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Five-Year Incidence of Age-related Macular Degeneration
Five-Year Incidence of Age-related Macular Degeneration The Beijing Eye Study Qi Sheng You, MD,1 Liang Xu, MD,1 Hua Yang, MD,1 Yi Bin Li, MD,1 Shuang Wang, MD,1 Jin Da Wang, MD,1 Jing Shang Zhang, MD,1 Ya Xing Wang, MD,1 Jost B. Jonas, MD1,2 Purpose: To examine the incidence of age-related macular degeneration (AMD) and its associated factors in an adult Chinese population. Design: Population-based study. Participants: The Beijing Eye Study, which included 4439 subjects (age ⱖ40 years) in 2001, was repeated in 2006 with 3251 (73.2%) subjects participating. Methods: Fundus photographs were graded using the International Age-related Maculopathy Epidemiological Study Group grading system. Main Outcome Measures: Incidence of AMD. Results: Gradable slides were available on 3049 (93.9%) subjects who participated in the survey of 2001 and again in 2006. The incidence of early, late, and neovascular AMD per eye was 2.6% (95% confidence interval [CI], 2.2–3.0), 0.1% (95% CI, 0.00 – 0.2), and 0.1% (95% CI, 0.00 – 0.2), respectively. The incidence of early, late, and neovascular AMD per person was 4.2⫾0.4% (95% CI, 3.5–5.0), 0.1⫾0.1% (95% CI, 0.0 – 0.2), and 0.1⫾0.1% (95% CI, 0.0 – 0.2), respectively. By multivariate analysis, incident early AMD was associated significantly with greater age at baseline (P ⫽ 0.01; odds ratio [OR], 1.03; 95% CI, 1.01–1.06), smaller optic disc size (P ⫽ 0.007; OR, 0.50; 95% CI, 0.30 – 0.83), smaller scleral spur distance (P ⫽ 0.04; OR, 0.59; 95% CI, 0.36 – 0.98), and hyperopic refractive error (P ⫽ 0.057; OR, 1.15; 95% CI, 1.00 –1.33), with the latter being significant only marginally. It was not associated with the systemic parameters of gender, body height, body mass index, region of habitation, level of education, profession, smoking, arterial blood pressure, diabetes mellitus, fasting blood concentrations of glucose, triglycerides, high-density or low-density lipoproteins; or the ocular parameters of intraocular pressure, retinal arterial and vein diameters, retinal microvascular abnormalities, amount of nuclear cataract, cortical cataract or subcapsular cataract, pseudophakia, glaucoma, nonglaucomatous optic neuropathy, retinal vein occlusions, size of the beta zone of parapapillary atrophy, or progression of the zone of atrophy during the follow-up from 2001 to 2006. Conclusions: Hyperopia, short interscleral spur distance, and small optic disc size were, beside older age, the main factors associated with incident early AMD. This may point to a small globe size, potentially in relation to a firmly attached vitreous, playing a role in early incident AMD. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article. Ophthalmology 2012;119:2519 –2525 © 2012 by the American Academy of Ophthalmology.
Age-related macular degeneration (AMD) is among most common causes of visual impairment and blindness in the adult population in Western countries.1,2 Its incidence has been assessed in previous longitudinal population-based studies on whites, such as the Beaver Dam Eye Study in Wisconsin, the Rotterdam Study in The Netherlands, the Blue Mountains Eye Study in Australia, and the Los Angeles Eye Study in California; on blacks in the Barbados Incidence Study of Eye Disease; and on Japanese in the Hisayama study.3–12 None of the these longitudinal studies was focused on Chinese populations. Given the wide variation in the prevalence and incidence of AMD, in particular considering that the prevalence of AMD seems to be lower © 2012 by the American Academy of Ophthalmology Published by Elsevier Inc.
among Chinese than Caucasians,13–17 it is desirable to have specific data on the incidence of AMD from a Chinese study population rather than extrapolating findings from other ethnic groups to persons of Chinese ancestry. It was therefore the purpose of this study to examine the incidence and rate of progression of AMD and its associated factors in the population from mainland China. The information gained may be helpful in understanding whether or not there is a difference between mainland Chinese and other ethnic groups in the occurrence of AMD, and whether or not there is a difference between ethnic groups in the risk factors for this condition. Increased knowledge of the risk factors of AMD may be useful for better prevention of the disease in ISSN 0161-6420/12/$–see front matter http://dx.doi.org/10.1016/j.ophtha.2012.06.043
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Ophthalmology Volume 119, Number 12, December 2012 the case of modifiable risk factors; it may provide hints to the pathogenesis of the disease and the data may be helpful for planning public health strategies.
Methods The Beijing Eye Study is a population-based study in Northern China. It was carried out in 4 communities in the urban district of Haidian in the north of central Beijing and in 3 communities in the village area of Yufa of the Daxing District south of Beijing. The urban district of central Beijing consists of an area extending about 5 km from Tianamen Place. The rural communities are located about 50 km from central Beijing and are easily accessible by car in about an hour via an express motorway. The study has been described in detail recently.13 The Medical Ethics Committee of Beijing Tongren Hospital approved the study protocol and all participants provided informed consent, according to the Declaration of Helsinki. At the time of the initial survey, in the year 2001, a total of 5324 individuals aged ⱖ40 years resided in the 7 communities, of which 4439 individuals (2505 women) participated in the eye examination (response rate, 83.4%). The study was divided into a rural part (1973 [44.4%] subjects) and an urban part (2466 [55.6%] subjects). Mean age of the participants was 56.2⫾10.6 years (range, 40 –101). In 2006, the study was repeated by reinviting all participants of the 2001 survey. All examinations were carried out in schoolhouses or community houses within the community being surveyed. Examinations performed in 2001 included measurement of uncorrected and best-corrected visual acuity, visual field examinations using frequency-doubling perimetry, pneumotonometry, slit-lamp– based biomicroscopy of the anterior segment, digital photography of the cornea, and retroilluminated photography of the lens. Monoscopic photographs of the macula and optic disc were obtained with a fundus camera (type CR6-45NM, Canon Inc, Melville, NY). Trained research technicians asked each study participant questions from a standard questionnaire, which yielded information on demographic variables and the known presence of the more common diseases, such as arterial hypertension, diabetes mellitus, coronary heart disease, hyperlipidemia, and stroke. Socioeconomic status of the participants was assessed with questions regarding level of education, occupation, and family income. The level of education was categorized into the stages of “illiteracy,” “half illiteracy with knowledge of some Chinese words,” “primary school education,” “middle school education,” and “college or higher education.” In the survey performed in 2006, additional examinations were carried out, such as optical coherence tomography of the anterior segment17 and blood sampling for biochemical analysis. Optical coherence tomography (Heidelberg Engineering, Dossenheim, Germany; scan size, maximum,15 mm; scan depth, 7 mm; lateral optical resolution capacity, 20 –100 m; axial optical resolution capacity, ⬍25 m; diode laser, 1310 nm) of the anterior segment was performed on the right eyes of each subject. The anterior chamber depth, scleral spur distance, and anterior chamber angle in the temporal and nasal regions were measured using a software program supplied with the device.17 Body height and weight were also assessed; blood pressure was measured. Using optic disc photographs, glaucoma was determined using the International Society of Geographical and Epidemiological Ophthalmology classification.18 Optic disc size was measured on digitized color optic disc photographs. The optic disc was defined as the entire area inside the peripapillary ring. Magnification by the optic media of the eye was corrected according to Littmann’s method, which took into account refractive error, as described previously.18 Diabetic retinopathy was defined as described by the criteria of the Early Treatment of Diabetic Retinopathy Study.19
