Risk models for progression to advanced age-related macular degeneration using demographic, environmental, genetic, and ocular factors
Open accessAbstract
Purpose To expand our predictive models for progression to advanced stages of age-related macular degeneration (AMD) based on demographic, environmental, genetic, and ocular factors, using longer follow-up, time varying analyses, calculation of absolute risks, adjustment for competing risks, and detailed baseline AMD and drusen status.Design Prospective, longitudinal study.Participants We included 2937 individuals in the Age-Related Eye Disease Study, of which 819 subjects progressed to advanced AMD during 12 years of follow-up.Methods Cox proportional hazards regression analyses were performed to calculate hazard ratios for progression. Covariates included demographic and environmental factors, 6 variants in 5 genes, baseline macular drusen size, and presence and type of advanced AMD in 1 eye at baseline. To assess the ability of risk scores based on all covariates to discriminate between progressors and nonprogressors, an algorithm was developed and the area under the receiver operating characteristic curve (AUC) was calculated. To validate the overall model, the total sample was randomly subdivided into derivation and test samples. Another model was built based on the derivation sample and assessed for calibration and discrimination in the test sample. Sample sizes needed for testing new treatments in clinical trials were estimated based on models with and without genetic variables.Main outcome measures Progression to advanced AMD, including geographic atrophy and neovascular disease.Results In multivariate models, age, smoking, body mass index, single nucleotide polymorphisms in the CFH, ARMS2/HTRA1, C3, C2, and CFB genes, as well as presence of advanced AMD in 1 eye and drusen size in both eyes were all independently associated with progression. The AUC for progression at 10 years in the model with genetic factors, drusen size, and environmental covariates was 0.915 in the total sample. In the test sample, based on a model estimated from the derivation sample, the AUC was 0.908. The sample sizes needed for clinical trials were estimated to be lower when genetic susceptibility was considered.Conclusions Factors reflective of nature and nurture were incorporated into an expanded algorithm for risk prediction, which performed very well in both derivation and test samples. Risk scores and predicted progression rates will be useful for AMD surveillance and for designing clinical trials.Financial disclosure(s) Proprietary or commercial disclosure may be found after the references.
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Because the prediction model included only genetic risk factors, the performance of advanced AMD risk assessment is expected to improve with additional environmental and demographic factors in prospective studies.
“As this prediction model only included genetic risk factors, we expect an improvement of the performance of advanced AMD risk assessment with additional environmental and demographic factors in prospective studies as in our previous calculations (18,19).”
From Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration (2011) · cites this paper as [18]
A combined risk score including multiple genetic loci along with demographic, environmental and macular characteristics which modify risk is highly predictive of progression from early and intermediate stages of AMD to advanced stages which cause visual loss.
“A combined risk score including these multiple genetic loci along with demographic, environmental and macular characteristics which modify risk is highly predictive of progression from the early and intermediate stages of AMD to the advanced stages which cause visual loss (18,19).”
From Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration (2011) · cites this paper as [18]
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- Authors
- Seddon, J. M., Reynolds, R., Yu, Y., Daly, M. J., & Rosner, B.
- Affiliations
- Tufts University (US)
- Massachusetts General Hospital (US)
- Harvard University (US)
- Corresponding author
- Seddon, Johanna M.
- Venue
- Ophthalmology
- Publisher
- Elsevier BV
- Published
- 2011-11
- Volume
- 118
- Issue
- 11
- Pages
- 2203-2211
- ISSN
- 0161-6420 (ISSN-L)
- PMC
- PMC4097877
- OpenAlex
- W2053517908
- Cited by
- 198
- References
- 39
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 3 · 2023: 6 · 2022: 8 · 2021: 10 · 2020: 11 · 2019: 9 · 2018: 11 · 2017: 12 · 2016: 13 · 2015: 18 · 2014: 21 · 2013: 39 · 2012: 22
- FWCI
- 24.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Ophthalmology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Eye Institute (U10EY011309, R01 EY 11309, R01EY011309)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Retinal Imaging and Analysis
- Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
- Keywords
- age-related macular degeneration, disease progression, risk prediction model, macular drusen, genetic susceptibility, complement factor H, complement genes, smoking, body mass index, geographic atrophy, neovascular AMD, sample size determination, competing risks, AREDS
- MeSH terms
- Aged, Algorithms, Demography, Environment, Female, Follow-Up Studies, Genotype, Humans, Macular Degeneration, Male, Models, Biological, Phenotype, Prospective Studies, Risk Factors, Proportional Hazards Models, Disease Progression, Genetic Predisposition to Disease
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