Deep Learning for Glaucoma Detection and Identification of Novel Diagnostic Areas in Diverse Real-World Datasets.

Purpose: To develop a three-dimensional (3D) deep learning algorithm to detect glaucoma using spectral-domain optical coherence tomography (SD-OCT) optic nerve head (ONH) cube scans and validate its performance on ethnically diverse real-world datasets and on cropped ONH scans. Methods: In total, 2461 Cirrus SD-OCT ONH scans of 1012 eyes were obtained from the Glaucoma Clinic Imaging Database at the Byers Eye Institute, Stanford University, from March 2010 to December 2017. A 3D deep neural network was trained and tested on this unique raw OCT cube dataset to identify a multimodal definition of glaucoma excluding other concomitant retinal disease and optic neuropathies. A total of 1022 scans of 363 glaucomatous eyes (207 patients) and 542 scans of 291 normal eyes (167 patients) from Stanford were included in training, and 142 scans of 48 glaucomatous eyes (27 patients) and 61 scans of 39 normal eyes (23 patients) were included in the validation set. A total of 3371 scans (Cirrus SD-OCT) from four different countries were used for evaluation of the model: the non overlapping test dataset from Stanford (USA) consisted of 694 scans: 241 scans from 113 normal eyes of 66 patients and 453 scans of 157 glaucomatous eyes of 89 patients. The datasets from Hong Kong (total of 1625 scans; 666 OCT scans from 196 normal eyes of 99 patients and 959 scans of 277 glaucomatous eyes of 155 patients), India (total of 672 scans; 211 scans from 147 normal eyes of 98 patients and 461 scans from 171 glaucomatous eyes of 101 patients), and Nepal (total of 380 scans; 158 scans from 143 normal eyes of 89 patients and 222 scans from 174 glaucomatous eyes of 109 patients) were used for external evaluation. The performance of the model was then evaluated on manually cropped scans from Stanford using a new algorithm called DiagFind. The ONH region was cropped by identifying the appropriate zone of the image in the expected location relative to Bruch's Membrane Opening (BMO) using a commercially available imaging software. Subgroup analyses were performed in groups stratified by eyes, myopia severity of glaucoma, and on a set of glaucoma cases without field defects. Saliency maps were generated to highlight the areas the model used to make a prediction. The model's performance was compared to that of a glaucoma specialist using all available information on a subset of cases. Results: The 3D deep learning system achieved area under the curve (AUC) values of 0.91 (95% CI, 0.90-0.92), 0.80 (95% CI, 0.78-0.82), 0.94 (95% CI, 0.93-0.96), and 0.87 (95% CI, 0.85-0.90) on Stanford, Hong Kong, India, and Nepal datasets, respectively, to detect perimetric glaucoma and AUC values of 0.99 (95% CI, 0.97-1.00), 0.96 (95% CI, 0.93-1.00), and 0.92 (95% CI, 0.89-0.95) on severe, moderate, and mild myopia cases, respectively, and an AUC of 0.77 on cropped scans. The model achieved an AUC value of 0.92 (95% CI, 0.90-0.93) versus that of the human grader with an AUC value of 0.91 on the same subset of scans (\(P=0.99\)). The performance of the model in terms of recall on glaucoma cases without field defects was found to be 0.76 (0.68-0.85). Saliency maps highlighted the lamina cribrosa in glaucomatous eyes versus superficial retina in normal eyes as the regions associated with classification. Conclusions: A 3D convolutional neural network (CNN) trained on SD-OCT ONH cubes can distinguish glaucoma from normal cases in diverse datasets obtained from four different countries. The model trained on additional random cropping data augmentation performed reasonably on manually cropped scans, indicating the importance of lamina cribrosa in glaucoma detection. Translational Relevance: A 3D CNN trained on SD-OCT ONH cubes was developed to detect glaucoma in diverse datasets obtained from four different countries and on cropped scans. The model identified lamina cribrosa as the region associated with glaucoma detection.