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For the assessment of AMD, the International Age-related Maculopathy Epidemiological Study Group Grading system was used.13,20 A grid with 3 concentric circles with projected radii of 500, 1500, and 3000 m was applied to the fundus and 4 radial lines dividing the photograph into 9 subfields was used. A set of 5 circles, with corresponding sizes of 63, 125, 175, 250, and 500 m in diameter, was applied to estimate drusen size and the area involved by drusen or retinal pigmentary abnormalities. All slides were graded by a trained examiner (Y.Q.S.). The examiner first graded the slides obtained for the survey of 2006 in a masked manner, without any knowledge of the findings of either the 2001 survey or of age or gender of the participant. For the second step, the same examiner reassessed all slides with any lesion indicating AMD from either the baseline examination of 2001 or the follow-up examination of 2006. The 2 slides of the same eye were projected side by side, without the examiner knowing which slide was the more recent. If no difference between slides was detected, it was concluded that there was no change. If the more recent slide showed more severe damage, it was considered to be progression; if less damage was seen, it was considered regression. In a third step, performed 1 month later, 5% of the slides from 2006 were randomly reassessed by the same grader. In a fourth step, all slides showing late stage AMD and randomly selected slides of eyes with early AMD were reassessed by a panel of ophthalmologists (including Y.Q.S., X.L., J.B.J.). The early stage of AMD was defined as absence of any late AMD plus the presence of soft indistinct drusen, or any drusen (except hard drusen) combined with retinal pigment epithelium changes in the macular area. The late stage of AMD was defined as either neovascular AMD or geographic atrophy. Neovascular AMD included serous or hemorrhagic detachment of the retinal pigment epithelium or sensory retina; intraretinal or subretinal hemorrhages or hemorrhages beneath the retinal pigment epithelium, or a combination thereof; or subretinal fibrous scars. A definition of the incidence, progression, regression, and disappearance of AMD and associated lesions was similar to that seen in the Beaver Dam Eye Study.5 Briefly, incident late AMD (by subject) was defined by the appearance of late AMD lesions, that is, neovascular AMD or geographic atrophy involving the macular area in either eye at follow-up of persons in whom no late AMD was present at baseline. Incident early AMD (by subject) was defined as absence of late AMD in addition to the new appearance of soft indistinct drusen or any drusen (excluding hard drusen) combined with retinal pigment epithelium abnormalities in the macular area in either eye at the follow-up examination of persons in whom no early or late AMD was present at baseline. Data were presented by eye and by subject. A person with early AMD lesions in 1 eye at baseline and who developed early AMD in the second eye at follow-up was not counted as a subject with incident early AMD subject, but the second eye was counted as an incident early AMD eye when the results were tabulated by eye. The same rule was applied to late AMD. We assessed the most advanced type of drusen in each eye. A person with soft indistinct drusen at follow-up in either eye with only soft or no drusen at baseline was counted as incident indistinct drusen. The same rule applied to the other types of drusen. Progression was present if the same lesion was present at the 2001 examination and at the 2006 examination, but extended from the outer circle into the inner circle, involved ⱖ2 subfields of the grid, or, in the case of neovascular AMD, showed more severe lesions, for example, advancing from exudates at 2001 to a subretinal scar at 2006. Regression meant that the same lesion was no longer present in ⱖ2 subfields, or was no longer present in the central subfield. Disappearance meant the lesion had disappeared at the time of the 2006 examination, although it was present at the 2001 examination. Persons without late AMD in either eye at baseline were counted as at risk
You et al 䡠 Incidence of AMD in Beijing Eye Study Table 1. Demographic Data on the Participants of the Beijing Eye Study 2001/2006, Compared with Subjects Excluded Owing to Death During Follow-up or to Nonparticipation in 2006 Characteristics at Baseline 2001
Participants from 2001 and Included in 2006
Participants from 2001 Not Participating in 2006
P
Participants from 2001 Who Died during Follow-up
n Mean age (yrs) Women (%) Currently married (%) History of diabetes (%) History of hypertension (%) History of coronary heart disease (%) Stroke history (%) History of hyperlipidemia (%) Ever smoking (%) Alcohol consumption (%) Best corrected visual acuity (right eye) Prevalence of early AMD in 2001 (%) Prevalence of late AMD in 2001 (%) Prevalence of neovascular AMD in 2001 (%)
3049 54.9⫾9.8 56.5 96.0 (%) 6.2 22.7 13.6 3.5 23.4 22.7 12.4 0.92⫾0.18 5.2 0.2 0.1
1247 58.4⫾11.5 58.2 93.8 (%) 6.8 20.8 12.3 3.8 20.5 21.2 9.1 0.86⫾0.26 5.3 0.5 0.4
— ⬍0.001 0.441 ⬍0.001 0.513 0.219 0.326 0.657 0.093 0.333 0.047 ⬍0.001 0.911 0.106 0.021
143 65.7⫾10.4 43.4 79.0 (%) 15.7 33.1 19.8 17.4 20.3 30.6 18.2 0.72⫾0.33 5.0 0.0 0.0
AMD ⫽ age-related macular degeneration. Data for age and visual acuity are given as mean values ⫾ standard deviation.
of incident late AMD; those without early or late AMD in either eye at baseline were counted as at risk of incident early AMD. Persons with early AMD but absent late AMD in either eye at 2001 were at risk of incident late AMD, but were excluded for assessment of incident early AMD. Statistical analysis was performed using a commercially available statistical software package (SPSS for Windows, version 19.0, IBM-SPSS, Chicago, IL). The data were presented as mean values ⫾ standard deviations; odds ratios (OR) were calculated. Chi-square tests were used to compare proportions. Logistic regression was used to investigate the associations between incident AMD and continuous or categorical independent variables, such as age, gender, and refractive error. Confidence intervals (CI) of 95% are presented. All P-values are 2-sided and were considered significant when the values were ⬍0.05.
Results Of the 4439 subjects examined in 2001 and invited for reexamination in 2006, 3251 (73.2%) returned; 143 (3.2%) subjects had
died and 1045 (23.5%) subjects were alive but did not agree to be reexamined. Gradable fundus slides of the 2006 survey were available on 5957 eyes of 3079 (94.7%) persons. Gradable slides for the examination of 2001 and for the examination of 2006 were available on 5831 eyes of 3049 persons, who are included in the present study. At the baseline examination of 2001, the mean age of these 3049 subjects (1331 [43.7%] males) was 54.9⫾9.8 (range, 40 – 82 years), and 1403 (46%) participants resided in 1 of the rural areas. The group of subjects included in the present study, compared with the subjects not included, was significantly younger, tended to be currently married, and their best-corrected visual acuity was significantly better (Table 1). The incidence of early, late, and neovascular AMD per eye (mean ⫾ standard error) was 2.6⫾0.2% (95% CI, 2.2–3.0), 0.1⫾0.04% (95% CI, 0.00 – 0.2), and 0.1⫾0.04% (95% CI, 0.00 – 0.2), respectively (Table 2). The incidence of early, late, and neovascular AMD per person was 4.2⫾0.4% (95% CI, 3.5–5.0), 0.1⫾0.1% (95% CI, 0.0 – 0.2), and 0.1⫾0.1% (95% CI, 0.0 – 0.2), respectively (Table 3). Data on the progression, regression and disappearance of AMD lesions are shown in Table 4. Including only subjects with an age of ⱖ50 years at baseline resulted in
Table 2. Incidence of Age-Related Macular Degeneration (AMD) per Eye in the Beijing Eye Study 2001/2006 Stratified by Age and Type of Macular Lesion Age Group 40–49 n Hard drusen 265/1889 Intermediate drusen (63–125 m) 48/2053 Soft distinct drusen (⬎125 m) 27/2113 Soft indistinct drusen (⬎125 m) 21/2145 Hyperpigmentation 70/2109 Hypopigmentation 63/1979 Geographic atrophy (ⱖ175 m) 0/2145 Early AMD 31/2099 Late AMD 0/2144 Neovascular AMD 0/2144
50–59
ⱖ70
60–69
Incidence, %
n
Incidence, %
n
Incidence, %
n
Incidence, %
Total Incidence
14.0 2.3 1.3 1.0 3.3 3.2 0.0 1.5 0.2 0.2
240/1382 65/1541 32/1593 26/1648 60/1600 41/1485 1/1651 43/1605 1/1650 1/1650
17.4 4.2 2.0 1.6 3.8 2.8 0.1 2.7 0.1 0.1
148/1268 62/1414 36/1497 38/1594 53/1546 32/1443 0/1592 56/1537 2/1589 2/1589
11.7 4.4 2.4 2.4 3.4 2.2 0.0 3.6 0.1 0.1
27/350 24/378 14/402 12/435 6/431 6/407 0/440 16/421 2/439 2/439
7.7 6.3 3.5 2.8 1.4 1.5 0.0 3.8 0.5 0.5
13.9 3.7 1.9 1.7 3.3 2.7 0.02 2.6 0.1 0.1
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Ophthalmology Volume 119, Number 12, December 2012 Table 3. Incidence of Age-Related Macular Degeneration (AMD) per Subject in the Beijing Eye Study 2001/2006, Stratified by Age and Gender Age Group (yrs)
Men Early AMD Late AMD Neovascular AMD Women Early AMD Late AMD Neovascular AMD
40–49
50–59
60–69
ⱖ70
Total
3.0⫾0.9 (1.2–4.8) 0 0
5.1⫾1.2 (2.7–7.5) 0.3⫾0.3 (0.0–1.0) 0.3⫾0.3 (0.0–1.0)
3.6⫾1.0 (1.6–5.6) 0.3⫾0.3 (0.0–0.9) 0.3⫾0.3 (0.0–0.9)
4.3⫾1.7 (1.0–7.6) 0.7⫾0.7 (0.0–2.1) 0.7⫾0.7 (0.0–2.1)
3.9⫾0.6 (2.7–5.1) 0.2⫾0.1 (0.0–0.4) 0.2⫾0.1 (0.0–0.4)
2.5⫾0.6 (1.3–3.7) 0 0
4.2⫾0.9 (2.4–6.0) 0 0
7.0⫾1.3 (4.5–9.5) 0 0
9.1⫾3.3 (2.6–15.6) 0 0
4.5⫾0.5 (3.5–5.5) 0 0
Values are presented as mean ⫾ standard error and 95% confidence interval.
