Associations of Mortality With Ocular Disorders and an Interventionof High-Dose Antioxidants and Zinc in the Age-Related Eye Disease Study:  AREDS Report No. 13 FREE

Various ocular disorders (eg, visual impairment and cataract and thosein persons with diabetes mellitus, severe retinopathy, or visual impairment)have been reported^1- 17 tobe significant predictors of a decreased life span, often even after extensiveadjustment for potential confounders. Cataract surgery has been associatedwith decreased survival in many^1- 5 butnot all^6- 8 studies.A common finding is the association between nuclear opacities, in particular,and decreased survival.^6- 7,9- 11 Age-relatedmacular degeneration (AMD), on the other hand, has not been found to be relatedto decreased survival in the few studies^6,8- 9 thathave examined the relationship, although the ability to find an associationis limited because few participants in these studies had advanced disease(neovascular AMD or geographic atrophy).

Why ocular factors should be associated with decreased survival is unclear.Inadequate adjustment for factors such as age or underlying disease relatedto the ocular conditions and mortality could explain the findings. The lossof vision could have a direct effect on mortality if it results in a susceptibilityto accidents such as fatal falls or in depression, which has been reportedto increase mortality.^18- 19 Also,ocular disorders, in particular cataract, may be markers of systemic processesthat are associated with accelerated physiologic aging and earlier death.^9,20 For example, generalized oxidativedamage might play a role in the development of cataract and the aging process.

We undertook this study to determine whether visual impairment, typeof lens opacity, cataract surgery, and advanced AMD are associated with overallor cause-specific mortality in participants in the Age-Related Eye DiseaseStudy (AREDS), a long-term study of the clinical course of age-related cataractand AMD. Because AREDS included a randomized controlled trial of high-doseantioxidants and zinc used for a median of 6.5 years, we also examined therelationship between high-dose dietary supplements and mortality.

Details of the AREDS design have been published previously.²¹ AREDS is an ongoing, multicenter study of the clinicalcourse of cataract and AMD. The study included a randomized clinical trialthat evaluated the effect of high daily doses of selected oral supplements(vitamin C, 500 mg; vitamin E, 400 IU; beta carotene, 15 mg; and zinc, 80mg as zinc oxide with 2 mg of cupric oxide) on the incidence and progressionof the 2 conditions. A total of 4757 persons aged 55 to 81 years at enrollmentwere entered into the study at 11 clinical centers between November 13, 1992,and January 15, 1998.

The ocular eligibility requirements were largely determined by the AMDcomponent of AREDS. Stereoscopic color fundus photographs taken at baselinewere used to assess macular status for this study. Photographs were assessedusing the AREDS system for classifying AMD²² bytrained and certified readers at a reading center, who classified each participantinto 1 of 4 AMD categories: Category 1, few if any small drusen; Category2, extensive small drusen or nonextensive intermediate-sized drusen; Category3, extensive intermediate-sized drusen, at least 1 large druse, or noncentralgeographic atrophy; and Category 4, unilateral advanced AMD or unilateralvision loss to worse than 20/32 attributable to AMD.

Except for the requirement that all participants have at least 1 eyewith visual acuity of 20/32 or better and that the media be sufficiently clearfor reasonable-quality fundus photography, lens opacity status was not otherwiseconsidered in selecting participants. The large sample size requirements forthe AMD component of the study and the expected high prevalence of lens opacitiesin the targeted age group made it likely that a diverse array of age-relatedlens opacities would be present in the cohort.

The AREDS system for classifying cataracts²³ wasused to assess the presence and severity of nuclear, cortical, and posteriorsubcapsular (PSC) lens opacities at baseline. Lens photographs were evaluatedat a reading center by trained and certified examiners masked to the participants'vision status. Nuclear opacities were graded on a decimal scale using cutoffpoints set by a series of standard slitlamp photographs with increasinglysevere nuclear sclerosis. Nuclear opacity grades ranged from 0.9 (severityless than the lowest lens standard photograph) to 6.1 (severity exceedingthe highest lens standard photograph). Each participant was classified into1 of 2 nuclear opacity groups, irrespective of the presence of cortical orPSC opacities: less than grade 4 in both eyes or in the phakic eye if thereis a history of unilateral cataract surgery vs grade 4 or higher in at least1 eye.

The extent of cortical and PSC opacities was graded by estimating thearea of lens involvement as seen on retroillumination photographs. Each participantwas classified into 1 of 2 cortical opacity groups, irrespective of the presenceof nuclear or PSC opacities: 5% or less of the central 5-mm area in both eyesor in the phakic eye if there is a history of unilateral cataract surgeryvs greater than 5% of the central 5-mm area in at least 1 eye.

