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1.  Retinal vascular caliber and the development of hypertension: a meta-analysis of individual participant data 
Journal of hypertension  2014;32(2):207-215.
Microvascular dysfunction has been suggested to be a major pathogenic factor for the development of hypertension. We examined the association between retinal vascular caliber, a marker of systemic microvascular dysfunction, and incident hypertension on a meta-analysis of individual participant data.
We performed a systematic review with relevant studies identified through a search of electronic databases, a review of reference lists, and correspondence with experts. Studies were included if participants were selected from a general population, retinal vascular caliber was measured from photographs using computer-assisted methods at baseline, and individuals were followed up to ascertain the incidence of hypertension. Prespecified individual recorded data from six population-based prospective cohort studies were included. Discrete time proportional odds models were constructed for each study with adjustment for hypertension risk factors. Log odds ratios (ORs) per 20-μm difference were pooled using random-effects meta-analysis.
Among 10 229 participants without prevalent hypertension, diabetes, or cardiovascular disease, 2599 developed new-onset hypertension during median follow-up periods ranging from 2.9 to 10 years. Both narrower retinal arterioles [pooled multivariate-adjusted OR per 20-μm difference 1.29, 95% confidence interval (CI) 1.20–1.39] and wider venules (OR per 20-μm difference 1.14, 95% CI 1.06–1.23) were associated with an increased risk of hypertension. Each 20 μm narrower arterioles at baseline were associated with a 1.12 mmHg (95% CI 0.25–1.99) greater increase in SBP over 5 years.
Retinal arteriolar narrowing and venular widening were independently associated with an increased risk of hypertension. These findings underscore the importance of microvascular remodeling in the pathogenesis of hypertension.
PMCID: PMC4120649  PMID: 24322199
hypertension; meta-analysis; microvascular dysfunction
2.  Racial Variations in the Prevalence of Refractive Errors in the United States: The Multi-Ethnic Study of Atherosclerosis 
American journal of ophthalmology  2013;155(6):1129-1138.e1.
To describe racial variations in the prevalence of refractive errors among adult white, Chinese, Hispanic, and black subjects in the United States.
Cross-sectional data from a prospective cohort study—the Multi-Ethnic Study of Atherosclerosis (MESA).
A total of 6000 adults aged 45 to 84 years living in the United States participated in the study. Refractive error was assessed, without cycloplegia, in both eyes of all participants using an autorefractor. After excluding eyes with cataract, cataract surgery, or previous refractive surgery, the eye with the larger absolute spherical equivalent (SE) value for each participant was used to classify refractive error. Any myopia was defined as SE of −1.0 diopters (D) or less; high myopia was defined as SE of −5.0 D or less; any hyperopia was defined as SE of +1.0 D or more; clinically significant hyperopia was defined as SE of +3.0 D or more. Astigmatism was defined as a cylinder value of +1.0 D or more.
After excluding 508 participants with cataracts in both eyes, 838 participants with cataract surgery, 90 participants with laser refractive surgery, and 134 participants who refused to remove their contact lenses for the refraction measurement, 4430 adults with refractive error assessment in at least 1 eye contributed to the analysis. The prevalence of myopia among MESA participants was 25.1%, with lowest rates in Hispanic participants (14.2%), followed by black (21.5%) and white participants (31.0%), and highest rates in Chinese participants (37.2%). The overall rates of high myopia and astigmatism were 4.6% and 45.0%, respectively, with Chinese subjects also having the highest rates of high myopia (11.8%) and astigmatism (53.4%). The overall prevalence of any hyperopia was 38.2% and clinically significant hyperopia was 6.1%, with Hispanic participants having the highest rates of hyperopia (50.2%) and clinically significant hyperopia (8.8%). In multivariate analyses adjusting for age, sex, race, and study site, higher education level, being employed, and being taller were associated with a higher prevalence of myopia. In contrast, lower educational level and being shorter were associated with a higher prevalence of hyperopia.
Myopia and astigmatism were most prevalent in the Chinese population, with Chinese subjects having 3 times the prevalence of myopia as Hispanic subjects. Hyperopia was most common in Hispanic subjects. These findings provide further insights into variations in refractive errors among different racial groups and have important implications for the eye care services in the United States.
PMCID: PMC3759975  PMID: 23453694
3.  Global Prevalence and Major Risk Factors of Diabetic Retinopathy 
Diabetes Care  2012;35(3):556-564.
To examine the global prevalence and major risk factors for diabetic retinopathy (DR) and vision-threatening diabetic retinopathy (VTDR) among people with diabetes.
A pooled analysis using individual participant data from population-based studies around the world was performed. A systematic literature review was conducted to identify all population-based studies in general populations or individuals with diabetes who had ascertained DR from retinal photographs. Studies provided data for DR end points, including any DR, proliferative DR, diabetic macular edema, and VTDR, and also major systemic risk factors. Pooled prevalence estimates were directly age-standardized to the 2010 World Diabetes Population aged 20–79 years.
A total of 35 studies (1980–2008) provided data from 22,896 individuals with diabetes. The overall prevalence was 34.6% (95% CI 34.5–34.8) for any DR, 6.96% (6.87–7.04) for proliferative DR, 6.81% (6.74–6.89) for diabetic macular edema, and 10.2% (10.1–10.3) for VTDR. All DR prevalence end points increased with diabetes duration, hemoglobin A1c, and blood pressure levels and were higher in people with type 1 compared with type 2 diabetes.