analysis was performed in a stepwise manner. In the first step, the binary logistic analysis included the presence or absence of incident early AMD as a dependent variable and the systemic parameters of age, body height, region of habitation, level of education, profession, and smoker as dependent variables. It revealed that incident early AMD remained significantly associated with higher age only (P ⫽ 0.001), whereas the associations with body height (P ⫽ 0.32), region of habitation (P ⫽ 0.95), level of education (P ⫽ 0.38), profession (P ⫽ 0.42), and smoking (P ⫽ 0.24) were no longer significant. In the second step of the multivariate analysis, ocular parameters of refractive error, anterior corneal curvature, anterior chamber volume, scleral spur distance, and amount of nuclear cataract and optic disc size (Table 5) were added as independent parameters. This showed that incident early AMD was significantly associated with higher age at baseline (P ⫽ 0.01), smaller optic disc size (P ⫽ 0.007), smaller scleral spur distance (P ⫽ 0.04), and, marginally, with more hyperopic refractive error (P ⫽ 0.057), while anterior corneal curvature (P ⫽ 0.46), anterior chamber volume (P ⫽ 0.88), and amount of nuclear cataract were no longer associated significantly (P ⫽ 0.67; Table 6). If high myopia (defined as a myopic refractive error of more than – 8 diopters) were added to the multivariate analysis, the associations between incident early AMD and age (P ⫽ 0.02), hyperopic refractive error (P ⫽ 0.02), smaller optic disc size (P ⫽ 0.002), and smaller scleral spur distance (P ⫽ 0.04) remained significant, whereas high myopia was not associated significantly (P ⫽ 0.12) with incident early AMD. The numbers of eyes with incident late AMD (n ⫽ 5), including incident neovascular AMD (n ⫽ 5) and geographic atrophy (n ⫽ 1; 1 eye revealed simultaneous neovascularization and incident geographic atrophy), were too low for a meaningful analysis.
incidence figures (per eye) of 3.2⫾0.3% (95% CI, 2.7–3.8), 0.1⫾0.1% (95% CI, 0.0 – 0.3), and 0.1⫾0.1% (95% CI, 0.0 – 0.3) for early, late, and neovascular AMD, respectively. Incidence figures (per subjects) of 5.1⫾0.5% (95% CI, 4.1– 6.1), 0.1⫾0.1% (95% CI, 0.0 – 0.3), and 0.1⫾0.1% (95% CI, 0.0 – 0.3), for early, late, and neovascular AMD, respectively. Men and women did not differ significantly in the incidence of early (P ⫽ 0.79), late (P ⫽ 0.08), or neovascular AMD (P ⫽ 0.08; Table 3). By univariate analysis, incident early AMD was significantly associated with the systemic parameters of higher age (P⬍0.001), urban versus rural region of habitation (P ⫽ 0.002), lower level of education (P ⫽ 0.007), lower self-reported income (P ⫽ 0.006), profession (P⬍0.001), and smoking (P ⫽ 0.04); and with the ocular variables of more hyperopic refractive error (P⬍0.001), more marked nuclear cataract (P ⫽ 0.007), smaller scleral spur distance (P ⫽ 0.02), less anterior chamber volume (P ⫽ 0.02), and smaller optic disc size (P ⫽ 0.01; Table 5, available at http:// aaojournal.org). Incident early AMD was not significantly associated with gender, body height, body weight, body mass index, arterial blood pressure, presence of diabetes mellitus, fasting blood concentrations of glucose, triglycerides, high- or low-density lipoproteins, intraocular pressure, retinal arterial and vein diameters, retinal microvascular abnormalities, amount of cortical cataract or subcapsular cataract, pseudophakia, glaucomatous optic neuropathy in general and prevalence of open-angle glaucoma and angleclosure glaucoma in particular, presence of nonglaucomatous optic neuropathy, retinal vein occlusions, diabetic retinopathy, size of beta zone of parapapillary atrophy, or progression of the beta zone from 2001 to 2006 (Table 5). A multivariate binary logistic regression analysis included all parameters for which the P value of the association with incident early AMD was ⱕ0.10 in the univariate analysis. This multivariate
Table 4. Change of Age-Related Macular Degeneration (AMD) Lesions in the Beijing Eye Study 2001/2006 Progression
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Regression
Disappearing
Lesions
n
%
n
%
n
%
Hard drusen Intermediate drusen (63–125 m) Soft distinct drusen (⬎125 m) Soft indistinct drusen (⬎125 m) Hyperpigmentation Hypopigmentation Geographic atrophy Neovascular AMD
4/407 5/220 1/217 2/10 25/250 11/519 1/6 1/5
1.0 2.1 0.4 20 10 2.1 16.7 20
1/407 0/220 1/217 0/10 0/250 7/519 0/6 0/5
0.2 0 0.4 0 0 1.3 0 0
1/407 1/220 1/217 0/10 0/250 0/519 0/6 0/5
0.2 0.4 0.4 0 0 0 0 0
You et al 䡠 Incidence of AMD in Beijing Eye Study Table 6. Associations between Incident Early Age-Related Macular Degeneration and Systemic and Ocular Parameters in Multivariate Analysis in the Beijing Eye Study 2001/2006 Parameter
P
Odds Ratio
95% Confidence Interval
Age (yrs) Optic disc size (mm2) Scleral spur distance (mm) Refractive error (diopters) Anterior corneal curvature Nuclear cataract
0.01 0.007 0.04 0.057 0.54 0.65
1.03 0.50 0.59 1.15 — —
1.01–1.06 0.30–0.83 0.36–0.98 1.00–1.33 — —
Discussion The present report provides the 5-year cumulative incidence and changes in AMD lesions in an adult Chinese population living in the Greater Beijing area. The incidence of early, late, and neovascular AMD per eye was 2.6%, 0.1%, and 0.1%, respectively, and was 4.2%, 0.1%, and 0.1%, respectively, per subject. By multivariate analysis, incident early AMD was associated significantly with older age (P ⫽ 0.01; OR, 1.03), smaller optic disc size (P ⫽ 0.007; OR, 0.50), shorter scleral spur distance (P ⫽ 0.04; OR, 0.59), and hyperopic refractive error (P ⫽ 0.057; OR, 1.15; Table 6). Incident early AMD was not associated significantly with the systemic parameters of gender, body height, body mass index, region of habitation, level of education, profession, smoking, arterial blood pressure, diabetes mellitus, fasting blood concentrations of glucose, triglycerides, or high- or low-density lipoproteins, nor was it associated significantly with ocular parameters, such as intraocular pressure, retinal arterial and vein diameters, retinal microvascular abnormalities, amount of nuclear cataract, cortical cataract, subcapsular cataract, pseudophakia, glaucoma, nonglaucomatous optic neuropathy, retinal vein occlusions, size of beta zone of parapapillary atrophy, or progression of the beta zone during the follow-up period (2001 to 2006). The incidence of AMD found in our study on adult Chinese in Greater Beijing was less than that of incident AMD reported from 5-year studies on other ethnic groups, such as the Beaver Dam Eye Study incident (early/late AMD, 8.2%/0.9%; age at baseline, ⱖ43 years),3 the Blue Mountains Eye Study (early/late AMD, 8.7%/1.1%; age at baseline, ⱖ49 years),5 the Visual Impairment Project (early/ late AMD, 17.3/0.5%; age at baseline, ⱖ40 years),6 and the Japanese Hisayama Study (early/late AMD, 8.5%/0.8%; age, ⱖ50 years at baseline) compared with 5.1%/0.1% in our study population aged ⱖ50 years.11 It does, however, confirm previous findings of a lower prevalence of AMD in the population of the Beijing Eye Study and in the populations of other studies on Chinese, compared with investigations in Western populations.1–3,13–16 Correspondingly, the prevalence figures for early and late AMD did not differ markedly from the various studies of Chinese populations, such as the Taiwanese Shihpai Eye Study,14 the Handan Study,15 and the Multi-Ethnic Study of Atherosclerosis.21 The finding that incident early AMD was associated with hyperopia confirms previous prevalence studies in which hyperopia, besides age, was the strongest risk factor for