Similarly, each participant was classified into 1 of 2 PSC opacity groups,irrespective of the presence of nuclear or cortical opacities: 5% or lessof the central 5-mm area in both eyes or in the phakic eye if there is a historyof unilateral cataract surgery vs greater than 5% of the central 5-mm areain at least 1 eye.

Participants were also classified (yes or no) according to whether theyhad a history of cataract surgery.

Baseline best-corrected visual acuity was measured in each eye accordingto the ETDRS protocol as the number of letters read correctly, with scoresranging from 0 (<20/800) to 100 (20/10). Each participant was classifiedinto 1 of 2 visual acuity groups: 20/40 or better in both eyes (equivalentto >69 letters) vs worse than 20/40 in 1 eye.

At enrollment, AREDS participants had to be free of any illness or conditionthat would, in the opinion of the enrolling physician, make long-term follow-upor compliance with use of the study interventions unlikely or difficult. Personswith a history of cancer with a poor prognosis for 7-year survival or a majorcardiovascular or cerebrovascular event within the year before enrollmentwere ineligible for AREDS. Also excluded were persons with more than minimaldiabetic retinopathy, previous ocular surgery (except cataract surgery andunilateral photocoagulation for AMD), and the presence of any other eye diseasethat could complicate assessment of the progression of lens opacities or AMDor that could affect visual acuity (eg, optic atrophy and acute uveitis).

Simple randomization, stratified by AREDS clinical center and AMD category,was used to enroll participants in the 2 × 2 factorial design of antioxidantsand zinc. Participants in AMD categories 2 through 4 were assigned with aprobability of 0.25 to receive placebo, antioxidants, zinc, or antioxidantsand zinc. Participants in AMD Category 1 were assigned with a probabilityof 0.50 to receive placebo or antioxidants. The potential risks of high-dosezinc supplements²⁴ if given to Category 1 participantswere unlikely to be balanced by any possible benefits. This group was at lowrisk of developing vision loss due to AMD during the planned 5- to 8-yearfollow-up phase of the clinical trial, and there is no published evidencethat taking zinc might reduce the risk of lens opacities.

Data on age, sex, race (white, other), education level (high schoolor less, more than high school), and smoking status (never, former, current)were available from an interviewer-administered baseline questionnaire. Dataon diabetes mellitus, arthritis, angina, and cancer were based on solicitedself-report. As part of the clinical trial component of AREDS, participantswere given the option of taking a daily multivitamin supplement containingthe recommended daily allowance of nutrients (Centrum; Wyeth Consumer HealthCare International Inc, Madison, NJ). At the baseline examination, trainedobservers measured each participant's height and weight, which were used tocalculate body mass index. Hypertension was defined as systolic blood pressuregreater than 160 mm Hg or diastolic blood pressure greater than 90 mm Hg orcurrent use of antihypertensive medications. Data on the use of cholesterol-loweringmedications, aspirin, or anti-inflammatory medications were also collected.

The primary outcome variable for this study is all-cause mortality.When mortality was reported, death was confirmed and the cause of death wasabstracted from hospital records and from death certificates. Cause-specificmortality was based on International Classification of Diseases,Ninth Revision (ICD-9) codes, and analyses were performed for the major,broadly grouped causes of death. Codes were assigned by a certified ICD-9 diagnostic coder and reviewed by a physician medicalmonitor. A Morbidity and Mortality Committee consisting of 2 physicians anda diagnostic coder reviewed the assigned codes, and discrepancies were resolvedby the medical monitor. Hospital discharge summaries were provided when availableto assist in the review. The underlying cause of death was usually selectedas the primary cause. In the absence of an underlying cause, immediate causewas selected as the primary cause. Cause of death was unknown for 37 deathswithout a death certificate or an informative hospitalization history.

Age- and sex-adjusted Cox proportional hazards models predicting mortalitywere created with AMD category, visual acuity status, nuclear opacity status,cortical opacity status, PSC opacity status, history of cataract surgery,and assigned AREDS treatment at baseline as independent variables. We alsoconstructed age- and sex-adjusted models predicting mortality with the followinghealth status indicators: race, education, smoking status, and body mass index;use of Centrum, aspirin/anti-inflammatory drugs, or cholesterol-lowering medications;and the presence of angina, cancer, diabetes mellitus, hypertension, and arthritis.If a health status indicator adjusted for age and sex was not related to mortality,it was not considered further (P>.05). Significanthealth status indicators (P<.05) were added tomodels that examined the effect of each of the ocular characteristics on mortality.In addition, models that included statistically significant covariates andAMD and opacity characteristics simultaneously were assessed. Last, AMD andmortality analyses were conducted on the subset of AREDS participants whodid not receive any zinc to evaluate whether the association between AMD andmortality is independent of an association between zinc supplements and mortality.Statistical significance was determined using P =.05, without adjustment for multiple comparisons. All analyses were carriedout using SAS version 8.0 (SAS Institute Inc, Cary, NC).

