Prevalence of Age-related Maculopathy in the Atherosclerosis Risk in Communities Study FREE

AGE-RELATED MACULAR degeneration is an important cause of loss of vision as people age.^{1 - 4} Limited data are available regarding the prevalence of this condition in different racial and ethnic groups.^{5 - 10} Clinical observations suggest that choroidal neovascularization is less frequent in blacks than whites.^{5 - 7} In the Baltimore Eye Survey, late stages of age-related maculopathy (ARM) accounted for 30% of bilateral blindness in whites and 0% in blacks.¹¹

Early signs of ARM may also be less frequent in blacks than whites.^{9 - 10} Data from the National Health and Nutrition Examination Survey III showed that, after 60 years of age, non-Hispanic blacks had a 50% lower odds of having signs of ARM than non-Hispanic whites.⁹ In a predominantly black population in Barbados, whereas signs of early ARM, particularly drusen, occurred commonly in blacks, signs of early ARM were less frequent than in whites in other populations.¹⁰ Findings from histopathologic studies have also suggested that the frequency of some lesions may be different in blacks and whites.¹² It has been postulated that melanin, perhaps acting as a free-radical scavenger, may protect the pigment epithelium, Bruch's membrane, choroid, or the outer retina from degenerative changes predisposing the patient to choroidal neovascularization.¹³ The purposes of this report are to describe the prevalence of ARM in blacks and whites participating in the Atherosclerosis Risk in Communities (ARIC) study and to examine the association of ARM with cardiovascular disease and its risk factors.

In 1987 to 1989, a probability sample of 26,427 potentially eligible women and men were selected from 45- to 64-year-old residents of 4 US communities: Forsyth County, North Carolina; the city of Jackson, Miss; suburbs of Minneapolis, Minn; and Washington County, Maryland.¹⁴ Black residents only were selected in Jackson, whereas residents were selected without regard to ethnicity in the other communities. Initial participation rates (with the total sample as a denominator) were 46% in Jackson and approximately 65% in the other communities. Of those examined at baseline, 14,346 (93% of the survivors) returned for a second examination 3 years later and 12,887 (82% of the survivors) returned for a third examination 6 years later (1993-1995). Differences between participants and nonparticipants have been presented elsewhere.¹⁵

To add an assessment of microvascular disease to the assessment of macrovascular disease, retinal photographs were taken of 1 eye of each participant at the third examination when the participants were 48 to 72 years of age.^{16 - 17} The eye to be photographed was selected on the basis of the subject's 6-digit identification number. When the number was even, the right eye was photographed, and when it was odd, the left eye was photographed. If the eye specified by this algorithm was considered too difficult or not possible to photograph (eg, eye missing, inability to dilate to at least 4 mm, inability to fixate adequately for proper photographic field definition, and opacities of the media preventing a reasonably clear view of the retina) with adequate photographic quality, the fellow eye was photographed instead. Of the 12,887 participants who returned for a third examination, 38 of those whose race was neither black nor white were excluded from the analyses. Of the remaining 12,849 participants, photographs were unavailable for 245 persons and could not be evaluated because of poor quality resulting from media opacities or small pupil size in 1072 persons (8.5%). Comparisons between participants with (n=11,532) and without (n=1317) gradable fundus photographs are presented in Table 1. Persons without gradable fundus photographs were older and, after adjusting for age, substantially more likely to be black, take antihypertensive medications, have diabetes mellitus, have a cerebral infarct on magnetic resonance imaging, and have a higher lipoprotein(a) level than persons with gradable fundus photographs. Of those examined at the first visit, white women (4808/6050 [79.5%]) were slightly more likely than white men (4176/5428 [76.9%]; P=.001) and black women (1613/2635 [61.2%]) were slightly more likely than black men (935/1631 [57.3%]; P=.01) to have gradable fundus photographs for ARM at the third visit. Race interaction terms for every item in Table 1 were determined to examine whether the difference between those included in the analyses and those not included varied by black-white differences for the specific factors. Statistically significant interactions (P<.01) for blacks compared with whites were found for mean blood pressure, systolic blood pressure, and diabetes status.

