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Cited by 692Retinal Diseases and TreatmentsRetinal Imaging and AnalysisOcular Diseases and Behçet’s Syndrome

Risk Factors for the Incidence of Advanced Age-Related Macular Degeneration in the Age-Related Eye Disease Study (AREDS)AREDS report no. 19

Open access
⁎·2005·Ophthalmology
DOI 10.1016/j.ophtha.2004.10.047PMC PMC1513667
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Abstract

Purpose To describe the association of demographic, behavioral, medical, and nonretinal ocular factors with the incidence of neovascular age-related macular degeneration (AMD) and central geographic atrophy (CGA) in the Age-Related Eye Disease Study (AREDS), a randomized trial of antioxidants and zinc supplementation prophylaxis for development of advanced AMD.Design Clinic-based prospective cohort study.Participants Of individuals with early or intermediate AMD at baseline with a median follow-up of 6.3 years, 788 were at risk of developing advanced AMD in one eye (the fellow eye had advanced AMD), and 2506 were at risk in both eyes.Methods The incidence of neovascular AMD and CGA was assessed from stereoscopic color fundus photographs taken at baseline and at annual visits beginning at year 2.Main outcome measures Neovascular AMD was defined as photocoagulation for choroidal neovascularization, or photographic documentation at the reading center of any of the following: nondrusenoid retinal pigment epithelial detachment, serous or hemorrhagic retinal detachment, hemorrhage under the retina or the retinal pigment epithelium, and subretinal fibrosis. Central geographic atrophy was defined as geographic atrophy involving the center of the macula.Results In multivariable models, in persons at risk of advanced AMD in both eyes, while controlling for age, gender, and AREDS treatment group, the following variables were statistically significantly associated with the incidence of neovascular AMD: race (odds ratio [OR], white vs. black, 6.77; 95% confidence interval [CI], 1.24-36.9) and larger amount smoked (OR, >10 vs. < or =10 pack-years [a pack-year is an average of 1 pack of cigarette smoked per day for a year], 1.55; 95% CI, 1.15-2.09). The following were statistically significantly associated with the incidence of CGA: less education (OR, high school graduate or less vs. college graduate, 1.75; 95% CI, 1.10-2.78), greater body mass index (BMI) (OR, obese vs. nonobese, 1.93; 95% CI, 1.25-2.65), larger amount smoked (OR, >10 pack-years vs. < or =10 pack-years, 1.82; 95% CI, 1.25-2.65), and antacid use (OR, 0.29; 95% CI, 0.09-0.91). In persons at risk of developing advanced AMD in one eye, the incidence of neovascular AMD was associated with diabetes (OR, 1.88; 95% CI, 1.07-3.31), and the incidence of CGA was associated with use of antiinflammatory medications (OR, 0.22; 95% CI, 0.08-0.59).Conclusions Results suggest that, among persons with early or intermediate AMD, smoking and BMI are modifiable factors associated with progression to advanced AMD, and suggest other associations (e.g., use of antacids and antiinflammatory medications) that warrant further study. This article contains additional online-only material available at http://www.ophsource.org/periodicals/ophtha. .

AI snapshot

Written from the paper’s full text.

TL;DR

In AREDS participants with early or intermediate AMD, smoking and obesity were associated with progression to advanced AMD, while several other demographic, medical, and medication factors showed associations requiring further study. The report identifies white race and smoking for incident neovascular AMD, and less education, obesity, smoking, and antacid use for central geographic atrophy.

Key findings

  • Among 2506 bilateral drusen participants, 256 (10%) developed neovascular AMD in at least one eye and 140 (6%) developed central GA; among 788 unilateral advanced AMD participants, 278 (35%) developed a neovascular outcome and 83 (10%) developed central GA.
  • In multivariable models for bilateral drusen participants, incident neovascular AMD was associated with white race (OR 6.77; 95% CI 1.24–36.9) and smoking >10 vs ≤10 pack-years (OR 1.55; 95% CI 1.15–2.09).
  • Incident central GA in bilateral drusen participants was associated with less education (OR 1.75; 95% CI 1.10–2.78), obesity (OR 1.93; 95% CI 1.25–2.65), smoking >10 vs ≤10 pack-years (OR 1.82; 95% CI 1.25–2.65), and antacid use (OR 0.29; 95% CI 0.09–0.91).
  • In unilateral advanced AMD participants, incident neovascular AMD was associated with diabetes (OR 1.88; 95% CI 1.07–3.31), and incident central GA was associated with antiinflammatory medication use (OR 0.22; 95% CI 0.08–0.59).

