- Email: [email protected]
Mortality and Ocular Diseases
Mortality and Ocular Diseases The Beijing Eye Study Liang Xu, MD,1 Ya Xing Wang, MD,1 Jian Wang, MD,1 Jost J. Jonas, MD1,2 Objective: To examine the relationship between mortality and major ocular diseases. Design: Population-based study. Participants: At baseline in 2001, the Beijing Eye Study examined 4439 subjects with an age of 40 years or more. The mean age was 56.2⫾10.6 years (range, 40 –101 years). In 2006, all study participants were invited for a follow-up examination. Methods: The participants underwent a detailed ophthalmic examination and answered questions regarding their socioeconomic background. Rate of mortality was determined in the follow-up survey of 2006. Main Outcome Measures: Factors associated with mortality. Results: Of the 4439 subjects examined in the 2001, 3251 (73.2%) subjects returned for the follow-up examination, whereas 143 (3.2%) subjects had died and 1045 (23.5%) subjects were alive but did not agree to be reexamined. In binary logistic regression analysis, mortality was significantly associated with the systemic parameters of higher age (P⬍0.001; odds ratio [OR], 1.07), male gender (P ⫽ 0.01; OR, 0.55), lower level of education (P⬍0.001; OR, 0.65), smoking status (P ⫽ 0.023; OR, 1.25), and with the ocular parameters of level of diabetic-like retinopathy (P ⫽ 0.036; OR, 1.02), presence of angle-closure glaucoma (P ⫽ 0.013; OR, 3.74), and presence of nonglaucomatous optic nerve damage (P ⫽ 0.027; OR, 3.41). Presence of retinal vein occlusions was associated marginally with mortality (P ⫽ 0.059; OR, 2.59). Mortality was not significantly associated with best-corrected visual acuity (P ⫽ 0.14) in multivariate analysis, nor with age-related macular degeneration, open-angle glaucoma, trachoma, any type of cataract, visual field defects, intraocular pressure, or refractive error. Conclusions: If socioeconomic parameters, age, gender, and smoking status were taken into account, ocular parameters associated with an increased mortality were diabetic-like retinopathy, angle-closure glaucoma, and nonglaucomatous optic nerve damage. Retinal vein occlusions were marginally associated. Other major ocular disorders such as any form of cataract, open-angle glaucoma, age-related macular degeneration, trachoma, pterygia, and high myopia or high hyperopia were not significantly related to mortality. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2009;116:732–738 © 2009 by the American Academy of Ophthalmology.
The major ocular diseases such as the glaucomas, macular degeneration, and cataract are strongly related with higher age, independent of ethnic background.1– 6 Because higher age is the major risk factor for mortality, the major ocular diseases also are strongly related to increased mortality if, in a univariate analysis, age and other confounding factors are not taken into account. As with any other major disease, the question of whether ocular disorders are associated with an increased risk of death or whether the association between increased mortality and the occurrence of the ocular diseases is caused simply by the relationship with higher age is unclear. This question has clinical importance because if an ocular disease is associated with increased mortality, its development should initiate a major clinical examination to detect the underlying disorder, leading to the ophthalmic disease and the increased mortality. To detect associations between ocular diseases and mortality also may provide information regarding the pathogenesis of the ocular disease. Previous studies have suggested that subjects with glaucoma, subcapsular cataract, retinal vein occlusions, and low
732
© 2009 by the American Academy of Ophthalmology Published by Elsevier Inc.
vision in general may have increased mortality.7–39 Most of these studies were focused, however, only on one ocular disease, and socioeconomic parameters mostly were not taken into account. In addition, only a few investigations of the Chinese population have been carried out, which is the society with the largest population worldwide. Therefore, the purpose of this study was to examine the multivariate relationships between mortality and the major ocular diseases in a population-based investigation in mainland China.
Patients and 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 study has been described in detail recently.40,41 The Medical Ethics Committee of the Beijing Tongren Hospital approved the study protocol and all participants gave informed consent, according to the Declaration of Helsinki. At the time of the first survey ISSN 0161-6420/09/$–see front matter doi:10.1016/j.ophtha.2008.11.003
Xu et al 䡠 Mortality and Ocular Diseases in the year 2001, the 7 communities had a total population of 5324 individuals aged 40 years or older. In total, 4439 individuals (2505 women) participated in the eye examination, corresponding to an overall response rate of 83.4%. The study was divided into a rural part (1973 subjects; 1143 women) and an urban part (2466 subjects; 1362 women). The mean age was 56.2⫾10.6 years (median, 56 years; range, 40 –101 years). In 2006, the study was repeated by inviting all participants from the survey from 2001 to be reexamined. All examinations were carried out in the communities, either in schoolhouses or in community houses. Uncorrected visual acuity was measured (Snellen charts) in a distance of 5 m. Automatic refractometry (Auto Refractometer AR-610; Nidek Co., Ltd., Tokyo, Japan) was performed if uncorrected visual acuity was lower than 1.0. Visual field examinations were performed by frequencydoubling perimetry using the screening program C-20-1 (ZeissHumphrey, Dublin, CA). Intraocular pressure was measured using a noncontact pneumotonometer (CT-60 computerized tonometer; Topcon, Ltd., Tokyo, Japan) by an experienced technician. A slit-lamp examination was carried out by an ophthalmologist. The anterior chamber depth was assessed using the method of van Herick et al.42 Gonioscopy was performed routinely by an experienced glaucoma specialist for all study participants with glaucoma and all glaucoma suspects. Glaucoma suspects were all those with an intraocular pressure of more than 21 mmHg, an abnormal result in frequency doubling perimetry, an abnormal finding in slit-lamp biomicroscopy such as a shallow anterior chamber, or changes in the anterior segment of the eye suggesting glaucoma, such as peripheral anterior synechiae, iris whirling, and glaukomflecken of the lens. Gonioscopy was performed before the pupil dilatation. The pupil was dilated using tropicamide once or twice, until the pupil diameter was at least 6 mm. Digital photographs of the cornea and retroilluminated photographs of the lens were obtained using the Neitz CT-R camera (Neitz Instruments Co., Tokyo, Japan). Monoscopic photographs (on film) of the macula and optic disc were obtained using a fundus camera (Type CR6-45NM; Canon, Inc., Tokyo, Japan). According to the classification of the World Health Organization,43 diagnostic criteria for trachoma were trachomatous inflammation characterized by 5 follicles or more, at least 0.5 mm in size, on the flat surface of the upper tarsal conjunctiva (stage 1); intensive trachomatous inflammation characterized by inflammatory thickening of the upper tarsal conjunctiva with more than half of the normal deep tarsal vessels obscured (stage 2); trachomatous scarring with scarring of the tarsal conjunctiva (stage 3); trachomatous trichiasis with at least 1 eyelash rubbing on the eyeball or evidence of eyelash removal (stage 4); and corneal opacity when at least a part of the pupil was blurred or obscured (stage 5). On the corneal photographs, the cornea was examined for the presence of a pterygium. A pterygium was defined as an extension of conjunctiva onto the clear cornea for which there was no alternative explanation such as ocular trauma. Using the lens photographs, the degree of nuclear cataract was graded in 6 grades according to the lens photographs using the classifying scheme for cataract of the Age-Related Eye Disease Study.44 Standard photographs 6 and 7 were combined into 1 grade, that is, grade 6. Grade 1 was no nuclear opacity in the lens, and grade 6 was very dense nuclear lens opacity. The degree of cortical lens opacification and posterior subcapsular lens opacification was graded using 2 photographs obtained using retroillumination with the Neitz CT-R camera. Cortical and posterior subcapsular opacities appeared as darkly shaded areas on the white background through the computer screen. The percent area of opacity was measured using a grid. The optic disc photographs were digitized and the optic disc structures were measured by outlining the borders of the optic disc, optic cup, peripapillary scleral ring, and ␣ zone and  zone of
peripapillary atrophy border on the computer screen.41 Additionally, the occurrence of optic disc hemorrhages was noted. Glaucomatous optic nerve damage was defined by the appearance of the optic nerve head as described in detail recently.41 Open-angle glaucoma was characterized by an open anterior chamber angle and a normal depth of the anterior chamber as assessed by slitlamp biomicroscopy and gonioscopy. In angle-closure glaucoma, the anterior chamber angle was occluded, or there was appositional contact between the peripheral iris and the cornea for at least 15°; that is, the Schwalbe line could not be visualized. In addition, other features for angle-closure glaucoma were peripheral anterior synechiae, iris whirling (distortion of the radially orientated iris structures), and glaukomflecken in the anterior subcapsular lens region, in combination with a narrow anterior chamber angle. Nonglaucomatous optic nerve damage was characterized by a decreased visibility of the retinal nerve fiber layer, a decreased diameter of the retinal arteries, an increased pallor of the neuroretinal rim, a normal shape of the neuroretinal rim, and a normal appearance of the peripapillary region with respect to ␣ zone and  zone of peripapillary atrophy.45 Using the fundus photographs (nonstereoscopic photograph of 50° of the central fundus), diabetic or diabetic-like retinopathy was assessed according to the Early Treatment of Diabetic Retinopathy Study (ETDRS) criteria.46 The photographs were examined in a masked manner and were assigned a degree of retinopathy differentiating between the levels of mild, moderate, and severe nonproliferative diabetic-like retinopathy and proliferative diabeticlike retinopathy. The eventual diagnosis for each patient was determined from the grading of the worse eye. The minimum criterion for diagnosis of diabetic-like retinopathy was the presence of at least 1 microaneurysm. Mild nonproliferative diabeticlike retinopathy was defined as an ETDRS level of 20 or more with at least 1 microaneurysm; moderate nonproliferative diabetic-like retinopathy was defined as an ETDRS level of 43 or more, severe nonproliferative diabetic-like retinopathy had an ETDRS level of 53 or more, and proliferative diabetic-like retinopathy showed an ETDRS level of 61 or more. For the assessment of age-related maculopathy, the international classification and grading system for age-related maculopathy and age-related macular degeneration from the International ARM Epidemiological Study Group was used.47 Recent retinal vein occlusion was defined by the presence of retinal edema, optic disc hyperemia or edema, scattered superficial or deep hemorrhages, and venous dilatation. Old retinal vein occlusions were characterized by occluded and sheathed retinal veins.8 For the evaluation of the retinal vascular abnormalities, focal narrowing of arterioles, generalized narrowing of arterioles, sheathing of arterioles, and arteriovenous crossing abnormalities (arteriovenous nicking) were assessed. For the assessment of generalized narrowing of the retinal arterioles, the arterial diameter was compared with the corresponding veins, unless the veins were engorged and tortuous.48 If the arterioles appeared to be narrow in comparison with the veins, generalized arteriolar narrowing was graded as questionable. If some arterioles in the eye were markedly narrowed or thready, but appeared to be normal in other quadrants of the fundus, generalized arteriolar narrowing was graded as definite. If the arterioles were small threads throughout the entire eye, generalized arteriolar narrowing was graded as severe. Additionally, the presence of retinal hemorrhages, retinal microaneurysms, hard exudates, and cotton wool spots was assessed. The technique has been described in detail recently. Trained research technicians asked the study participants questions from a standard questionnaire providing information on demographic variables such as age, gender, known diagnosis and current treatment of arterial hypertension, arterial hypotension, diabetes mellitus, thyroid disorders, cerebral hemorrhages, coro-
733
Ophthalmology Volume 116, Number 4, April 2009 nary heart diseases, and hyperlipidemia. The socioeconomic status was assessed with questions for the 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. For study purposes, diabetes mellitus was diagnosed by a self-reported history of physician diagnosis or by drug treatment for diabetes (insulin or oral hypoglycemic agents). Arterial hypertension was defined as a self-reported history of physician diagnosis or subjects who were receiving drug treatment for hypertension. Coronary artery disease was diagnosed based on a history of documented myocardial infarction, drug treatment for coronary heart disease (aspirin or nitrates), or both. Additionally, individuals were classified as self-reported nonsmokers or self-reported current smokers. The causes of death were determined by several approaches. In the rural region, the physicians in charge of the health of the village population were asked for the presumed cause of death. In addition, the death certificate was checked. In the urban region, hospital medical records were available for most people who had died in the follow-up period. For those subjects who had not attended a hospital before dying, the local physician in the suburban area was contacted. For 9 (6.3%) subjects, a cause of death could not be found. Statistical analysis was performed using a commercially available statistical software package (SPSS for Windows, version 16.0; SPSS, Inc., Chicago, IL). The data on frequencies are given as mean⫾standard error; all other data on the means are presented as mean⫾standard deviation. Logistic regression was used to investigate the associations of the binary dependent variable mortality with the continuous or categorical independent variables, such as age, gender, and presence of glaucoma. Ninety-five percent confidence intervals (95% CIs) and odds ratios (ORs) were presented. All P values were 2 sided and were considered statistically significant when the values were less than 0.05.
