Refractive Errors and 10-Year Incidence of Age-Related Maculopathy

Abstract

purpose. To describe the relationship of refractive errors to the 10-year incidence of age-related maculopathy (ARM) in a defined white population.

methods. Persons aged 43 to 86 years of age in Beaver Dam, Wisconsin, were invited for a baseline examination from 1988 through 1990, and follow-up examinations 5 and 10 years later (n = 3684). Refraction was measured at baseline, with myopia defined as a spherical equivalent of −1.00 D or less, emmetropia as −0.75 to +0.75 D and hyperopia as +1.00 D or more. At each examination, signs of ARM were ascertained from grading stereoscopic color fundus photographs based on a standard protocol. The association between baseline refractive status and the 10-year incidence and progression of ARM was analyzed.

results. The 10-year cumulative incidence for early ARM was 7.1%, 7.7%, and 11.7%, in eyes with myopia, emmetropia, and hyperopia, respectively. The corresponding 10-year cumulative incidence for late ARM was 0.3%, 0.8%, and 2.2%. When age was controlled for, there was no association between myopia and incident early (relative risk [RR] 1.0, 95% confidence interval [CI], 0.7–1.3) and late (RR 0.5, 95% CI, 0.2–1.5) ARM. Similarly, after controlling for age, hyperopia was not associated with incident early (RR 0.9, 95% CI, 0.7–1.1) or late (RR 1.2, 95% CI, 0.6–2.3) ARM.

conclusions. These prospective population-based data provide no evidence of an association between refractive errors and risk of ARM.

Age-related maculopathy (ARM) is the leading cause of irreversible blindness in people 65 years of age and older. ¹ Identifying possible risk factors for ARM is an important goal in ocular research, because it may offer insights into the pathogenesis of ARM. An association between hyperopia and risk of ARM has been reported in several case–control studies. ^{2 3 4 5 6 7} Most recently, the Age-Related Eye Disease Study (AREDS) found that people 60 to 80 years or age with hyperopia were 1.3 times (95% confidence interval [CI], 1.0–1.6) as likely to have large drusen and 2.3 times (95% CI, 1.7–3.2) as likely to have exudative ARM as persons who had myopia. ⁷ However, population-based studies have not found a consistent association between either hyperopia or myopia and ARM. ^{8 9 10 11} In the National Health and Nutrition Examination Survey, the prevalence of ARM was reportedly higher in persons with hyperopia than in those with emmetropia. ⁸ In contrast, a population-based study in the United Kingdom found an association between myopia and ARM. ⁹ However, these studies made no distinction between different severities of refractive error and different forms of ARM. In the Blue Mountains Eye Study in Australia, the only study to evaluate the specific association of increasing severities of myopia and hyperopia with early and late ARM, a weak association was reported between hyperopia and early ARM. ¹¹ Using the average of the refraction in the right and left eyes to define the refractive status of an individual, the investigators showed that persons with moderate to high hyperopia (greater than +3.00 D) were more likely to have prevalent early ARM than persons with emmetropia (odds ratio, 2.0; 95% CI, 1.2–3,4) although this association was substantially weaker in analyses that combined data from both eyes (odds ratio, 1.3; 95% CI, 0.9–1.9). 

Regardless, existing studies are cross sectional. Few prospective data are available that evaluate whether refractive errors are risk factors for ARM. In the Beaver Dam Eye Study, we did not find a significant association between hyperopia or myopia and the 5-year incidence of ARM, although the small sample of cases of incident ARM limited the power to detect associations. ¹² The purpose of the present study is to examine the relationship between refractive errors and the 10-year incidence of early and late ARM in the Beaver Dam population. 

Methods

Study Population

The Beaver Dam Eye Study is a population-based cohort study of ocular diseases in adults. Its study population, research methodology, and findings are described in detail in other reports. ^{13 14 15} Briefly, a private census of the population of Beaver Dam, Wisconsin, composed of predominantly white persons, was performed from fall 1987 through spring 1988. Of the 5924 people who were in the 43- to 84-year eligibility age range for the study, 4926 participated in the baseline examination from 1988 through 1990. ¹³ Of these, 3684 (81.1% of survivors) participated in the 5-year follow-up examination from 1993 through 1995, ¹⁴ and 2764 (82.9%) participated in the 10-year follow-up examination in 1998 through 2000. ¹⁵ Comparisons of data on participants and nonparticipants at the baseline, 5-year, and 10-year examinations have been published. ^{13 14 15} In general, persons who were alive but did not participate at the 10-year examination were older at baseline and, after adjusting for age, were more likely to have completed fewer years of education; to have a lower income, poorer visual acuity, and poorer cardiovascular risk profile; and to have a history of never drinking alcohol and of smoking more pack-years than persons who participated. ¹⁵ After we adjusted for age and gender, participants with early ARM at baseline were as likely to participate as those in whom ARM was absent. ¹⁶  

The examination procedures for refraction and ARM at baseline and follow-up examinations were based on the same standardized protocols described in detail elsewhere. ^{16 17 18 19} Tenets of the Declaration of Helsinki were observed throughout the study. 

