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1.  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.
PURPOSE
To describe racial variations in the prevalence of refractive errors among adult white, Chinese, Hispanic, and black subjects in the United States.
DESIGN
Cross-sectional data from a prospective cohort study—the Multi-Ethnic Study of Atherosclerosis (MESA).
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.1016/j.ajo.2013.01.009
PMCID: PMC3759975  PMID: 23453694
2.  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.
doi:10.1093/hmg/ddt116
PMCID: PMC3674806  PMID: 23474815
3.  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.
doi:10.1177/0956797612470959
PMCID: PMC3713191  PMID: 23678508
4.  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.
doi:10.1371/journal.pone.0101072
PMCID: PMC4076243  PMID: 24979237
5.  Global Prevalence and Major Risk Factors of Diabetic Retinopathy 
Diabetes Care  2012;35(3):556-564.
OBJECTIVE
To examine the global prevalence and major risk factors for diabetic retinopathy (DR) and vision-threatening diabetic retinopathy (VTDR) among people with diabetes.
RESEARCH DESIGN AND METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.2337/dc11-1909
PMCID: PMC3322721  PMID: 22301125
6.  Common genetic determinants of breast-cancer risk in East Asian women: a collaborative study of 23 637 breast cancer cases and 25 579 controls 
Human Molecular Genetics  2013;22(12):2539-2550.
In a consortium including 23 637 breast cancer patients and 25 579 controls of East Asian ancestry, we investigated 70 single-nucleotide polymorphisms (SNPs) in 67 independent breast cancer susceptibility loci recently identified by genome-wide association studies (GWASs) conducted primarily in European-ancestry populations. SNPs in 31 loci showed an association with breast cancer risk at P < 0.05 in a direction consistent with that reported previously. Twenty-one of them remained statistically significant after adjusting for multiple comparisons with the Bonferroni-corrected significance level of <0.0015. Eight of the 70 SNPs showed a significantly different association with breast cancer risk by estrogen receptor (ER) status at P < 0.05. With the exception of rs2046210 at 6q25.1, the seven other SNPs showed a stronger association with ER-positive than ER-negative cancer. This study replicated all five genetic risk variants initially identified in Asians and provided evidence for associations of breast cancer risk in the East Asian population with nearly half of the genetic risk variants initially reported in GWASs conducted in European descendants. Taken together, these common genetic risk variants explain ∼10% of excess familial risk of breast cancer in Asian populations.
doi:10.1093/hmg/ddt089
PMCID: PMC3658167  PMID: 23535825
7.  Is the Pediatric Quality of Life Inventory Valid for Use in Preschool Children with Refractive Errors? 
Purpose
To determine the psychometric validity of the pediatric quality of life inventory (PedsQL 4.0) in assessing the impact of refractive errors on health-related quality of life (HRQoL) in preschool children in Singapore.
Methods
Parents of toddlers (aged 25 to 48 months) and young children (49 to 72 months) completed the PedsQL 4.0, an HRQoL scale as part of population-based trial in Singapore. The outcome measures were the overall score, and the “physical”; “emotional”; “social”; and “school” functioning subscales. Rasch analysis was used to validate the PedsQL 4.0.
Results
Parents of 939 (48.9%) toddlers and 982 (51.1%) young children completed the PedsQL 4.0 survey. The overall mean (±standard deviation) spherical equivalence for the right eye was 0.47 ± 1.13 diopter (D) for toddlers and 0.74 ± 1.22 D for young children. One hundred forty-nine (15.9%) toddlers and 90 (9.2%) young children were considered myopic (≥−0.50 D). Most participants (n = 1286, 89.6%) had presenting visual acuity 6/9 or better. Rasch analysis showed evidence of disordered category thresholds and poor person-item targeting for both groups. The separation reliability was 0.00 for toddlers and 0.03 for young children, indicating there was no variance in both samples. The PedsQL 4.0 overall and subscale scores displayed substantial multidimensionality as the variance values explained by the measures was <25% in both groups. A minimum value of 60% is usually considering acceptable.
Conclusions
The PedsQL 4.0 in its current state is not a valid psychometric scale to effectively evaluate the impact of refractive errors on HRQoL in preschool children in Singapore.
doi:10.1097/OPX.0b013e3181f6fb84
PMCID: PMC4041332  PMID: 20852452
refractive errors; preschool children; Rasch analysis; health-related quality of life
9.  10-Year Longitudinal Changes in Retinal Microvascular Lesions: The Atherosclerosis Risk in Communities Study 
Ophthalmology  2011;118(8):1612-1618.
Objective
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.
Design
Prospective cohort
Participants
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.
Methods
. 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.
Results
. 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)
Conclusions
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.
doi:10.1016/j.ophtha.2011.01.003
PMCID: PMC3150229  PMID: 21529953
microvascular signs; hypertension; microcirculation; retina; ARIC
10.  Diabetic Retinopathy Is Related to Both Endothelium-Dependent and -Independent Responses of Skin Microvascular Flow 
Diabetes Care  2011;34(6):1389-1393.