Results Of the 4439 subjects examined in 2001 and invited for reexamination in 2006, 3251 (73.2%) subjects returned for the follow-up examination, whereas 143 (3.2%) subjects were dead and 1045 (23.5%) subjects were alive but did not agree to be reexamined. Cerebrovascular events were the most common cause of death (n ⫽ 41; 29%), followed by malignancies (n ⫽ 37; 26%), heart disorders (n ⫽ 31; 22%), and other causes (n ⫽ 34; 24%) such as nonmalignant lung diseases (n ⫽ 6), and liver (n ⫽ 3) and kidney (n ⫽ 2) problems. In univariate analysis, mortality rates were correlated significantly with higher age (P⬍0.001), male gender (P ⫽ 0.002), low family income (P⬍0.001), low level of education (P⬍0.001), rural versus urban region (P⬍0.001), higher frequency of current smoking (P ⫽ 0.035) and smoking history (P⬍0.001), low bestcorrected visual acuity (P⬍0.001), higher degree of visual field defects (P⬍0.001), higher prevalence of trachoma and pterygia (P⬍0.001), higher amount of nuclear cataract (P⬍0.001), cortical cataract (P ⫽ 0.001), subcapsular posterior cataract (P⬍0.001), a larger  zone of peripapillary atrophy (P ⫽ 0.008), and higher prevalence of open-angle glaucoma (P ⫽ 0.006), angle-closure glaucoma (P⬍0.001), nonglaucomatous optic nerve damage (P ⫽ 0.001), retinal vein occlusions (P ⫽ 0.034), and diabetic-like retinopathy (P ⫽ 0.002; Table 1). It was not significantly associated with the presence of early (P ⫽ 0.89) or late (P ⫽ 1.00) age-related macular degeneration nor with intraocular pressure (P ⫽ 0.23). Because most of the independent parameters depended on age and other potentially confounding parameters, a binary logistic
734
regression analysis was performed. The first step of this analysis included the parameter occurrence of death as dependent variable and age, gender, rural or urban region, level of education, and smoking status as independent systemic parameters. It revealed that mortality was significantly associated with age (P⬍0.001), male gender (P ⫽ 0.006), lower level of education (P⬍0.001), and package years of smoking (P ⫽ 0.01). In a second step of the analysis, each of the parameters that were associated significantly with mortality in univariate analysis was added to the list of parameters (age, gender, rural or urban region, level of education, and smoking status) as additional single parameters. It showed that refractive error (P ⫽ 0.68), presence of trachoma (P ⫽ 0.32), presence of pterygium (P ⫽ 0.44), amount of nuclear cataract (P ⫽ 0.13), degree of cortical cataract (P ⫽ 0.91), amount of subcapsular posterior cataract (P ⫽ 0.19), presence of open-angle glaucoma (P ⫽ 0.91), amount of visual field defects (P ⫽ 0.20), and size of  zone of peripapillary atrophy (P ⫽ 0.23) were not associated significantly with mortality in that multivariate analysis. Mortality was associated significantly with the parameters best-corrected visual acuity (P ⫽ 0.006), presence of angle-closure glaucoma (P ⫽ 0.03), level of diabetic-like retinopathy (P ⫽ 0.01), and presence of a nonglaucomatous optic nerve damage (P ⫽ 0.03) if these parameters were added as single parameter to the list of variables consisting of age, gender, rural or urban region, level of education, and smoking status. The association between mortality and the prevalence of retinal vein occlusions was statistically marginal (P ⫽ 0.07). The third step of the statistical analysis included all parameters that were associated significantly with mortality in the second step of the analysis. It revealed that mortality was still associated significantly with age, male gender, lower level of education, and smoking status as systemic variables and level of diabetic retinopathy, presence of angle-closure glaucoma, and presence of nonglaucomatous optic nerve damage as ocular parameters (Table 2). Again, the association between mortality and the prevalence of retinal vein occlusions was statistically marginal in the multivariate analysis (P ⫽ 0.059; Table 2). Mortality no longer significantly was associated with best-corrected visual acuity (P ⫽ 0.14). Because parameters associated with mortality may differ between various causes of death, a subgroup analysis was performed including only subjects who were alive and subjects (n ⫽ 72 subjects who died of a heart disease [with 3251 subjects being alive and re-participating in the study, and with 1045 subjects being alive in 2006, but not participating in the survey of 2006]) with a cerebrovascular or heart disease as cause of death. A multivariate analysis including the same parameters as mentioned previously for the third step of the analysis revealed that mortality resulting from cerebrovascular or heart disease was significant for age (P⬍0.001; OR, 1.07 [per year]), male gender (P⬍0.001; OR, 0.33), lower level of education (P⬍0.001; OR, 0.55 [per 1 of 5 levels of education]), presence of angle-closure glaucoma (P ⫽ 0.01; OR, 3.93), and presence of a nonglaucomatous optic nerve damage (P⬎0.001; OR, 6.4). In a subgroup analysis taking into account only those subjects who were alive in 2006 and subjects (n ⫽ 37 subjects who died of a malignancy [with 3251 subjects being alive and re-participating in the study, and with 1045 subjects being alive in 2006, but not participating in the survey of 2006]) who were dead because of a malignancy, mortality was significantly associated with age (P⬍0.001; OR, 1.07), lower level of education (P ⫽ 0.005; OR, 0.64), and level of diabetic-like retinopathy (P⬍0.001; OR, 1.04), whereas gender (P ⫽ 0.19) and presence of angle-closure glaucoma (P ⫽ 1.0) were not significantly associated with mortality resulting from malignancies.