At baseline, the median age of the 4757 AREDS participants was 69 years.Between November 13, 1992, and October 12, 2001, 534 (11%) of the 4753 participantswith follow-up data for mortality died. Mortality rates, after adjustmentfor age and sex, for the median follow-up (6.5 years), are given in Table 1. Adjusted rates are higher forolder persons, men, "other" races, those with less formal education, currentand former smokers, participants with diabetes mellitus, participants witha lean body mass index, and those diagnosed as having comorbid conditions,such as cancer, hypertension, and angina.

All-cause mortality rates increased with increasing severity of maculardisease (Table 2).After adjustment for age and sex, participants with advanced AMD in 1 eye(AMD Category 4) compared with participants with few, if any, drusen (AMDCategory 1) had a significantly increased risk of mortality, and this associationremained statistically significant after adjustment for demographic, lifestyle,and comorbid conditions (relative risk [RR], 1.41; 95% confidenceinterval [CI], 1.08-1.86).

In analyses adjusted for age, sex, and statistically significant covariates, the presence of nuclear opacity in at least 1 eye was associated witha statistically significant increased risk in all-cause mortality (RR, 1.40;95% CI, 1.12-1.75). A possible increased risk was also found for cortical(RR, 1.18; 95% CI, 0.92-1.51) and PSC (RR, 1.33; 95% CI, 0.82-2.18) opacities,but these increases were not statistically significant.Cataract surgery was statistically significantly associated withan increased risk of all-cause mortality (RR, 1.55; 95% CI, 1.18-2.05).

Among AREDS participants eligible to be randomly assigned to receivezinc (AMD Categories 2, 3, and 4), age- and sex-adjustedall-cause mortality, as given in Table 2, was statistically significantly reduced in the main effects analysesfor participants randomly assigned to receive any zinc (zinc alone group andantioxidants plus zinc group) compared with participants not randomly assignedto receive zinc (placebo group and antioxidants alone group) (RR, 0.76; 95%CI, 0.63-0.92). The relationship persisted after adjustment for statisticallysignificant covariates (RR, 0.73; 95% CI, 0.61-0.89). No statistical associationwas found with randomization to receive high-dose antioxidants and mortalitywhether assessing the antioxidants main effect or the antioxidants alone effect. Covariate-adjusted survival curves for AREDS treatment and statisticallysignificant ocular characteristics are shown in Figure 1. The comparison of individuals randomly assigned to receivezinc alone vs those assigned to receive placebo is statistically significantonly after adjustment for all covariates (RR, 0.72; 95% CI, 0.55-0.95).

The AREDS clinical trial results reported²⁵ thatindividuals randomly assigned to receive antioxidants and zinc reduced theirrisk of progression to AMD and loss of visual acuity. To examine whether theassociation between AMD and mortality was independent of the association foundfor zinc and mortality, an analysis was conducted assessing AMD and mortalityin the subgroup of AREDS participants in AMD Categories 2 through 4 not randomlyassigned to receive any zinc-containing supplement along with participantsin AMD Category 1. In this subgroup of participants, advanced AMD remaineda statistically significant risk factor for mortality in a covariate-adjustedmodel (RR, 1.53; 95% CI, 1.13-2.07).

Compared with participants having better than 20/40 visual acuity inboth eyes, those with visual acuity worse than 20/40 in 1 eye had a statisticallysignificantly increased risk of all-cause mortality (RR, 1.36; 95% CI, 1.12-1.65).Ninety-one percent of participants who had reduced vision at baseline (visualacuity <20/40 in 1 eye) were in AMD Category 4. Thus, the association betweenvisual impairment and mortality cannot be distinguished from the associationbetween AMD and mortality.

When AMD category and "any" lens opacity (defined as nuclear, cortical,or PSC opacity or cataract surgery) are included in a covariate-adjusted model(model 1), AMD Category 4 and "any" opacity are statistically significantlyassociated with all-cause mortality (Table3). Two additional models were developed to determine whether advancedAMD along with specific lens opacities are particularly associated with mortality.In model 2, nuclear opacity replaces any lens opacity from model 1 and, alongwith AMD Category 4, remains statistically significant. Finally, in model3, cataract surgery replaces any lens opacity from model 1 and, along withAMD Category 4, remains statistically significantly associated with mortalityin a multivariate model.