Methods

  • Clinic-based prospective cohort study within AREDS; analyses included 2506 participants with bilateral drusen (categories 2 and 3a) and 788 with unilateral advanced AMD (category 4a), with median follow-up of 6.3 years.
  • Outcomes were incident neovascular AMD and central GA, assessed from stereoscopic color fundus photographs at baseline and annual visits beginning at year 2, using standardized reading-center definitions.
  • Risk factors were evaluated in a two-stage process using repeated-measures logistic regression (GENMOD/GEE): stage 1 univariable analyses adjusted for age, gender, and AREDS treatment retained variables at P<0.15; stage 2 multivariable modeling with model simplification yielded ORs and 95% CIs.

Limitations

  • The paper states that many possible risk factors and multiple significance tests were studied, so some significant findings may be due to chance; it also notes possible bias, unadjusted confounding, insensitive measurements (e.g., sunlight exposure), and selective survival.
  • The paper reports weak power for some associations, e.g., among 181 bilateral drusen participants with diabetes, only 16 developed neovascular AMD and 6 developed central GA; relative risks would need to be >2.3 and >5.2, respectively, for 85% power.
  • The paper notes that adding baseline retinal risk factors minimally changed OR estimates for nonretinal factors but widened CIs and could reduce statistical significance; analyses also excluded category 1, 3b, and 4b participants, so findings apply to the selected AMD categories studied.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.ophtha.2004.10.047

Cites

60 of 60 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 69 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In AREDS participants with early or intermediate AMD at risk of advanced AMD in both eyes, obesity (BMI ≥30 vs nonobese) is statistically significantly associated with increased incidence of central geographic atrophy, controlling for age, gender, and AREDS treatment group (OR 1.93; 95% CI 1.25-2.65).

    “greater body mass index (BMI) (OR, obese vs. nonobese, 1.93; 95% CI, 1.25-2.65)”
    • Also stated in: § Central Geographic Atrophy · plain
      “being obese, smoking more than 10 pack-years, and not using antacids.”
    Quote in the paperSubstantial claim
  • Findingown data

    In AREDS participants with early or intermediate AMD at risk of developing advanced AMD in one eye, diabetes is statistically significantly associated with increased incidence of neovascular AMD (OR 1.88; 95% CI 1.07-3.31).

    “In persons at risk of developing advanced AMD in one eye, the incidence of neovascular AMD was associated with diabetes (OR, 1.88; 95% CI, 1.07-3.31)”
    • Also stated in: § Incident Neovascular Age-Related Macular Degeneration · plain
      “Similar staged analyses done for the participants with unilateral advanced AMD (online-only Table 2, available at http://www.ophsource.org/periodicals/ophtha;Table 3) found that presence of diabetes mellitus increased risk.”
    Quote in the paperSubstantial claim
  • Findingown data

    In AREDS participants with early or intermediate AMD at risk of advanced AMD in both eyes, smoking more than 10 pack-years is statistically significantly associated with increased incidence of neovascular AMD, controlling for age, gender, and AREDS treatment group (OR 1.55; 95% CI 1.15-2.09).

    “and larger amount smoked (OR, >10 vs. ≤10 pack-years [a packyear is an average of 1 pack of cigarette smoked per day for a year], 1.55; 95% CI, 1.15-2.09).”
    • Also stated in: § Incident Neovascular Age-Related Macular Degeneration · plain
      “white race and smoking more than 10 pack-years were independently associated with incident neovascular AMD.”
    Quote in the paperSubstantial claim
  • Findingown data

    In AREDS participants with early or intermediate AMD at risk of advanced AMD in both eyes, antacid use is statistically significantly associated with decreased incidence of central geographic atrophy, controlling for age, gender, and AREDS treatment group (OR 0.29; 95% CI 0.09-0.91).

    “and antacid use (OR, 0.29; 95% CI, 0.09-0.91).”
    • Also stated in: § Central Geographic Atrophy · plain
      “In stage 2 analyses of the bilateral drusen group (Table 3), the following variables were independently associated with incident central GA: fewer years of formal education, being obese, smoking more than 10 pack-years, and not using antacids.”
    Quote in the paperSubstantial claim
  • Findingown data

    In AREDS participants with early or intermediate AMD at risk of developing advanced AMD in one eye, use of antiinflammatory medications is statistically significantly associated with decreased incidence of central geographic atrophy (OR 0.22; 95% CI 0.08-0.59).

    “and the incidence of CGA was associated with use of antiinflammatory medications (OR, 0.22; 95% CI, 0.08-0.59).”
    • Also stated in: § Central Geographic Atrophy · plain
      “The risk was lower for persons using antiinflammatory drugs (OR, 0.22; 95% CI, 0.08-0.59).”
    Quote in the paperSubstantial claim
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 15
  • May combine two claims. 9

  • The quote only partly states this claim.

