Charumathi Sabanayagam

Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss.

Diabetic retinopathy (DR) is a leading cause of vision-loss globally. Of an estimated 285 million people with diabetes mellitus worldwide, approximately one third have signs of DR and of these, a further one third of DR is vision-threatening DR, including diabetic macular edema (DME). The identification of established modifiable risk factors for DR such as hyperglycemia and hypertension has provided the basis for risk factor control in preventing onset and progression of DR. Additional research investigating novel risk factors has improved our understanding of multiple biological pathways involved in the pathogenesis of DR and DME, especially those involved in inflammation and oxidative stress. Variations in DR prevalence between populations have also sparked interest in genetic studies to identify loci associated with disease susceptibility. In this review, major trends in the prevalence, incidence, progression and regression of DR and DME are explored, and gaps in literature identified. Established and novel risk factors are also extensively reviewed with a focus on landmark studies and updates from the recent literature.

Retinal Microvasculature as a Model to Study the Manifestations of Hypertension

The retinal vasculature allows direct noninvasive visualization of the body’s mircrovasculature. Because the retina and other end organs (brain and kidney) share similar anatomical features and physiological properties, the retinal vessels offer a unique and easily accessible window to study the health and disease of the human microcirculation. Advanced retinal vascular imaging technologies have been developed to allow a more objective and precise assessment of retinal vascular changes. The changes in the retinal vasculature associated with hypertension can be broadly divided into 3 groups: (1) classic retinal vascular changes in response to blood pressure (referred to as hypertensive retinopathy signs), (2) changes in retinal vascular caliber, and (3) changes in more global geometrical patterns of the retina. In this review, we summarize the current understanding of the relationship between retinal vascular changes and blood pressure, the evidence for the retinal vasculature as a biological model to study the manifestation and early pathogenic correlates of hypertension, the latest advances in retinal vascular imaging technologies, and the future opportunities and challenges of retinal vascular imaging. We suggest that further development of retinal vascular analyses and standardized measurement protocols, evaluation of the clinical use of retinal vascular imaging in assessing cardiovascular risk prediction, and using retinal vascular imaging to test antihypertensive treatments will allow the translation of retinal vascular imaging as a tool to improve the diagnosis, prognosis, and management of hypertension in clinical practice.

Bisphenol A and Peripheral Arterial Disease: Results from the NHANES

Background: Bisphenol A (BPA) is a common chemical used in the manufacture of polycarbonate plastics and epoxy resins, and > 93% of U.S. adults have detectable levels of urinary BPA. Recent animal studies have suggested that BPA exposure may have a role in several mechanisms involved in the development of cardiovascular disease (CVD), including weight gain, insulin resistance, thyroid dysfunction, endothelial dysfunction, and oxidative stress. However, few human studies have examined the association between markers of BPA exposure and CVD. Peripheral arterial disease (PAD) is a subclinical measure of atherosclerotic vascular disease and a strong independent risk factor for CVD and mortality. Objective: We examined the association between urinary BPA levels and PAD in a nationally representative sample of U.S. adults. Methods: We analyzed data from 745 participants in the National Health and Nutritional Examination Survey 2003–2004. We estimated associations between urinary BPA levels (in tertiles) and PAD (ankle–brachial index < 0.9, n = 63) using logistic regression models adjusted for potential confounders (age, sex, race/ethnicity, education, smoking, body mass index, diabetes mellitus, hypertension, urinary creatinine, estimated glomerular filtration rate, and serum cholesterol levels). Results: We observed a significant, positive association between increasing levels of urinary BPA and PAD before and after adjusting for confounders. The multivariable-adjusted odds ratio for PAD associated with the highest versus lowest tertile of urinary BPA was 2.69 (95% confidence interval: 1.02, 7.09; p-trend = 0.01). Conclusions: Urinary BPA levels were significantly associated with PAD, independent of traditional CVD risk factors.

Urinary bisphenol a levels and measures of obesity: results from the national health and nutrition examination survey 2003-2008.