The ICD-9 codes for cause of death were availablefor 497 of the deaths (93%). Most of these deaths were from diseases of thecirculatory system (40%) and neoplasms (34%). We grouped all other causesof death, except "unknown" (n = 37), into an "other" category (27%). The specificcauses of death for each of these broad categories are given in Table 4.

In covariate-adjusted analyses of cause-specific mortality, AMD Category4 was statistically significantly associated with cardiovascular deaths (RR,1.92; 95% CI, 1.18-3.12) (Table 5).Nuclear opacity (RR, 1.56; 95% CI, 1.05-2.31) and cataract surgery (RR, 2.29;95% CI, 1.45-3.60) were statistically significantly associated with cancerdeaths. Nuclear opacity was also statistically significantly associated with"other" deaths (RR, 1.64; 95% CI, 1.07-2.51).

Given the suggestion of a mortality benefit for participants supplementingwith zinc, analysis of cause-specific mortality in AMD Category 2 through4 participants was performed. Zinc supplementation did not show a protectiveassociation with circulatory or neoplasm causes of death. A protective effectwas found for "other" causes (RR, 0.64; 95% CI, 0.43-0.96). Further analysisof this group found a nonsignificant protective effect for respiratory causes,the largest subgroup of the other causes (RR, 0.78; 95% CI, 0.41-1.47). Nocause-specific associations of antioxidants with mortality were found.

All-cause mortality was 11% during a median of 6.5years of follow-up and was increased in AREDS participants in AMD Category4 and in those with nuclear lens opacities or a history of cataract surgerywhen potentially confounding covariates were taken into account. No statisticallysignificant associations with all-cause mortality were noted for persons withless severe age-related macular changes (AMD Categories 2 and 3), corticallens opacities, or PSC lens opacities.

In an analysis of cause-specific mortality, AMD Category 4 was associatedwith an increased risk of death caused by diseases of the circulatory system.Persons with nuclear opacities or a history of cataract surgery had increasedmortality from neoplasms and "other" causes compared with persons withoutthese lens-related characteristics.

A statistically significant predictor of mortality in AREDS was AMDCategory 4. Three population-based studies^6,8- 9 havereported no association between mortality and AMD, but each had few participantswith advanced AMD. With eligibility criteria that permitted visual impairmentonly in 1 eye (all AREDS participants had at least 1 eye with 20/32 or bettervisual acuity at baseline), we noted an association between impaired visionand increased mortality. However, the AREDS mortality findings for visualacuity and AMD were not independent. Ninety-one percent of participants inAREDS who had visual acuity less than 20/40 at baseline in 1 eye were in AMDCategory 4. This explains the similarity of findings for AMD and visual impairmentand mortality.

Large population-based studies have reported associations between impairedvision and increased mortality. In 2 of these studies,^6,9 visionimpairment was defined as corrected acuity of 20/40 or worse in the bettereye. In age- and sex-adjusted analyses, the Beaver Dam Eye Study⁹ noteda statistically significant 57% increase in mortality for persons with impairedvision, but the finding was not significant after adjustment for various systemiccharacteristics. The 70% increased mortality risk for persons with visualimpairment in the Blue Mountains Eye Study⁶ wasstatistically significant, even after adjustment for potentially importantcovariates. Data from that study suggested that the visual impairment findingwas independent of the presence of cataract. The Melbourne Visual ImpairmentProject⁸ noted a significant increase in mortalityamong persons with mild visual impairment, defined as best-corrected acuityless than 6/12. Data from the National Health Interview Survey,¹⁷ whichuses self-reports of visual impairment and ocular disease, suggest that afteradjustment for various covariates, including the presence of cataract, glaucoma,and retinopathy (but not AMD), women who reported bilateral severe visualimpairment (bilateral "blindness") and lesser degrees of visual impairment,compared with women who reported no impairment, had significantly higher all-causeand cardiovascular disease–related mortality. Since data on AMD werenot collected in the National Health Interview Survey, it was not possibleto examine whether the presence of AMD was related to the visual impairmentfindings.