    Findingown data

    In AREDS participants with early or intermediate AMD at risk of advanced AMD in both eyes, white race is statistically significantly associated with increased incidence of neovascular AMD, controlling for age, gender, and AREDS treatment group (OR 6.77; 95% CI 1.24-36.9).

    “In stage 2 analyses (Table 3), in which all variables nominally significant in stage 1 analyses were entered in a similarly controlled multivariable regression, white race and smoking more than 10 pack-years were independently associated with incident neovascular AMD.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    There were 181 participants in the AREDS bilateral drusen group who also had diabetes.

    “For example, there were 181 participants in the AREDS bilateral drusen group who also had diabetes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    When baseline retinal risk factors are included in multivariable analyses, there is minimal impact on the magnitude of OR estimates for nonretinal factors, but confidence intervals may be widened and statistical significance may exceed traditional levels.

    “When these baseline retinal risk factors are included in our multivariable analyses, there is minimal impact on the magnitude of estimates of ORs for the nonretinal factors, but CIs may be widened and statistical significance may exceed levels traditionally considered significant (data not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Of these 181 participants, only 16 developed neovascular AMD and 6 developed central GA during the study.

    “Of these, only 16 developed neovascular AMD and 6 developed central GA during the course of the study.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Among persons with early or intermediate AMD, smoking and BMI are associated with progression to advanced AMD.

    “Results suggest that, among persons with early or intermediate AMD, smoking and BMI are modifiable factors associated with progression to advanced AMD”
    • Also stated in: § Discussion · plain
      “In the AREDS, individuals with more pack-years of smoking had an increased risk of incident neovascular AMD and central GA.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The AREDS participants with early or intermediate AMD are representative of persons with early or intermediate AMD generally.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    Most of the AREDS risk factors for incident AMD are similar to those found in other studies.

    “Most of the AREDS risk factors for incident AMD are similar to those found in other studies.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductcitation

    Outcomes and retinal risk categories were assessed photographically.

    “Strengths include the standardized protocols for obtaining data, standardized definitions for risk exposure, photographic assessment of the outcomes and retinal risk categories, the large size of the cohort (n = 3394) at risk for these conditions, and the relatively large number of outcomes (534 for neovascular AMD and 223 for central GA).4,9,18,20,24”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [4]

      Not checked in the free run.

    • cites [9]

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    • cites [18]

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    • cites [20]

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    • cites [24]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The study used standardized definitions for risk exposure.

    “Strengths include the standardized protocols for obtaining data, standardized definitions for risk exposure, photographic assessment of the outcomes and retinal risk categories, the large size of the cohort (n = 3394) at risk for these conditions, and the relatively large number of outcomes (534 for neovascular AMD and 223 for central GA).4,9,18,20,24”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [4]

      Not checked in the free run.

    • cites [9]

      Not checked in the free run.

    • cites [18]

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    • cites [20]

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    • cites [24]

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The analyses adjusted for age, gender, and AREDS treatment.

    “In stage 1, each risk factor was included separately in a univariable analysis adjusted for age, gender, and AREDS treatment.”
    • Also stated in: § Statistical Modeling and Analyses · plain
      “In stage 2, all variables retained from stage 1 from any of the regressions were entered as a group into a single multivariable repeated-measures logistic regression, and then model simplification consistent with chi-square tests of change in deviance was performed.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    Cigarette smoke may affect macular luteal pigment, increases oxidative stress, and impairs the choroidal microcirculation.

    “Cigarette smoke may affect macular luteal pigment, and it increases oxidative stress and impairs the choroidal microcirculation, all mechanisms hypothesized to be involved in the pathogenesis of AMD.[30][31][32][33]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30][31][32][33]

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Although the incidence of neovascular AMD in blacks is lower than in whites, it is not negligible.

    “Although the incidence of neovascular AMD in blacks is lower, it is not negligible.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The study used standardized protocols for obtaining data.

    “Strengths include the standardized protocols for obtaining data, standardized definitions for risk exposure, photographic assessment of the outcomes and retinal risk categories, the large size of the cohort (n = 3394) at risk for these conditions, and the relatively large number of outcomes (534 for neovascular AMD and 223 for central GA).4,9,18,20,24”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [4]

      Not checked in the free run.

    • cites [9]

      Not checked in the free run.

    • cites [18]

      Not checked in the free run.

    • cites [20]

      Not checked in the free run.

    • cites [24]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The AREDS treatment was randomly assigned in the clinical trial.

    “The AREDS treatment was randomly assigned in the clinical trial: daily oral supplements with antioxidants (vitamin C, 500 mg; vitamin E, 400 IU; and beta carotene, 15 mg) alone, zinc (zinc, 80 mg; copper, 2 mg) alone, antioxidants plus zinc, or a placebo.4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Significant risk factors for incidence of advanced AMD in this study (education, smoking, race, age, and BMI) were also significant in the earlier AREDS report on prevalence of AMD.