Translation and cross-cultural adaptation of a Nepali version of the Dutch Participation and Activity Inventory for Children and Youth (PAI - CY) with visual impairment.

BACKGROUND: Visual impairment is an important cause of disability in children. There is a lack of information on rehabilitation needs and low vision support services for children with visual impairment in Nepal. This is a pilot study designed to translate, culturally adapt and pre-test the Dutch version of the Participation and Activity Inventory for Children and Youth (PAI-CY) with visual impairment aged 7-17 years to develop a Nepali version. Questionnaires (PAI-CY versions for 7-12 and 13-17 years) were translated using standardized methods and were culturally adapted by a panel of experts. They were pretested to evaluate comprehensibility and relevance among six children with visual impairment and blindness. Finally, participants completed a questionnaire evaluation form. RESULTS: The translation and cultural adaptation process resulted in the adaptation of nine items to make them suitable for Nepali culture. Most children had comprehensibility problems with some specific items because of vocabulary, sentence structure and the composition of items. Most of the children were satisfied with the questionnaires. CONCLUSION: The study resulted in the development of a Nepali version of the PAI-CY. We worked with a small group of content experts and a small but representative sample of children which allowed us to use rigorous translation procedures to address language and cultural differences. A population based study has been planned to investigate the psychometric properties of these questionnaires.

Glycated Serum Protein Genetics and Pleiotropy with Cardiometabolic Risk Factors.

Measurements of fasting glucose (FG) or glycated hemoglobin A1c (HbA1c) are two clinically approved approaches commonly used to determine glycemia, both of which are influenced by genetic factors. Obtaining accurate measurements of FG or HbA1c is not without its challenges, though. Measuring glycated serum protein (GSP) offers an alternative approach for assessing glycemia. The aim of this study was to estimate the heritability of GSP and GSP expressed as a percentage of total serum albumin (%GA) using a variance component approach and localize genomic regions (QTLs) that harbor genes likely to influence GSP and %GA trait variation in a large extended multigenerational pedigree from Jiri, Nepal (n = 1,800). We also performed quantitative bivariate analyses to assess the relationship between GSP or %GA and several cardiometabolic traits. Additive genetic effects significantly influence variation in GSP and %GA levels (p values: 1.15 × 10-5 and 3.39 × 10-5, respectively). We localized a significant (LOD score = 3.18) and novel GSP QTL on chromosome 11q, which has been previously linked to type 2 diabetes. Two common (MAF > 0.4) SNPs within the chromosome 11 QTL were associated with GSP (adjusted pvalue < 5.87 × 10-5): an intronic variant (rs10790184) in the DSCAML1 gene and a 3'UTR variant (rs8258) in the CEP164 gene. Significant positive correlations were observed between GSP or %GA and blood pressure, and lipid traits (p values: 0.0062 to 1.78 × 10-9). A significant negative correlation was observed between %GA and HDL cholesterol (p = 1.12 × 10-5). GSP is influenced by genetic factors and can be used to assess glycemia and diabetes risk. Thus, GSP measurements can facilitate glycemic studies when accurate FG and/or HbA1c measurements are difficult to obtain. GSP can also be measured from frozen blood (serum) samples, which allows the prospect of retrospective glycemic studies using archived samples.

Prevalence and risk factors of diabetic retinopathy among an elderly population with diabetes in Nepal: the Bhaktapur Retina Study.