AMD, such as in the Rotterdam Study,22 the French Les Préventions de la Dégénérescence Maculaire Liée à l’Age (DMLA) Study,23 the Beijing Eye Study,24 the Age-Related Eye Disease Study,25 and in some hospital-based studies.26,27 It also confirms previous studies in which shorter axial length was significantly associated with the prevalence of AMD, such as in the Singapore Malay Eye or the Central India Eye and Medical Study.28,29 In contrast, the Beaver Dam Eye Study did not report an association between refractive errors and either the 5- or 10-year incidence of AMD.30 The Blue Mountains Eye Study described a weak cross-sectional association between AMD and hyperopia, which was not confirmed in a subsequent report on the 5-year incidence of AMD in the same study population.31 Interestingly, a small optic disc was associated with an increased incidence of early AMD in our study, after adjusting for age, refractive error, and scleral spur distance. This is a new finding, because previous studies did not test for potential associations between optic disc size and the incidence of AMD, although it is not in line with a previous cross-sectional analysis of AMD done in the Beaver Dam Eye Study, in which the vertical optic disc and cup measurements were not related to the presence or severity of AMD.32 To further strengthen the finding, we reperformed the multivariate analysis and added high myopia as an independent parameter because previous studies suggested that myopia was reversely associated with the prevalence of AMD.25 This analysis revealed that the association between incident early AMD and small disc size remained significant (P ⫽ 0.002), although the reason for this association remains unknown. It can be postulated that the association between optic disc size and size of the globe, as observed in a post mortem study, may have an influence.33 In that study, optic disc size was related to horizontal and vertical globe diameters, in addition to axial length. In small globes, compared with large eyes, the vitreous body is firmer, with a lower prevalence of posterior vitreous detachment. Because the horizontal and vertical globe diameter seem to have only an indirect association with refractive error, it may explain why disc size, in addition to refractive error and scleral spur distance, is related to incident AMD. If further studies confirm this finding, it may serve as an additional marker of risk for the development of early AMD. In a parallel manner, incident AMD was associated significantly with a shorter distance between the scleral spur, which, in addition to a small optic disc and hyperopia, again points to the association of a small globe and incident early AMD. The question arises why a small globe, as indicated by the associations between incident AMD and smaller optic disc, shorter scleral spur distance, and hyperopia, was a risk factor for incident AMD in our study, as well as for a risk factor for the prevalence of AMD in other investigations.22,26,28 Potential causes for the association may be differences in the properties of the vitreous body and in the prevalence of a posterior vitreous detachment,34 hemodynamic factors,26 or differences in the intraocular concentration of cytokines between myopic eyes and hyperopic eyes.35 The finding that the incidence of AMD was not related significantly to retinal microvascular abnormalities nor to retinal vessel diameters (Table 5) is in agreement with a
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Ophthalmology Volume 119, Number 12, December 2012 previous study of the same study population.36 The finding that incident early AMD was not associated with smoking (P ⫽ 0.24) after adjustment for age is in agreement with a previous study of the same population in which hyperopic refractive error, besides age, was the single most important risk factor for AMD, whereas smoking was not associated (P ⫽ 0.66) with AMD.25 This finding, of no relationship between incident AMD and smoking, disagrees with the results of the Beaver Dam Study, in which, after controlling for age, gender, and baseline severity of AMD, smoking was related to the long-term incidence and progression of AMD.37 The question arises whether the described association between smoking and AMD may be due, at least in part, to a confounding effect. Smoking is associated with a low socioeconomic background,38 and a low level of education is associated with a hyperopic refractive error.39 Correspondingly, smokers versus nonsmokers were significantly more hyperopic in a previous population-based study.38 Hyperopia has, however, been described to be associated with AMD in the present and in previous studies, so by combining it can be inferred that AMD may be more common in hyperopic subjects, who have a lower socioeconomic background and a higher frequency of smoking.40 Correspondingly, smoking was associated significantly (P ⫽ 0.04; OR, 1.62; 95% CI, 1.04 –2.52) with incident AMD in the univariate analysis in our study; and after adjustment for age and parameters of globe size (disc size, scleral spur distance, refractive error), smoking was no longer associated with incident AMD. In our study, men and women did not differ significantly in the incidence of early AMD, late AMD, or neovascular AMD (Table 3), in contrast with the Hisayama study, in which men had a significantly higher incidence of late AMD and of pigmentary abnormalities as part of early AMD than did women.11 In agreement with that study, the Singapore Malay Eye Study showed that late (1.0% vs 0.4%) and early AMD (6.1% vs 3.8%) were more prevalent in men than in women, although the difference was not significant after adjusting for age and smoking.28 Similarly, a recent meta-analysis revealed that Asian men had a higher point estimate of late AMD prevalence (18.6%) than did white men (10.1%), although Asian women had a lower point estimate prevalence (2.6%) than did white women (19.1%).16 It remains unclear whether there is an actual gender difference based on ethnicity in the incidence and prevalence of early or late AMD. Potential limitations of our study should be mentioned. First, a major concern, and a problem inherent to any epidemiologic study, is nonparticipation. The Beijing Eye Study 2006 had a reasonable response rate of the subjects who participated in the original 2001 survey; however, differences between participants and nonparticipants could have led to selection bias. Second, a specific limitation of our study could be because the group who had an examination in 2001 but declined participation in the second examination (2006) had a significantly lower visual acuity at baseline. If that group were affected by AMD, the estimates reported for progression to late AMD may have been underestimated, although the prevalence of early AMD and late AMD in the nonparticipating group was significantly higher than seen in the group that did participate (Table 1).
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Third, 91% of the study population was ⬍70 years of age (being 40 – 69), 9% of the study population was 70 to 79 years old, and only 0.6% (19 persons) was ⱖ80 years at baseline. The relatively low participation among older individuals, especially those who were ⱖ80 years of age, may also have led to an underestimation of the incidence of AMD. Fourth, cataract may have prevented precise examination of the fundus in some subjects, which also could have artificially reduced the incidence figures for AMD in the present study. Fifth, as a population-based study, fluorescein angiography and indocyanine green angiographies were not performed routinely, so the exudative or the neovascular form of AMD may have been confused with polypoidal choroidal vasculopathy. However, because the number of patients with exudative or neovascular AMD was rather small, this weakness may not have markedly influenced the results and conclusions of our investigation. One of the strengths of our study is that it is a population-based study with a relatively large sample size; furthermore, it is the first longitudinal, population-based study on the incidence of AMD in the population of China. In conclusion, the incidence of early, late, and neovascular AMD per eye and per subject was 2.6%/4.2%, 0.1%/ 0.1%, and 0.1%/0.1%, respectively. The incidence of early AMD was associated significantly with increased age, smaller optic disc size, and shorter interscleral spur distance and with a hyperopic refractive error. These factors are associated with early AMD, which may point to a small globe size, potentially in relation to a firmly attached vitreous, playing a role in early incident AMD.
References 1. Rahmani B, Tielsch JM, Katz J, et al. The cause-specific prevalence of visual impairment in an urban population: the Baltimore Eye Survey. Ophthalmology 1996;103:1721– 6. 2. Klaver CC, Wolfs RC, Vingerling JR, et al. Age-specific prevalence and causes of blindness and visual impairment in an older population: the Rotterdam Study. Arch Ophthalmol 1998;116:653– 8. 3. Klein R, Klein BE, Jensen SC, Meuer SM. The five-year incidence and progression of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 1997;104:7–21. 4. Klaver CC, Assink JJ, van Leeuwen R, et al. Incidence and progression rates of age-related maculopathy: the Rotterdam Study. Invest Ophthalmol Vis Sci 2001;42:2237– 41. 5. Mitchell P, Wang JJ, Foran S, Smith W. Five-year incidence of age-related maculopathy lesions: the Blue Mountains Eye Study. Ophthalmology 2002;109:1092–7. 6. Mukesh BN, Dimitrov PN, Leikin S, et al. Five-year incidence of age-related maculopathy: the Visual Impairment Project. Ophthalmology 2004;111:1176 – 82. 7. Varma R, Foong AW, Lai MY, et al, Los Angeles Latino Eye Study Group. Four-year incidence and progression of agerelated macular degeneration: the Los Angeles Latino Eye Study. Am J Ophthalmol 2010;149:741–51. 8. Leske MC, Wu SY, Hyman L, et al, Barbados Eye Studies Group. Four-year incidence of macular changes in the Barbados Eye Studies. Ophthalmology 2004;111:706 –11. 9. Buch H, Nielsen NV, Vinding T, et al. 14-year incidence, progression, and visual morbidity of age-related maculopathy: the Copenhagen City Eye Study. Ophthalmology 2005;112:787–98.