Bisphenol A (BPA) is a widely used chemical. We examined the association between urinary BPA levels and obesity in the National Health and Nutritional Examination Survey (NHANES) 2003–2008. The main outcome of interest was obesity defined as (1) body mass index (BMI) ≥ 30 Kg/m2 and (2) waist circumference (WC) ≥ 102 cm in men and ≥ 88 cm in women. Urinary BPA levels were examined in quartiles. Overall, we observed a positive association between increasing levels of urinary BPA and both measures of obesity, independent of potential confounding factors including, smoking, alcohol consumption, and serum cholesterol levels. Compared to quartile 1 (referent), the multivariate-adjusted odds ratio (95% confidence interval) associated with quartile 4 for BMI-based obesity was 1.69 (1.30–2.20); P-trend < 0.0001 and for WC-based obesity was 1.59 (1.21–2.09); P-trend = 0.0009. This association between BPA and both measures of obesity was consistently present across gender and race-ethnic groups (all P-trend < 0.05). Elevated levels of urinary BPA are associated with measures of obesity independent of traditional risk factors. This association is consistently present across gender and race-ethnic groups. Future prospective studies are needed to confirm or disprove this finding.

Retinal Microvascular Caliber and Chronic Kidney Disease in an Asian Population

Retinal arteriolar narrowing is a marker of microvascular damage from elevated blood pressure. Between August 2004 and June 2006, the authors examined the association between retinal vascular diameter and chronic kidney disease in a population-based cohort of 3,280 community-dwelling adults of Malay ethnicity aged 40-80 years living in Singapore. Chronic kidney disease was defined as 1) an estimated glomerular filtration rate (eGFR) of <60 mL/minute/1.73 m(2) from serum creatinine or 2) the presence of micro/macroalbuminuria defined as urinary albumin:creatinine ratios of > or = 17 mg/g for men and > or = 25 mg/g for women. Retinal arteriolar and venular diameters were measured and summarized as central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE). Individuals with reduced CRAE were more likely to have chronic kidney disease than those with increased CRAE. After controlling for age, gender, education, smoking, diabetes, hypertension, body mass index, and total and high density lipoprotein cholesterol, the authors found the odds ratio comparing the smallest with the largest CRAE quartile to be 1.42 (95% confidence interval: 1.03, 1.96; P(trend) = 0.02) for eGFR of <60 mL/minute/1.73 m(2) and 1.80 (95% confidence interval: 1.11, 2.91; P(trend) = 0.01) for micro/macroalbuminuria. Retinopathy was also found to be positively associated with both eGFR and micro/macroalbuminuria. Retinal venular diameter was not associated with chronic kidney disease. These data suggest that retinal arteriolar narrowing is associated with chronic kidney disease, independent of diabetes and hypertension.

The association between active smoking, smokeless tobacco, second-hand smoke exposure and insufficient sleep.

BACKGROUND Studies have shown that cigarette smoking is associated with sleep disorders in the general population. But studies examining the association between smokeless tobacco use, second-hand smoke exposure and insufficient rest/sleep are limited. METHODS We examined the association between smoking, smokeless tobacco use (n=83,072), second-hand smoke exposure (n=28,557) and insufficient rest/sleep among adults aged ≥20 years in the state-based 2008 Behavioral Risk Factor Surveillance System. Exposure to second-hand smoke was defined as >1 day of exposure to cigarette smoking either at home or in the workplace in the preceding 7 days. Insufficient rest/sleep was defined as not getting enough rest/sleep everyday in the preceding 30 days. RESULTS Compared to never smokeless tobacco users, the odds ratio (OR; 95% confidence interval [CI]) of insufficient rest/sleep was 1.16 (1.00-1.36) and 1.74 (1.37-2.22) among former and current users. Compared to non-smokers/non-smokeless tobacco users, the OR (95% CI) of insufficient rest/sleep for those who were both current smokers and current smokeless tobacco users was 2.21 (1.66-2.94). Regarding second-hand smoke exposure among non-smokers, those with second-hand smoke exposure had higher odds for insufficient rest/sleep than those without. In contrast, the odds of insufficient rest/sleep were similar among current smokers with or without second-hand smoke exposure. CONCLUSIONS In a multiethnic sample of US adults, compared to non-smokers/non-smokeless tobacco users, those who were both current smokers and current smokeless tobacco users had twice the odds of insufficient sleep. Second-hand smoke exposure was associated with insufficient rest/sleep among non-smokers.