There are approximately 93 million people with DR, 17 million with proliferative DR, 21 million with diabetic macular edema, and 28 million with VTDR worldwide. Longer diabetes duration and poorer glycemic and blood pressure control are strongly associated with DR. These data highlight the substantial worldwide public health burden of DR and the importance of modifiable risk factors in its occurrence. This study is limited by data pooled from studies at different time points, with different methodologies and population characteristics.
PMCID: PMC3322721  PMID: 22301125
4.  10-Year Longitudinal Changes in Retinal Microvascular Lesions: The Atherosclerosis Risk in Communities Study 
Ophthalmology  2011;118(8):1612-1618.
There are limited data on the natural history and longitudinal changes of retinal microvascular lesions. We examined 10-year changes in retinal microvascular lesions, focusing on those related to hypertension and shown to predict development of cardiovascular disease.
Prospective cohort
1,120 middle-aged participants without diabetes of the Atherosclerosis Risk in Communities (ARIC) Study in 1993–5 and again 10 years later in 2003–5.
. Retinal microvascular lesions were graded from retinal photographs using the same protocol at both examinations, with changes (incidence or disappearance) adjudicated by a side-by-side comparison of photographs. The study sample was stratified by carotid intima-media thickness (IMT) and ARIC field center; thus all analyses were weighted by these factors. Persons with diabetes were excluded because the frequency and pathophysiology of diabetic retinal lesions is different.
Main Outcome Measures
Incidence and disappearance rates of lesions.
. The 10 year incidence of focal arteriolar narrowing, arteriovenous (AV) nicking, and retinopathy in persons without diabetes was 3.4% (95% confidence intervals 2.3–4.9), 2.5% (1.6–3.9), and 2.2% (1.3–3.5) respectively. Over the 10 year period, of 32, 219, and 24 eyes with focal arteriolar narrowing, AV nicking and retinopathy at baseline, 50.3% (28.6–71.9), 40.7% (32.7–49.4) and 65.9% (42.4–83.5), respectively, disappeared. Higher baseline plasma fibrinogen and white cell count were associated with incident focal arteriolar narrowing; antihypertensive medication use associated with incident AV nicking; and higher diastolic blood pressure, carotid IMT and white cell count associated with incident retinopathy. Higher fasting serum glucose was not significantly associated with incident retinopathy, though this may be related to the small number of lesions.(Odds ratio 5.88, 95% confidence interval 0.74–46.64 per standard deviation difference)
In this sample of middle-aged adults, new retinal microvascular lesions appeared at a rate between 2–4% over 10 years. A high percentage of lesions (40% or more) disappeared over the same period, suggesting considerable remodeling in the retinal microvasculature.
PMCID: PMC3150229  PMID: 21529953
microvascular signs; hypertension; microcirculation; retina; ARIC
5.  Diabetic Retinopathy Is Related to Both Endothelium-Dependent and -Independent Responses of Skin Microvascular Flow 
Diabetes Care  2011;34(6):1389-1393.
Endothelial dysfunction has been hypothesized as a possible pathogenic factor in the development of diabetic retinopathy (DR). We examined the relationship of DR to endothelium-dependent and endothelium-independent responses in skin microvascular flow.
Participants consisted of 224 individuals with diabetes: 85 with type 1 diabetes and 139 with type 2 diabetes. Sodium nitroprusside (SNP) and acetylcholine (ACh) were delivered across the skin by iontophoresis. Laser Doppler flowmetry was used to assess the skin microcirculation response to SNP (endothelium-independent response) and ACh (endothelium-dependent response). The presence and severity of DR were graded from retinal photographs using a standard protocol.
Of 224 participants, 64.3% had DR. After multivariable adjustment, participants with reduced responses to SNP or ACh were more likely to have DR, with an odds ratio (OR) of 2.33 (95% CI 1.09–5.01) for SNP and 2.20 (1.05–4.61) for ACh, comparing participants with responses below and above the median values. Participants with reduced responses (below the median) to both SNP and ACh were nearly four times more likely to have DR (OR 3.86 [1.45–10.3]) than those with SNP and ACh both above the median values.
The presence of DR was associated with a reduction in skin microcirculation responses to iontophoresis of both SNP and ACh, suggesting that vascular processes associated with both endothelial dysfunction and endothelial function-independent mechanisms may be pathogenically related to DR.
PMCID: PMC3114354  PMID: 21515845
7.  The Prevalence of Retinal Vein Occlusion: Pooled Data from Population Studies from the United States, Europe, Asia, and Australia 
Ophthalmology  2010;117(2):313-9.e1.
To summarize the prevalence of retinal vein occlusion (RVO) from studies in the United States, Europe, Asia, and Australia.
Pooled analysis using individual population-based data.
Individual participant data from population-based studies around the world that had ascertained RVO from fundus photographs.
Each study provided data on branch RVO and central RVO by age, sex, and ethnicity. Prevalence rates were directly age and sex standardized to the 2008 world population aged 30 years and older. Estimates were calculated by study and, after pooling, by ethnicity. Summary estimates included studies in which RVO was assessed from fundus photographs on ≥2 fields of both eyes.