Xu et al 䡠 Mortality and Ocular Diseases Table 1. Association (Univariate Analysis) between Mortality and Ocular and General Parameters in the Beijing Eye Study P Value*
Odds Ratio (95% Confidence Interval†)
⬍0.001 0.002 ⬍0.001 ⬍0.001
1.09 (1.07–1.11) 0.58 (0.42–0.81) 0.28 (0.19–0.41) 0.57 (0.51–0.64)
36 11 36 44 16 588⫾757 45.5⫾4.5 30.6⫾4.2 9.1⫾11.5 0.16⫾2.72 0.50⫾0.31 0.78⫾0.28 15.7⫾4.27 28.1⫾3.9 1.26⫾2.98 23.0⫾3.6 8.4⫾2.3 41.8⫾4.3 18.8⫾3.5 11.8⫾2.9
⬍0.001 ⬍0.001 0.035 0.001 0.006 0.002 ⬍0.001 0.23 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 0.001 ⬍0.001
545 (386–706) 2.14 (1.49–3.08) 1.53 (1.03–2.27) 3.68 (1.60–5.76) 1.14 (1.04–1.26) 0.17 (0.05–0.52) 0.05 (0.03–0.08) 0.97 (0.92–1.02) 3.68 (2.50–5.41) 1.11 (1.06–1.17) 3.12 (2.12–4.59) 3.30 (1.78–6.13) 4.95 (3.47–7.06) 2.22 (1.41–3.50) 3.24 (1.85–5.68)
10.5⫾2.6 5.6⫾1.9 4.9⫾1.8 5.6⫾1.9
⬍0.001 0.006 ⬍0.001 0.001
4.08 (2.32–7.17) 2.83 (1.35–5.96) 6.86 (2.97–15.82) 6.31 (2.90–13.73)
0.034 0.002 ⬍0.001 0.89 (n.s.) 1.00 (n.s.) 0.35 (n.s.) 0.55 (n.s.) 0.30 (n.s.) 0.008
2.74 (1.08–6.96) 2.67 (1.42–5.01) 1.03 (1.01–1.04) 0.94 (0.41–2.16) 0 (0–0) 0.82 (0.55–1.24) 0.56 (0.08–3.67) 1.86 (0.57–6.03) 1.14 (1.04–1.25)
Parameter
Subjects Alive
Subjects Dead
No. Age (yrs) Males/females Rural/urban region Level of education Illiterate Half-illiterate Primary school Middle school College or more Income (Yuan RMB) With smoking history (%) Current smoker Package years of cigarettes Refractive error (diopters) Uncorrected visual acuity (Snellen) Best-corrected visual acuity Intraocular pressure (mmHg) Visual field defects (%) Amount of visual field defects Presence of trachoma (%) Presence of pterygium (%) Nuclear cataract (%) Cortical cataract (%) Subcapsular cataract (%) Presence of glaucomatous Optic nerve damage (%) Open-angle glaucoma Angle-closure glaucoma Nonglaucomatous (%) Optic nerve damage Retinal vein occlusions Diabetic retinopathy (%) Diabetic retinopathy (score) Early AMD Late AMD Optic disc size (mm2) Neuroretinal rim (mm2)‡ Disc hemorrhages (%)  Zone of parapapillary atrophy (mm2)
4296 55.9⫾10.5 1853/2443 1868/2428
143 65.7⫾10.4 81/62 105/38
318 115 630 1741 1453 1133⫾3213 28.0⫾0.7 22.4⫾0.7 5.4⫾9.7 ⫺0.38⫾0.30 0.72⫾0.32 0.95⫾0.15 16.1⫾3.48 9.5⫾0.5 0.43⫾2.00 8.7⫾0.4 2.7⫾0.2 12.7⫾0.5 9.4⫾0.5 3.7⫾0.3 2.8⫾0.3 2.0⫾0.2 0.7⫾0.1 0.9⫾0.1 1.3⫾0.2 6.4⫾0.4 1.84⫾6.87 5.3⫾0.3 0.3⫾0.1 2.61⫾0.50 1.68⫾0.33 1.1⫾0.2 0.38⫾1.24
3.5⫾1.5 15.4⫾4.1 4.11⫾11.82 5.0⫾2.0 0 2.56⫾0.53 1.86⫾0.40 2.1⫾1.2 0.73⫾1.88
Frequencies are given as mean⫾standard error; all other parameters are given as mean⫾standard deviation. AMD ⫽ age-related macular degeneration; n.s. ⫽ not statistically significant. *Statistical significance of the difference between both groups. † 95% confidence intervals of the difference between the 2 groups. ‡ Measured in randomly selected eyes.
Discussion In the adult Chinese population with an age of 40 years or more and living in the Greater Beijing area, 3.2% of subjects died during a follow-up period of 5 years. Besides the systemic parameters of higher age (P⬍0.001), male gender (P ⫽ 0.01), lower level of education (P⬍0.001), and smoking (P ⫽ 0.02), ocular parameters with a significant association with mortality were level of diabetic-like retinopathy (P ⫽ 0.036), presence of angle-closure glaucoma (P ⫽ 0.013), and presence of nonglaucomatous optic nerve damage (P ⫽ 0.027). The presence of retinal vein occlusions was associated marginally with mortality (P ⫽ 0.059). In the multivariate analysis, the mortality was not associated
significantly with age-related macular degeneration, openangle glaucoma, visual field defects, best-corrected visual acuity, intraocular pressure, presence of trachoma, amount of nuclear cataract, amount of cortical cataract, amount of subcapsular posterior cataract, and refractive error. The results of the present study complement previous smaller investigations from the same study population. In the previous investigations, the multivariate analysis did not include all the systemic parameters (i.e., age, gender, region, smoking status, level of education) in the multivariate analysis, nor did the multivariate analysis include all ocular conditions that were examined in the present study. With respect to the systemic factors of age, male gender, smoking status, and lower socioeconomic status as mea-
735
Ophthalmology Volume 116, Number 4, April 2009 Table 2. Results of the Binary Logistic Regression Analysis between Mortality and Ocular Parameters in the Beijing Eye Study Parameter
Odds 95% Confidence P Value* Regression Ratio Interval
Age (per yr) ⬍0.001 Gender (male ⫽ 1; 0.01 female ⫽ 2) ‡ Level of education ⬍0.001 Package years of 0.023 cigarettes Level of diabetic-like 0.036 retinopathy§ Angle-closure 0.013 glaucoma Nonglaucomatous 0.027 Optic nerve damage Retinal vein 0.059 occlusion Presence of 0.16 (n.s.) pterygium
0.07 ⫺0.61
1.07 0.55
1.05–1.09 0.34–0.87
⫺0.44 0.22
0.65 1.25
0.56–0.75 1.03–1.51
0.02
1.02
1.01–1.04
3.74
41.9
2.22–790
1.23
3.41
1.15–10.10
0.95
2.59
0.96–6.95
0.53
1.71
0.82–3.56
n.s. ⫽ statistically not significant. *Statistical significance of the difference between both groups. † Of the odds ratio. ‡ Per 1 of 5 levels of education. § Per Early Treatment of Diabetic Retinopathy Study unit.
sured by the level of education, the findings of this study confirm previous investigations in which these systemic parameters were significantly associated with mortality. With respect to the ocular parameters of diabetic-like retinopathy and presence of retinal vein occlusions, the present study confirms previous population-based studies such as the Blue Mountains Eye Study and the Beaver Dam Study of other ethnic groups in which both diseases were correlated with an increased risk of mortality.7,8 Interestingly, the present study adds angle-closure glaucoma to the list of ocular disorders that were associated significantly with an increased mortality. The pathogenic reasons for this association have remained unclear so far. It may be unlikely that repeated angle-closure attacks with marked pain may have led to a bad general condition of the patient, eventually resulting in death. A similar pathomechanism has been postulated for the cause of death of Johann Sebastian Bach.49 Another reason may be more likely. Recent population-based studies have shown that the anterior chamber depth is correlated with body length.50 –52 Because a shallow anterior chamber is the main risk factor for angle-closure glaucoma,53–55 the prevalence of angleclosure glaucoma was significantly associated with body length. Body length, however, is associated with socioeconomic status, with smaller subjects having a lower level of education and lower income in the Chinese population (own data). In a parallel manner, a recent analysis of the data of the Beijing Eye Study showed that a higher level of education was associated with the systemic parameters of younger age, male gender, living in the urban region, taller body height and lower body mass index, and with the ocular parameters of myopic refractive error, higher best-corrected visual acuity, lower degree of nuclear cataract, and lower
736
prevalence of angle-closure glaucoma (own data). Although the level of education as parameter for the socioeconomic background of the subjects was taken into account in the multivariate analysis of the present investigation, one may postulate that Chinese subjects with angle-closure and an associated smaller body stature and low level of education may have had an additional, yet unknown, risk factor compared with subjects with a low socioeconomic background but a taller body stature and no angle-closure glaucoma. Because body height was not measured in the survey of 2001 of the Beijing Eye Study, body height could not be added to the list of independent parameters in the multivariate analysis of mortality. Another factor added to the list of ocular factors associated with mortality was the presence of nonglaucomatous optic nerve damage. In the multivariate analysis, subjects with nonglaucomatous optic nerve damage had higher mortality than those with a healthy-appearing optic nerve head on the optic disc photographs. It may reflect the clinical situation that in the case of a cerebrovascular or heart insufficiency, the retina with the retinal ganglion cells and their axons and the optic nerve in the brain experience microvascular disturbances. There are limitations of the present study. As in any population-based study, nonparticipation can be of major concern. In the Beijing Eye Study at the time of the original survey in 2001, 4439 of 5324 invited individuals participated in the study, resulting in a participation rate of 83.4%. Of these 4439 subjects, 3251 subjects or 73.2% of the participants from 2001 returned for the reexamination in the year 2006, whereas 143 (3.2%) subjects were dead and 1045 (23.5%) subjects were alive but did not agree to be reexamined. Although a response rate of 73.2% in the survey of 2006 may be reasonable, the participants of the 2006 study represent only 61.1% of the 5324 subjects originally invited to participate in the year 2001. However, this may not have influenced the conclusions of this study because one knew whether the nonparticipating subjects were dead or alive, independent of whether they participated in the second survey. Another limitation of the investigation is the relatively low number of 143 people or 3.2% who died, decreasing the power of the statistical analysis. A further limitation of the study is that the cause of death usually was not confirmed by a pathologic examination. Because of the usually chronic illness before death, however, it may have been relatively clear which disease was the major cause of death. In addition, the main outcome parameter in this study was not the cause of death, but rather the factors associated with mortality in general. For a detailed analysis of the differences in the risk factors between the various causes of death, this study might have been too small. Another limitation of the study is that the multivariate analysis did not include the presence of diabetes mellitus as an independent factor potentially influencing the rate of death. The reason is that blood samples were not obtained in 2001, so that data on the blood glucose concentration were available only for the survivors attending the survey of 2006. This limitation of the study was partially compensated for by including the parameter diabetic-like retinopathy, which was examined on the fundus photographs obtained in 2001, into the sta-
Xu et al 䡠 Mortality and Ocular Diseases tistical analysis. A further limitation of the study design is that the socioeconomic parameters such as level of education were assessed based on an interview without rechecking the data in a scientific manner. In conclusion, the present study suggests that if socioeconomic parameters, age, gender, and smoking status are taken into account, ocular parameters associated with an increased mortality were higher level of diabetic-like retinopathy and presence of angle-closure glaucoma, nonglaucomatous optic nerve damage, and (marginally significant) retinal vein occlusions. Other major ocular disorders such as any form of cataract, open-angle glaucoma, age-related macular degeneration, trachoma, pterygia, and high myopia or high hyperopia were not significantly related with an increased mortality in multivariate analysis. These findings may have clinical importance because patients in whom one of the associated ocular conditions is detected may undergo an intensified general body examination to detect reasons for it to prevent early death. The findings may be interesting pathogenetically because the associations and the lack of associations between the ocular disorders and mortality may give some hints regarding their pathogenesis.
