Imaging, Genetic, and Demographic Factors Associated With Conversion to Neovascular Age-Related Macular Degeneration: Secondary Analysis of a Randomized Clinical Trial

Abstract

Importance: Risk factors associated with the development of neovascular age-related macular degeneration (AMD) have been identified. However, population size and methods to integrate imaging, genetic, and demographic factors associated with conversion to neovascular AMD are limited, specifically when treatment is administered in 1 eye.

Objective: To determine the imaging, genetic, and demographic factors associated with conversion from nonneovascular to neovascular AMD in fellow eyes.

Design, setting, and participants: This post hoc secondary analysis of the 24-month phase 3 multicenter, double-masked, active treatment-controlled HARBOR trial included 686 fellow eyes with nonneovascular AMD at baseline. Imaging features describing the presence, number, extent, density, and relative reflectivity of drusen were automatically extracted from spectral-domain optical coherence tomography scans. Genetic analysis included 34 single-nucleotide polymorphisms. Least absolute shrinkage and selection operator regression was performed to narrow imaging features. Survival analysis and Cox proportional hazards regression were performed to determine the association of the selected imaging features and genetic and demographic factors with conversion to neovascular AMD. Data were collected from November 2016 through October 2017 and analyzed from October 2017 through October 2018.

Exposure: Nonneovascular AMD in the fellow eye.

Main outcomes and measures: Features associated with conversion to neovascular AMD. Hazard ratios (HRs) and their 95% CIs were calculated.

Results: Among the 686 fellow eyes included in the analysis (406 [59.2%] women; mean [SD] age, 78.12 [8.28] years), 154 (22.4%) converted to neovascular AMD. Female sex was significantly associated with conversion to neovascular AMD (HR, 1.57; 95% CI, 1.11-2.20; P = .009). After controlling for demographic and treatment effects, drusen area within 3 mm of the fovea (HR, 1.45; 95% CI, 1.24-1.69; HR for 1-SD increase, 1.36 [95% CI, 1.20-1.54]) and mean drusen reflectivity (HR, 3.97; 95% CI, 1.11-14.18; HR for 1-SD increase, 1.32 [95% CI, 1.02-1.71]) were significantly associated with conversion to neovascular AMD. In addition, 1 genetic variant (rs61941274) was found to be associated with conversion to neovascular AMD.

Conclusions and relevance: Two imaging features (total en face area of drusen restricted to a circular area 3 mm from the fovea and mean drusen reflectivity) and 1 genetic variant (ACAD10 locus) were associated with conversion to neovascular AMD. Drusen characteristics may be associated with conversion to neovascular AMD despite treatment in 1 eye.

Trial registration: ClinicalTrials.gov identifier: NCT00891735.

Conflict of interest statement

Conflict of Interest Disclosures: Dr de Sisternes reported being employed by Carl Zeiss Meditec, Inc, outside the submitted work and issue of patent US9737205B2 for evaluating the progression of age-related macular degeneration. Dr Osborne reported receiving grants from Genentech during the conduct of the study and personal fees from Genentech/Roche outside the submitted work. Dr Yaspan reported employment by Genentech/Roche outside the submitted work and stock and stock options from Genentech/Roche. Dr Rubin reported receiving grants from Stanford University during the conduct of the study and issue of patent US9737205B2 for evaluating the progression of age-related macular degeneration. Dr Leng reported receiving grants from Genentech/Roche during the conduct of the study and receiving grants from Topcon and personal fees from Zeiss, Regeneron, Allergan, Iridex, 23&Me, and Valeant outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Kaplan-Meier Survival Curves for Eyes With Conversion From Nonneovascular to Neovascular Age-Related Macular Degeneration by Sex

Log-rank test indicates a statistically significant difference between men and women.

Figure 2.. Kaplan-Meier Survival Curves for Eyes With Conversion From Nonneovascular to Neovascular Age-Related Macular Degeneration by rs61941274 (ACAD10 locus) Status

Log-rank test indicates a statistically significant difference between genotypes, with GG as reference. HR indicates hazard ratio.

Figure 3.. Automated Least Absolute Shrinkage and Selection Operator Regression to Select Imaging Features Associated With Conversion From Nonneovascular to Neovascular Age-Related Macular Degeneration

Drusen area within 3 mm of the fovea and drusen reflectivity are the main features that were included in the selected model based on the Schwarz information criteria (SBC). Standardized coefficients are shown as a function of the step number. The normalized tuning values are the L1 norm of the regression coefficients divided by the L1 norm of the ordinary least squares solution. The vertical line indicates the selected step.