Retinal arteriolar narrowing increases the likelihood of chronic kidney disease in hypertension.

Background Retinal arteriolar narrowing is a marker of chronic microvascular damage from hypertension. We hypothesized that the presence of retinal arteriolar narrowing increases the likelihood of chronic kidney disease (CKD) associated with hypertension. Methods We examined 3602 persons of Chinese, Malay and Indian ethnicities, aged at least 24 years residing in Singapore. CKD was defined as an estimated glomerular filtration rate of less than 60 ml/min per 1.73 m2. Hypertension was defined as SBP of at least 140 mmHg or DBP of at least 90 mmHg or self-reported physician-diagnosed hypertension. Retinal arteriolar caliber was measured from retinal photographs and summarized. The lowest arteriolar caliber quartile was defined as retinal arteriolar narrowing. Results Both hypertension and retinal arteriolar narrowing were associated with CKD (n = 185), independent of major confounders, with multivariable odds ratio of 2.10 (95% confidence interval 1.46–3.02) for CKD associated with hypertension and odds ratio of 1.68 (95% confidence interval 1.04–2.71) for retinal arteriolar narrowing. The association between hypertension and CKD was stronger in the presence of retinal arteriolar narrowing (P for interaction 0.09), and joint exposure to both hypertension and retinal arteriolar narrowing was associated with a three-fold odds of having CKD (multivariable odds ratio 3.61, 95% confidence interval 1.88–6.93) compared with absence of hypertension and arteriolar caliber in the highest quartile (quartile 4). Conclusion These findings show that the presence of microvascular disease in the retina increases the likelihood of CKD associated with hypertension and suggest that examination of the retinal vasculature may aid in stratification of CKD risk in hypertensive patients.

Development and Validation of a Deep Learning System for Diabetic Retinopathy and Related Eye Diseases Using Retinal Images From Multiethnic Populations With Diabetes

Importance A deep learning system (DLS) is a machine learning technology with potential for screening diabetic retinopathy and related eye diseases. Objective To evaluate the performance of a DLS in detecting referable diabetic retinopathy, vision-threatening diabetic retinopathy, possible glaucoma, and age-related macular degeneration (AMD) in community and clinic-based multiethnic populations with diabetes. Design, Setting, and Participants Diagnostic performance of a DLS for diabetic retinopathy and related eye diseases was evaluated using 494 661 retinal images. A DLS was trained for detecting diabetic retinopathy (using 76 370 images), possible glaucoma (125 189 images), and AMD (72 610 images), and performance of DLS was evaluated for detecting diabetic retinopathy (using 112 648 images), possible glaucoma (71 896 images), and AMD (35 948 images). Training of the DLS was completed in May 2016, and validation of the DLS was completed in May 2017 for detection of referable diabetic retinopathy (moderate nonproliferative diabetic retinopathy or worse) and vision-threatening diabetic retinopathy (severe nonproliferative diabetic retinopathy or worse) using a primary validation data set in the Singapore National Diabetic Retinopathy Screening Program and 10 multiethnic cohorts with diabetes. Exposures Use of a deep learning system. Main Outcomes and Measures Area under the receiver operating characteristic curve (AUC) and sensitivity and specificity of the DLS with professional graders (retinal specialists, general ophthalmologists, trained graders, or optometrists) as the reference standard. Results In the primary validation dataset (n = 14 880 patients; 71 896 images; mean [SD] age, 60.2 [2.2] years; 54.6% men), the prevalence of referable diabetic retinopathy was 3.0%; vision-threatening diabetic retinopathy, 0.6%; possible glaucoma, 0.1%; and AMD, 2.5%. The AUC of the DLS for referable diabetic retinopathy was 0.936 (95% CI, 0.925-0.943), sensitivity was 90.5% (95% CI, 87.3%-93.0%), and specificity was 91.6% (95% CI, 91.0%-92.2%). For vision-threatening diabetic retinopathy, AUC was 0.958 (95% CI, 0.956-0.961), sensitivity was 100% (95% CI, 94.1%-100.0%), and specificity was 91.1% (95% CI, 90.7%-91.4%). For possible glaucoma, AUC was 0.942 (95% CI, 0.929-0.954), sensitivity was 96.4% (95% CI, 81.7%-99.9%), and specificity was 87.2% (95% CI, 86.8%-87.5%). For AMD, AUC was 0.931 (95% CI, 0.928-0.935), sensitivity was 93.2% (95% CI, 91.1%-99.8%), and specificity was 88.7% (95% CI, 88.3%-89.0%). For referable diabetic retinopathy in the 10 additional datasets, AUC range was 0.889 to 0.983 (n = 40 752 images). Conclusions and Relevance In this evaluation of retinal images from multiethnic cohorts of patients with diabetes, the DLS had high sensitivity and specificity for identifying diabetic retinopathy and related eye diseases. Further research is necessary to evaluate the applicability of the DLS in health care settings and the utility of the DLS to improve vision outcomes.