Assessment of Baseline Refractive Status

Baseline refraction was obtained by documenting the refraction in the participant’s current prescription (if available). ¹⁷ This was followed by a standardized refraction with an automated refractor. This estimate was subjectively refined according to a modification of the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol to obtain the best corrected visual acuity in cases in which the automated refraction yielded visual acuity of 20/40 or worse. ¹⁷ The results of the automated refraction were used in the analyses for 96% of eyes at baseline, the results of ETDRS refraction were used in 4% of eyes, and refraction from the current prescription was used in the remaining eyes (<1%). Inter- and intraexaminer comparisons of refraction showed no significant differences. ¹⁷  

The refractive status of a particular eye was defined according to the baseline refraction. The spherical equivalent refraction was calculated to the nearest 0.25 D. Myopia was defined as a spherical equivalent of −1.00 D or less, hyperopia as a spherical equivalent of +1.00 D or more, and emmetropia as a spherical equivalent of between −0.75 and +0.75 D. 

Definition of Incident ARM

Similar procedures were used to evaluate and define ARM at the baseline, ¹⁸ 5-year, ¹⁹ and 10-year examinations. ¹⁶ In brief, stereoscopic 30° color fundus photographs centered on the disc (Diabetic Retinopathy Study standard field 1) and macula (standard field 2) and a nonstereoscopic color fundus photograph temporal to but including the fovea of each eye were taken. ^{16 18 19}  

Trained graders, masked to the participants’ characteristics (and refractive status) used the Wisconsin Age-Related Maculopathy Grading System to assess the presence and, subsequently, the incidence of specific lesions associated with ARM. ²⁰ The grading of ARM was performed separately at the baseline, 5-year follow-up, and 10-year follow-up examinations. For eyes that showed changes in specific ARM lesions between baseline and follow-up, the graders were then asked to make side-by-side comparisons between baseline, 5-year, and 10-year follow-up photographs. During these edits, the graders were masked as to whether the photographs were taken at baseline or follow up. ¹⁶  

Incidence was determined for the maximum size and type of each specific drusen class, increased drusen area, increased retinal pigment, retinal pigment epithelial (RPE) depigmentation, pigmentary abnormalities (defined as RPE depigmentation or increased retinal pigment), signs of exudative macular degeneration, and pure geographic atrophy. ¹⁶ The incidence of a specific lesion was defined by its presence at follow up when it was not present at baseline in any of the subfields that could be graded at both examinations (e.g., an eye was considered to have incident soft, indistinct drusen if none of the subfields had this lesion at baseline and this lesion was present in one or more subfields at follow up). 

Two summary variables of disease severity were also defined. The incidence of early ARM was defined by the presence of either soft, indistinct drusen or the presence of any type of drusen associated with RPE depigmentation or increased retinal pigment at follow up, when none of these lesions was present at baseline. ¹⁶ The incidence of late ARM was defined by the appearance of either exudative macular degeneration or pure geographic atrophy at follow up, when neither was present at baseline. ¹⁶  

Finally, for each eye, a six-level severity scale for ARM was defined (level 10 to level 60). ¹⁶ Progression of ARM in a participant was defined as an increase in the severity of maculopathy in either eye by two steps or more (from level 10 through 30) and one step or more (from level 40 or level 50) at the 5- or 10-year examination. 

Other Variables

All other characteristics in this analysis were defined from baseline data. ²¹ Age was defined as the age at the time of the baseline examination. Education, cigarette smoking, alcohol consumption, and use of vitamins were ascertained from examiner-administered questionnaires. Education level was categorized into four levels (fewer than 12 years, 12 years, 13–15 years, and >15 years). Cigarette smoking was defined as current, past, and never. A current heavy drinker was defined as a person who consumed four or more servings of alcoholic beverages daily, a former heavy drinker was one who had consumed four or more servings daily in the past but not in the previous year, and a non–heavy drinker was one who had never consumed four or more servings daily on a regular basis. Vitamin use was defined as use at least once a week over a 1-month period, and was categorized as current, past, and never. 