OBJECTIVE
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.
RESEARCH DESIGN AND METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.2337/dc10-1985
PMCID: PMC3114354  PMID: 21515845
12.  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.
Objective
To summarize the prevalence of retinal vein occlusion (RVO) from studies in the United States, Europe, Asia, and Australia.
Design
Pooled analysis using individual population-based data.
Participants
Individual participant data from population-based studies around the world that had ascertained RVO from fundus photographs.
Methods
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
Any RVO, CRVO, or BRVO.
Results
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.
Conclusions
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.
doi:10.1016/j.ophtha.2009.07.017
PMCID: PMC2945292  PMID: 20022117
13.  Personalized Medicine in Ophthalmology: From Pharmacogenetic Biomarkers to Therapeutic and Dosage Optimization 
Rapid progress in genomics and nanotechnology continue to advance our approach to patient care, from diagnosis and prognosis, to targeting and personalization of therapeutics. However, the clinical application of molecular diagnostics in ophthalmology has been limited even though there have been demonstrations of disease risk and pharmacogenetic associations. There is a high clinical need for therapeutic personalization and dosage optimization in ophthalmology and may be the focus of individualized medicine in this specialty. In several retinal conditions, such as age-related macular degeneration, diabetic macular edema, retinal vein occlusion and pre-threshold retinopathy of prematurity, anti-vascular endothelial growth factor therapeutics have resulted in enhanced outcomes. In glaucoma, recent advances in cytoskeletal agents and prostaglandin molecules that affect outflow and remodel the trabecular meshwork have demonstrated improved intraocular pressure control. Application of recent developments in nanoemulsion and polymeric micelle for targeted delivery and drug release are models of dosage optimization, increasing efficacy and improving outcomes in these major eye diseases.
doi:10.3390/jpm3010040
PMCID: PMC3947950  PMID: 24624293
personalized medicine; pharmacogenetics; clinical utility; ophthalmology; VEGF; age-related macular degeneration; glaucoma; retinopathy; drug delivery; nanotechnology
14.  Challenges in elucidating the genetics of diabetic retinopathy 
JAMA ophthalmology  2014;132(1):96-107.
Importance
In the past decade, significant progress in genomic medicine and technological advances have revolutionized our approach to common complex disorders in many areas of medicine, including ophthalmology. A major disorder that still needs major genetic progress is diabetic retinopathy (DR), one of the leading causes of blindness in adults.
Objective
To perform a literature review, present the current findings, and highlight some key challenges.
Methods
Thorough literature review of the genetic factors for DR, including heritability scores, twin studies, family studies, candidate gene studies, linkage studies, and genome-wide association studies (GWAS).
Results
While there is clear demonstration of a genetic contribution in the development and progression of DR, the identification of susceptibility loci through candidate gene approaches, linkage studies, and GWAS is still in its infancy. The greatest obstacles remain a lack of power due to small sample size of available studies and a lack of phenotype standardization. In this review, we also discuss novel technologies and novel approaches, such as intermediate phenotypes for biomarkers, proteomics, metabolomics, exome chips, and next-generation sequencing that may facilitate future studies of DR.
Conclusions and Relevance
The field of the genetics of DR is still in its infancy and is a challenge due to the complexity of the disease itself. This review outlines some strategies and lessons for future investigation to improve our understanding of this most complex of genetic disorders.
doi:10.1001/jamaophthalmol.2013.5024
PMCID: PMC3947937  PMID: 24201651
15.  Rates of Progression in Diabetic Retinopathy During Different Time Periods 
Diabetes Care  2009;32(12):2307-2313.
OBJECTIVE
This meta-analysis reviews rates of progression of diabetic retinopathy to proliferative diabetic retinopathy (PDR) and/or severe visual loss (SVL) and temporal trends.
RESEARCH DESIGN AND METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.2337/dc09-0615
PMCID: PMC2782996  PMID: 19940227
16.  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.
doi:10.1093/aje/kwp306
PMCID: PMC2800263  PMID: 19884126
cohort studies; meta-analysis; retinal vessels; risk; stroke
17.  Flicker Light–Induced Retinal Vasodilation in Diabetes and Diabetic Retinopathy 
Diabetes Care  2009;32(11):2075-2080.
OBJECTIVE
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.
RESEARCH DESIGN AND METHODS
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.
RESULTS
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).
CONCLUSIONS
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.
doi:10.2337/dc09-0075
PMCID: PMC2768208  PMID: 19641162
18.  Efficacy and safety of multiple intravitreal triamcinolone injections for refractory diabetic macular oedema 
The British Journal of Ophthalmology  2007;91(10):1323-1326.