We found that nuclear opacities and a history of cataract surgery wereassociated with decreased survival. Unlike the case for AMD, the cataractvariables were less closely linked with visual impairment (visual acuity <20/40in the worse eye) in the AREDS population. Only 20% of the visually impairedindividuals had nuclear opacities, and 24% of those with nuclear opacitieshad visual impairment

Our findings for nuclear cataract are largely consistent with thosefrom earlier studies. Five population-based studies^6- 7,9- 11 havereported that nuclear opacities are important predictors of mortality independentof covariate adjustment. The fact that the association between nuclear cataractand mortality has been noted across studies of different racial groups indifferent geographical areas and using different cataract classification systemsstrengthens the validity of the observation that cataracts, in particularnuclear cataracts, are associated with decreased survival. Our finding thatsurvival might be decreased for persons with a history of cataract surgery,however, is not consistently supported by earlier studies. Higher mortalityhas been reported^1- 5 forpersons undergoing cataract surgery compared with those in the general populationor those undergoing other elective surgical procedures. On the other hand,several population-based studies^6- 8 thatreported relationships between cataract and decreased survival found no relationshipbetween mortality and history of cataract surgery at baseline. The many selectivefactors, including the presence of comorbid conditions, that determine whethera person undergoes an elective procedure such as cataract surgery make itdifficult to interpret cataract surgery and mortality data.

As in several other studies^7,10,26 thathave examined cause-specific mortality, we found that persons with nuclearopacities were at higher risk of death from neoplasms. In the Salisbury EyeEvaluation Project,⁷ mixed cataracts that includeda nuclear component were associated with a more than 2-fold increase in riskof death from cancer. Similarly, the Barbados Eye Studies¹⁰ reportedthat compared with persons without cataract, persons with mixed and "any"nuclear opacities tended to have a higher risk of death from neoplasms. Ina follow-up study of persons who had participated in the Italian-AmericanCase-Control Study of Age-related Cataract,²⁶ personswith mixed cataract had a significantly increased RR of mortality from malignancies.None of these published studies, including ours, found a statistically significantassociation between lens opacities and death caused by circulatory diseases,although such an association has been suggested in a study⁵ ofpersons with cataract extraction.

It is not clear how ocular disorders might be related to decreased survival.One possibility is that adjustment for important comorbid conditions may havebeen incomplete. A hypothesis suggested by this study, and supported at leastin part by other studies, is that nuclear cataract and AMD might each be associatedwith a major cause of death, that is, cancer and diseases of the circulatorysystem, respectively. This study and others^7,10,26 suggesta link between nuclear cataract and cancer mortality. Even when history ofcancer at the baseline examination was included as a covariate in the fullmodel, nuclear cataract was significantly associated with increased mortality.However, adjustment for cancer was probably incomplete because limited lifeexpectancy from diseases such as cancer was an exclusion criterion for thestudy, and, therefore, most life-threatening cancers probably became manifestsubsequent to the baseline examination. It is possible that similarities inthe developmental processes of the 2 conditions or the development of cataractas a by-product of cancer therapy (an explanation suggested by West et al⁷) could explain the link. The association we notedbetween AMD and all-cause mortality and death from circulatory diseases maybe explained by an underlying vascular basis for AMD, a hypothesis suggestedby some epidemiologic studies.^27- 30 Evenwith adjustment for some risk factors possibly associated with cardiovasculardeath and AMD (ie, age, smoking, and hypertension), the relationship persisted,but, as for cataract, adjustment may have been incomplete.

Other investigators^6- 7 haveraised the possibility of a more direct effect of vision disorders on mortality,perhaps from the depression and dependency that can accompany vision loss.Depression has been associated with earlier death.^18- 19 TheAREDS eligibility requirement that participants have at least 1 eye with 20/32or better vision may have decreased the possibility of ocular-related depression.Also, an increased risk of falls and automobile accidents in the visuallyimpaired might result in excess mortality. There were few deaths from accidentsin our cohort, and our cause-specific analyses showed no evidence that theexcess mortality we noted for persons with the ocular conditions was due todeath from accidents.

Persons randomly assigned to receive zinc either alone or in combinationwith antioxidants compared with persons not randomly assigned to receive zinc(placebo or antioxidants alone) had significantly improved survival from allcauses. The positive association of zinc with decreased all-cause mortalitydid not seem to be due to reduction in deaths involving cardiovascular/circulatorydisease or cancer (Table 5). Otherresearchers³¹ have reported a beneficial effectof moderate doses of zinc and selenium in improving immunity and resistanceto infections in an elderly institutionalized population. It is possible thatthe beneficial effects of zinc on mortality in this study may be related toan improved immune response, which is known to decrease with aging. A separatecause-specific analysis found that the zinc effect was in the protective directionfor respiratory-specific mortality compared with no zinc, but this findingwas not statistically significant (RR, 0.78; 95% CI, 0.41-1.47). We know thatin the AREDS population, an intake of 80 mg of zinc oxide and 2 mg of cupricoxide, with or without antioxidant vitamins, for 5 years resulted in a medianincrease in serum zinc levels of 17% compared with 2% for participants notassigned to receive zinc. Whether zinc supplementation has an effect on mortalitycannot be determined from this study alone. Additional studies are necessarybefore any conclusions can be made regarding the health benefits of zinc supplementation.