AIM: Diabetic retinopathy (DR) is an emerging cause of blindness in developing countries. This study aimed to explore the prevalence and risk factors of DR in an elderly population in Nepal. SUBJECTS AND METHODS: This is a population-based, cross-sectional study. A total of 1860 subjects at the age 60 years and above participated (response rate 88.6%). A detailed history was obtained, presenting and best-corrected visual acuity were measured, and anterior segment and posterior segment examinations were carried out. Blood pressure and random blood sugar were recorded; body mass index was calculated, and abdominal girth was measured. DR was graded by clinical examination using Early Treatment Diabetic Retinopathy Study criteria. RESULTS: Diabetes was found in 168 (9%) subjects (mean age 69.6 years), 31 (18.5%) of whom were newly diagnosed. The prevalence of DR was 23.8% (95% confidence interval [CI]: 17.7%-31%) among the persons with diabetes. The prevalence of DR among newly diagnosed subjects with diabetes was 6.5% (95% CI: 0.8%-21.4%). The prevalence of vision-threatening DR was 9.5% (95% CI: 5.5%-15%) and was higher in males. The prevalence of DR was 83.3% (95% CI: 35.9%-99.6%) among those with diabetes for over 20 years. In multivariable logistic regression analysis, duration of diabetes, hypertension, and alcohol consumption were significantly associated with DR. CONCLUSION: DR is a common problem among the elderly population with diabetes in Nepal. The duration of diabetes, hypertension, and alcohol consumption are the risk factors for the development of DR. Strategies have to be developed for timely diagnosis of diabetes and screening for DR.

Prevalence and causes of low vision and blindness in an elderly population in Nepal: the Bhaktapur retina study.

BACKGROUND: This study aims to explore the prevalence and causes of low vision and blindness focused on retinal disease in a population above 60 years in Nepal. METHODS: Two thousand one hundred subjects were enrolled in a population-based cross-sectional study. History, presenting and best corrected visual acuity after subjective refraction, anterior and posterior segment examinations was obtained in detail. RESULTS: Among the total subjects, 1860 (88.57%) had complete information. Age varies from 60 to 95 (mean age: 69.64 ± 7.31) years. Low vision and blindness in both eyes at presentation was found in 984 (52.90%, 95% confidence interval (CI): 50.60-55.19) and 36 (1.94%, 95% CI: 1.35-2.66) subjects respectively. After best correction, bilateral low vision and blindness was found in 426 (22.92%, 95% CI: 21.01-24.88), and 30 (1.61%, 95% CI: 0.10-2.30) subjects respectively. As compared to 60-69 years old, risk of visual impairment was four times higher (95% CI:3.26-5.58) in the 70-79 year olds and 14 times higher (95% CI: 9.72-19.73) in the age group 80 years and above. Major causes of bilateral low vision were cataract (68.07%), followed by retinal disorders (28.64%), and for blindness; retinal disorders (46.66%), followed by cataract (43.33%). Illiteracy was significantly associated with visual impairment. CONCLUSION: Among the elderly population, prevalence of visual impairment was high. Refractive error, cataract and retinal disorders were the major cause of low vision. Screening the population at the age 60 years and above, focused on cataract and posterior segment diseases, providing glasses and timely referral can help reduce visual impairment.

Prevalence, pattern and risk factors of retinal vein occlusion in an elderly population in Nepal: the Bhaktapur retina study.

BACKGROUND: This study aims to explore the prevalence, pattern and risk factors of retinal vein occlusion (RVO) in an elderly population of Nepal. METHOD: One thousand eight hundred sixty subjects of age 60 years and above were enrolled in a population-based, cross-sectional study. Detailed history, visual acuity, anterior segment and posterior segment examinations were done. Blood pressure, non-fasting blood sugar, body mass index and abdominal girth were measured. Retinal vein occlusions were further divided into branch retinal (BRVO), hemi-retinal and central retinal vein occlusion (CRVO). RESULT: Age ranged from 60 to 95 years with a mean of 69.64 ± 7.31 years. Overall population prevalence for RVO was 2.95% (95% Confidence interval (CI): 2.23-3.83), BRVO 2.74% (95% CI: 2.05-3.58) and CRVO 0.21% (95% CI: 0.06-0.55). BRVO was seen in 51 subjects (92.73%) and CRVO in 4 (7.27%). Among the total RVO, unilateral and bilateral involvement was 85.45% and 14.55%, respectively. Among the subjects with BRVO and CRVO, 37.25% and 50% had low vision, respectively. The risk of RVO increased with ageing and was more among males. There was an increased risk of RVO among those with hypertension, and with diabetes and hypertension. There was also an increased risk of RVO among subjects with hypermetropia, those with pseudophakia and those who were smokers and consumed alcohol. CONCLUSION: Retinal vein occlusion is a common retinal vascular disorder in the elderly population of Nepal. The main risk factors for RVO were increasing age and hypertension.