Fractal analysis of the retinal vasculature and chronic kidney disease

BACKGROUND. Fractal analysis provides a global index of the geometric complexity and optimality of vascular networks. In this study, we investigated the relationship between fractal measurements of the retinal vasculature and chronic kidney disease (CKD). METHODS. This was a population-based case-control study which included participants from the Singapore Prospective Study Program. We identified 261 participants with CKD, defined as estimated glomerular filtration rate of <60 mL/min/1.73 m(2), and 651 controls. The retinal fractal dimension (D(f)) was quantified from digitized fundus photographs using a computer-based programme. RESULTS. The mean D(f) was 1.43 +/- 0.048 in the participants with CKD and 1.44 +/- 0.042 in controls (P = 0.013). Suboptimal D(f) in the lowest (first) and highest (fifth) quintiles were associated with an increased prevalence of CKD after adjusting for age, systolic blood pressure, diabetes and other risk factors [odds ratio (OR) 2.10, 95% confidence interval (CI) 1.15, 3.83 and OR 1.84, 95% CI 1.06, 3.17; compared to the fourth quintile, respectively). This association was present even in participants without diabetes or hypertension. CONCLUSIONS. Our study found that an abnormal retinal vascular network is associated with an increased risk of CKD, supporting the hypothesis that deviations from optimal microvascular architecture may be related to kidney damage.

Serum 25-Hydroxyvitamin D Levels and Prediabetes Among Subjects Free of Diabetes

OBJECTIVE Animal studies suggest that low serum 25-hydroxyvitamin D (25[OH]D) may impair insulin synthesis and secretion and be involved in the pathogenesis of diabetes. Results in studies in humans have not been consistent, however. Prediabetes is a stage earlier in the hyperglycemia/diabetes continuum where individuals are at increased risk of developing diabetes and where prevention efforts have been shown to be effective in delaying or preventing the onset of diabetes. However, previous studies have not examined the association between low serum 25(OH)D levels and prediabetes. RESEARCH DESIGN AND METHODS We examined the 12,719 participants (52.5% women) in the third National Health and Nutrition Examination Survey aged >20 years who were free of diabetes. Serum 25(OH)D levels were categorized into quartiles (≤17.7, 17.8–24.5, 24.6–32.4, >32.4 ng/mL). Prediabetes was defined as a 2-h glucose concentration of 140–199 mg/dL, or a fasting glucose concentration of 110–125 mg/dL, or an A1C value of 5.7–6.4%. RESULTS Lower serum 25(OH)D levels were associated with prediabetes after adjusting for age, sex, race/ethnicity, season, geographic region, smoking, alcohol intake, BMI, outdoor physical activity, milk consumption, dietary vitamin D, blood pressure, serum cholesterol, C-reactive protein, and glomerular filtration rate. Compared with quartile 4 of 25(OH)D (referent), the odds ratio of prediabetes associated with quartile 1 was 1.47 (95% CI 1.16–1.85; P = 0.001 for trend). Subgroup analyses examining the relation between 25(OH)D and prediabetes by sex, BMI, and hypertension categories also showed a consistent positive association. CONCLUSIONS Lower serum 25(OH)D levels are associated with prediabetes in a representative sample of U.S. adults.