Prediction of age-related macular degeneration in the general population: the Three Continent AMD Consortium

Abstract

Purpose: Prediction models for age-related macular degeneration (AMD) based on case-control studies have a tendency to overestimate risks. The aim of this study is to develop a prediction model for late AMD based on data from population-based studies.

Design: Three population-based studies: the Rotterdam Study (RS), the Beaver Dam Eye Study (BDES), and the Blue Mountains Eye Study (BMES) from the Three Continent AMD Consortium (3CC).

Participants: People (n = 10,106) with gradable fundus photographs, genotype data, and follow-up data without late AMD at baseline.

Methods: Features of AMD were graded on fundus photographs using the 3CC AMD severity scale. Associations with known genetic and environmental AMD risk factors were tested using Cox proportional hazard analysis. In the RS, the prediction of AMD was estimated for multivariate models by area under receiver operating characteristic curves (AUCs). The best model was validated in the BDES and BMES, and associations of variables were re-estimated in the pooled data set. Beta coefficients were used to construct a risk score, and risk of incident late AMD was calculated using Cox proportional hazard analysis. Cumulative incident risks were estimated using Kaplan-Meier product-limit analysis.

Main outcome measures: Incident late AMD determined per visit during a median follow-up period of 11.1 years with a total of 4 to 5 visits.

Results: Overall, 363 participants developed incident late AMD, 3378 participants developed early AMD, and 6365 participants remained free of any AMD. The highest AUC was achieved with a model including age, sex, 26 single nucleotide polymorphisms in AMD risk genes, smoking, body mass index, and baseline AMD phenotype. The AUC of this model was 0.88 in the RS, 0.85 in the BDES and BMES at validation, and 0.87 in the pooled analysis. Individuals with low-risk scores had a hazard ratio (HR) of 0.02 (95% confidence interval [CI], 0.01-0.04) to develop late AMD, and individuals with high-risk scores had an HR of 22.0 (95% CI, 15.2-31.8). Cumulative risk of incident late AMD ranged from virtually 0 to more than 65% for those with the highest risk scores.

Conclusions: Our prediction model is robust and distinguishes well between those who will develop late AMD and those who will not. Estimated risks were lower in these population-based studies than in previous case-control studies.

Figure 2

Distribution of risk score in incident late age-related macular degeneration (AMD) and no late AMD in the Three Continent AMD Consortium, and hazard ratio (HRs) of incident late AMD. The x-axis represents the risk score category, the left y-axis represents frequency as percentages, and the right y-axis represents the HR of incident late AMD. The dark grey bars represent no late AMD, and the light grey bar represents incident late AMD. The black line represents the HR of incident late AMD. Category 3 is the reference category (R) and has an HR of 1.00. Risk scores −3 to 0 and 6 to 8 were combined for HR. Error bars indicate the 95% confidence interval of the HRs.

Figure 3

Cumulative risk of incident late age-related macular degeneration (AMD) prior to and after testing of prediction model in the Three Continent AMD Consortium (3CC). A, Overall cumulative risk of incident late AMD in 3CC; the x-axis represents the age of onset for incident late AMD cases and age at last examination for noncases; y-axis represents the cumulative risk of incident late AMD. The number at risk for each decade is presented underneath the figure. B, Cumulative risk of incident late AMD stratified for risk strata 0–6 in 3CC; x-axis represents the age of onset for incident late AMD cases and age at last examination for noncases; y-axis represents the cumulative risk of incident late AMD. The risk scores are depicted by various colors. The number at risk for each decade and each risk score is presented underneath the figure.