You et al 䡠 Incidence of AMD in Beijing Eye Study 10. Sparrow JM, Dickinson AJ, Duke AM, et al. Seven year follow-up of age-related maculopathy in an elderly British population. Eye (Lond) 1997;11:315–24. 11. Miyazaki M, Kiyohara Y, Yoshida A, et al. The 5-year incidence and risk factors for age-related maculopathy in a general Japanese population: the Hisayama study. Invest Ophthalmol Vis Sci 2005;46:1907–10. 12. Yasuda M, Kiyohara Y, Hata Y, et al. Nine-year incidence and risk factors for age-related macular degeneration in a defined Japanese population: the Hisayama study. Ophthalmology 2009;116:2135– 40. 13. Li Y, Xu L, Jonas JB, et al. Prevalence of age-related maculopathy in the adult population in China: the Beijing Eye Study. Am J Ophthalmol 2006;142:788 –93. 14. Chen SJ, Cheng CY, Peng KL, et al. Prevalence and associated risk factors of age-related macular degeneration in an elderly Chinese population in Taiwan: the Shihpai Eye Study. Invest Ophthalmol Vis Sci 2008;49:3126 –33. 15. Yang K, Liang YB, Gao LQ, et al. Prevalence of age-related macular degeneration in a rural Chinese population: the Handan Eye Study. Ophthalmology 2011;118:1395– 401. 16. Kawasaki R, Yasuda M, Song SJ, et al. The prevalence of age-related macular degeneration in Asians: a systematic review and meta-analysis. Ophthalmology 2010;117:921–7. 17. Xu L, Cao WF, Wang YX, et al. Anterior chamber depth and chamber angle and their associations with ocular and general parameters. The Beijing Eye Study. Am J Ophthalmol 2008; 145:929 –36. 18. Wang YX, Xu L, Yang H, Jonas JB. Prevalence of glaucoma in North China: the Beijing Eye Study. Am J Ophthalmol 2010;150:917–24. 19. Xie XW, Xu L, Wang YX, Jonas JB. Prevalence and associated factors of diabetic retinopathy: the Beijing Eye Study 2006. Graefes Arch Clin Exp Ophthalmol 2008;246:1519 –26. 20. Bird AC, Bressler NM, Bressler SB, et al, International ARM Epidemiological Study Group. An international classification and grading system for age-related maculopathy and age-related macular degeneration. Surv Ophthalmol 1995;39:367–74. 21. Klein R, Klein BE, Knudtson MD, et al. Prevalence of agerelated macular degeneration in 4 racial/ethnic groups in the Multi-ethnic Study of Atherosclerosis. Ophthalmology 2006; 113:373– 80. 22. Ikram MK, van Leeuwen R, Vingerling JR, et al. Relationship between refraction and prevalent as well as incident agerelated maculopathy: the Rotterdam Study. Invest Ophthalmol Vis Sci 2003;44:3778 – 82. 23. Chaine G, Hullo A, Sahel J, et al, FRANCE-DMLA Study Group. Case-control study of the risk factors for age related macular degeneration. Br J Ophthalmol 1998;82:996 –1002. 24. Age-Related Eye Disease Study Research Group. Risk factors associated with age-related macular degeneration: a casecontrol study in the Age-Related Eye Disease Study: AgeRelated Eye Disease Study report number 3. Ophthalmology 2000;107:2224 –32.
25. Xu L, Li Y, Zheng Y, Jonas JB. Associated factors for age-related maculopathy in the adult population in China: the Beijing Eye Study. Br J Ophthalmol 2006;90:1087–90. 26. Böker T, Fang T, Steinmetz R. Refractive error and choroidal perfusion characteristics in patients with choroidal neovascularization and age-related macular degeneration. Ger J Ophthalmol 1993;2:10 –3. 27. Tao Y, Jonas JB. Refractive error and smoking habits in exudative age-related macular degeneration in a hospitalbased setting. Eye (Lond) 2010;24:648 –52. 28. Lavanya R, Kawasaki R, Tay WT, et al. Hyperopic refractive error and shorter axial length are associated with age-related macular degeneration: the Singapore Malay Eye Study. Invest Ophthalmol Vis Sci 2010;51:6247–52. 29. Jonas JB, Nangia V, Kulkarni M, et al. Associations of early age-related macular degeneration with ocular and general parameters: the Central India Eyes and Medical Study [report online]. Acta Ophthalmol 2012;90:e185–91. 30. Wong TY, Klein R, Klein BE, Tomany SC. Refractive errors and 10-year incidence of age-related maculopathy. Invest Ophthalmol Vis Sci 2002;43:2869 –73. 31. Wang JJ, Jakobsen KB, Smith W, Mitchell P. Refractive status and the 5-year incidence of age-related maculopathy: the Blue Mountains Eye Study. Clin Experiment Ophthalmol 2004;32: 255– 8. 32. Hall ER, Klein BE, Knudtson MD, et al. Age-related macular degeneration and optic disk cupping: the Beaver Dam Eye Study. Am J Ophthalmol 2006;141:494 –7. 33. Papastathopoulos KI, Jonas JB, Panda-Jonas S. Large optic discs in large eyes, small optic discs in small eyes. Exp Eye Res 1995;60:459 – 61. 34. Hayreh SS, Jonas JB. Posterior vitreous detachment: clinical correlations. Ophthalmologica 2004;218:333– 43. 35. Jonas JB, Tao Y, Neumaier M, Findeisen P. VEGF and refractive error [letter]. Ophthalmology 2010;117:2234. 36. Xu L, Wang S, Li Y, Jonas JB. Retinal vascular abnormalities and prevalence of age-related macular degeneration in adult Chinese: the Beijing Eye Study. Am J Ophthalmol 2006;142: 688 –9. 37. Klein R, Knudtson MD, Cruickshanks KJ, Klein BE. Further observations on the association between smoking and the long-term incidence and progression of age-related macular degeneration: the Beaver Dam Eye Study. Arch Ophthalmol 2008;126:115–21. 38. Wang YX, Xu L, Wang S, Jonas JB. Prevalence of smoking and its associations with ocular parameters in adult Chinese: the Beijing Eye Study [report online] [letter]. Acta Ophthalmol 2011;89:e210 –2. 39. Xu L, Wang YX, Jonas JB. Level of education associated with ophthalmic diseases: the Beijing Eye Study. Graefes Arch Clin Exp Ophthalmol 2010;248:49 –57. 40. Jonas JB, Xu L. Smoking and age-related macular degeneration [letter]. Arch Ophthalmol 2009;127:826 –7; author reply 827.
Footnotes and Financial Disclosures Originally received: December 29, 2011. Final revision: June 13, 2012. Accepted: June 26, 2012. Available online: August 24, 2012. 1
Manuscript no. 2012-1.
Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing, China. 2 Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University, Heidelberg, Germany.
Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article. Supported by Beijing Nova Program (No. 2010B032) and National Natural Science Foundation of China (No. 81170890). Correspondence: Prof Liang Xu, Beijing Institute of Ophthalmology, 17 Hougou Lane, Chong Wen Men, 100005 Beijing, China. E-mail: [email protected].
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Age-related macular degeneration (AMD) is among most common causes of visual impairment and blindness in the adult population in Western countries.1,2 Its incidence has been assessed in previous longitudinal population-based studies on whites, such as the Beaver Dam Eye Study in Wisconsin, the Rotterdam Study in The Netherlands, the Blue Mountains Eye Study in Australia, and the Los Angeles Eye Study in California; on blacks in the Barbados Incidence Study of Eye Disease; and on Japanese in the Hisayama study.3–12 None of the these longitudinal studies was focused on Chinese populations. Given the wide variation in the prevalence and incidence of AMD, in particular considering that the prevalence of AMD seems to be lower © 2012 by the American Academy of Ophthalmology Published by Elsevier Inc.
among Chinese than Caucasians,13–17 it is desirable to have specific data on the incidence of AMD from a Chinese study population rather than extrapolating findings from other ethnic groups to persons of Chinese ancestry. It was therefore the purpose of this study to examine the incidence and rate of progression of AMD and its associated factors in the population from mainland China. The information gained may be helpful in understanding whether or not there is a difference between mainland Chinese and other ethnic groups in the occurrence of AMD, and whether or not there is a difference between ethnic groups in the risk factors for this condition. Increased knowledge of the risk factors of AMD may be useful for better prevention of the disease in ISSN 0161-6420/12/$–see front matter http://dx.doi.org/10.1016/j.ophtha.2012.06.043
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Ophthalmology Volume 119, Number 12, December 2012 the case of modifiable risk factors; it may provide hints to the pathogenesis of the disease and the data may be helpful for planning public health strategies.