Strengths of this study include the large number of participants withthe ocular disorders of interest (in particular advanced AMD), the use ofstandardized techniques for diagnosing the eye conditions, the relativelylong follow-up, the near complete collection of mortality data, the abilityto perform cause-specific analyses because of the large number of deaths,and the availability of data on potentially important covariates. A concernin interpreting the findings, as in all clinic-based studies, was the potentialfor bias, in particular selection bias. The control group for AMD (Category1) and persons with intermediate-sized drusen or extensive small drusen (Category2) were substantially more likely to have been volunteers from nonmedicalsources. It has been shown that volunteers for prevention studies have moreformal education, are more health conscious, and are more often employed inprofessional and skilled positions. Indeed, persons with no drusen to intermediate-sizeddrusen at enrollment had greater educational achievement and smoked less thanpersons in AMD Categories 3 and 4. There is less concern that selection biasmight explain the cataract findings because the cataract cases were more evenlydistributed across the AMD categories, making the distribution of volunteersmore comparable among those with and without cataract. Inclusion of AMD categoryin the cataract analyses should also have compensated for residual imbalancesin the distribution of volunteers among those with and without cataract.

This is the first large randomized trial to report a potential benefitof the use of high doses of zinc on survival. Other randomized studies ofzinc supplementation and mortality are needed to confirm these findings. Theocular results of this study are consistent with those of other studies showinga potential link between various ocular disorders and survival. Cumulativeevidence from clinic- and population-based studies suggests that cataractand AMD may reflect systemic rather than only local processes.

The Eye Center at Memorial (Albany, NY)

Principal Investigator: Aaron Kassoff, MD; Co-Investigator: Jordan Kassoff, MD; Clinic Coordinators: JoAnne Buehler; Mary Eglow, RN; Susan Silverman; Photographer: Michel Mehu (Past ParticipatingPersonnel: Co-Investigator: Shalom Kieval, MD; ClinicCoordinator: Francine Kaufman; Examiner: MichaelMairs, MD; Photographers: Barbara Graig, RN; AndreaQuattrocchi; Technicians: Denise Jones; Joan Locatelli,RN)

Associated Retinal Consultants, PC (Royal Oak,Mich)

Principal Investigator: Alan Ruby, MD; Co-Investigators: Antonio Capone, Jr, MD; Bruce Garretson,MD; Tarek Hassan, MD; Michael T. Trese, MD; George A. Williams, MD; Clinic Coordinators: Virginia Regan, RN; Patricia Manatrey,RN; Photographers: Patricia Streasick; Lynette Szydlowski;Fran McIver; Craig Bridges; Technicians: Cheryl Stanley;Kristi Cumming, RN; Beth Mitchell, RN; Joanne Holloway, RN; Bobbie Lewis,RN; Mary Zajechowski (Past Participating Personnel: PrincipalInvestigator: Raymond R. Margherio, MD [deceased]; Co-Investigators: Morton S. Cox, MD; Jane Camille Werner, MD; Photographers: Rachel Falk; Patricia Siedlak; Technician: Cheryl Neubert, RN)

Devers Eye Institute (Portland, Ore)

Principal Investigator: Michael L. Klein, MD; Co-Investigators: J. Timothy Stout, MD, PhD; Andreas K.Lauer, MD; Clinic Coordinator: Carolyn Beardsley; Photographers: Hiroko Anderson; Patrick Wallace; Technicians: Garland Smith; Shannon Howard (Past Participating Personnel: Principal Investigator: Richard F. Dreyer,MD; Co-Investigators: Colin Ma, MD; Richard G. Chenoweth,MD; John D. Zilis, MD; Adrian O'Malley, MD; Joseph E. Robertson, MD; DavidJ. Wilson, MD; Photographers: Milton Johnson; PatrickRice; Howard Daniel; Technicians: Harold Crider;Sheryl Parker; Kathryn Sherman)

Emory University (Atlanta, Ga)

Principal Investigator: Daniel F. Martin, MD; Co-Investigators: Thomas M. Aaberg Sr, MD; G. Baker Hubbard,MD; Enrique Garcia, MD; Clinic Coordinator: LindaT. Curtis; Photographers: Alex DeLeon; Bob Myles; Research Associate: Hannah Yi (Past ParticipatingPersonnel: Principal Investigators: Antonio Capone Jr, MD; MichaelLambert, MD; Travis Meredith, MD; Co-Investigators: ThomasM. Aaberg Jr, MD; Paul Sternberg, Jr, MD; David Saperstein, MD; Jennifer I.Lim, MD; Clinic Coordinators: Barbara Stribling;Bora Ju; Photographers: Denise Armiger; Jim Gilman;Debbie Jordan; Sandra Strittman; Ray Swords