Evaluations at baseline, including assessment of established risk factors for atherosclerotic vascular disease,¹⁸ were performed under common written protocols and monitored for adherence to protocol. The methods used to collect these data and the definitions of the systemic variables appear elsewhere.¹⁸ The retinal photography performed at the third triennial clinic examination and the interpretation of the retinal photographs are described in detail elsewhere.^{19 - 20} Briefly, a 45° retinal photograph was taken of 1 eye, centered on the region of the optic disc and the macula, by means of an automatically focusing camera. The eye chosen was based on the identification number received by the participant. Pupillary dilation was achieved after the participant spent 5 minutes in a dark room, without use of pharmacological mydriatic drops. Photographic methods were standardized with written protocols, and the photographer's performance was monitored with periodic feedback to ensure optimal performance. Photographs were evaluated at the Fundus Photograph Reading Center in Madison, Wis, where they were graded for quality of the images, then viewed with an 8-power lens by a grader, masked to subject information, for signs of ARM, retinopathy, arteriolar narrowing, and arteriovenous nicking. In addition, the diameters of retinal vessels were quantitatively assessed after conversion of the fundus photographs to digital images with a high-resolution scanner. Diameters of all arterioles and venules in the area located in an area lying between one-half and 1 disc diameter from the margin of the optic disc were measured.

For ARM, the presence of soft drusen, retinal pigment epithelial (RPE) depigmentation, increased retinal pigment, pure geographic atrophy, and signs of exudative macular degeneration (subretinal hemorrhage, subretinal fibrous scar, RPE detachment, and/or serous detachment of the sensory retina) were determined by a modification of the Wisconsin Age-Related Maculopathy grading system.^{21 - 22} For grading, a grid consisting of 2 circles concentric with the center of the macula and 4 radial lines was superimposed over the photograph. The lesions used to determine presence and severity of maculopathy were those that were identified in the macular area circumscribed by the outermost circle of the grading grid. The circle had a radius that corresponded to 3450 µm in the fundus of an average eye.

Soft drusen were defined as having a diameter larger than 63 µm. Depigmentation of the RPE, increased retinal pigment associated with ARM (the presence of granules or clumps of gray or black pigment in or beneath the retina), and pigmentary abnormalities were defined as present or as absent or questionable.

Early ARM was defined as the presence of soft drusen alone, RPE depigmentation alone, or a combination of soft drusen with increased retinal pigment and/or depigmentation in the absence of late ARM. Late ARM was defined as the presence of signs of exudative ARM degeneration or pure geographic atrophy. Methods used to measure and define characteristics in ARIC are provided elsewhere.^{23 - 33}

For quality control, assessment of photographs was repeated for 520 participants at visit 3. For better precision in estimating intergrader and intragrader reliability, participants with focal narrowing and arteriovenous nicking were oversampled. Consequently, repeatability analyses were weighted by the inverse of sampling probabilities to get unbiased estimates for the study population. The κ statistic was chosen to assess agreement.³⁴ The κ statistics were undefined for intragrader comparisons for RPE depigmentation and both intergrader and intragrader comparisons for late ARM because of the infrequency of these lesions. Weighted κ values ranged from 0.67 to 0.81 for intragrader comparisons and from 0.55 to 0.92 for intergrader comparisons, which indicated good to excellent agreement among repeated readings from the same grader and repeated readings from different graders, except for the intergrader reading comparison for soft drusen, which was equal to 0.22.