References 1. Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 1992;99:933– 43. 2. Vingerling JR, Dielemans I, Hofman A, et al. The prevalence of age-related maculopathy in the Rotterdam Study. Ophthalmology 1995;102:205–10. 3. Leske MC, Connell AM, Wu SY, et al. Prevalence of lens opacities in the Barbados Eye Study. Arch Ophthalmol 1997; 115:105–11. 4. Varma R, Torres M, Los Angeles Latino Eye Study Group. Prevalence of lens opacities in Latinos: the Los Angeles Latino Eye Study. Ophthalmology 2004;111:1449 –56. 5. Foster PJ, Wong TY, Machin D, et al. Risk factors for nuclear, cortical and posterior subcapsular cataracts in the Chinese population of Singapore: the Tanjong Pagar Survey. Br J Ophthalmol 2003;87:1112–20. 6. Foster PJ, Oen FT, Machin D, et al. The prevalence of glaucoma in Chinese residents of Singapore: a cross-sectional population survey of the Tanjong Pagar district. Arch Ophthalmol 2000;118:1105–11. 7. Cugati S, Wang JJ, Knudtson MD, et al. Retinal vein occlusion and vascular mortality: pooled data analysis of 2 populationbased cohorts. Ophthalmology 2007;114:520 – 4. 8. Xu L, Liu WW, Wang YX, et al. Retinal vein occlusions and mortality: the Beijing Eye Study. Am J Ophthalmol 2007;144: 972–3. 9. Wong TY, Klein R, Klein BE, et al. Retinal microvascular abnormalities and their relationship with hypertension, cardiovascular disease, and mortality. Surv Ophthalmol 2001;46: 59 – 80. 10. Wong TY, Klein R, Nieto FJ, et al. Retinal microvascular abnormalities and 10-year cardiovascular mortality: a populationbased case-control study. Ophthalmology 2003;110:933– 40. 11. van Hecke MV, Dekker JM, Nijpels G, et al. Retinopathy is associated with cardiovascular and all-cause mortality in both diabetic and nondiabetic subjects: the Hoorn Study [letter]. Diabetes Care 2003;26:2958.
12. Mitchell P, Wang JJ, Wong TY, et al. Retinal microvascular signs and risk of stroke and stroke mortality. Neurology 2005; 65:1005–9. 13. Hirai FE, Moss SE, Knudtson MD, et al. Retinopathy and survival in a population without diabetes: the Beaver Dam Eye Study. Am J Epidemiol 2007;166:724 –30. 14. Cheung N, Wang JJ, Klein R, et al. Diabetic retinopathy and the risk of coronary heart disease: the Atherosclerosis Risk in Communities Study. Diabetes Care 2007;30:1742– 6. 15. Juutilainen A, Lehto S, Rönnemaa T, et al. Retinopathy predicts cardiovascular mortality in type 2 diabetic men and women. Diabetes Care 2007;30:292–9. 16. Xu L, Wang YX, Xie XW, Jonas JB. Retinopathy and mortality: the Beijing Eye Study. Graefes Arch Clin Exp Ophthalmol 2008;246:923–5. 17. Borger PH, van Leeuwen R, Hulsman CA, et al. Is there a direct association between age-related eye diseases and mortality? The Rotterdam Study. Ophthalmology 2003; 110:1292– 6. 18. Cugati S, Cumming RG, Smith W, et al. Visual impairment, age-related macular degeneration, cataract, and long-term mortality: The Blue Mountains Eye Study. Arch Ophthalmol 2007;125:917–24. 19. Wong TY, Tikellis G, Sun C, et al. Age-related macular degeneration and risk of coronary heart disease: the Atherosclerosis Risk in Communities Study. Ophthalmology 2007; 114:86 –91. 20. Cheung N, Shankar A, Klein R, et al, Atherosclerosis Risk in Communities (ARIC) Study Investigators. Age-related macular degeneration and cancer mortality in the Atherosclerosis Risk in Communities Study. Arch Ophthalmol 2007;125: 1241–7. 21. Xu L, Li YB, Wang YX, Jonas JB. Age-related macular degeneration and mortality: the Beijing Eye Study. Ophthalmologica 2008;222:378 –9. 22. Wang JJ, Mitchell P, Simpson JM, et al. Visual impairment, age-related cataract, and mortality. Arch Ophthalmol 2001; 119:1186 –90. 23. Xu L, Cui TT, Wang YX, Jonas JB. Cataract and mortality: the Beijing Eye Study. Graefes Arch Clin Exp Ophthalmol 2008;246:615–7. 24. Lee AJ, Wang JJ, Kifley A, Mitchell P. Open-angle glaucoma and cardiovascular mortality: the Blue Mountains Eye Study. Ophthalmology 2006;2113:1069 –76. 25. Xu L, Wang YX, Jonas JB. Glaucoma and mortality in the Beijing Eye Study. Eye 2008;22:434 – 8. 26. Thompson JR, Gibson JM, Jagger C. The association between visual impairment and mortality in elderly people. Age Ageing 1989;18:83– 8. 27. Klein R, Klein BE, Moss SE. Age-related eye diseases and survival: the Beaver Dam Eye Study. Arch Ophthalmol 1995: 113:333–9. 28. McCarty CA, Nanjan MB, Taylor HR. Visual impairment predicts 5 year mortality. Br J Ophthalmol 2001;85:322– 6. 29. Ramrattan RS, Wolfs RC, Panda-Jonas S, et al. Prevalence and causes of visual field loss in the elderly and associations with impairment in daily functioning: the Rotterdam Study. Arch Ophthalmol 2001;119:1788 –94. 30. Wang YX, Xu L, Jonas JB, et al. Non-glaucomatous optic nerve damage and mortality in the Beijing Eye Study. Acta Ophthalmol 2008;86:923-4. 31. Lee DJ, Gomez-Marin O, Lam BL, Zheng DD. Visual acuity impairment and mortality in US adults. Arch Ophthalmol 2002;120:1544 –50. 32. AREDS Research Group. Associations of mortality with ocular disorders and an intervention of high-dose antioxidants
737
Ophthalmology Volume 116, Number 4, April 2009
33.
34. 35. 36.
37.
38. 39. 40. 41. 42. 43.
44.
and zinc in the Age-Related Eye Disease Study: AREDS report no. 13. Arch Ophthalmol 2004;122:716 –26. Thiagarajan M, Evans JR, Smeeth L, et al. Cause-specific visual impairment and mortality: results from a populationbased study of older people in the United Kingdom. Arch Ophthalmol 2005;123:1397– 403. Freeman EE, Egleston BL, West SK, et al. Visual acuity change and mortality in older adults. Invest Ophthalmol Vis Sci 2005;46:4040 –5. Knudtson MD, Klein BE, Klein R. Age-related eye disease, visual impairment, and survival: the Beaver Dam Eye Study. Arch Ophthalmol 2006;124:243–9. Saw SM, Foster PJ, Gazzard G, Seah S. Causes of blindness, low vision, and questionnaire-assessed poor visual function in Singaporean Chinese adults: the Tanjong Pagar Survey. Ophthalmology 2004;111:1161– 8. Rumsfeld JS, Jones PG, Whooley MA, et al. Depression predicts mortality and hospitalization in patients with myocardial infarction complicated by heart failure. Am Heart J 2005; 150:961–7. Foong AW, Fong CW, Wong TY, et al. Visual acuity and mortality in a Chinese population: the Tanjong Pagar Study. Ophthalmology 2008;115:802–7. Wu SY, Nemesure B, Hennis A, et al, Barbados Eye Studies Group. Open-angle glaucoma and mortality: the Barbados Eye Studies. Arch Ophthalmol 2008;126:365–70. Xu L, Xie X, Wang S, et al. Prevalence of diabetes mellitus in China. Exp Clin Endocrinol Diabetes 2008;116:69 –70. Xu L, Wang Y, Wang S, et al. High myopia and glaucoma susceptibility: the Beijing Eye Study. Ophthalmology 2007; 114:216 –20. Van Herick W, Shaffer RN, Schwartz A. Estimation of width of angle of anterior chamber: incidence and significance of the narrow angle. Am J Ophthalmol 1969;68:626 –9. Liu H, Ou B, Paxton A, et al. Rapid assessment of trachoma in Hainan Province, China: validation of the new World Health Organization methodology. Ophthalmic Epidemiol 2002;29:97– 104. Age-Related Eye Disease Study Research Group. The AgeRelated Eye Disease Study (AREDS) system for classifying cataracts from photographs: AREDS report no. 4. Am J Ophthalmol 2001;131:167–75.
45. Jonas JB, Budde WM, Panda-Jonas S. Ophthalmoscopic evaluation of the optic nerve head. Surv Ophthalmol 1999;43:293– 320. 46. Early Treatment of Diabetic Retinopathy Study Research Group. Grading diabetic retinopathy from stereoscopic color fundus photographs: an extension of the modified Airlie House classification. ETDRS report number 10. Ophthalmology 1991;98:786 – 806. 47. 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. 48. Wang S, Xu L, Jonas JB, et al. Retinal vascular abnormalities in adult Chinese in rural and urban Beijing: the Beijing Eye Study. Ophthalmology 2006;113:1752–7. 49. David HT, Mendel A, eds. The New Bach Reader: A Life of Johann Sebastian Bach in Letters and Documents. New York: WW Norton; 1999:432. 50. Wong TY, Foster PJ, Johnson GJ, et al. The relationship between ocular dimensions and refraction with adult stature: the Tanjong Pagar Survey. Invest Ophthalmol Vis Sci 2001; 42:1237– 42. 51. Eysteinsson T, Jonasson F, Arnarsson A, et al. Relationships between ocular dimensions and adult stature among participants in the Reykjavik Eye Study. Acta Ophthalmol Scand 2005;83:734 – 8. 52. 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. 53. Congdon NG, Youlin Q, Quigley H, et al. Biometry and primary angle-closure glaucoma among Chinese, white, and black populations. Ophthalmology 1997;104:1489 –95. 54. Devereux JG, Foster PJ, Baasanhu J, et al. Anterior chamber depth measurement as a screening tool for primary angleclosure glaucoma in an East Asian population. Arch Ophthalmol 2000;118:257– 63. 55. Nolan WP, See JL, Chew PT, et al. Detection of primary angle closure using anterior segment optical coherence tomography in Asian eyes. Ophthalmology 2007;114:33–9.