Methods The Beijing Eye Study is a population-based study in Northern China. It was carried out in 4 communities in the urban district of Haidian in the north of central Beijing and in 3 communities in the village area of Yufa of the Daxing District south of Beijing. The urban district of central Beijing consists of an area extending about 5 km from Tianamen Place. The rural communities are located about 50 km from central Beijing and are easily accessible by car in about an hour via an express motorway. The study has been described in detail recently.13 The Medical Ethics Committee of Beijing Tongren Hospital approved the study protocol and all participants provided informed consent, according to the Declaration of Helsinki. At the time of the initial survey, in the year 2001, a total of 5324 individuals aged ⱖ40 years resided in the 7 communities, of which 4439 individuals (2505 women) participated in the eye examination (response rate, 83.4%). The study was divided into a rural part (1973 [44.4%] subjects) and an urban part (2466 [55.6%] subjects). Mean age of the participants was 56.2⫾10.6 years (range, 40 –101). In 2006, the study was repeated by reinviting all participants of the 2001 survey. All examinations were carried out in schoolhouses or community houses within the community being surveyed. Examinations performed in 2001 included measurement of uncorrected and best-corrected visual acuity, visual field examinations using frequency-doubling perimetry, pneumotonometry, slit-lamp– based biomicroscopy of the anterior segment, digital photography of the cornea, and retroilluminated photography of the lens. Monoscopic photographs of the macula and optic disc were obtained with a fundus camera (type CR6-45NM, Canon Inc, Melville, NY). Trained research technicians asked each study participant questions from a standard questionnaire, which yielded information on demographic variables and the known presence of the more common diseases, such as arterial hypertension, diabetes mellitus, coronary heart disease, hyperlipidemia, and stroke. Socioeconomic status of the participants was assessed with questions regarding level of education, occupation, and family income. The level of education was categorized into the stages of “illiteracy,” “half illiteracy with knowledge of some Chinese words,” “primary school education,” “middle school education,” and “college or higher education.” In the survey performed in 2006, additional examinations were carried out, such as optical coherence tomography of the anterior segment17 and blood sampling for biochemical analysis. Optical coherence tomography (Heidelberg Engineering, Dossenheim, Germany; scan size, maximum,15 mm; scan depth, 7 mm; lateral optical resolution capacity, 20 –100 m; axial optical resolution capacity, ⬍25 m; diode laser, 1310 nm) of the anterior segment was performed on the right eyes of each subject. The anterior chamber depth, scleral spur distance, and anterior chamber angle in the temporal and nasal regions were measured using a software program supplied with the device.17 Body height and weight were also assessed; blood pressure was measured. Using optic disc photographs, glaucoma was determined using the International Society of Geographical and Epidemiological Ophthalmology classification.18 Optic disc size was measured on digitized color optic disc photographs. The optic disc was defined as the entire area inside the peripapillary ring. Magnification by the optic media of the eye was corrected according to Littmann’s method, which took into account refractive error, as described previously.18 Diabetic retinopathy was defined as described by the criteria of the Early Treatment of Diabetic Retinopathy Study.19
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For the assessment of AMD, the International Age-related Maculopathy Epidemiological Study Group Grading system was used.13,20 A grid with 3 concentric circles with projected radii of 500, 1500, and 3000 m was applied to the fundus and 4 radial lines dividing the photograph into 9 subfields was used. A set of 5 circles, with corresponding sizes of 63, 125, 175, 250, and 500 m in diameter, was applied to estimate drusen size and the area involved by drusen or retinal pigmentary abnormalities. All slides were graded by a trained examiner (Y.Q.S.). The examiner first graded the slides obtained for the survey of 2006 in a masked manner, without any knowledge of the findings of either the 2001 survey or of age or gender of the participant. For the second step, the same examiner reassessed all slides with any lesion indicating AMD from either the baseline examination of 2001 or the follow-up examination of 2006. The 2 slides of the same eye were projected side by side, without the examiner knowing which slide was the more recent. If no difference between slides was detected, it was concluded that there was no change. If the more recent slide showed more severe damage, it was considered to be progression; if less damage was seen, it was considered regression. In a third step, performed 1 month later, 5% of the slides from 2006 were randomly reassessed by the same grader. In a fourth step, all slides showing late stage AMD and randomly selected slides of eyes with early AMD were reassessed by a panel of ophthalmologists (including Y.Q.S., X.L., J.B.J.). The early stage of AMD was defined as absence of any late AMD plus the presence of soft indistinct drusen, or any drusen (except hard drusen) combined with retinal pigment epithelium changes in the macular area. The late stage of AMD was defined as either neovascular AMD or geographic atrophy. Neovascular AMD included serous or hemorrhagic detachment of the retinal pigment epithelium or sensory retina; intraretinal or subretinal hemorrhages or hemorrhages beneath the retinal pigment epithelium, or a combination thereof; or subretinal fibrous scars. A definition of the incidence, progression, regression, and disappearance of AMD and associated lesions was similar to that seen in the Beaver Dam Eye Study.5 Briefly, incident late AMD (by subject) was defined by the appearance of late AMD lesions, that is, neovascular AMD or geographic atrophy involving the macular area in either eye at follow-up of persons in whom no late AMD was present at baseline. Incident early AMD (by subject) was defined as absence of late AMD in addition to the new appearance of soft indistinct drusen or any drusen (excluding hard drusen) combined with retinal pigment epithelium abnormalities in the macular area in either eye at the follow-up examination of persons in whom no early or late AMD was present at baseline. Data were presented by eye and by subject. A person with early AMD lesions in 1 eye at baseline and who developed early AMD in the second eye at follow-up was not counted as a subject with incident early AMD subject, but the second eye was counted as an incident early AMD eye when the results were tabulated by eye. The same rule was applied to late AMD. We assessed the most advanced type of drusen in each eye. A person with soft indistinct drusen at follow-up in either eye with only soft or no drusen at baseline was counted as incident indistinct drusen. The same rule applied to the other types of drusen. Progression was present if the same lesion was present at the 2001 examination and at the 2006 examination, but extended from the outer circle into the inner circle, involved ⱖ2 subfields of the grid, or, in the case of neovascular AMD, showed more severe lesions, for example, advancing from exudates at 2001 to a subretinal scar at 2006. Regression meant that the same lesion was no longer present in ⱖ2 subfields, or was no longer present in the central subfield. Disappearance meant the lesion had disappeared at the time of the 2006 examination, although it was present at the 2001 examination. Persons without late AMD in either eye at baseline were counted as at risk
You et al 䡠 Incidence of AMD in Beijing Eye Study Table 1. Demographic Data on the Participants of the Beijing Eye Study 2001/2006, Compared with Subjects Excluded Owing to Death During Follow-up or to Nonparticipation in 2006 Characteristics at Baseline 2001
Participants from 2001 and Included in 2006
Participants from 2001 Not Participating in 2006
P
Participants from 2001 Who Died during Follow-up
n Mean age (yrs) Women (%) Currently married (%) History of diabetes (%) History of hypertension (%) History of coronary heart disease (%) Stroke history (%) History of hyperlipidemia (%) Ever smoking (%) Alcohol consumption (%) Best corrected visual acuity (right eye) Prevalence of early AMD in 2001 (%) Prevalence of late AMD in 2001 (%) Prevalence of neovascular AMD in 2001 (%)
3049 54.9⫾9.8 56.5 96.0 (%) 6.2 22.7 13.6 3.5 23.4 22.7 12.4 0.92⫾0.18 5.2 0.2 0.1
1247 58.4⫾11.5 58.2 93.8 (%) 6.8 20.8 12.3 3.8 20.5 21.2 9.1 0.86⫾0.26 5.3 0.5 0.4
— ⬍0.001 0.441 ⬍0.001 0.513 0.219 0.326 0.657 0.093 0.333 0.047 ⬍0.001 0.911 0.106 0.021
143 65.7⫾10.4 43.4 79.0 (%) 15.7 33.1 19.8 17.4 20.3 30.6 18.2 0.72⫾0.33 5.0 0.0 0.0
AMD ⫽ age-related macular degeneration. Data for age and visual acuity are given as mean values ⫾ standard deviation.
of incident late AMD; those without early or late AMD in either eye at baseline were counted as at risk of incident early AMD. Persons with early AMD but absent late AMD in either eye at 2001 were at risk of incident late AMD, but were excluded for assessment of incident early AMD. Statistical analysis was performed using a commercially available statistical software package (SPSS for Windows, version 19.0, IBM-SPSS, Chicago, IL). The data were presented as mean values ⫾ standard deviations; odds ratios (OR) were calculated. Chi-square tests were used to compare proportions. Logistic regression was used to investigate the associations between incident AMD and continuous or categorical independent variables, such as age, gender, and refractive error. Confidence intervals (CI) of 95% are presented. All P-values are 2-sided and were considered significant when the values were ⬍0.05.