Main Outcome Measures
The combined pooled data contained 68,751 individuals from 15 studies, with participants’ ages ranging from 30 to 101 years. In analyses of 11 studies that assessed ≥2 fundus fields of both eyes (n=49,869), the age- and sex-standardized prevalence was 5.20 per 1000 (confidence interval [CI], 4.40–5.99) for any RVO, 4.42 per 1000 (CI, 3.65–5.19) for BRVO, and 0.80 per 1000 (CI, 0.61–0.99) for CRVO. Prevalence varied by race/ethnicity and increased with age, but did not differ by gender. The age- and sex-standardized prevalence of any RVO was 3.7 per 1000 (CI, 2.8–4.6) in whites (5 studies), 3.9 per 1000 (CI, 1.8–6.0) in blacks (1 study), 5.7 per 1000 (CI, 4.5–6.8) in Asians (6 studies), and 6.9 per 1000 (CI, 5.7–8.3) in Hispanics (3 studies). Prevalence for CRVO was lower than BRVO in all ethnic populations. On the basis of these data, an estimated 16.4 million (CI, 13.9–18.9) adults are affected by RVO, with 2.5 million (CI, 1.9–3.1) affected by CRVO and 13.9 million (CI, 11.5–16.4) affected by BRVO. Study limitations include non-uniform sampling frames in identifying study participants and in acquisition and grading of RVO data.
Our study provides summary data on the prevalence of RVO and suggests that approximately 16 million people may have this condition. Research on preventive and treatment strategies for this sight-threatening eye disease is needed.
PMCID: PMC2945292  PMID: 20022117
8.  Rates of Progression in Diabetic Retinopathy During Different Time Periods 
Diabetes Care  2009;32(12):2307-2313.
This meta-analysis reviews rates of progression of diabetic retinopathy to proliferative diabetic retinopathy (PDR) and/or severe visual loss (SVL) and temporal trends.
This systematic literature review and meta-analysis of prospective studies assesses progression of retinopathy among diabetic patients without treatment for retinopathy at baseline. Studies published between 1975 to February 2008 were identified. Outcomes of interest were rates of progression to PDR and/or SVL. Pooled baseline characteristics and outcome measures were summarized using weighted averages of counts and means. Baseline characteristics and outcomes were compared between two periods: 1975–1985 and 1986–2008.
A total of 28 studies comprising 27,120 diabetic patients (mean age 49.8 years) were included. After 4 years, pooled incidence rates for PDR and SVL were 11.0 and 7.2%, respectively. Rates were lower among participants in 1986–2008 than in 1975–1985. After 10 years, similar patterns were observed. Participants in 1986–2008 studies had lower proportions of PDR and non-PDR at all time points than participants in 1975–1985 studies.
Since 1985, diabetic patients have lower rates of progression to PDR and SVL. These findings may reflect an increased awareness of retinopathy risk factors; earlier identification and initiation of care for patients with retinopathy; and improved medical management of glucose, blood pressure, and serum lipids. Differences in baseline characteristics, particularly in the prevalence and severity of retinopathy, could also have contributed to these temporal differences.
PMCID: PMC2782996  PMID: 19940227
9.  Prediction of Incident Stroke Events Based on Retinal Vessel Caliber: A Systematic Review and Individual-Participant Meta-Analysis 
American Journal of Epidemiology  2009;170(11):1323-1332.
The caliber of the retinal vessels has been shown to be associated with stroke events. However, the consistency and magnitude of association, and the changes in predicted risk independent of traditional risk factors, are unclear. To determine the association between retinal vessel caliber and the risk of stroke events, the investigators combined individual data from 20,798 people, who were free of stroke at baseline, in 6 cohort studies identified from a search of the Medline (National Library of Medicine, Bethesda, Maryland) and EMBASE (Elsevier B.V., Amsterdam, the Netherlands) databases. During follow-up of 5–12 years, 945 (4.5%) incident stroke events were recorded. Wider retinal venular caliber predicted stroke (pooled hazard ratio = 1.15, 95% confidence interval: 1.05, 1.25 per 20-μm increase in caliber), but the caliber of retinal arterioles was not associated with stroke (pooled hazard ratio = 1.00, 95% confidence interval: 0.92, 1.08). There was weak evidence of heterogeneity in the hazard ratio for retinal venular caliber, which may be attributable to differences in follow-up strategies across studies. Inclusion of retinal venular caliber in prediction models containing traditional stroke risk factors reassigned 10.1% of people at intermediate risk into different, mostly lower, risk categories.
PMCID: PMC2800263  PMID: 19884126
cohort studies; meta-analysis; retinal vessels; risk; stroke
10.  Flicker Light–Induced Retinal Vasodilation in Diabetes and Diabetic Retinopathy 
Diabetes Care  2009;32(11):2075-2080.
Flicker light–induced retinal vasodilation may reflect endothelial function in the retinal circulation. We investigated flicker light–induced vasodilation in individuals with diabetes and diabetic retinopathy.
Participants consisted of 224 individuals with diabetes and 103 nondiabetic control subjects. Flicker light–induced retinal vasodilation (percentage increase over baseline diameter) was measured using the Dynamic Vessel Analyzer. Diabetic retinopathy was graded from retinal photographs.
