Validated Prediction Models for Macular Degeneration Progression and Predictors of Visual Acuity Loss Identify High-Risk Individuals

Abstract

Purpose: To determine predictive factors and risk scores for conversion to overall advanced age-related macular degeneration (AMD), geographic atrophy (GA), neovascular disease (NV), and loss of vision, and to validate the model for AMD in an external cohort.

Methods: Progression to advanced AMD was evaluated using stepwise survival analysis. Risk scores including genetic, demographic, behavioral, and ocular factors were derived for 3 AMD endpoints and were validated and calibrated in a large independent cohort. Vision loss of 15 or more letters was evaluated as a new endpoint in genetic analyses.

Results: Eight common and rare variants in genes CFH, C3, ARMS2, COL8A1, and HSPH1/B3GALTL conferred a significantly higher risk of transition to advanced AMD. Three loci (C2, CFB, RAD51B) were associated with lower rate of progression. A protective effect was suggested for CTRB1 and PELI3. The age-adjusted area under the curve (AUC) for the composite model including 13 loci model was 0.900 over 12 years (0.896 in the validation cohort). Generally, progressors had a higher risk category and nonprogressors had a lower risk category when genetic factors were considered. Furthermore, there was heterogeneity between models for GA and NV. The model was calibrated in the validation cohort. Determinants of visual loss included age, education, body mass index, smoking, and several common and rare genetic variants.

Conclusion: Eyes with the same baseline macular grade had a wide range of estimated probability of subsequent progression and visual loss based on the validated risk score. Identifying high-risk individuals at an earlier stage using predictive modeling could lead to improved preventive and therapeutic strategies in the era of precision medicine.

FIGURE 1.

Flow chart illustrating the selection of participants for inclusion in the validation cohort from the Seddon Longitudinal Age-Related Macular Degeneration Cohort.

FIGURE 2.

Genetic loci in the composite risk model associated with progression to advanced age-related macular degeneration over 12 years. The forest plot displays risk of progression per effective allele based on multivariate stepwise models. Hazard ratios (HRs.) and 95% confidence intervals (CIs) are presented for each locus on a log scale. Results are shown for the derivation cohort (top) and validation cohort (bottom).

FIGURE 3.

Probability of progression to advanced age-related macular degeneration endpoint (AMD) over 5 years and 10 years among eyes with intermediate disease at baseline based on demographic, behavioral, ocular, and genetic variables (the risk score) in the derivation cohort group. Probability of progression was defined as 1) very low (< 1%); 2) low (1% to < 10%); 3) medium (10% to < 30%); 4) high (30% to < 50%); 5) very high (≥ 50%).

FIGURE 4.

Probability of progression to geographic atrophy (GA) and neovascular disease (NV) endpoints over 5 years and 10 years among eyes with intermediate disease at baseline based on demographic, behavioral, ocular, and genetic variables (risk score) in the derivation cohort group. Probability of progression was defined as 1) very low (< 1%); 2) low (1% to < 10%); 3) medium (10% to < 30%); 4) high (30% to < 50%); 5) very high (≥ 50%).

FIGURE 5.

Boxplot depicting risk score percentile for progressors to advanced AMD over 10 years and non-progressors among eyes with intermediate disease at baseline. The percentiles were calculated from the sample of non-progressing eyes. The horizontal line represents the median and the + sign represents the arithmetic mean. The top and bottom of the box depicts the upper and lower 25^th percentile.

FIGURE 6.

Plot of percent of eyes which progressed over 5 or 10 years according to risk score deciles.

FIGURE 7.

Receiver operating characteristic curve for 12 year progression to overall advanced age-related macular degeneration in the validation cohort according to the validated risk model that includes demographic, lifestyle, ocular, and genetic factors. AUC = 0.896.

FIGURE 8.

Distribution of risk scores for progressors to incident advanced age-related macular degeneration over 12 years and for non-progressors separately in the validation cohort, according to the composite risk score based on demographic, behavioral, ocular, and genetic variables.

FIGURE 9.

Calibration of the risk model for progression to advanced age-related macular degeneration over 5 years comparing observed and expected number of eyes progressing in the validation cohort.