Footnotes and Financial Disclosures Originally received: July 25, 2008. Final revision: November 3, 2008. Accepted: November 3, 2008. Available online: February 4, 2009.
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Manuscript no. 2008-898.
1
Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital University of Medical Science, Beijing, China. 2
Department of Ophthalmology, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Mannheim, Germany.
738
Supported by the Beijing Natural Science Foundation, Beijing, China. Correspondence: Liang Xu, MD, Beijing Institute of Ophthalmology, 17 Hougou Street, Chong Wen Men, 100005 Beijing, China. E-mail: Jost.Jonas@augen. ma.uni-heidelberg.de.
The major ocular diseases such as the glaucomas, macular degeneration, and cataract are strongly related with higher age, independent of ethnic background.1– 6 Because higher age is the major risk factor for mortality, the major ocular diseases also are strongly related to increased mortality if, in a univariate analysis, age and other confounding factors are not taken into account. As with any other major disease, the question of whether ocular disorders are associated with an increased risk of death or whether the association between increased mortality and the occurrence of the ocular diseases is caused simply by the relationship with higher age is unclear. This question has clinical importance because if an ocular disease is associated with increased mortality, its development should initiate a major clinical examination to detect the underlying disorder, leading to the ophthalmic disease and the increased mortality. To detect associations between ocular diseases and mortality also may provide information regarding the pathogenesis of the ocular disease. Previous studies have suggested that subjects with glaucoma, subcapsular cataract, retinal vein occlusions, and low
732
© 2009 by the American Academy of Ophthalmology Published by Elsevier Inc.
vision in general may have increased mortality.7–39 Most of these studies were focused, however, only on one ocular disease, and socioeconomic parameters mostly were not taken into account. In addition, only a few investigations of the Chinese population have been carried out, which is the society with the largest population worldwide. Therefore, the purpose of this study was to examine the multivariate relationships between mortality and the major ocular diseases in a population-based investigation in mainland China.
Patients and 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 study has been described in detail recently.40,41 The Medical Ethics Committee of the Beijing Tongren Hospital approved the study protocol and all participants gave informed consent, according to the Declaration of Helsinki. At the time of the first survey ISSN 0161-6420/09/$–see front matter doi:10.1016/j.ophtha.2008.11.003
Xu et al 䡠 Mortality and Ocular Diseases in the year 2001, the 7 communities had a total population of 5324 individuals aged 40 years or older. In total, 4439 individuals (2505 women) participated in the eye examination, corresponding to an overall response rate of 83.4%. The study was divided into a rural part (1973 subjects; 1143 women) and an urban part (2466 subjects; 1362 women). The mean age was 56.2⫾10.6 years (median, 56 years; range, 40 –101 years). In 2006, the study was repeated by inviting all participants from the survey from 2001 to be reexamined. All examinations were carried out in the communities, either in schoolhouses or in community houses. Uncorrected visual acuity was measured (Snellen charts) in a distance of 5 m. Automatic refractometry (Auto Refractometer AR-610; Nidek Co., Ltd., Tokyo, Japan) was performed if uncorrected visual acuity was lower than 1.0. Visual field examinations were performed by frequencydoubling perimetry using the screening program C-20-1 (ZeissHumphrey, Dublin, CA). Intraocular pressure was measured using a noncontact pneumotonometer (CT-60 computerized tonometer; Topcon, Ltd., Tokyo, Japan) by an experienced technician. A slit-lamp examination was carried out by an ophthalmologist. The anterior chamber depth was assessed using the method of van Herick et al.42 Gonioscopy was performed routinely by an experienced glaucoma specialist for all study participants with glaucoma and all glaucoma suspects. Glaucoma suspects were all those with an intraocular pressure of more than 21 mmHg, an abnormal result in frequency doubling perimetry, an abnormal finding in slit-lamp biomicroscopy such as a shallow anterior chamber, or changes in the anterior segment of the eye suggesting glaucoma, such as peripheral anterior synechiae, iris whirling, and glaukomflecken of the lens. Gonioscopy was performed before the pupil dilatation. The pupil was dilated using tropicamide once or twice, until the pupil diameter was at least 6 mm. Digital photographs of the cornea and retroilluminated photographs of the lens were obtained using the Neitz CT-R camera (Neitz Instruments Co., Tokyo, Japan). Monoscopic photographs (on film) of the macula and optic disc were obtained using a fundus camera (Type CR6-45NM; Canon, Inc., Tokyo, Japan). According to the classification of the World Health Organization,43 diagnostic criteria for trachoma were trachomatous inflammation characterized by 5 follicles or more, at least 0.5 mm in size, on the flat surface of the upper tarsal conjunctiva (stage 1); intensive trachomatous inflammation characterized by inflammatory thickening of the upper tarsal conjunctiva with more than half of the normal deep tarsal vessels obscured (stage 2); trachomatous scarring with scarring of the tarsal conjunctiva (stage 3); trachomatous trichiasis with at least 1 eyelash rubbing on the eyeball or evidence of eyelash removal (stage 4); and corneal opacity when at least a part of the pupil was blurred or obscured (stage 5). On the corneal photographs, the cornea was examined for the presence of a pterygium. A pterygium was defined as an extension of conjunctiva onto the clear cornea for which there was no alternative explanation such as ocular trauma. Using the lens photographs, the degree of nuclear cataract was graded in 6 grades according to the lens photographs using the classifying scheme for cataract of the Age-Related Eye Disease Study.44 Standard photographs 6 and 7 were combined into 1 grade, that is, grade 6. Grade 1 was no nuclear opacity in the lens, and grade 6 was very dense nuclear lens opacity. The degree of cortical lens opacification and posterior subcapsular lens opacification was graded using 2 photographs obtained using retroillumination with the Neitz CT-R camera. Cortical and posterior subcapsular opacities appeared as darkly shaded areas on the white background through the computer screen. The percent area of opacity was measured using a grid. The optic disc photographs were digitized and the optic disc structures were measured by outlining the borders of the optic disc, optic cup, peripapillary scleral ring, and ␣ zone and  zone of
peripapillary atrophy border on the computer screen.41 Additionally, the occurrence of optic disc hemorrhages was noted. Glaucomatous optic nerve damage was defined by the appearance of the optic nerve head as described in detail recently.41 Open-angle glaucoma was characterized by an open anterior chamber angle and a normal depth of the anterior chamber as assessed by slitlamp biomicroscopy and gonioscopy. In angle-closure glaucoma, the anterior chamber angle was occluded, or there was appositional contact between the peripheral iris and the cornea for at least 15°; that is, the Schwalbe line could not be visualized. In addition, other features for angle-closure glaucoma were peripheral anterior synechiae, iris whirling (distortion of the radially orientated iris structures), and glaukomflecken in the anterior subcapsular lens region, in combination with a narrow anterior chamber angle. Nonglaucomatous optic nerve damage was characterized by a decreased visibility of the retinal nerve fiber layer, a decreased diameter of the retinal arteries, an increased pallor of the neuroretinal rim, a normal shape of the neuroretinal rim, and a normal appearance of the peripapillary region with respect to ␣ zone and  zone of peripapillary atrophy.45 Using the fundus photographs (nonstereoscopic photograph of 50° of the central fundus), diabetic or diabetic-like retinopathy was assessed according to the Early Treatment of Diabetic Retinopathy Study (ETDRS) criteria.46 The photographs were examined in a masked manner and were assigned a degree of retinopathy differentiating between the levels of mild, moderate, and severe nonproliferative diabetic-like retinopathy and proliferative diabeticlike retinopathy. The eventual diagnosis for each patient was determined from the grading of the worse eye. The minimum criterion for diagnosis of diabetic-like retinopathy was the presence of at least 1 microaneurysm. Mild nonproliferative diabeticlike retinopathy was defined as an ETDRS level of 20 or more with at least 1 microaneurysm; moderate nonproliferative diabetic-like retinopathy was defined as an ETDRS level of 43 or more, severe nonproliferative diabetic-like retinopathy had an ETDRS level of 53 or more, and proliferative diabetic-like retinopathy showed an ETDRS level of 61 or more. For the assessment of age-related maculopathy, the international classification and grading system for age-related maculopathy and age-related macular degeneration from the International ARM Epidemiological Study Group was used.47 Recent retinal vein occlusion was defined by the presence of retinal edema, optic disc hyperemia or edema, scattered superficial or deep hemorrhages, and venous dilatation. Old retinal vein occlusions were characterized by occluded and sheathed retinal veins.8 For the evaluation of the retinal vascular abnormalities, focal narrowing of arterioles, generalized narrowing of arterioles, sheathing of arterioles, and arteriovenous crossing abnormalities (arteriovenous nicking) were assessed. For the assessment of generalized narrowing of the retinal arterioles, the arterial diameter was compared with the corresponding veins, unless the veins were engorged and tortuous.48 If the arterioles appeared to be narrow in comparison with the veins, generalized arteriolar narrowing was graded as questionable. If some arterioles in the eye were markedly narrowed or thready, but appeared to be normal in other quadrants of the fundus, generalized arteriolar narrowing was graded as definite. If the arterioles were small threads throughout the entire eye, generalized arteriolar narrowing was graded as severe. Additionally, the presence of retinal hemorrhages, retinal microaneurysms, hard exudates, and cotton wool spots was assessed. The technique has been described in detail recently. Trained research technicians asked the study participants questions from a standard questionnaire providing information on demographic variables such as age, gender, known diagnosis and current treatment of arterial hypertension, arterial hypotension, diabetes mellitus, thyroid disorders, cerebral hemorrhages, coro-
733
Ophthalmology Volume 116, Number 4, April 2009 nary heart diseases, and hyperlipidemia. The socioeconomic status was assessed with questions for the 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. For study purposes, diabetes mellitus was diagnosed by a self-reported history of physician diagnosis or by drug treatment for diabetes (insulin or oral hypoglycemic agents). Arterial hypertension was defined as a self-reported history of physician diagnosis or subjects who were receiving drug treatment for hypertension. Coronary artery disease was diagnosed based on a history of documented myocardial infarction, drug treatment for coronary heart disease (aspirin or nitrates), or both. Additionally, individuals were classified as self-reported nonsmokers or self-reported current smokers. The causes of death were determined by several approaches. In the rural region, the physicians in charge of the health of the village population were asked for the presumed cause of death. In addition, the death certificate was checked. In the urban region, hospital medical records were available for most people who had died in the follow-up period. For those subjects who had not attended a hospital before dying, the local physician in the suburban area was contacted. For 9 (6.3%) subjects, a cause of death could not be found. Statistical analysis was performed using a commercially available statistical software package (SPSS for Windows, version 16.0; SPSS, Inc., Chicago, IL). The data on frequencies are given as mean⫾standard error; all other data on the means are presented as mean⫾standard deviation. Logistic regression was used to investigate the associations of the binary dependent variable mortality with the continuous or categorical independent variables, such as age, gender, and presence of glaucoma. Ninety-five percent confidence intervals (95% CIs) and odds ratios (ORs) were presented. All P values were 2 sided and were considered statistically significant when the values were less than 0.05.