Mean ± SD age was 56.5 ± 11.8 years for those with diabetes and 48.0 ± 16.3 years for control subjects. Mean arteriolar and venular dilation after flicker light stimulation were reduced in participants with diabetes compared with those in control subjects (1.43 ± 2.10 vs. 3.46 ± 2.36%, P < 0.001 for arteriolar and 2.83 ± 2.10 vs. 3.98 ± 1.84%, P < 0.001 for venular dilation). After adjustment for age, sex, diabetes duration, fasting glucose, cholesterol and triglyceride levels, current smoking status, systolic blood pressure, and use of antihypertensive and lipid-lowering medications, participants with reduced flicker light–induced vasodilation were more likely to have diabetes (odds ratio 19.7 [95% CI 6.5–59.1], P < 0.001 and 8.14 [3.1–21.4], P < 0.001, comparing lowest vs. highest tertile of arteriolar and venular dilation, respectively). Diabetic participants with reduced flicker light–induced vasodilation were more likely to have diabetic retinopathy (2.2 [1.2–4.0], P = 0.01 for arteriolar dilation and 2.5 [1.3–4.5], P = 0.004 for venular dilation).
Reduced retinal vasodilation after flicker light stimulation is independently associated with diabetes status and, in individuals with diabetes, with diabetic retinopathy. Our findings may therefore support endothelial dysfunction as a pathophysiological mechanism underlying diabetes and its microvascular manifestations.
PMCID: PMC2768208  PMID: 19641162
11.  Efficacy and safety of multiple intravitreal triamcinolone injections for refractory diabetic macular oedema 
The British Journal of Ophthalmology  2007;91(10):1323-1326.
The efficacy and safety of repeated injections of intravitreal triamcinolone (IVTA) for diabetic macular oedema is unclear, with results of previous reports conflicting.
This is a prospective, observational case series of 27 eyes receiving IVTA for diabetic macular oedema. LogMAR visual acuity (VA) and central macular thickness (CMT) were measured at baseline and in 3 to 6 monthly intervals for up to 24 months, then correlated with the number of IVTA injections given.
One IVTA injection was required in 6 (18%) eyes, 2 in 8 (24%) eyes, 3 in 13 (39%) eyes and 4–5 in 6 (18%) eyes. VA improved in all patients, but neither the final improvement in VA nor the absolute improvement in CMT from baseline to 24 months correlated with the number of injections received (p = 0.44 and 0.84, respectively). Cataract surgery was more frequent in eyes receiving more injections (p = 0.01).
This study suggests that repeated injections of IVTA continue to be as effective as the first over a 2‐year period. The probability of cataract surgery increases with an increasing number of injections.
PMCID: PMC2000996  PMID: 17405800
12.  Inflammatory, Hemostatic, and Other Novel Biomarkers for Diabetic Retinopathy 
Diabetes Care  2009;32(9):1704-1709.
There are conflicting data regarding relationships of systemic biomarkers of inflammation, hemostasis, and homocysteine with diabetic retinopathy. We examined these relationships in the Multi-Ethnic Study of Atherosclerosis.
A total of 921 participants with diabetes were included. Diabetic retinopathy was graded from retinal photographs. We defined two outcomes: any diabetic retinopathy and vision-threatening diabetic retinopathy (severe nonproliferative diabetic retinopathy or worse). Systemic markers analyzed were C-reactive protein, homocysteine, fibrinogen, plasmin-α2-antiplasmin complex (PAP), interleukin-6, d-dimer, factor VIII, serum creatinine, and urinary albumin-to-creatinine (UAC) ratio.
Prevalence of diabetic retinopathy was 33.2% and vision-threatening diabetic retinopathy 7.1%. After adjusting for established risk factors (diabetes duration, A1C, systolic blood pressure, waist-to-hip ratio, and use of diabetes medications), fibrinogen (odds ratio 1.14 [95% CI 1.01–1.32], P = 0.05) and PAP (1.25 [1.05–1.50], P = 0.01) were associated with any diabetic retinopathy, while PAP (1.54 [1.13–2.11], P = 0.007) and homocysteine (1.57 [1.16–2.11], P = 0.003) were associated with vision-threatening diabetic retinopathy. Only PAP remained significant after additional adjustment for serum creatinine and UAC ratio. Area under receiver-operator characteristic curve (AUROC) for diabetic retinopathy was constructed for established and novel risk factors. Established risk factors accounted for a 39.2% increase of the AUROC, whereas novel markers (fibrinogen, PAP, homocysteine, serum creatinine, and UAC ratio) only accounted for an additional 2.2%.
There were few associations of novel markers of inflammation, hemostasis, and homocysteine with diabetic retinopathy after controlling for established risk factors. These data suggest that there is limited clinical use of these biomarkers for prediction of diabetic retinopathy.
PMCID: PMC2732144  PMID: 19549733
13.  Retinal Vessel Caliber and Risk for Coronary Heart Disease: A Systematic Review and Meta-Analysis 
Annals of internal medicine  2009;151(6):404-413.
Retinal vessel caliber may be a novel risk marker of coronary heart disease (CHD) risk. However, the gender specific effect, magnitude of association and effect independent of traditional CHD disease risk factors remain unclear.
To determine the association between retinal vessel caliber and risk of CHD.
Data sources
Relevant studies were identified through MEDLINE (1950 to June 2009) and EMBASE (1950 to June 2009) databases.
Study Selection
Studies were included if derived from a general population, retinal vessel caliber was measured from retinal photographs and incident CHD events were documented.
Data Extraction
Six population-based prospective cohort studies were identified and provided data for individual participant meta-analysis.