Aim
The efficacy and safety of repeated injections of intravitreal triamcinolone (IVTA) for diabetic macular oedema is unclear, with results of previous reports conflicting.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1136/bjo.2006.113167
PMCID: PMC2000996  PMID: 17405800
19.  Inflammatory, Hemostatic, and Other Novel Biomarkers for Diabetic Retinopathy 
Diabetes Care  2009;32(9):1704-1709.
OBJECTIVE
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.
RESEARCH DESIGN AND METHODS
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.
RESULTS
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%.
CONCLUSIONS
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.
doi:10.2337/dc09-0102
PMCID: PMC2732144  PMID: 19549733
20.  Retinal Vessel Caliber and Risk for Coronary Heart Disease: A Systematic Review and Meta-Analysis 
Annals of internal medicine  2009;151(6):404-413.
Background
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.
Purpose
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.
Limitations
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.
Conclusion
Retinal vessel caliber changes were independently associated with an increased risk of CHD events in women.
PMCID: PMC2887687  PMID: 19755365
21.  Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus 
Lu, Yi | Vitart, Veronique | Burdon, Kathryn P | Khor, Chiea Chuen | Bykhovskaya, Yelena | Mirshahi, Alireza | Hewitt, Alex W | Koehn, Demelza | Hysi, Pirro G | Ramdas, Wishal D | Zeller, Tanja | Vithana, Eranga N | Cornes, Belinda K | Tay, Wan-Ting | Tai, E Shyong | Cheng, Ching-Yu | Liu, Jianjun | Foo, Jia-Nee | Saw, Seang Mei | Thorleifsson, Gudmar | Stefansson, Kari | Dimasi, David P | Mills, Richard A | Mountain, Jenny | Ang, Wei | Hoehn, René | Verhoeven, Virginie J M | Grus, Franz | Wolfs, Roger | Castagne, Raphaële | Lackner, Karl J | Springelkamp, Henriët | Yang, Jian | Jonasson, Fridbert | Leung, Dexter Y L | Chen, Li J | Tham, Clement C Y | Rudan, Igor | Vatavuk, Zoran | Hayward, Caroline | Gibson, Jane | Cree, Angela J | MacLeod, Alex | Ennis, Sarah | Polasek, Ozren | Campbell, Harry | Wilson, James F | Viswanathan, Ananth C | Fleck, Brian | Li, Xiaohui | Siscovick, David | Taylor, Kent D | Rotter, Jerome I | Yazar, Seyhan | Ulmer, Megan | Li, Jun | Yaspan, Brian L | Ozel, Ayse B | Richards, Julia E | Moroi, Sayoko E | Haines, Jonathan L | Kang, Jae H | Pasquale, Louis R | Allingham, R Rand | Ashley-Koch, Allison | Mitchell, Paul | Wang, Jie Jin | Wright, Alan F | Pennell, Craig | Spector, Timothy D | Young, Terri L | Klaver, Caroline C W | Martin, Nicholas G | Montgomery, Grant W | Anderson, Michael G | Aung, Tin | Willoughby, Colin E | Wiggs, Janey L | Pang, Chi P | Thorsteinsdottir, Unnur | Lotery, Andrew J | Hammond, Christopher J | van Duijn, Cornelia M | Hauser, Michael A | Rabinowitz, Yaron S | Pfeiffer, Norbert | Mackey, David A | Craig, Jamie E | Macgregor, Stuart | Wong, Tien Y
Nature genetics  2013;45(2):155-163.
Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10−8). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4–1.88, P = 2.7 × 10−10, and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29–1.68, P = 4.9 × 10−9). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10−4; tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.
doi:10.1038/ng.2506
PMCID: PMC3720123  PMID: 23291589
22.  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.
doi:10.1016/j.amjcard.2008.02.094
PMCID: PMC2491714  PMID: 18572036
Coronary disease; retinal vascular disease; retinal imaging; risk prediction
23.  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.
doi:10.1016/j.survophthal.2006.12.003
PMCID: PMC2698026  PMID: 17355856
age-related maculopathy; body mass index; cataract; eye disease; glaucoma; obesity; pseudotumor celebri; retinal artery occlusion; retinal vein occlusion; retinopathy
24.  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.
SUMMARY
Background
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.
Methods
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.
Findings
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.
Interpretation
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.
doi:10.1016/S0140-6736(08)60343-8
PMCID: PMC2350208  PMID: 18313502
25.  The 3 Year Incidence and Cumulative Prevalence of Retinopathy 
American journal of ophthalmology  2007;143(6):970-976.
Purpose
To describe the 3 year incidence and cumulative prevalence of retinopathy and its risk factors.
Design
Population-based, prospective cohort study in four U.S. communities
Methods
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.
Results
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.
Conclusions
Retinopathy signs occur frequently in middle-aged people, even in those without diabetes. Hypertension and hyperglycemia are risk factors for incident retinopathy.
doi:10.1016/j.ajo.2007.02.020
PMCID: PMC1950734  PMID: 17399675

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