Ingalls Memorial Hospital (Harvey, Ill)

Principal Investigator: David H. Orth, MD; Co-Investigators: Timothy P. Flood, MD; Joseph Civantos,MD; Serge deBustros, MD; Kirk H. Packo, MD; Pauline T. Merrill, MD; Jack A.Cohen, MD; David Chow, MD; Clinic Coordinators: CelesteFigliulo; Chris Morrison; Photographers: DouglasA. Bryant; Don Doherty; Marian McVicker (Past ParticipatingPersonnel: Technician: Tana Drefcinski)

Massachusetts Eye and Ear Infirmary (Boston,Mass)

Principal Investigator: Johanna M. Seddon,MD, ScM; Co-Investigator: Michael K. Pinnolis, MD; Clinic Coordinators: Mala Sachdeva; Tatyana Taytsel; IleneBurton; Photographers: David Walsh; Charlene Callahan; Technicians: Claudia Evans, OD (PastParticipating Personnel: Clinic Coordinators: Kristin K. Snow, MS;Desiree A. Jones-Devonish; Valerie D. Crouse, MS; N. Jennifer Rosenberg, RN,MPH; Nancy Davis; Photographer: Jennifer Dubois-Moran)

National Eye Institute Clinical Center (Bethesda,Md)

Principal Investigator: Emily Y. Chew, MD; Co-Investigators: Karl Csaky, MD, PhD; Frederick L. FerrisIII, MD; Clinic Coordinators: Katherine Hall Shimel,RN; Merria A. Woods; Photographers: Denise Cunningham;Ernest M. Kuehl; Marilois Palmer; Technicians: GloriaBabilonia-Ayukawa, RN, MHCA; Guy E. Foster; Young Ja Kim, RN; Iris J. Kivitz;Dessie Koutsandreas; Antoinette LaReau; Richard F. Mercer; Roula Nashwinter;John Rowan; Greg Short (Past Participating Personnel: ClinicCoordinator: Sally A. McCarthy, RN, MSN; Photographer: Patrick F. Ciatto; Technicians: Leanne M.Ayres; Linda Goodman; Patrick Lopez; Cheryl Perry; Anne Randalls)

University of Pittsburgh (Pittsburgh, Pa)

Principal Investigator: Thomas R. Friberg,MD, MS; Co-Investigators: Andrew W. Eller, MD; MichaelB. Gorin, MD, PhD; Clinic Coordinator: Barbara Mack; Photographers: Diane Y. Curtin; Phyllis P. Ostroska; EdwardFijewski (Past Participating Personnel: Clinic Coordinators: Jane Alexander; Shannon Nixon; Technicians:Melissa K. Paine; Patricia S. Corbin; Photographer: JosephWarnicki)

Wilmer Eye Institute, Johns Hopkins University Schoolof Medicine (Baltimore, Md)

Principal Investigator: Susan B. Bressler,MD; Co-Investigators: Neil M. Bressler, MD; GaryCassel, MD; Daniel Finkelstein, MD; Morton Goldberg, MD; Julia A. Haller,MD; Lois Ratner, MD; Andrew P. Schachat, MD; Steven H. Sherman, MD; JanetS. Sunness, MD; Clinic Coordinators: Sherrie Schenning;Catherine Sackett, RN; Photographers: Dennis Cain;David Emmert; Mark Herring; Jacquelyn McDonald; Rachel Falk; Technician: Stacy Wheeler (Past Participating Personnel:Clinic Coordinator: Mary Mcmillan; Photographer: Terry George)

Elman Retina Group, PA (Baltimore, Md)

Principal Investigator: Michael J. Elman, MD; Co-Investigators: Rex Ballinger, OD; Arturo Betancourt,MD; Michael Herr, MD; Joyce Lammlein, MD; Robert Z. Raden, MD; Ronald Seff,MD; Martin Shuman, MD; Clinic Coordinators: JoAnnStarr; Dena Firestone; Michelle Sloan; Photographers: PeterSotirakos; Theresa Cain; Technician: Terri Mathews (Past Participating Personnel: Co-Investigators: DavidGlasser, MD; Dahlia Hirsch, MD; Daniel Killingsworth, MD; Paul Kohlhepp, MD; Clinic Coordinators: Christine Ringrose; Anita Carrigan)

University of Wisconsin (Madison, Wis)