Data Synthesis
Proportional hazards models were constructed for retinal vessel caliber and incident CHD in women and men, while adjusting for traditional CHD risk factors. 2,219 (10.0%) incident CHD events were recorded from 22,159 individuals (mean age 62 years) free of CHD followed for 5–14 years. Retinal vessel caliber changes (wider retinal venules and narrower arterioles) were each associated with an increased risk of CHD in women but not men, with pooled multivariable-adjusted hazard ratios of 1.16 (95% confidence interval, CI, 1.06 to 1.26) per 20μm increase in venular caliber, and 1.17 (95% CI, 1.07 to 1.28) per 20μm decrease in arteriolar caliber in women, and 1.02 (95% CI, 0.94 to 1.10) per 20μm increase in venular caliber and 1.02 (95% CI, 0.95, 1.10) per 20μm decrease in arteriolar caliber in men. Higher hazard ratios were found amongst women without hypertension or diabetes.
Error in the measurement of retinal vessel caliber and Framingham variables was not taken into account, and may over or underestimate the true association between retinal vessel caliber and CHD.
Retinal vessel caliber changes were independently associated with an increased risk of CHD events in women.
PMCID: PMC2887687  PMID: 19755365
14.  Risk Prediction of Coronary Heart Disease based on Retinal Vascular Caliber (From The Atherosclerosis Risk in Communities [ARIC] Study) 
Recent studies show that retinal vascular signs such as quantitative retinal vascular caliber are associated with an increased risk of incident coronary heart disease (CHD), but whether these retinal vascular signs add to the prediction of CHD over and above traditional CHD risk factors has not been addressed. We investigated whether these signs add to the prediction of CHD over and above the Framingham risk score amongst people (n=9,155) without diabetes selected from the Atherosclerosis Risk in Communities (ARIC) study. Incident CHD was ascertained using standardized methods and retinal vascular caliber and other retinal signs were measured from retinal photographs. After a mean of 8.8 years of follow up, there were 700 incident CHD events. Women with wider retinal venular caliber (hazard ratio 1.27 per 1 standard deviation increase [95% confidence interval, 1.08, 1.50]) and narrower retinal arteriolar caliber (1.31 per 1 standard deviation decrease [1.10, 1.56]) had a higher risk of incident CHD after adjusting for the Framingham risk score variables. The area under the receiver operator characteristic curve increased from 0.695 to 0.706 (1.7% increase) with the addition of retinal vascular caliber to the Framingham risk model. The risk prediction models with and without the retinal vascular caliber both fitted the data and were well calibrated for women. In men, retinal vascular caliber was not associated with CHD risk after adjustment. Other retinal vascular signs were not associated with 10-year incident CHD in men or women. In conclusion, although retinal vascular caliber independently predicts CHD risk in women, the incremental predictive ability over that of the Framingham model is modest, and unlikely to translate meaningfully into clinical practice.
PMCID: PMC2491714  PMID: 18572036
Coronary disease; retinal vascular disease; retinal imaging; risk prediction
15.  Obesity and Eye Diseases 
Survey of ophthalmology  2007;52(2):180-195.
The prevalence of obesity has reached epidemic proportions in many countries. While its impact on overall health is well documented, less is known about the ocular manifestations of obesity. Amongst different eye diseases, obesity has been linked with age-related cataract, glaucoma, age-related maculopathy, and diabetic retinopathy. Numerous population-based and prospective studies support an association between obesity and risk of age-related cataract. However, the nature and strength of these associations, particularly with the different cataract subtypes, remains to be determined. There is strong evidence that obesity is associated with elevated intraocular pressure, but there is no convincing data to support a more direct association between obesity and glaucomatous optic neuropathy. Studies to date have not found a consistent pattern of association between obesity and risk of age-related maculopathy or diabetic retinopathy. Thus, while obesity may be a risk factor for many ocular conditions, the present literature is inadequate to establish any convincing associations. Furthermore, whether weight loss reduces the risk of eye diseases remains unresolved. Because of the potential public health impact of obesity, there is a greater need to understand its ocular effects.
PMCID: PMC2698026  PMID: 17355856
age-related maculopathy; body mass index; cataract; eye disease; glaucoma; obesity; pseudotumor celebri; retinal artery occlusion; retinal vein occlusion; retinopathy
16.  Lancet Revision, D-07-06757 The Relationship of Fasting Glucose to Retinopathy: Re-visiting a Key Criterion Used to Diagnose Diabetes 
Lancet  2008;371(9614):736-743.
The World Health Organization and American Diabetes Association criteria for diagnosing diabetes assume the presence of a glycemic threshold with high sensitivity for identifying retinopathy. However, this assumption is based on data from three previous studies that had significant limitations in detecting retinopathy.
We examined the relationship of fasting plasma glucose (FPG) with retinopathy in three cross-sectional populations: the Blue Mountains Eye Study (BMES, Australia, n=3162), the Australian Diabetes, Obesity and Lifestyle Study (AusDiab, Australia, n=2182), and the Multi-Ethnic Study of Atherosclerosis (MESA, USA, n=6079). Retinopathy was defined from multiple retinal photographs of each eye, graded according to the modified Airlie House Classification system.