Statistical Methods

We examined the relationships of refractive status at baseline to the 10-year cumulative incidence of early and late ARM, their components, and progression of ARM. The cumulative incidence for each end point was estimated using the Kaplan-Meier approach, which allowed persons who were not seen after the 5-year examination due to death or nonparticipation to contribute information to the incidence estimates. ²² Relative risks of ARM end points were estimated from discrete linear logistic models. ²³ Data from right and left eyes were initially analyzed separately and then combined by using the generalized estimating equation (GEE) method described by Liang and Zeger, ^{24 25} which adjusts for the correlation between two eyes in a single person. In age-adjusted models, we adjusted for age in years. In multivariate models, we further adjusted for gender, education, cigarette smoking, heavy alcohol consumption, and vitamin use. A computer and statistical analysis software (SAS Institute, Inc., Cary, NC) was used for all analyses. 

Results

The study population was derived from participants who had incident ARM data (the 3648 who returned for at least the 5-year follow-up examination). Of the 3648 eligible participants, 378 were excluded because of previous cataract surgery, confounding retinal lesions (e.g., non-ARM chorioretinal scarring, retinal detachment) or unavailable refractive and ARM data in their right eyes, leaving 3306 who provided right-eye data for these analyses. Comparison of baseline characteristics between these persons (n = 3306) and those excluded (n = 378) are presented in Table 1 . In general, persons included were younger and, after adjustment for age, had more years of completed education, were less likely to have diabetes, and had lower systolic and diastolic blood pressure. After age adjustment, persons included were less likely to have early and late ARM at baseline than those who were excluded (Table 1) . In analyses of left eyes, 346 were similarly excluded because of previous cataract surgery, confounding retinal lesions, or unavailable data, leaving 3338 participants who provided data. Because the results were largely similar between the right and left eyes, remaining analyses are presented for right eyes only. 

The frequency of myopia in the right eye was 24.8% in men and 27.7% in women, and the frequency of hyperopia was 49.1% in men and 49.6% in women. During a 10-year period, 209 and 30 persons showed development of incident early and late ARM in their right eyes, respectively. Table 2 shows the baseline refraction of persons who showed signs of ARM compared with those who did not. In general, after age adjustment, mean baseline refraction was similar in people with and without incident ARM. 

The 10-year cumulative incidence and relative risk (RR) for early and late ARM, according to refractive status, are shown in Table 3 . The 10-year incidence of early ARM was 7.1%, 7.7%, and 11.7%, in eyes with myopia, emmetropia, and hyperopia, respectively. The corresponding incidence of late ARM was 0.3%, 0.8%, and 2.2%, respectively. Age had a strong effect on the association of hyperopia and ARM. For example, the crude RR of early ARM associated with hyperopia was 1.5 (95% confidence intervals [CI], 1.2–1.8) but the age-adjusted RR was 0.9 (95% CI, 0.7–1.1). After controlling for age, there was no association between myopia or hyperopia and incident early or late ARM. When refraction was categorized into five groups, there was no association between levels of refraction and incident early or late ARM (Table 3) . Further adjustment for gender, education, cigarette smoking, heavy alcohol consumption, and vitamin use had little impact on these results (e.g., RRs of early ARM associated with myopia and hyperopia were 1.0, 95% CI, 0.8–1.4; and 0.8, 95% CI, 0.6–1.1, respectively). 

Table 4 shows the age-adjusted RRs of specific signs of ARM associated with myopia and hyperopia. In general, there was no statistically significant (i.e., P < 0.05) association between refractive errors and any ARM lesions. 

Finally, refraction was analyzed as a continuous variable (+0.25-D increments). No consistent associations were found between refraction and incident ARM (data not shown). 

Discussion

The literature is inconsistent regarding possible associations between refractive errors and ARM. ^{2 3 4 5 6 7 8 9 10 11 12} Several studies conducted among clinic populations have reported that hyperopia may be a risk factor for ARM, particularly for exudative ARM. ^{2 3 4 5 6 7} In two large multicenter case–control studies, the Eye Disease Case–Control Study ² and the AREDS, ⁷ after adjustment for age and other risk factors, persons with hyperopia were 1.5 to 2.3 times more likely to have exudative ARM than were those who were myopic. However, a biologically plausible explanation for these observations is not apparent. Boker et al. ²⁶ have hypothesized that the association between hyperopia and ARM may be related to a reduction in choroidal blood flow in eyes with shorter axial lengths, which may predispose these eyes to development of choroidal neovascularization. ²⁷ An alternative explanation is that hyperopia and ARM are common biological markers of aging. ²⁸ Nonetheless, a spurious association cannot be excluded, particularly because clinic-based studies such as the AREDS may be subjected to selection biases (e.g., persons with refractive error and ARM may be more likely to participate). 