Multivariate linear regression was used to calculate the adjusted means and the corresponding SEs. The adjusted and unadjusted odds ratios (ORs) were obtained through multiple logistic regression. The quartiles for cardiovascular risk factors were based on those of the entire ARIC study population, that is, the quartiles were created before exclusions in the analyses were made. The linear trend tests were done by assigning consecutive integer scores to the ordered quartiles, regressing the dependent variable on this score variable, then testing for zero slope for the score variable. Significant tests for frequencies, proportions, or prevalences were conducted via χ² tests for contingency tables. Commercially available software (SAS; SAS Institute, Cary, NC) was used for all analyses.³⁵

The prevalence of lesions of ARM and ARM severity by race, sex, and age are shown in Table 2. The estimated total prevalence of any ARM in the population 48 to 72 years of age was 5.2% (596/11,532), of which 2.5% (15/596) had signs of late ARM. Prevalence of the specific ARM lesions (soft drusen, increased retinal pigment, and RPE depigmentation) and early and late ARM increased with age in whites. The prevalence of soft drusen increased with age in black men. After controlling for sex, persons 65 to 72 years of age were 3.06 times (95% confidence interval [CI], 2.34-4.00) as likely to have signs of ARM present as persons 48 to 54 years of age. After controlling for age, the prevalence of any ARM tended to be higher in men than women (OR, 1.13; 95% CI, 0.96-1.34). However, this association did not reach statistical significance (P>.05) and was not entirely consistent across races.

The estimated prevalence of any ARM was lower in blacks than whites (crude rates, 3.7% vs 5.6%; OR, 0.65; 95% CI, 0.52-0.81; Table 2 and Table 3). These differences remained after controlling for age and sex (OR, 0.73; 95% CI, 0.58-0.91; Table 3). Specific early ARM lesions and early ARM were all less frequent in blacks than whites (Table 2). The logistic regression models, unadjusted for age or sex, showed significantly lower ORs for soft drusen, increased retinal pigment, RPE depigmentation, and any ARM in blacks than whites (Table 3). After controlling for age and sex, there was little difference in the adjusted and unadjusted ORs comparing blacks with whites. Only the relation between race and soft drusen was no longer statistically significant.

The differences in frequencies of specific early ARM lesions between whites and blacks increased with age, especially for women. Among persons aged 60 to 72 years, white men had the highest prevalence of any ARM, while black women this age had the lowest frequency (Table 2). We ran models that included terms for the interactions between race and sex and between race and current age. These interactions were not statistically significant (P>.05) and were therefore dropped from the model (data not shown).

Cardiovascular disease and its risk factors have been hypothesized to be related to ARM.^{36 - 37} The factors measured and the cycle of the ARIC examination in which they were measured are listed in Table 1. The age-, race-, and sex-adjusted relationships of these factors to ARM were examined, and the only associations found with a statistical significance of P<.05 were between presence of carotid artery plaque and RPE depigmentation (OR, 1.77; 95% CI, 1.18-2.65) and between focal retinal arteriolar narrowing and RPE depigmentation (OR, 1.79; 95% CI, 1.07-2.98).

We examined whether cardiovascular disease and its risk factors explained the differences in prevalence of retinal lesions between whites and blacks. First we looked for risk factors by considering independent variables that had a P value of less than .10 for trend for any of the 5 end points (soft drusen, increased retinal pigment, RPE depigmentation, pigmentary abnormalities, and any ARM). After compiling these 5 lists, we created 1 inclusive list of all risk factors and considered this list for all 5 end points. We created 11 groups of risk factors from the overall lists: (1) mean blood pressure; (2) mean systolic blood pressure; (3) mean diastolic blood pressure; (4) total serum cholesterol–high-density lipoprotein (HDL) cholesterol ratio and serum HDL cholesterol level; (5) serum HDL cholesterol-3 and HDL cholesterol-2 levels; (6) lipoprotein(a); (7) carotid arterial plaque, popliteal arterial intima-media wall thickness; (8) hematocrit, white blood cell count; (9) apolipoprotein A-I; (10) focal retinal arteriolar narrowing, presence of retinopathy; and (11) height. Each model included race (black), sex (male), age (years), and 1 group of risk factors defined above. In addition, we also ran models including interaction terms for race and the variables in a risk factor group. There were no significant interactions at the .001 level (chosen because of the large number of statistical tests performed and in the absence of a priori hypotheses of differential ARM risk factor associations by race). Results of the models are summarized in Table 4. Adjusting for the risk factors singly (or when the risk factors were rerun in a single model, data not shown) did not cause a meaningful change in the ORs or the direction of the relation found in the age- and sex-adjusted models.