The overall prevalence of retinopathy was 11.5% (95% confidence interval, CI 10.4–12.6%, BMES), 9.6% (CI 8.4–10.9%, AusDiab) and 15.8% (CI 14.9–16.7%, MESA). In contrast to the findings of the three previous studies, we found inconsistent evidence of a uniform glycemic threshold for prevalent and incident retinopathy, with analyses suggesting a continuous relationship. The widely used diabetes FPG cut-off of ≥ 7.0 mmol/l had sensitivity less than 40% (range 14.8–39.1%) for detecting retinopathy, with specificity between 80.8–95.8%. The area under receiver operating characteristic curves for FPG and retinopathy was low and ranged from 0.56 to 0.61.
There was no evidence of a clear and consistent glycemic threshold for the presence or incidence of retinopathy across different populations. The current FPG cut-off of 7.0 mmol/l used to diagnose diabetes performed poorly at identifying persons with and without retinopathy. These findings suggest that the criteria for diagnosing diabetes may require re-evaluation.
PMCID: PMC2350208  PMID: 18313502
17.  The 3 Year Incidence and Cumulative Prevalence of Retinopathy 
American journal of ophthalmology  2007;143(6):970-976.
To describe the 3 year incidence and cumulative prevalence of retinopathy and its risk factors.
Population-based, prospective cohort study in four U.S. communities
In the Atherosclerosis Risk in Communities Study, 981 participants had retinal photography of one randomly selected eye at the 3rd examination (1993-95) and 3 years later at the 4th examination (1996). Photographs were graded on both occasions for retinopathy signs (e.g., microaneurysm, retinal hemorrhage, cotton wool spots). Incidence was defined as participants without retinopathy at the 3rd examination who developed retinopathy at the 4th examination, and cumulative prevalence was defined to include incident retinopathy as well as participants who had retinopathy at both the 3rd and 4th examinations.
The 3-year incidence anad cumulative prevalence of any retinopathy in the whole cohort was 3.8% and 7.7%, respectively. In multivariable analysis, incident retinopathy was related to higher mean arterial blood pressure (OR 1.5, 95% CI 1.0, 2.3, per standard deviation increase in risk factor levels), fasting serum glucose (OR 1.6, 95% CI, 1.3, 2.1), serum total cholesterol (OR 1.4, 95% CI, 1.0, 2.0), and plasma fibrinogen (OR 1.4, 95% CI, 1.1, 1.9). Among persons without diabetes, the 3 year incidence and cumulative prevalence of non-diabetic retinopathy was 2.9% and 4.3%, respectively. Incident non-diabetic retinopathy was related to higher mean arterial blood pressure (OR 1.4, 95% CI, 0.9, 2.3) and fasting serum glucose (OR 1.5, 95% CI, 1.0, 2.3). Among persons with diabetes, the 3-year incidence and cumulative prevalence of diabetic retinopathy was 10.1% and 27.2%, respectively.
Retinopathy signs occur frequently in middle-aged people, even in those without diabetes. Hypertension and hyperglycemia are risk factors for incident retinopathy.
PMCID: PMC1950734  PMID: 17399675
18.  Retinal Microvascular Abnormalities and Risk of Renal Failure in Asian Populations 
PLoS ONE  2015;10(2):e0118076.
Retinal microvascular signs may provide insights into the structure and function of small vessels that are associated with renal disease. We examined the relationship of retinal microvascular signs with both prevalent and incident end-stage renal disease (ESRD) in a multi-ethnic Asian population.
A total of 5763 subjects (aged ≥40 years) from two prospective population-based studies (the Singapore Malay Eye Study and the Singapore Prospective Study) were included for the current analysis. Retinopathy was graded using the modified Airlie House classification system. Retinal vascular parameters were measured using computer-assisted programs to quantify the retinal vessel widths (arteriolar and venular caliber) and retinal vascular network (fractal dimension). Data on ESRD was obtained by record linkage with the ESRD cases registered by National Registry of Diseases Office, Singapore. Multi-variable adjusted regression analyses were performed to assess the associations of baseline retinal vascular parameters and prevalent and incident ESRD.
At baseline, 21(0.36%) persons had prevalent ESRD. During a median follow-up of 4.3 years, 33 (0.57%) subjects developed ESRD. In our analyses, retinopathy was associated with prevalent ESRD (multi-variable adjusted odds ratio [OR], 3.21, 95% confidence interval [CI]: 1.28–8.05) and incident ESRD (multi-variable adjusted hazard ratio [HR], 2.51, 95%CI: 1.14–5.54). This association was largely seen in person with diabetes (HR, 2.60, 95%CI: 1.01–6.66) and not present in persons without diabetes (HR, 1.65, 95%CI: 0.14–18.98). Retinal arteriolar caliber, retinal venular caliber and retinal vascular fractal dimension were not associated with ESRD.
Retinopathy signs in persons with diabetes are related to an increased risk of ESRD; however, other microvascular changes in the retina are not associated with ESRD.
PMCID: PMC4320082  PMID: 25658337
19.  Associations of Candidate Genes to Age-related Macular Degeneration Among Racial/Ethnic Groups in the Multi-Ethnic Study of Atherosclerosis 
American journal of ophthalmology  2013;156(5):10.1016/j.ajo.2013.06.004.
To describe the relationships of selected candidate genes to the prevalence of early age-related macular degeneration (AMD) in a cohort of whites, blacks, Hispanics, and Chinese Americans.
Cross-sectional study.
Multicenter study.