In contrast to clinic-based investigations, most population-based studies have reported no or weak associations between refractive errors and ARM. ^{8 9 10 11 12} In the present study in Beaver Dam, we found no evidence of an association between refractive errors and the 10-year incidence and progression of early and late ARM. These results support our previous observations that refractive errors were not significant risk factors for 5-year incident ARM. ¹²  

The strengths of our study include its population-based nature, high attendence rates at baseline and follow-up examinations, and use of standardized methods to examine refraction and ARM. Several limitations of this study should be discussed. First, it is uncertain whether nonparticipation may have masked these associations. For example, the failure to observe the association between hyperopia and incident late ARM may be due to excluded persons’ having a higher prevalence of hyperopia and greater likelihood of developing late ARM at baseline. We note that the prevalence of early ARM at baseline (a risk factor for late ARM) was higher in persons excluded (14.5%) than in those included (12.2%; Table 1 ). Second, statistical power was modest, particularly for the less frequent signs of incident ARM (e.g., exudative ARM). With regard to the association between hyperopia and incident exudative ARM, our study provided sufficient power (80%) to detect odds ratios of 2.4 or greater. Thus, weaker associations between refractive errors and ARM may have been missed. 

In conclusion, refractive errors are extremely common conditions that affect up to 75% of adults older than 40 years. ¹⁷ These population-based data provide no evidence that refractive errors are important risk factors in the development of ARM. 

 Supported by American Diabetes Association Mentor Fellowship Award and the National University of Singapore (TYW), and National Institutes of Health Grant EYO6594 (RK, BEKK).

 Submitted for publication December 19, 2001; revised April 22, 2002; accepted May 16, 2002.

 Commercial relationships policy: N.

 The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked “advertisement” in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Table 1.

 

 

Comparison of Baseline Characteristics by Persons Included and Excluded on Basis of Right Eye Data, Adjusted for Age

Table 1.

 

Comparison of Baseline Characteristics by Persons Included and Excluded on Basis of Right Eye Data, Adjusted for Age

Baseline Characteristics	Included			Excluded			P *
		n	Adjusted Mean or %	n	Adjusted Mean or %
Systemic characteristics
Age, years	3,306	59.3	378	69.9	0.005
Female (%)	3,306	56.0	378	59.6	0.24
Education (y)	3,304	12.3	378	11.8	0.005
Hypertension (%)	3,305	33.1	377	38.1	0.19
Diabetes (%)	3,304	5.3	377	8.9	0.006
Systolic blood pressure (mm Hg)	3,305	130.5	378	132.9	0.02
Diastolic blood pressure (mm Hg)	3,305	78.0	378	76.8	0.003
Current cigarette smoking (%)	3,305	19.0	378	20.7	0.24
Current heavy alcohol drinking (%)	3,302	2.2	377	2.3	0.82
Current vitamin use (%)	3,285	33.9	378	38.5	0.09
Ocular characteristics, right eyes
Refraction (mean D)	3,306	0.15 (2.27)	0	—	—
Early ARM (%)	3,234	12.2	270	14.5	0.05
Late ARM (%)	3,246	0.4	293	3.6	<0.001

*  Comparison of age-adjusted mean or percentage between persons included and excluded from study.

Table 2.

 

 

Age-Adjusted Mean Refraction at Baseline, Comparing Persons Who Did and Did Not Develop Incident ARM, Data from Right Eyes

Table 2.

 

Age-Adjusted Mean Refraction at Baseline, Comparing Persons Who Did and Did Not Develop Incident ARM, Data from Right Eyes

Specific ARM Lesions	Persons with Incident ARM			Persons without ARM			P *
		n	Age-Adjusted Baseline Refraction (D)	n	Age-Adjusted Baseline Refraction (D)
Early ARM	209	0.18	2,565	0.24	0.55
Drusen size >125 μm	99	0.20	2,976	0.62	0.09
Soft, indistinct drusen	195	0.19	2,712	0.35	0.76
Increased pigment	142	0.19	2,807	0.26	0.42
RPE depigmentation	106	0.21	2,933	0.47	0.55
Pigmentary abnormalities	141	0.24	2,801	0.37	0.59
Late ARM	30	0.91, †	3,096	0.83, †	0.41
Geographical atrophy	14	0.84, †	3,156	0.83, †	0.99
Exudative ARM	16	0.88, †	3,089	0.82, †	0.31
Progression of ARM	169	0.42	2,951	0.20	0.53

*  Comparison of difference in mean refraction at baseline, adjusted for age.