Results Of the 4439 subjects examined in 2001 and invited for reexamination in 2006, 3251 (73.2%) returned; 143 (3.2%) subjects had
died and 1045 (23.5%) subjects were alive but did not agree to be reexamined. Gradable fundus slides of the 2006 survey were available on 5957 eyes of 3079 (94.7%) persons. Gradable slides for the examination of 2001 and for the examination of 2006 were available on 5831 eyes of 3049 persons, who are included in the present study. At the baseline examination of 2001, the mean age of these 3049 subjects (1331 [43.7%] males) was 54.9⫾9.8 (range, 40 – 82 years), and 1403 (46%) participants resided in 1 of the rural areas. The group of subjects included in the present study, compared with the subjects not included, was significantly younger, tended to be currently married, and their best-corrected visual acuity was significantly better (Table 1). The incidence of early, late, and neovascular AMD per eye (mean ⫾ standard error) was 2.6⫾0.2% (95% CI, 2.2–3.0), 0.1⫾0.04% (95% CI, 0.00 – 0.2), and 0.1⫾0.04% (95% CI, 0.00 – 0.2), respectively (Table 2). The incidence of early, late, and neovascular AMD per person was 4.2⫾0.4% (95% CI, 3.5–5.0), 0.1⫾0.1% (95% CI, 0.0 – 0.2), and 0.1⫾0.1% (95% CI, 0.0 – 0.2), respectively (Table 3). Data on the progression, regression and disappearance of AMD lesions are shown in Table 4. Including only subjects with an age of ⱖ50 years at baseline resulted in
Table 2. Incidence of Age-Related Macular Degeneration (AMD) per Eye in the Beijing Eye Study 2001/2006 Stratified by Age and Type of Macular Lesion Age Group 40–49 n Hard drusen 265/1889 Intermediate drusen (63–125 m) 48/2053 Soft distinct drusen (⬎125 m) 27/2113 Soft indistinct drusen (⬎125 m) 21/2145 Hyperpigmentation 70/2109 Hypopigmentation 63/1979 Geographic atrophy (ⱖ175 m) 0/2145 Early AMD 31/2099 Late AMD 0/2144 Neovascular AMD 0/2144
50–59
ⱖ70
60–69
Incidence, %
n
Incidence, %
n
Incidence, %
n
Incidence, %
Total Incidence
14.0 2.3 1.3 1.0 3.3 3.2 0.0 1.5 0.2 0.2
240/1382 65/1541 32/1593 26/1648 60/1600 41/1485 1/1651 43/1605 1/1650 1/1650
17.4 4.2 2.0 1.6 3.8 2.8 0.1 2.7 0.1 0.1
148/1268 62/1414 36/1497 38/1594 53/1546 32/1443 0/1592 56/1537 2/1589 2/1589
11.7 4.4 2.4 2.4 3.4 2.2 0.0 3.6 0.1 0.1
27/350 24/378 14/402 12/435 6/431 6/407 0/440 16/421 2/439 2/439
7.7 6.3 3.5 2.8 1.4 1.5 0.0 3.8 0.5 0.5
13.9 3.7 1.9 1.7 3.3 2.7 0.02 2.6 0.1 0.1
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Ophthalmology Volume 119, Number 12, December 2012 Table 3. Incidence of Age-Related Macular Degeneration (AMD) per Subject in the Beijing Eye Study 2001/2006, Stratified by Age and Gender Age Group (yrs)
Men Early AMD Late AMD Neovascular AMD Women Early AMD Late AMD Neovascular AMD
40–49
50–59
60–69
ⱖ70
Total
3.0⫾0.9 (1.2–4.8) 0 0
5.1⫾1.2 (2.7–7.5) 0.3⫾0.3 (0.0–1.0) 0.3⫾0.3 (0.0–1.0)
3.6⫾1.0 (1.6–5.6) 0.3⫾0.3 (0.0–0.9) 0.3⫾0.3 (0.0–0.9)
4.3⫾1.7 (1.0–7.6) 0.7⫾0.7 (0.0–2.1) 0.7⫾0.7 (0.0–2.1)
3.9⫾0.6 (2.7–5.1) 0.2⫾0.1 (0.0–0.4) 0.2⫾0.1 (0.0–0.4)
2.5⫾0.6 (1.3–3.7) 0 0
4.2⫾0.9 (2.4–6.0) 0 0
7.0⫾1.3 (4.5–9.5) 0 0
9.1⫾3.3 (2.6–15.6) 0 0
4.5⫾0.5 (3.5–5.5) 0 0
Values are presented as mean ⫾ standard error and 95% confidence interval.
analysis was performed in a stepwise manner. In the first step, the binary logistic analysis included the presence or absence of incident early AMD as a dependent variable and the systemic parameters of age, body height, region of habitation, level of education, profession, and smoker as dependent variables. It revealed that incident early AMD remained significantly associated with higher age only (P ⫽ 0.001), whereas the associations with body height (P ⫽ 0.32), region of habitation (P ⫽ 0.95), level of education (P ⫽ 0.38), profession (P ⫽ 0.42), and smoking (P ⫽ 0.24) were no longer significant. In the second step of the multivariate analysis, ocular parameters of refractive error, anterior corneal curvature, anterior chamber volume, scleral spur distance, and amount of nuclear cataract and optic disc size (Table 5) were added as independent parameters. This showed that incident early AMD was significantly associated with higher age at baseline (P ⫽ 0.01), smaller optic disc size (P ⫽ 0.007), smaller scleral spur distance (P ⫽ 0.04), and, marginally, with more hyperopic refractive error (P ⫽ 0.057), while anterior corneal curvature (P ⫽ 0.46), anterior chamber volume (P ⫽ 0.88), and amount of nuclear cataract were no longer associated significantly (P ⫽ 0.67; Table 6). If high myopia (defined as a myopic refractive error of more than – 8 diopters) were added to the multivariate analysis, the associations between incident early AMD and age (P ⫽ 0.02), hyperopic refractive error (P ⫽ 0.02), smaller optic disc size (P ⫽ 0.002), and smaller scleral spur distance (P ⫽ 0.04) remained significant, whereas high myopia was not associated significantly (P ⫽ 0.12) with incident early AMD. The numbers of eyes with incident late AMD (n ⫽ 5), including incident neovascular AMD (n ⫽ 5) and geographic atrophy (n ⫽ 1; 1 eye revealed simultaneous neovascularization and incident geographic atrophy), were too low for a meaningful analysis.
incidence figures (per eye) of 3.2⫾0.3% (95% CI, 2.7–3.8), 0.1⫾0.1% (95% CI, 0.0 – 0.3), and 0.1⫾0.1% (95% CI, 0.0 – 0.3) for early, late, and neovascular AMD, respectively. Incidence figures (per subjects) of 5.1⫾0.5% (95% CI, 4.1– 6.1), 0.1⫾0.1% (95% CI, 0.0 – 0.3), and 0.1⫾0.1% (95% CI, 0.0 – 0.3), for early, late, and neovascular AMD, respectively. Men and women did not differ significantly in the incidence of early (P ⫽ 0.79), late (P ⫽ 0.08), or neovascular AMD (P ⫽ 0.08; Table 3). By univariate analysis, incident early AMD was significantly associated with the systemic parameters of higher age (P⬍0.001), urban versus rural region of habitation (P ⫽ 0.002), lower level of education (P ⫽ 0.007), lower self-reported income (P ⫽ 0.006), profession (P⬍0.001), and smoking (P ⫽ 0.04); and with the ocular variables of more hyperopic refractive error (P⬍0.001), more marked nuclear cataract (P ⫽ 0.007), smaller scleral spur distance (P ⫽ 0.02), less anterior chamber volume (P ⫽ 0.02), and smaller optic disc size (P ⫽ 0.01; Table 5, available at http:// aaojournal.org). Incident early AMD was not significantly associated with gender, body height, body weight, body mass index, arterial blood pressure, presence of diabetes mellitus, fasting blood concentrations of glucose, triglycerides, high- or low-density lipoproteins, intraocular pressure, retinal arterial and vein diameters, retinal microvascular abnormalities, amount of cortical cataract or subcapsular cataract, pseudophakia, glaucomatous optic neuropathy in general and prevalence of open-angle glaucoma and angleclosure glaucoma in particular, presence of nonglaucomatous optic neuropathy, retinal vein occlusions, diabetic retinopathy, size of beta zone of parapapillary atrophy, or progression of the beta zone from 2001 to 2006 (Table 5). A multivariate binary logistic regression analysis included all parameters for which the P value of the association with incident early AMD was ⱕ0.10 in the univariate analysis. This multivariate
Table 4. Change of Age-Related Macular Degeneration (AMD) Lesions in the Beijing Eye Study 2001/2006 Progression
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Regression
Disappearing
Lesions
n
%
n
%
n
%
Hard drusen Intermediate drusen (63–125 m) Soft distinct drusen (⬎125 m) Soft indistinct drusen (⬎125 m) Hyperpigmentation Hypopigmentation Geographic atrophy Neovascular AMD
4/407 5/220 1/217 2/10 25/250 11/519 1/6 1/5
1.0 2.1 0.4 20 10 2.1 16.7 20
1/407 0/220 1/217 0/10 0/250 7/519 0/6 0/5
0.2 0 0.4 0 0 1.3 0 0
1/407 1/220 1/217 0/10 0/250 0/519 0/6 0/5
0.2 0.4 0.4 0 0 0 0 0
You et al 䡠 Incidence of AMD in Beijing Eye Study Table 6. Associations between Incident Early Age-Related Macular Degeneration and Systemic and Ocular Parameters in Multivariate Analysis in the Beijing Eye Study 2001/2006 Parameter
P
Odds Ratio
95% Confidence Interval
Age (yrs) Optic disc size (mm2) Scleral spur distance (mm) Refractive error (diopters) Anterior corneal curvature Nuclear cataract
0.01 0.007 0.04 0.057 0.54 0.65
1.03 0.50 0.59 1.15 — —
1.01–1.06 0.30–0.83 0.36–0.98 1.00–1.33 — —
Discussion The present report provides the 5-year cumulative incidence and changes in AMD lesions in an adult Chinese population living in the Greater Beijing area. The incidence of early, late, and neovascular AMD per eye was 2.6%, 0.1%, and 0.1%, respectively, and was 4.2%, 0.1%, and 0.1%, respectively, per subject. By multivariate analysis, incident early AMD was associated significantly with older age (P ⫽ 0.01; OR, 1.03), smaller optic disc size (P ⫽ 0.007; OR, 0.50), shorter scleral spur distance (P ⫽ 0.04; OR, 0.59), and hyperopic refractive error (P ⫽ 0.057; OR, 1.15; Table 6). Incident early AMD was not associated significantly with the systemic parameters of gender, body height, body mass index, region of habitation, level of education, profession, smoking, arterial blood pressure, diabetes mellitus, fasting blood concentrations of glucose, triglycerides, or high- or low-density lipoproteins, nor was it associated significantly with ocular parameters, such as intraocular pressure, retinal arterial and vein diameters, retinal microvascular abnormalities, amount of nuclear cataract, cortical cataract, subcapsular cataract, pseudophakia, glaucoma, nonglaucomatous optic neuropathy, retinal vein occlusions, size of beta zone of parapapillary atrophy, or progression of the beta zone during the follow-up period (2001 to 2006). The incidence of AMD found in our study on adult Chinese in Greater Beijing was less than that of incident AMD reported from 5-year studies on other ethnic groups, such as the Beaver Dam Eye Study incident (early/late AMD, 8.2%/0.9%; age at baseline, ⱖ43 years),3 the Blue Mountains Eye Study (early/late AMD, 8.7%/1.1%; age at baseline, ⱖ49 years),5 the Visual Impairment Project (early/ late AMD, 17.3/0.5%; age at baseline, ⱖ40 years),6 and the Japanese Hisayama Study (early/late AMD, 8.5%/0.8%; age, ⱖ50 years at baseline) compared with 5.1%/0.1% in our study population aged ⱖ50 years.11 It does, however, confirm previous findings of a lower prevalence of AMD in the population of the Beijing Eye Study and in the populations of other studies on Chinese, compared with investigations in Western populations.1–3,13–16 Correspondingly, the prevalence figures for early and late AMD did not differ markedly from the various studies of Chinese populations, such as the Taiwanese Shihpai Eye Study,14 the Handan Study,15 and the Multi-Ethnic Study of Atherosclerosis.21 The finding that incident early AMD was associated with hyperopia confirms previous prevalence studies in which hyperopia, besides age, was the strongest risk factor for