Study Population
2456 persons aged 45–84 years with genotype information and fundus photographs.
Twelve of 2862 single nucleotide polymorphisms (SNPs) from 11 of 233 candidate genes for cardiovascular disease were selected for analysis based on screening with marginal unadjusted P value <0.001 within 1 or more racial/ethnic groups. Logistic regression models tested for association in case-control samples.
Main Outcome Measure
Prevalence of early AMD.
Early AMD was present in 4.0% of the cohort and varied from 2.4% in blacks to 6.0% in whites. The odds ratio increased from 2.3 for one to 10.0 for four risk alleles in a joint effect analysis of Age-Related Maculopathy Susceptibility 2 rs10490924 and Complement Factor H Y402H (P for trend=4.2×10−7). Frequencies of each SNP varied among the racial/ethnic groups. Adjusting for age and other factors, few statistically significant associations of the 12 SNPs with AMD were consistent across all groups. In a multivariate model, most candidate genes did not attenuate the comparatively higher odds of AMD in whites. The higher frequency of risk alleles for several SNPs in Chinese Americans may partially explain their AMD frequency approaching that of whites.
The relationships of 11 candidate genes to early AMD varied among 4 racial/ethnic groups, and partially explained the observed variations in early AMD prevalence among them.
PMCID: PMC3812928  PMID: 23938121
20.  Intraocular pressure rise is predictive of vision improvement after intravitreal triamcinolone acetonide for diabetic macular oedema: a retrospective analysis of data from a randomised controlled trial 
BMC Ophthalmology  2014;14(1):123.
Intravitreal triamcinolone acetonide (IVTA) is an effective treatment for recalcitrant diabetic macular oedema (DMO). It has been shown to improve vision with benefits persisting up to five years. The most common initial side effect of IVTA treatment is rise in intraocular pressure, occurring in approximately 50% of patients within the first 6 months of treatment. We evaluated whether there is a correlation between the development of intraocular pressure rise and improvement in vision.
Analysis of individual data from 33 eyes of 33 participants treated with IVTA for DMO from a prospective, randomised, double-masked, placebo controlled trial. The degree of intraocular pressure (IOP) rise was correlated with improvement in best-corrected visual acuity (BCVA) at 1 and 6 months.
The proportion of eyes gaining 5 or more logMAR letters was higher in eyes with greater IOP rise (p = 0.044). Better absolute improvement in BCVA at 6 months (p = 0.045) was also found in eyes with greater IOP rise. Regression analyses revealed a correlation between IOP rise of 10 or more mmHg and absolute BCVA improvement at 6 months (odds ratio 1.22, 95% confidence interval 1.01-1.48, p = 0.039), but not at 1 month.
IOP rise and vision improvement appear to be correlated following IVTA for DMO, suggesting that the mechanisms that cause both may be linked.
Trial Registration
Clinical NCT00167518, September 5, 2005.
PMCID: PMC4223852  PMID: 25335434
Intravitreal triamcinolone; Diabetic macular oedema; Vision improvement; Intraocular pressure rise; Adverse events; Efficacy
21.  Hypertensive Retinopathy and Risk of Stroke 
Hypertension  2013;62(4):706-711.
Although assessment of hypertensive retinopathy signs has been recommended for determining end-organ damage and stratifying vascular risk in hypertensive persons, its value remains unclear. In this study, we examine whether hypertensive retinopathy predicts the long-term risk of stroke in hypertensives.
A total of 2907 hypertensive participants aged 50–73 at the 1993–1995 examination, who had gradable retinal photographs, no history of diabetes, stroke and coronary heart disease at baseline and data on incident stroke were included from the Atherosclerosis Risk in Communities (ARIC) Study. Retinal photographs were assessed for hypertensive retinopathy signs and classified as none, mild, and moderate/severe. Incident events of any stroke, cerebral infarction and hemorrhagic stroke were identified and validated.
After a mean follow-up period of 13.0 years, 165 persons developed incident stroke (146 cerebral infarctions and 15 hemorrhagic strokes). After adjusting for age, sex, blood pressure, and other risk factors, persons with moderate hypertensive retinopathy were more likely to have stroke (multivariable hazard ratios (HR), moderate versus no retinopathy: 2.37, 95%CI 1.39-4.02). In hypertensives on medication with good control of blood pressure, hypertensive retinopathy was related to an increased risk of cerebral infarction (HR, mild retinopathy: 1.96, 95%CI 1.09-3.55; moderate retinopathy: 2.98, 95%CI 1.01-8.83).
Hypertensive retinopathy predicts the long-term risk of stroke, independent of blood pressure, even in treated hypertensives with good hypertension control. Retinal photographic assessment of hypertensive retinopathy signs may be useful for assessment of stroke risk.
PMCID: PMC4085393  PMID: 23940194
Hypertension; Hypertensive retinopathy; Stroke; Cerebral infarction
22.  Association of Levels of Fasting Glucose and Insulin with Rare Variants at the Chromosome 11p11.2-MADD Locus: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study 
Common variation at the 11p11.2 locus, encompassing MADD, ACP2, NR1H3, MYBPC3 and SPI1, has been associated in genome-wide association studies with fasting glucose (FG) and insulin (FI). In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study, we sequenced five gene regions at 11p11.2 to identify rare, potentially functional variants influencing FG or FI levels.