Co-Principal Investigators: Suresh R. Chandra,MD; Justin L. Gottlieb, MD; Co-Investigators: MichaelS. Ip, MD; Ronald Klein, MD, MPH; T. Michael Nork, MD, MS; Thomas S. Stevens,MD; Barbara A. Blodi, MD; Michael Altaweel, MD; Barbara E. K. Klein, MD; MatthewD. Davis, MD; Clinic Coordinators: Michelle Olson;Alyson Skoldberg; Erika Christianson; Barbara Soderling; Jennie R. Perry-Raymond;Kathryn Burke; Photographers: Gene Knutson; JohnPeterson; Denise Krolnik; Technicians: Robert Harrison;Guy Somers, RN (Past Participating Personnel: PrincipalInvestigator: Frank L. Myers, MD; Co-Investigators: Ingolf Wallow, MD; Timothy W. Olsen, MD; George Bresnik, MD; G. DeVenecia, MD; Clinic Coordinators: Tracy Perkins,MPH; Wendy Walker; Jennifer L. Miller; Margo Blatz; Photographers: Michael Neider; Hugh D. Wabers; Greg Weber; Technicians: Beth Amspaugh; Jennifer Buechner; Helen E. Lyngaas Myers)

University of Wisconsin-Reading Center (Madison,Wis)

Co-Principal Investigators: Matthew D. Davis,MD; Barbara E. K. Klein, MD, MPH; Ronald Klein, MD, MPH; Co-Investigators: Barbara Blodi, MD; Ronald Danis, MD; Larry Hubbard; Photography Protocol Monitors: Michael Neider; Pamela Vargo;Hugh D. Wabers; Senior Grader: Jane Armstrong; Graders: Wendy Benz; Kristi L. Dohm; Christina Fink; TrinaHarding; Cynthia Hurtenbach; Kristine Lang; Susan Reed; Statisticians: Marian R. Fisher, PhD; Ronald Gangnon, PhD; Li-Yin Lee; Head of Computing and Statistician: Alistair Carr; Computing Staff: James Baliker; DataManager: Linda Kastorff; Associate Director, Operations: Nancy Robinson; Research Project Manager: KathleenE. Glander; Grants/Contracts Administrator: JeanSurfus (Past Participating Personnel: Senior Graders: SarahAnsay; Yvonne L. Magli; Graders: Darlene Badal; ShirleyCraanen; Julee Elledge; Barbara Esser; Patricia L. Geithman; Kathleen D. Miner;James Reimers; Mary Webster; Statisticians: ChunyangGai; William King; Computing Staff: Kurt Osterby; Administration Program Specialist: James Onofrey; Coordination Staff: Judith Brickbauer)

Centers for Disease Control and Prevention–CentralLaboratory (Atlanta, Ga)

Rosemary L. Schleicher, PhD; Dayton T. Miller, PhD; Anne L. Sowell,PhD; Elaine W. Gunter, MT (Past Participating Personnel: Barbara A. Bowman, PhD)

Coordinating Center–The EMMES Corporation (Rockville,Md)

Principal Investigators: Anne S. Lindblad,PhD; Roy C. Milton, PhD; Traci E. Clemons, PhD; Co-Investigators: Gary Gensler, MS; Molly Rankin, MS; Genetics Monitor: Alice Henning, MS; Ophthalmic Training & Certification: Gary Entler; Project Manager: Wendy McBee,MA; Database Administrators: Valerie Watson; CandiceDavis; Elaine Stine; Computer Analysts: Stuart H.Berlin; Kumar Thotapally; Administration: MichelleJackson (Past Participating Personnel: Administration: KateTomlin; Sophia Pallas; Phyllis R. Scholl; Susan A. Mengers; Co-Investigators: Fred Ederer, MA, FACE; Ravinder Anand, PhD; Protocol Monitor: Kiana Roberts)

National Eye Institute Project Office (Bethesda,Md)

Study Chairman and Principal Investigator: FrederickL. Ferris III, MD; Co-Investigators: Robert D. Sperduto,MD; Natalie Kurinij, PhD; Emily Y. Chew, MD; John Paul SanGiovanni, ScD

Corresponding author and reprints: AREDS Coordinating Center, TheEMMES Corp, 401 N Washington St, Suite 700, Rockville, MD 20850-1707 (e-mail: aredspub@emmes.com).

Submitted for publication April 7, 2003; final revision received September25, 2003; accepted October 14, 2003.

The Writing Team is from The EMMES Corp, Rockville, Md (Dr Clemons);the National Eye Institute, Bethesda, Md (Drs Kurinij and Sperduto); and theJohns Hopkins Medical Institutions, Baltimore (Dr Bressler).

This study was supported by contracts from the National Eye Institute,National Institutes of Health, Department of Health and Human Services, withadditional support from Bausch & Lomb Inc, Rochester, NY.