†  Excludes people 43–54 years of age at baseline (no incident cases of late ARM, geographical atrophy, or exudative ARM).

Table 3.

 

 

Incidence and Relative Risk of Early and Late ARM, by Baseline Refractive Status, Data from Both Eyes, Using Generalized Estimating Equations

Table 3.

 

Incidence and Relative Risk of Early and Late ARM, by Baseline Refractive Status, Data from Both Eyes, Using Generalized Estimating Equations

Baseline Refractive Status	Incident Early ARM							Incident Late ARM
		At Risk* (n)	With Event, † (n, %)	Crude RR (95% CI), ‡	Age-Adjusted RR (95% CI)	At Risk* (n)	With Event, † (n, %)	Crude RR (95% CI), ‡	Age-Adjusted RR (95% CI)
Myopia	1,434	98 (7.1)	0.9 (0.6–1.1)	1.0 (0.7–1.3)	1,541	4 (0.3)	0.4 (0.1–1.1)	0.5 (0.2–1.5)
Emmetropia	2,101	150 (7.7)	1.0	1.0	2,330	16 (0.8)	1.0	1.0
Hyperopia	2,020	204 (11.7)	1.5 (1.2–1.8)	0.9 (0.7–1.1)	2,422	43 (2.2)	2.8 (1.5–5.2)	1.2 (0.6–2.3)
Refraction (D)
Less than −3.00	484	25 (5.7)	0.7 (0.4–1.1)	0.8 (0.5–1.4)	510	2 (0.5)	0.6 (0.1–2.6)	0.9 (0.2–3.8)
−1.00 to −3.00	950	68 (7.7)	0.9 (0.7–1.3)	1.1 (0.8–1.5)	1,031	2 (0.2)	0.3 (0.1–2.6)	0.3 (0.1–1.5)
−0.75 to +0.75	2,101	150 (7.7)	1.0	1.0	2,330	16 (0.8)	1.0	1.0
+1.00 to +2.25	1,431	130 (10.5)	1.3 (1.0–1.7)	0.8 (0.6–1.1)	1,694	27 (2.0)	2.5 (1.3–4.9)	1.2 (0.6–2.5)
More than +2.50	589	74 (14.6)	1.9 (1.4–2.6)	0.9 (0.7–1.3)	728	16 (2.6)	3.6 (1.7–7.5)	1.2 (0.5–2.6)

 Myopia: −1.00 D or less; emmetropia: between −0.75 and +0.75 D; hyperopia: +1.00 D or more.

*  Number of eyes at risk.

†  Number (cumulative incidence) of ARM.

‡  Crude relative risk of early or late ARM, comparing refractive errors with emmetropia, using data from both eyes.

Table 4.

 

 

Relative Risk of Early and Late ARM, by Baseline Refractive Status, Data from Both Eyes, Using Generalized Estimating Equation

Table 4.

 

Relative Risk of Early and Late ARM, by Baseline Refractive Status, Data from Both Eyes, Using Generalized Estimating Equation

	Age-Adjusted RR (95% CI)*
		Myopia	Hyperopia
Early ARM	1.1 (0.8–1.4)	0.9 (0.7–1.1)
Drusen size >125 μm	0.8 (0.5–1.2)	1.3 (0.9–1.8)
Soft, indistinct drusen	1.0 (0.7–1.3)	0.8 (0.6–1.0)
Increased pigment	1.0 (0.7–1.3)	1.0 (0.8–1.4)
RPE depigmentation	0.7 (0.5–1.1)	0.9 (0.7–1.3)
Pigmentary abnormalities	0.9 (0.7–1.3)	1.1 (0.8–1.4)
Late ARM, †	0.6 (0.2–1.9)	1.3 (0.7–2.4)
Geographical atrophy, †	0.6 (0.2–1.9)	0.9 (0.4–2.3)
Exudative ARM, †	0.8 (0.2–2.7)	1.6 (0.8–3.3)
Progression of ARM	0.9 (0.6–1.3)	1.0 (0.8–1.3)

*  Age-adjusted relative risk (95% confidence interval) of ARM associated with myopia (versus emmetropia or hyperopia) and hyperopia (versus emmetropia or myopia), using data from both eyes.

†  Excludes people 43–54 years of age at baseline (no incident cases of late ARM, geographical atrophy, and exudative ARM).