    “We note that significant risk factors for incidence of advanced AMD in this study (education, smoking, race, age, and BMI) were also significant in the earlier AREDS report on prevalence of AMD. 9”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9]

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    The study examined a large number of possible risk factors and conducted multiple tests of significance.

    “We have studied a large number of possible risk factors and conducted multiple tests of significance.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Still other studies have reported an association between lean body mass and increased risk of GA.

    “whereas still others have reported an association of lean body mass with increased risk of GA”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [2]

      Not checked in the free run.

    • cites [7]

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    • cites [10]

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    • cites [45]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cross-sectional data from the Finnish Oulu study suggested a relationship between greater body mass and AMD.

    “Cross-sectional data from the Finnish Oulu study suggested a relationship with greater body mass”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Failure to find associations may also be due to insensitivity of some risk factor measurements (e.g., sunlight exposure) or to selective survival.

    “Failure to find associations may also be due to the insensitivity of some of the risk factor measurements (e.g., sunlight exposure) or due to selective survival.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Reduced physical activity has been found to be related to progression of AMD and to a higher risk of neovascular AMD, but not incident GA.

    “which was also found to be related to progression of AMD and has been shown to be related to a higher risk of neovascular AMD, but not incident GA.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10]

      Not checked in the free run.

    • cites [12]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Some of the relations reported may be due to chance, bias, and unadjusted confounding.

    “Conversely, some of the relations we report may be due to chance, bias, and unadjusted confounding.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    That study also found an association between progression of AMD and waist-hip ratio and waist circumference as measures of abdominal adiposity.

    “That study also found an association between progression of AMD and waist-hip ratio and waist circumference as measures of abdominal adiposity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12]

      Not checked in the free run.

21 of 21

  • The paper relies on this without support.

    Smoking and BMI are modifiable factors.

    “Results suggest that, among persons with early or intermediate AMD, smoking and BMI are modifiable factors associated with progression to advanced AMD”

  • The paper relies on this without support.

    The AREDS participants with early or intermediate AMD are representative of persons with early or intermediate AMD generally.

    “Results suggest that, among persons with early or intermediate AMD, smoking and BMI are modifiable factors associated with progression to advanced AMD”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Antacid confidence interval differs between abstract and Table 3

    Minor

    For the antacid OR of 0.29, the abstract reports a lower confidence limit of 0.09, but Table 3 prints 0.9. The printed table interval also excludes its own point estimate.

  • Obesity confidence interval differs between abstract and Table 3

    Minor

    The abstract gives a 95% CI of 1.25-2.65 for the obesity OR of 1.93, whereas Table 3 gives 1.16-3.21 for that OR.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Age-Related Eye Disease Study Research Group. Risk factors associated with age-related macular degeneration: a case-control study in the Age-Related Eye Disease Study. Age-Related Eye Disease Study report number 3. Ophthalmology 2000;107:2224-32. [PubMed: 11097601]

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Related

Authors
⁎
Affiliations
Emmes (United States) (US)
Corresponding author
⁎
Venue
Ophthalmology
Publisher
Elsevier BV
Published
2005-04
Volume
112
Issue
4
Pages
533-539.e1
ISSN
0161-6420 (ISSN-L)
DOI
10.1016/j.ophtha.2004.10.047
PMC
PMC1513667
OpenAlex
W95909858
Semantic Scholar
987c96d1acf0037533dc33e358c0783ec4cf0756
Cited by
692
References
60
Citations by year
2026: 18 · 2025: 33 · 2024: 29 · 2023: 23 · 2022: 29 · 2021: 35 · 2020: 26 · 2019: 26 · 2018: 29 · 2017: 28 · 2016: 36 · 2015: 33 · 2014: 34 · 2013: 49 · 2012: 41
FWCI
33.51
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Ophthalmology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (1z01ey000394-01)
  • National Eye Institute (R01EY011309, Z01 EY000394-03)
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
neovascular age-related macular degeneration, advanced age-related macular degeneration, risk factors, smoking, race, educational attainment, body mass index, obesity, retinal pigment epithelium, choroidal neovascularization, retinal detachment, subretinal fibrosis, AREDS, incidence
MeSH terms
Aged, Aged, 80 and over, Antioxidants, Female, Follow-Up Studies, Humans, Macular Degeneration, Male, Middle Aged, Prospective Studies, Risk Factors, Smoking, Visual Acuity, Zinc, Body Mass Index, Incidence, Disease Progression, Dietary Supplements, Choroidal Neovascularization

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