AMD, such as in the Rotterdam Study,22 the French Les Préventions de la Dégénérescence Maculaire Liée à l’Age (DMLA) Study,23 the Beijing Eye Study,24 the Age-Related Eye Disease Study,25 and in some hospital-based studies.26,27 It also confirms previous studies in which shorter axial length was significantly associated with the prevalence of AMD, such as in the Singapore Malay Eye or the Central India Eye and Medical Study.28,29 In contrast, the Beaver Dam Eye Study did not report an association between refractive errors and either the 5- or 10-year incidence of AMD.30 The Blue Mountains Eye Study described a weak cross-sectional association between AMD and hyperopia, which was not confirmed in a subsequent report on the 5-year incidence of AMD in the same study population.31 Interestingly, a small optic disc was associated with an increased incidence of early AMD in our study, after adjusting for age, refractive error, and scleral spur distance. This is a new finding, because previous studies did not test for potential associations between optic disc size and the incidence of AMD, although it is not in line with a previous cross-sectional analysis of AMD done in the Beaver Dam Eye Study, in which the vertical optic disc and cup measurements were not related to the presence or severity of AMD.32 To further strengthen the finding, we reperformed the multivariate analysis and added high myopia as an independent parameter because previous studies suggested that myopia was reversely associated with the prevalence of AMD.25 This analysis revealed that the association between incident early AMD and small disc size remained significant (P ⫽ 0.002), although the reason for this association remains unknown. It can be postulated that the association between optic disc size and size of the globe, as observed in a post mortem study, may have an influence.33 In that study, optic disc size was related to horizontal and vertical globe diameters, in addition to axial length. In small globes, compared with large eyes, the vitreous body is firmer, with a lower prevalence of posterior vitreous detachment. Because the horizontal and vertical globe diameter seem to have only an indirect association with refractive error, it may explain why disc size, in addition to refractive error and scleral spur distance, is related to incident AMD. If further studies confirm this finding, it may serve as an additional marker of risk for the development of early AMD. In a parallel manner, incident AMD was associated significantly with a shorter distance between the scleral spur, which, in addition to a small optic disc and hyperopia, again points to the association of a small globe and incident early AMD. The question arises why a small globe, as indicated by the associations between incident AMD and smaller optic disc, shorter scleral spur distance, and hyperopia, was a risk factor for incident AMD in our study, as well as for a risk factor for the prevalence of AMD in other investigations.22,26,28 Potential causes for the association may be differences in the properties of the vitreous body and in the prevalence of a posterior vitreous detachment,34 hemodynamic factors,26 or differences in the intraocular concentration of cytokines between myopic eyes and hyperopic eyes.35 The finding that the incidence of AMD was not related significantly to retinal microvascular abnormalities nor to retinal vessel diameters (Table 5) is in agreement with a
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Ophthalmology Volume 119, Number 12, December 2012 previous study of the same study population.36 The finding that incident early AMD was not associated with smoking (P ⫽ 0.24) after adjustment for age is in agreement with a previous study of the same population in which hyperopic refractive error, besides age, was the single most important risk factor for AMD, whereas smoking was not associated (P ⫽ 0.66) with AMD.25 This finding, of no relationship between incident AMD and smoking, disagrees with the results of the Beaver Dam Study, in which, after controlling for age, gender, and baseline severity of AMD, smoking was related to the long-term incidence and progression of AMD.37 The question arises whether the described association between smoking and AMD may be due, at least in part, to a confounding effect. Smoking is associated with a low socioeconomic background,38 and a low level of education is associated with a hyperopic refractive error.39 Correspondingly, smokers versus nonsmokers were significantly more hyperopic in a previous population-based study.38 Hyperopia has, however, been described to be associated with AMD in the present and in previous studies, so by combining it can be inferred that AMD may be more common in hyperopic subjects, who have a lower socioeconomic background and a higher frequency of smoking.40 Correspondingly, smoking was associated significantly (P ⫽ 0.04; OR, 1.62; 95% CI, 1.04 –2.52) with incident AMD in the univariate analysis in our study; and after adjustment for age and parameters of globe size (disc size, scleral spur distance, refractive error), smoking was no longer associated with incident AMD. In our study, men and women did not differ significantly in the incidence of early AMD, late AMD, or neovascular AMD (Table 3), in contrast with the Hisayama study, in which men had a significantly higher incidence of late AMD and of pigmentary abnormalities as part of early AMD than did women.11 In agreement with that study, the Singapore Malay Eye Study showed that late (1.0% vs 0.4%) and early AMD (6.1% vs 3.8%) were more prevalent in men than in women, although the difference was not significant after adjusting for age and smoking.28 Similarly, a recent meta-analysis revealed that Asian men had a higher point estimate of late AMD prevalence (18.6%) than did white men (10.1%), although Asian women had a lower point estimate prevalence (2.6%) than did white women (19.1%).16 It remains unclear whether there is an actual gender difference based on ethnicity in the incidence and prevalence of early or late AMD. Potential limitations of our study should be mentioned. First, a major concern, and a problem inherent to any epidemiologic study, is nonparticipation. The Beijing Eye Study 2006 had a reasonable response rate of the subjects who participated in the original 2001 survey; however, differences between participants and nonparticipants could have led to selection bias. Second, a specific limitation of our study could be because the group who had an examination in 2001 but declined participation in the second examination (2006) had a significantly lower visual acuity at baseline. If that group were affected by AMD, the estimates reported for progression to late AMD may have been underestimated, although the prevalence of early AMD and late AMD in the nonparticipating group was significantly higher than seen in the group that did participate (Table 1).
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Third, 91% of the study population was ⬍70 years of age (being 40 – 69), 9% of the study population was 70 to 79 years old, and only 0.6% (19 persons) was ⱖ80 years at baseline. The relatively low participation among older individuals, especially those who were ⱖ80 years of age, may also have led to an underestimation of the incidence of AMD. Fourth, cataract may have prevented precise examination of the fundus in some subjects, which also could have artificially reduced the incidence figures for AMD in the present study. Fifth, as a population-based study, fluorescein angiography and indocyanine green angiographies were not performed routinely, so the exudative or the neovascular form of AMD may have been confused with polypoidal choroidal vasculopathy. However, because the number of patients with exudative or neovascular AMD was rather small, this weakness may not have markedly influenced the results and conclusions of our investigation. One of the strengths of our study is that it is a population-based study with a relatively large sample size; furthermore, it is the first longitudinal, population-based study on the incidence of AMD in the population of China. In conclusion, the incidence of early, late, and neovascular AMD per eye and per subject was 2.6%/4.2%, 0.1%/ 0.1%, and 0.1%/0.1%, respectively. The incidence of early AMD was associated significantly with increased age, smaller optic disc size, and shorter interscleral spur distance and with a hyperopic refractive error. These factors are associated with early AMD, which may point to a small globe size, potentially in relation to a firmly attached vitreous, playing a role in early incident AMD.
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Footnotes and Financial Disclosures Originally received: December 29, 2011. Final revision: June 13, 2012. Accepted: June 26, 2012. Available online: August 24, 2012. 1
Manuscript no. 2012-1.
Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing, China. 2 Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University, Heidelberg, Germany.
Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article. Supported by Beijing Nova Program (No. 2010B032) and National Natural Science Foundation of China (No. 81170890). Correspondence: Prof Liang Xu, Beijing Institute of Ophthalmology, 17 Hougou Lane, Chong Wen Men, 100005 Beijing, China. E-mail: [email protected].
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