Method & Results
Sequencing (mean depth 38×) across 16.1kb in 3,566 non-diabetic individuals identified 653 variants, 79.9% of which were rare (MAF <1%) and novel. We analyzed rare variants in five gene regions with FI or FG using the Sequence Kernel Association Test (SKAT). At NR1H3, 53 rare variants were jointly associated with FI (p=2.73 × 10−3); of these, seven were predicted to have regulatory function and showed association with FI (p=1.28 × 10−3). Conditioning on two previously associated variants at MADD (rs7944584, rs10838687) did not attenuate this association, suggesting that there are more than two independent signals at 11p11.2. One predicted regulatory variant, chr11:47227430 (hg18; MAF 0.00068), contributed 20.6% to the overall SKAT score at NR1H3, lies in intron 2 of NR1H3 and is a predicted binding site for FOXA1, a transcription factor associated with insulin regulation. In human HepG2 hepatoma cells, the rare chr11:47227430 A allele disrupted FOXA1 binding and reduced FOXA1-dependent transcriptional activity.
Sequencing at 11p11.2- NR1H3 identified rare variation associated with FI. One variant, chr11:47227430, appears to be functional, with the rare A allele reducing transcription factor FOXA1 binding and FOXA1-dependent transcriptional activity.
PMCID: PMC4066205  PMID: 24951664
fasting glucose; fasting insulin; chr11p11.2; target sequencing; next-generation sequencing
23.  Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associated with refractive error 
Human Molecular Genetics  2013;22(13):2754-2764.
Visual refractive errors (REs) are complex genetic traits with a largely unknown etiology. To date, genome-wide association studies (GWASs) of moderate size have identified several novel risk markers for RE, measured here as mean spherical equivalent (MSE). We performed a GWAS using a total of 7280 samples from five cohorts: the Age-Related Eye Disease Study (AREDS); the KORA study (‘Cooperative Health Research in the Region of Augsburg’); the Framingham Eye Study (FES); the Ogliastra Genetic Park-Talana (OGP-Talana) Study and the Multiethnic Study of Atherosclerosis (MESA). Genotyping was performed on Illumina and Affymetrix platforms with additional markers imputed to the HapMap II reference panel. We identified a new genome-wide significant locus on chromosome 16 (rs10500355, P = 3.9 × 10−9) in a combined discovery and replication set (26 953 samples). This single nucleotide polymorphism (SNP) is located within the RBFOX1 gene which is a neuron-specific splicing factor regulating a wide range of alternative splicing events implicated in neuronal development and maturation, including transcription factors, other splicing factors and synaptic proteins.
PMCID: PMC3674806  PMID: 23474815
24.  Retinal Vessel Caliber and Lifelong Neuropsychological Functioning: An Investigative Tool for Cognitive Epidemiology 
Psychological science  2013;24(7):1198-1207.
Why do more intelligent people live healthier and longer lives? One possibility is that intelligence tests assess health of the brain, but psychological science has lacked technology to evaluate this hypothesis. Digital retinal imaging, a new non-invasive method to visualize microcirculation in the eye, may reflect vascular conditions in the brain. We studied the association between retinal vessel caliber and neuropsychological functioning in the representative Dunedin birth cohort. Wider venular caliber was associated with poorer neuropsychological functioning at midlife, independent of potentially confounding factors. This association was not limited to any specific test domain, and extended to informant-reports of cognitive difficulties in everyday life. Moreover, wider venular caliber was associated with lower childhood IQ tested 25 years earlier. The finding indicates that retinal venular caliber may be an indicator of neuropsychological health years before dementing diseases’ onset, and suggests digital retinal imaging as an investigative tool for psychological science.
PMCID: PMC3713191  PMID: 23678508
25.  Estimated Cases of Blindness and Visual Impairment from Neovascular Age-Related Macular Degeneration Avoided in Australia by Ranibizumab Treatment 
PLoS ONE  2014;9(6):e101072.
Intravitreal injections of anti-vascular endothelial growth factor agents, such as ranibizumab, have significantly improved the management of neovascular age-related macular degeneration. This study used patient-level simulation modelling to estimate the number of individuals in Australia who would have been likely to avoid legal blindness or visual impairment due to neovascular age-related macular degeneration over a 2-year period as a result of intravitreal ranibizumab injections. The modelling approach used existing data for the incidence of neovascular age-related macular degeneration in Australia and outcomes from ranibizumab trials. Blindness and visual impairment were defined as visual acuity in the better-seeing eye of worse than 6/60 or 6/12, respectively. In 2010, 14 634 individuals in Australia were estimated to develop neovascular age-related macular degeneration who would be eligible for ranibizumab therapy. Without treatment, 2246 individuals would become legally blind over 2 years. Monthly 0.5 mg intravitreal ranibizumab would reduce incident blindness by 72% (95% simulation interval, 70–74%). Ranibizumab given as needed would reduce incident blindness by 68% (64–71%). Without treatment, 4846 individuals would become visually impaired over 2 years; this proportion would be reduced by 37% (34–39%) with monthly intravitreal ranibizumab, and by 28% (23–33%) with ranibizumab given as needed. These data suggest that intravitreal injections of ranibizumab, given either monthly or as needed, can substantially lower the number of cases of blindness and visual impairment over 2 years after the diagnosis of neovascular age-related macular degeneration.
PMCID: PMC4076243  PMID: 24979237

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