The ARIC study, an investigation of early atherosclerosis and clinical atherosclerotic disease, provided an opportunity to examine the prevalence of ARM and its relation to atherosclerosis in a large cohort of whites and blacks living in 4 US communities.¹⁴ Age-related maculopathy was measured by grading fundus photographs in a masked fashion by means of a standard classification system.^{16 ,20 - 21}

Cardiovascular disease and increased blood pressure, by their effects on the choroidal circulation,³⁸ and lipids, by deposition in Bruch's membrane,³⁹ have been hypothesized as possible pathogenetic factors for the development of macular degeneration. However, data from case-control and population-based studies regarding these relationships have been inconclusive,^{36 ,40 - 43} with few consistent strong risk factors for ARM identified, especially for early signs of ARM. The findings from the ARIC study are consistent in that, after controlling for age, race, and sex, only the presence of carotid plaque and focal retinal arteriolar narrowing was associated with RPE depigmentation. These findings, given the large number of models run, may have resulted from chance. There were not enough persons with signs of late ARM to confirm the previous finding of Vingerling et al⁴⁴ of an association of plaques at the carotid artery bifurcation as determined by carotid ultrasound examination with late ARM (OR, 4.7; 95% CI, 1.8-12.2 in that study).

The overall prevalence of ARM was lower in blacks (3.7%) than whites (5.6%) in the ARIC study. The prevalence of most of the component lesions that define early ARM was also lower in blacks than whites 60 years of age or older. These data are consistent with lower reported frequencies of early ARM in blacks than whites 60 years of age or older in the National Health and Nutrition Examination Survey III.⁹ The reason for the age difference in ARM between blacks and whites is not apparent. Possible risk factors were examined to determine if the prevalence patterns were explained by subgroup differences in exposures or degree of risk associated with a factor. There were few factors found to be associated with early ARM in this study, and no factor was found that substantially explained the lower risk in blacks than whites. This may be caused by other unmeasured factors^{45 - 48} (eg, light exposure^{49 - 50} ) that were not controlled for. It is also possible that differences in prevalences between blacks and whites in the ARIC study may result from genetic factors.

The strength of the association of pigmentary abnormalities and that of drusen differed with race. This has also been reported in the National Health and Nutrition Examination Survey III.⁹ The reasons for these differences in lesions associated with early ARM are not known. In the ARIC study, the odds ratio for the retinal outcome–race association was likely attenuated because of the poor reliability of classifying the presence of the soft drusen component (the κ was 0.22), assuming similar reliability for blacks and whites. Thus, the true race effect may be somewhat stronger. This effect may also be caused by a difference between the races in the ability to detect the lesions, because of variations in normal pigmentation of the fundus.

The overall prevalence of late ARM was low in the cohort, in large part because of the low upper limit of age (73 years) in this study. The frequency of late ARM in whites 65 to 72 years of age (0.4%) was lower than that found for whites 65 to 74 years of age in the Beaver Dam Eye Study (0.6%).⁵¹ Statistical comparisons of late ARM between whites and blacks in the ARIC study is not possible because of the low general frequency of these lesions and the small sample sizes of blacks 60 years of age and older in the population. In a large population-based study of black residents (n=4314) of Barbados, the prevalence of late ARM varied from 0.4% in those 40 to 49 years of age to 1.0% in those 70 to 79 years of age,¹⁰ which was higher than in younger whites in the Beaver Dam Eye Study (0% in those 43 to 49 years of age) but lower than in older whites in the Beaver Dam study (3.1% in those 70 to 79 years of age).⁵¹