Results Of the 4439 subjects examined in 2001 and invited for reexamination in 2006, 3251 (73.2%) subjects returned for the follow-up examination, whereas 143 (3.2%) subjects were dead and 1045 (23.5%) subjects were alive but did not agree to be reexamined. Cerebrovascular events were the most common cause of death (n ⫽ 41; 29%), followed by malignancies (n ⫽ 37; 26%), heart disorders (n ⫽ 31; 22%), and other causes (n ⫽ 34; 24%) such as nonmalignant lung diseases (n ⫽ 6), and liver (n ⫽ 3) and kidney (n ⫽ 2) problems. In univariate analysis, mortality rates were correlated significantly with higher age (P⬍0.001), male gender (P ⫽ 0.002), low family income (P⬍0.001), low level of education (P⬍0.001), rural versus urban region (P⬍0.001), higher frequency of current smoking (P ⫽ 0.035) and smoking history (P⬍0.001), low bestcorrected visual acuity (P⬍0.001), higher degree of visual field defects (P⬍0.001), higher prevalence of trachoma and pterygia (P⬍0.001), higher amount of nuclear cataract (P⬍0.001), cortical cataract (P ⫽ 0.001), subcapsular posterior cataract (P⬍0.001), a larger  zone of peripapillary atrophy (P ⫽ 0.008), and higher prevalence of open-angle glaucoma (P ⫽ 0.006), angle-closure glaucoma (P⬍0.001), nonglaucomatous optic nerve damage (P ⫽ 0.001), retinal vein occlusions (P ⫽ 0.034), and diabetic-like retinopathy (P ⫽ 0.002; Table 1). It was not significantly associated with the presence of early (P ⫽ 0.89) or late (P ⫽ 1.00) age-related macular degeneration nor with intraocular pressure (P ⫽ 0.23). Because most of the independent parameters depended on age and other potentially confounding parameters, a binary logistic
734
regression analysis was performed. The first step of this analysis included the parameter occurrence of death as dependent variable and age, gender, rural or urban region, level of education, and smoking status as independent systemic parameters. It revealed that mortality was significantly associated with age (P⬍0.001), male gender (P ⫽ 0.006), lower level of education (P⬍0.001), and package years of smoking (P ⫽ 0.01). In a second step of the analysis, each of the parameters that were associated significantly with mortality in univariate analysis was added to the list of parameters (age, gender, rural or urban region, level of education, and smoking status) as additional single parameters. It showed that refractive error (P ⫽ 0.68), presence of trachoma (P ⫽ 0.32), presence of pterygium (P ⫽ 0.44), amount of nuclear cataract (P ⫽ 0.13), degree of cortical cataract (P ⫽ 0.91), amount of subcapsular posterior cataract (P ⫽ 0.19), presence of open-angle glaucoma (P ⫽ 0.91), amount of visual field defects (P ⫽ 0.20), and size of  zone of peripapillary atrophy (P ⫽ 0.23) were not associated significantly with mortality in that multivariate analysis. Mortality was associated significantly with the parameters best-corrected visual acuity (P ⫽ 0.006), presence of angle-closure glaucoma (P ⫽ 0.03), level of diabetic-like retinopathy (P ⫽ 0.01), and presence of a nonglaucomatous optic nerve damage (P ⫽ 0.03) if these parameters were added as single parameter to the list of variables consisting of age, gender, rural or urban region, level of education, and smoking status. The association between mortality and the prevalence of retinal vein occlusions was statistically marginal (P ⫽ 0.07). The third step of the statistical analysis included all parameters that were associated significantly with mortality in the second step of the analysis. It revealed that mortality was still associated significantly with age, male gender, lower level of education, and smoking status as systemic variables and level of diabetic retinopathy, presence of angle-closure glaucoma, and presence of nonglaucomatous optic nerve damage as ocular parameters (Table 2). Again, the association between mortality and the prevalence of retinal vein occlusions was statistically marginal in the multivariate analysis (P ⫽ 0.059; Table 2). Mortality no longer significantly was associated with best-corrected visual acuity (P ⫽ 0.14). Because parameters associated with mortality may differ between various causes of death, a subgroup analysis was performed including only subjects who were alive and subjects (n ⫽ 72 subjects who died of a heart disease [with 3251 subjects being alive and re-participating in the study, and with 1045 subjects being alive in 2006, but not participating in the survey of 2006]) with a cerebrovascular or heart disease as cause of death. A multivariate analysis including the same parameters as mentioned previously for the third step of the analysis revealed that mortality resulting from cerebrovascular or heart disease was significant for age (P⬍0.001; OR, 1.07 [per year]), male gender (P⬍0.001; OR, 0.33), lower level of education (P⬍0.001; OR, 0.55 [per 1 of 5 levels of education]), presence of angle-closure glaucoma (P ⫽ 0.01; OR, 3.93), and presence of a nonglaucomatous optic nerve damage (P⬎0.001; OR, 6.4). In a subgroup analysis taking into account only those subjects who were alive in 2006 and subjects (n ⫽ 37 subjects who died of a malignancy [with 3251 subjects being alive and re-participating in the study, and with 1045 subjects being alive in 2006, but not participating in the survey of 2006]) who were dead because of a malignancy, mortality was significantly associated with age (P⬍0.001; OR, 1.07), lower level of education (P ⫽ 0.005; OR, 0.64), and level of diabetic-like retinopathy (P⬍0.001; OR, 1.04), whereas gender (P ⫽ 0.19) and presence of angle-closure glaucoma (P ⫽ 1.0) were not significantly associated with mortality resulting from malignancies.
Xu et al 䡠 Mortality and Ocular Diseases Table 1. Association (Univariate Analysis) between Mortality and Ocular and General Parameters in the Beijing Eye Study P Value*
Odds Ratio (95% Confidence Interval†)
⬍0.001 0.002 ⬍0.001 ⬍0.001
1.09 (1.07–1.11) 0.58 (0.42–0.81) 0.28 (0.19–0.41) 0.57 (0.51–0.64)
36 11 36 44 16 588⫾757 45.5⫾4.5 30.6⫾4.2 9.1⫾11.5 0.16⫾2.72 0.50⫾0.31 0.78⫾0.28 15.7⫾4.27 28.1⫾3.9 1.26⫾2.98 23.0⫾3.6 8.4⫾2.3 41.8⫾4.3 18.8⫾3.5 11.8⫾2.9
⬍0.001 ⬍0.001 0.035 0.001 0.006 0.002 ⬍0.001 0.23 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 0.001 ⬍0.001
545 (386–706) 2.14 (1.49–3.08) 1.53 (1.03–2.27) 3.68 (1.60–5.76) 1.14 (1.04–1.26) 0.17 (0.05–0.52) 0.05 (0.03–0.08) 0.97 (0.92–1.02) 3.68 (2.50–5.41) 1.11 (1.06–1.17) 3.12 (2.12–4.59) 3.30 (1.78–6.13) 4.95 (3.47–7.06) 2.22 (1.41–3.50) 3.24 (1.85–5.68)
10.5⫾2.6 5.6⫾1.9 4.9⫾1.8 5.6⫾1.9
⬍0.001 0.006 ⬍0.001 0.001
4.08 (2.32–7.17) 2.83 (1.35–5.96) 6.86 (2.97–15.82) 6.31 (2.90–13.73)
0.034 0.002 ⬍0.001 0.89 (n.s.) 1.00 (n.s.) 0.35 (n.s.) 0.55 (n.s.) 0.30 (n.s.) 0.008
2.74 (1.08–6.96) 2.67 (1.42–5.01) 1.03 (1.01–1.04) 0.94 (0.41–2.16) 0 (0–0) 0.82 (0.55–1.24) 0.56 (0.08–3.67) 1.86 (0.57–6.03) 1.14 (1.04–1.25)
Parameter
Subjects Alive
Subjects Dead
No. Age (yrs) Males/females Rural/urban region Level of education Illiterate Half-illiterate Primary school Middle school College or more Income (Yuan RMB) With smoking history (%) Current smoker Package years of cigarettes Refractive error (diopters) Uncorrected visual acuity (Snellen) Best-corrected visual acuity Intraocular pressure (mmHg) Visual field defects (%) Amount of visual field defects Presence of trachoma (%) Presence of pterygium (%) Nuclear cataract (%) Cortical cataract (%) Subcapsular cataract (%) Presence of glaucomatous Optic nerve damage (%) Open-angle glaucoma Angle-closure glaucoma Nonglaucomatous (%) Optic nerve damage Retinal vein occlusions Diabetic retinopathy (%) Diabetic retinopathy (score) Early AMD Late AMD Optic disc size (mm2) Neuroretinal rim (mm2)‡ Disc hemorrhages (%)  Zone of parapapillary atrophy (mm2)
4296 55.9⫾10.5 1853/2443 1868/2428
143 65.7⫾10.4 81/62 105/38
318 115 630 1741 1453 1133⫾3213 28.0⫾0.7 22.4⫾0.7 5.4⫾9.7 ⫺0.38⫾0.30 0.72⫾0.32 0.95⫾0.15 16.1⫾3.48 9.5⫾0.5 0.43⫾2.00 8.7⫾0.4 2.7⫾0.2 12.7⫾0.5 9.4⫾0.5 3.7⫾0.3 2.8⫾0.3 2.0⫾0.2 0.7⫾0.1 0.9⫾0.1 1.3⫾0.2 6.4⫾0.4 1.84⫾6.87 5.3⫾0.3 0.3⫾0.1 2.61⫾0.50 1.68⫾0.33 1.1⫾0.2 0.38⫾1.24
3.5⫾1.5 15.4⫾4.1 4.11⫾11.82 5.0⫾2.0 0 2.56⫾0.53 1.86⫾0.40 2.1⫾1.2 0.73⫾1.88
Frequencies are given as mean⫾standard error; all other parameters are given as mean⫾standard deviation. AMD ⫽ age-related macular degeneration; n.s. ⫽ not statistically significant. *Statistical significance of the difference between both groups. † 95% confidence intervals of the difference between the 2 groups. ‡ Measured in randomly selected eyes.
