes had more severe growth trajectories, and presence of a peripapillary component portended more severe outcomes. This may have implications for clinical trial interpretation and clinical prognostication.