Prevalence of and risk factors for age-related macular degeneration in Nepal: the Bhaktapur Retina Study.

AIM: This study aimed to explore the prevalence of and risk factors for age-related macular degeneration (AMD) in an elderly population in Nepal. SUBJECTS AND METHODS: This is a population-based, cross-sectional study. A sample size of 2,100 was calculated. A total of 1,860 (88.6%) subjects aged >60 years were enrolled for the study from 30 clusters in the district. Detailed history, visual acuity, and anterior segment and posterior segment examinations were performed. AMD was graded according to the International ARM Epidemiological Study Group. RESULTS: Among the total study population, 659 subjects had any AMD (35.43%; 95% confidence interval [CI]: 33.25-37.65), 484 had mild dry AMD (26.02%; 95% CI: 24.04-28.08), 143 had intermediate dry AMD (7.69%; 95% CI: 6.52-8.99), 19 had geographic atrophy (1.02%; 95% CI: 0.61-1.59), and 13 had wet AMD (0.70%; 95% CI: 0.37-1.19). The overall prevalence of early and late AMD was 33.71% and 1.72%, respectively. Among subjects with dry and wet AMD, 36.53% and 46.1% had visual impairment, while 2.78% and 23.08% were blind, respectively. In multivariate analysis, AMD was significantly higher in subjects with an increased number of cigarettes smoked per day (odds ratio [OR] 1.02, 95% CI: 1.01-1.04; P=0.007) and in subjects with pseudophakia (OR 1.45, 95% CI: 1.12-1.87; P=0.005). CONCLUSION: One-third of the population aged ≥60 years have some form of AMD. There was a significant association with the number of cigarettes consumed and with previous cataract surgery.

Intra- and inter-rater agreement between an ophthalmologist and mid-level ophthalmic personnel to diagnose retinal diseases based on fundus photographs at a primary eye center in Nepal: the Bhaktapur Retina Study.

BACKGROUND: Early detection can reduce irreversible blindness from retinal diseases. This study aims to assess the intra- and inter-rater agreement of retinal pathologies observed on fundus photographs between an ophthalmologist and two-mid level ophthalmic personnel (MLOPs). METHOD: A population-based, cross-sectional study was conducted among subjects 60 years and above in the Bhaktapur district of Nepal. Fundus photographs of 500 eyes of 500 subjects were assessed. The macula-centered 45-degree photographs were graded twice by one ophthalmologist and two MLOPs. Intra-rater and inter-rater agreements were assessed for the ophthalmologist and the MLOPs. RESULT: Mean age was 70.22 years ± 6.94 (SD). Retinal pathologies were observed in 55.6 % of photographs (age-related macular degeneration: 34.2 %; diabetic retinopathy: 4.2 %; retinal vein occlusion: 3.8 %). Twelve (2.4 %) fundus pictures were non-gradable. The intra-rater agreement for overall retinal pathologies, retinal hemorrhage, and maculopathy were substantial both for the ophthalmologist as well as for the MLOPs. There was moderate inter-rater agreement between the ophthalmologist and the first MLOP on second rating for overall retinal pathologies, [kappa (k); 95 % CI = 0.59 (0.51-0.66)], retinal hemorrhage [k; 95 % CI = 0.60 (0.41-0.78)], and maculopathy [k; 95 % CI = 0.52 (0.43-0.60)]. Inter-rater agreement between the ophthalmologist and the second MLOP for second rating was moderate for overall retinal pathologies [k; 95 % CI = 0.52 (0.44-0.60)], substantial agreement for retinal hemorrhage [k; 95 % CI = 0. 68 (0.52-0.84)], moderate agreement for maculopathy [k; 95 % CI = 0.59 (0.50-0.67)]. CONCLUSION: There is moderate agreement between the MLOPs and the ophthalmologist in grading fundus photographs for retinal hemorrhages and maculopathy.