Discussion In the adult Chinese population with an age of 40 years or more and living in the Greater Beijing area, 3.2% of subjects died during a follow-up period of 5 years. Besides the systemic parameters of higher age (P⬍0.001), male gender (P ⫽ 0.01), lower level of education (P⬍0.001), and smoking (P ⫽ 0.02), ocular parameters with a significant association with mortality were level of diabetic-like retinopathy (P ⫽ 0.036), presence of angle-closure glaucoma (P ⫽ 0.013), and presence of nonglaucomatous optic nerve damage (P ⫽ 0.027). The presence of retinal vein occlusions was associated marginally with mortality (P ⫽ 0.059). In the multivariate analysis, the mortality was not associated
significantly with age-related macular degeneration, openangle glaucoma, visual field defects, best-corrected visual acuity, intraocular pressure, presence of trachoma, amount of nuclear cataract, amount of cortical cataract, amount of subcapsular posterior cataract, and refractive error. The results of the present study complement previous smaller investigations from the same study population. In the previous investigations, the multivariate analysis did not include all the systemic parameters (i.e., age, gender, region, smoking status, level of education) in the multivariate analysis, nor did the multivariate analysis include all ocular conditions that were examined in the present study. With respect to the systemic factors of age, male gender, smoking status, and lower socioeconomic status as mea-
735
Ophthalmology Volume 116, Number 4, April 2009 Table 2. Results of the Binary Logistic Regression Analysis between Mortality and Ocular Parameters in the Beijing Eye Study Parameter
Odds 95% Confidence P Value* Regression Ratio Interval
Age (per yr) ⬍0.001 Gender (male ⫽ 1; 0.01 female ⫽ 2) ‡ Level of education ⬍0.001 Package years of 0.023 cigarettes Level of diabetic-like 0.036 retinopathy§ Angle-closure 0.013 glaucoma Nonglaucomatous 0.027 Optic nerve damage Retinal vein 0.059 occlusion Presence of 0.16 (n.s.) pterygium
0.07 ⫺0.61
1.07 0.55
1.05–1.09 0.34–0.87
⫺0.44 0.22
0.65 1.25
0.56–0.75 1.03–1.51
0.02
1.02
1.01–1.04
3.74
41.9
2.22–790
1.23
3.41
1.15–10.10
0.95
2.59
0.96–6.95
0.53
1.71
0.82–3.56
n.s. ⫽ statistically not significant. *Statistical significance of the difference between both groups. † Of the odds ratio. ‡ Per 1 of 5 levels of education. § Per Early Treatment of Diabetic Retinopathy Study unit.
sured by the level of education, the findings of this study confirm previous investigations in which these systemic parameters were significantly associated with mortality. With respect to the ocular parameters of diabetic-like retinopathy and presence of retinal vein occlusions, the present study confirms previous population-based studies such as the Blue Mountains Eye Study and the Beaver Dam Study of other ethnic groups in which both diseases were correlated with an increased risk of mortality.7,8 Interestingly, the present study adds angle-closure glaucoma to the list of ocular disorders that were associated significantly with an increased mortality. The pathogenic reasons for this association have remained unclear so far. It may be unlikely that repeated angle-closure attacks with marked pain may have led to a bad general condition of the patient, eventually resulting in death. A similar pathomechanism has been postulated for the cause of death of Johann Sebastian Bach.49 Another reason may be more likely. Recent population-based studies have shown that the anterior chamber depth is correlated with body length.50 –52 Because a shallow anterior chamber is the main risk factor for angle-closure glaucoma,53–55 the prevalence of angleclosure glaucoma was significantly associated with body length. Body length, however, is associated with socioeconomic status, with smaller subjects having a lower level of education and lower income in the Chinese population (own data). In a parallel manner, a recent analysis of the data of the Beijing Eye Study showed that a higher level of education was associated with the systemic parameters of younger age, male gender, living in the urban region, taller body height and lower body mass index, and with the ocular parameters of myopic refractive error, higher best-corrected visual acuity, lower degree of nuclear cataract, and lower
736
prevalence of angle-closure glaucoma (own data). Although the level of education as parameter for the socioeconomic background of the subjects was taken into account in the multivariate analysis of the present investigation, one may postulate that Chinese subjects with angle-closure and an associated smaller body stature and low level of education may have had an additional, yet unknown, risk factor compared with subjects with a low socioeconomic background but a taller body stature and no angle-closure glaucoma. Because body height was not measured in the survey of 2001 of the Beijing Eye Study, body height could not be added to the list of independent parameters in the multivariate analysis of mortality. Another factor added to the list of ocular factors associated with mortality was the presence of nonglaucomatous optic nerve damage. In the multivariate analysis, subjects with nonglaucomatous optic nerve damage had higher mortality than those with a healthy-appearing optic nerve head on the optic disc photographs. It may reflect the clinical situation that in the case of a cerebrovascular or heart insufficiency, the retina with the retinal ganglion cells and their axons and the optic nerve in the brain experience microvascular disturbances. There are limitations of the present study. As in any population-based study, nonparticipation can be of major concern. In the Beijing Eye Study at the time of the original survey in 2001, 4439 of 5324 invited individuals participated in the study, resulting in a participation rate of 83.4%. Of these 4439 subjects, 3251 subjects or 73.2% of the participants from 2001 returned for the reexamination in the year 2006, whereas 143 (3.2%) subjects were dead and 1045 (23.5%) subjects were alive but did not agree to be reexamined. Although a response rate of 73.2% in the survey of 2006 may be reasonable, the participants of the 2006 study represent only 61.1% of the 5324 subjects originally invited to participate in the year 2001. However, this may not have influenced the conclusions of this study because one knew whether the nonparticipating subjects were dead or alive, independent of whether they participated in the second survey. Another limitation of the investigation is the relatively low number of 143 people or 3.2% who died, decreasing the power of the statistical analysis. A further limitation of the study is that the cause of death usually was not confirmed by a pathologic examination. Because of the usually chronic illness before death, however, it may have been relatively clear which disease was the major cause of death. In addition, the main outcome parameter in this study was not the cause of death, but rather the factors associated with mortality in general. For a detailed analysis of the differences in the risk factors between the various causes of death, this study might have been too small. Another limitation of the study is that the multivariate analysis did not include the presence of diabetes mellitus as an independent factor potentially influencing the rate of death. The reason is that blood samples were not obtained in 2001, so that data on the blood glucose concentration were available only for the survivors attending the survey of 2006. This limitation of the study was partially compensated for by including the parameter diabetic-like retinopathy, which was examined on the fundus photographs obtained in 2001, into the sta-
Xu et al 䡠 Mortality and Ocular Diseases tistical analysis. A further limitation of the study design is that the socioeconomic parameters such as level of education were assessed based on an interview without rechecking the data in a scientific manner. In conclusion, the present study suggests that if socioeconomic parameters, age, gender, and smoking status are taken into account, ocular parameters associated with an increased mortality were higher level of diabetic-like retinopathy and presence of angle-closure glaucoma, nonglaucomatous optic nerve damage, and (marginally significant) retinal vein occlusions. Other major ocular disorders such as any form of cataract, open-angle glaucoma, age-related macular degeneration, trachoma, pterygia, and high myopia or high hyperopia were not significantly related with an increased mortality in multivariate analysis. These findings may have clinical importance because patients in whom one of the associated ocular conditions is detected may undergo an intensified general body examination to detect reasons for it to prevent early death. The findings may be interesting pathogenetically because the associations and the lack of associations between the ocular disorders and mortality may give some hints regarding their pathogenesis.