The ARIC study used 1 nonstereoscopic 45° fundus photograph of only 1 eye to determine the presence of ARM. Age-related maculopathy is less likely to be detected, and there may be more variability in the grading of specific lesions, such as soft drusen, by grading of fundus photographs taken through a nonpharmacologically dilated pupil than grading of 30° stereoscopic color fundus photographs taken through dilated pupils.⁵² In addition, although ARM is often symmetrical between eyes, we would expect to miss approximately 36% of people with early and 26% with late ARM because of the possibility of the involved eye not being photographed. Higher participation rates, grading of stereoscopic color fundus photographs, and the inclusion of 2 eyes from each subject explains, in part, the higher age-specific frequencies of ARM in whites in other population-based studies.^{51 ,53 - 54}

This study had a substantial rate of nonparticipation at several stages between identification of the study population and the obtaining of the fundus photographs and also a high rate of nongradable fundus photographs, and these differed between the race and sex groups. If nonparticipation and nongradable fundus photographs are associated with ARM (or its risk factors), then our results and conclusions may be affected. At this time, we have no reason to suspect that there is likely to have been differential nonparticipation based on symptoms, especially regarding ARM, because there is not likely to be any functional disturbance in vision in the presence of early lesions of ARM.² Late ARM, which is often associated with decreased visual acuity, was too infrequent to influence our results. It is possible that poorer dilation in blacks may have accounted in part for the higher frequency of ungradable photographs in this group than in whites. Although we have no data available on pupil size in the ARIC study, data from the National Health and Nutrition Examination Survey III suggest that, after controlling for age, pupil size was not statistically different in blacks and whites (R.K., unpublished data, 1995). It is also possible that a higher frequency of cataract might have also accounted for photographs that could not be examined for ARM. No data are available in the ARIC study regarding cataract status. However, data from the large population-based Salisbury Eye Study showed statistically significantly lower rates in blacks than whites for 2 types of cataract, nuclear sclerosis and posterior subcapsular cataract.⁵⁵ We cannot assess the possibility of differential nonparticipation by visual function status, as such measures for responders and nonresponders at all stages is not extant. Neither can we estimate effects of specific covariates on risk factors for ARM, especially since the magnitude of the effect of any risk factor for ARM is inconsistent even in other large studies with higher participation. However, we note that the generalizability of results is less a result of the differences between participants and nonparticipants than between participants as a reflection of all eligible persons. For diseases for which biasing effects of nonparticipation have been estimated, the differences in the ARIC data have been small.¹⁵ At this time there is no evidence to suggest that rates of ARM are more likely to be biased on the basis of nonparticipation than are the other health conditions measured in the ARIC study.

In summary, data from the ARIC study suggest lower frequencies of ARM in blacks than whites. Controlling for age and sex, atherosclerosis and its risk factors were not related to early ARM and did not change this finding.

Accepted for publication April 7, 1999.

This research was supported in part by grant EY06594 from the National Eye Institute, National Institutes of Health, Bethesda, Md (Drs R. Klein and B. E. K. Klein), a Senior Scientific Investigator Award from Research to Prevent Blindness Inc, New York, NY (Dr R. Klein), and contracts N01-HC-35125, N01-HC-35126, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022 from the National Heart, Lung, and Blood Institute, National Institutes of Health.

We acknowledge the contributions of Lloyd E. Chambless, PhD, Richard Zink, and A. Richey Sharrett, MD, PhD, for their assistance in analyses of the data and preparation of the manuscript.

Corresponding author: Ronald Klein, MD, MPH, Department of Ophthalmology and Visual Sciences, University of Wisconsin–Madison, 610 N Walnut St, Room 460 WARF, Madison, WI 53705-2397 (e-mail: kleinr@epi.ophth.wisc.edu).