References 1. Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 1992;99:933– 43. 2. Vingerling JR, Dielemans I, Hofman A, et al. The prevalence of age-related maculopathy in the Rotterdam Study. Ophthalmology 1995;102:205–10. 3. Leske MC, Connell AM, Wu SY, et al. Prevalence of lens opacities in the Barbados Eye Study. Arch Ophthalmol 1997; 115:105–11. 4. Varma R, Torres M, Los Angeles Latino Eye Study Group. Prevalence of lens opacities in Latinos: the Los Angeles Latino Eye Study. Ophthalmology 2004;111:1449 –56. 5. Foster PJ, Wong TY, Machin D, et al. Risk factors for nuclear, cortical and posterior subcapsular cataracts in the Chinese population of Singapore: the Tanjong Pagar Survey. Br J Ophthalmol 2003;87:1112–20. 6. Foster PJ, Oen FT, Machin D, et al. The prevalence of glaucoma in Chinese residents of Singapore: a cross-sectional population survey of the Tanjong Pagar district. Arch Ophthalmol 2000;118:1105–11. 7. Cugati S, Wang JJ, Knudtson MD, et al. Retinal vein occlusion and vascular mortality: pooled data analysis of 2 populationbased cohorts. Ophthalmology 2007;114:520 – 4. 8. Xu L, Liu WW, Wang YX, et al. Retinal vein occlusions and mortality: the Beijing Eye Study. Am J Ophthalmol 2007;144: 972–3. 9. Wong TY, Klein R, Klein BE, et al. Retinal microvascular abnormalities and their relationship with hypertension, cardiovascular disease, and mortality. Surv Ophthalmol 2001;46: 59 – 80. 10. Wong TY, Klein R, Nieto FJ, et al. Retinal microvascular abnormalities and 10-year cardiovascular mortality: a populationbased case-control study. Ophthalmology 2003;110:933– 40. 11. van Hecke MV, Dekker JM, Nijpels G, et al. Retinopathy is associated with cardiovascular and all-cause mortality in both diabetic and nondiabetic subjects: the Hoorn Study [letter]. Diabetes Care 2003;26:2958.
12. Mitchell P, Wang JJ, Wong TY, et al. Retinal microvascular signs and risk of stroke and stroke mortality. Neurology 2005; 65:1005–9. 13. Hirai FE, Moss SE, Knudtson MD, et al. Retinopathy and survival in a population without diabetes: the Beaver Dam Eye Study. Am J Epidemiol 2007;166:724 –30. 14. Cheung N, Wang JJ, Klein R, et al. Diabetic retinopathy and the risk of coronary heart disease: the Atherosclerosis Risk in Communities Study. Diabetes Care 2007;30:1742– 6. 15. Juutilainen A, Lehto S, Rönnemaa T, et al. Retinopathy predicts cardiovascular mortality in type 2 diabetic men and women. Diabetes Care 2007;30:292–9. 16. Xu L, Wang YX, Xie XW, Jonas JB. Retinopathy and mortality: the Beijing Eye Study. Graefes Arch Clin Exp Ophthalmol 2008;246:923–5. 17. Borger PH, van Leeuwen R, Hulsman CA, et al. Is there a direct association between age-related eye diseases and mortality? The Rotterdam Study. Ophthalmology 2003; 110:1292– 6. 18. Cugati S, Cumming RG, Smith W, et al. Visual impairment, age-related macular degeneration, cataract, and long-term mortality: The Blue Mountains Eye Study. Arch Ophthalmol 2007;125:917–24. 19. Wong TY, Tikellis G, Sun C, et al. Age-related macular degeneration and risk of coronary heart disease: the Atherosclerosis Risk in Communities Study. Ophthalmology 2007; 114:86 –91. 20. Cheung N, Shankar A, Klein R, et al, Atherosclerosis Risk in Communities (ARIC) Study Investigators. Age-related macular degeneration and cancer mortality in the Atherosclerosis Risk in Communities Study. Arch Ophthalmol 2007;125: 1241–7. 21. Xu L, Li YB, Wang YX, Jonas JB. Age-related macular degeneration and mortality: the Beijing Eye Study. Ophthalmologica 2008;222:378 –9. 22. Wang JJ, Mitchell P, Simpson JM, et al. Visual impairment, age-related cataract, and mortality. Arch Ophthalmol 2001; 119:1186 –90. 23. Xu L, Cui TT, Wang YX, Jonas JB. Cataract and mortality: the Beijing Eye Study. Graefes Arch Clin Exp Ophthalmol 2008;246:615–7. 24. Lee AJ, Wang JJ, Kifley A, Mitchell P. Open-angle glaucoma and cardiovascular mortality: the Blue Mountains Eye Study. Ophthalmology 2006;2113:1069 –76. 25. Xu L, Wang YX, Jonas JB. Glaucoma and mortality in the Beijing Eye Study. Eye 2008;22:434 – 8. 26. Thompson JR, Gibson JM, Jagger C. The association between visual impairment and mortality in elderly people. Age Ageing 1989;18:83– 8. 27. Klein R, Klein BE, Moss SE. Age-related eye diseases and survival: the Beaver Dam Eye Study. Arch Ophthalmol 1995: 113:333–9. 28. McCarty CA, Nanjan MB, Taylor HR. Visual impairment predicts 5 year mortality. Br J Ophthalmol 2001;85:322– 6. 29. Ramrattan RS, Wolfs RC, Panda-Jonas S, et al. Prevalence and causes of visual field loss in the elderly and associations with impairment in daily functioning: the Rotterdam Study. Arch Ophthalmol 2001;119:1788 –94. 30. Wang YX, Xu L, Jonas JB, et al. Non-glaucomatous optic nerve damage and mortality in the Beijing Eye Study. Acta Ophthalmol 2008;86:923-4. 31. Lee DJ, Gomez-Marin O, Lam BL, Zheng DD. Visual acuity impairment and mortality in US adults. Arch Ophthalmol 2002;120:1544 –50. 32. AREDS Research Group. Associations of mortality with ocular disorders and an intervention of high-dose antioxidants
737
Ophthalmology Volume 116, Number 4, April 2009
33.
34. 35. 36.
37.
38. 39. 40. 41. 42. 43.
44.
and zinc in the Age-Related Eye Disease Study: AREDS report no. 13. Arch Ophthalmol 2004;122:716 –26. Thiagarajan M, Evans JR, Smeeth L, et al. Cause-specific visual impairment and mortality: results from a populationbased study of older people in the United Kingdom. Arch Ophthalmol 2005;123:1397– 403. Freeman EE, Egleston BL, West SK, et al. Visual acuity change and mortality in older adults. Invest Ophthalmol Vis Sci 2005;46:4040 –5. Knudtson MD, Klein BE, Klein R. Age-related eye disease, visual impairment, and survival: the Beaver Dam Eye Study. Arch Ophthalmol 2006;124:243–9. Saw SM, Foster PJ, Gazzard G, Seah S. Causes of blindness, low vision, and questionnaire-assessed poor visual function in Singaporean Chinese adults: the Tanjong Pagar Survey. Ophthalmology 2004;111:1161– 8. Rumsfeld JS, Jones PG, Whooley MA, et al. Depression predicts mortality and hospitalization in patients with myocardial infarction complicated by heart failure. Am Heart J 2005; 150:961–7. Foong AW, Fong CW, Wong TY, et al. Visual acuity and mortality in a Chinese population: the Tanjong Pagar Study. Ophthalmology 2008;115:802–7. Wu SY, Nemesure B, Hennis A, et al, Barbados Eye Studies Group. Open-angle glaucoma and mortality: the Barbados Eye Studies. Arch Ophthalmol 2008;126:365–70. Xu L, Xie X, Wang S, et al. Prevalence of diabetes mellitus in China. Exp Clin Endocrinol Diabetes 2008;116:69 –70. Xu L, Wang Y, Wang S, et al. High myopia and glaucoma susceptibility: the Beijing Eye Study. Ophthalmology 2007; 114:216 –20. Van Herick W, Shaffer RN, Schwartz A. Estimation of width of angle of anterior chamber: incidence and significance of the narrow angle. Am J Ophthalmol 1969;68:626 –9. Liu H, Ou B, Paxton A, et al. Rapid assessment of trachoma in Hainan Province, China: validation of the new World Health Organization methodology. Ophthalmic Epidemiol 2002;29:97– 104. Age-Related Eye Disease Study Research Group. The AgeRelated Eye Disease Study (AREDS) system for classifying cataracts from photographs: AREDS report no. 4. Am J Ophthalmol 2001;131:167–75.
45. Jonas JB, Budde WM, Panda-Jonas S. Ophthalmoscopic evaluation of the optic nerve head. Surv Ophthalmol 1999;43:293– 320. 46. Early Treatment of Diabetic Retinopathy Study Research Group. Grading diabetic retinopathy from stereoscopic color fundus photographs: an extension of the modified Airlie House classification. ETDRS report number 10. Ophthalmology 1991;98:786 – 806. 47. 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. 48. Wang S, Xu L, Jonas JB, et al. Retinal vascular abnormalities in adult Chinese in rural and urban Beijing: the Beijing Eye Study. Ophthalmology 2006;113:1752–7. 49. David HT, Mendel A, eds. The New Bach Reader: A Life of Johann Sebastian Bach in Letters and Documents. New York: WW Norton; 1999:432. 50. Wong TY, Foster PJ, Johnson GJ, et al. The relationship between ocular dimensions and refraction with adult stature: the Tanjong Pagar Survey. Invest Ophthalmol Vis Sci 2001; 42:1237– 42. 51. Eysteinsson T, Jonasson F, Arnarsson A, et al. Relationships between ocular dimensions and adult stature among participants in the Reykjavik Eye Study. Acta Ophthalmol Scand 2005;83:734 – 8. 52. 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. 53. Congdon NG, Youlin Q, Quigley H, et al. Biometry and primary angle-closure glaucoma among Chinese, white, and black populations. Ophthalmology 1997;104:1489 –95. 54. Devereux JG, Foster PJ, Baasanhu J, et al. Anterior chamber depth measurement as a screening tool for primary angleclosure glaucoma in an East Asian population. Arch Ophthalmol 2000;118:257– 63. 55. Nolan WP, See JL, Chew PT, et al. Detection of primary angle closure using anterior segment optical coherence tomography in Asian eyes. Ophthalmology 2007;114:33–9.
Footnotes and Financial Disclosures Originally received: July 25, 2008. Final revision: November 3, 2008. Accepted: November 3, 2008. Available online: February 4, 2009.
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Manuscript no. 2008-898.
1
Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital University of Medical Science, Beijing, China. 2
Department of Ophthalmology, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Mannheim, Germany.
738
Supported by the Beijing Natural Science Foundation, Beijing, China. Correspondence: Liang Xu, MD, Beijing Institute of Ophthalmology, 17 Hougou Street, Chong Wen Men, 100005 Beijing, China. E-mail: Jost.Jonas@augen. ma.uni-heidelberg.de.