Population awareness of diabetic eye disease and age related macular degeneration in Nepal: the Bhaktapur Retina Study.

BACKGROUND: Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are among the leading causes of visual impairment and blindness in developing countries. This study aims to explore the awareness of these retinal diseases in Nepal. METHOD: A population based cross-sectional study conducted among individuals 60 years and older from the Bhaktapur district of Nepal. One thousand consecutive subjects were enrolled and subjected to a structured questionnaire. RESULT: Subject age ranged from 60 to 93 years with a meanof 69.5 years ± 7.1(S.D.). Males and females comprised 45.1 and 55.9 % of the population, respectively. The majority was illiterate (78.2 %), and agriculture was the predominant occupation (79.8 %). 12.1 % were aware of the effect of diabetes on the eye, and among them, 99 % were aware that diabetes was a blinding disease caused by DR.11.5 % of the subjects were aware of DR, and 10.1 % were aware that subjects with diabetes should undergo periodic eye examinations. Only 7.6 % of subjects were aware of AMD.7.5 and 7.4 % were aware about its aggravation with smoking and sunlight exposure, respectively. Younger age group, males, literates, service holders, best corrected visual acuity >0.3 LogMAR, were each significantly associated with an increase in awareness of diabetic retinopathy. Smokers and those with agricultural occupations were less aware regarding AMD. Those with diabetes,with or without DRwere significantly more aware than those not having the disease. CONCLUSION: Among the Bhaktapur population, awareness of DR and AMD was only 11.5 and7.6 % respectively. Older age groups, females, illiterates, farmers, and those with poor visual acuity were less aware of these blinding diseases. We recommend community-based eye health education programs targeted at raising awareness of these diseases and preventive measures.

Association of genetic variants with primary angle closure glaucoma in two different populations.

PURPOSE: A recent large genome-wide association study (GWAS) identified multiple variants associated with primary angle-closure glaucoma (PACG). The present study investigated the role of these variants in two cohorts with PACG recruited from Australia and Nepal. METHOD: Patients with PACG and appropriate controls were recruited from eye clinics in Australia (n = 232 cases and n = 288 controls) and Nepal (n = 106 cases and 204 controls). Single nucleotide polymorphisms (SNPs) rs3753841 (COL11A1), rs1015213 (located between PCMTD1 and ST18), rs11024102 (PLEKHA7), and rs3788317 (TXNRD2) were selected and genotyped on the Sequenom. Analyses were conducted using PLINK and METAL. RESULTS: After adjustment for age and sex, SNP rs3753841 was found to be significantly associated with PACG in the Australian cohort (p = 0.017; OR = 1.34). SNPs rs1015213 (p = 0.014; OR 2.35) and rs11024102 (p = 0.039; OR 1.43) were significantly associated with the disease development in the Nepalese cohort. None of these SNPs survived Bonferroni correction (p = 0.05/4 = 0.013). However, in the combined analysis, of both cohorts, rs3753841 and rs1015213 showed significant association with p-values of 0.009 and 0.004, respectively both surviving Bonferroni correction. SNP rs11024102 showed suggestive association with PACG (p-value 0.035) and no association was found with rs3788317. CONCLUSION: The present results support the initial GWAS findings, and confirm the SNP's contribution to PACG. This is the first study to investigate these loci in both Australian Caucasian and Nepalese populations.

Prevalence and pattern of vitreo-retinal diseases in Nepal: the Bhaktapur glaucoma study.

BACKGROUND: Vitreo-retinal diseases are among the leading causes of visual impairment and blindness worldwide. This study reports the prevalence and pattern of vitreo-retinal diseases in the Bhaktapur Glaucoma Study (BGS), a population based study conducted in Nepal. METHODS: BGS was a population based cross-sectional study involving 4800 subjects aged 40 years and over from Bhaktapur district. Subjects were selected using a cluster sampling methodology and a door-to-door enumeration. All subjects underwent a detailed ocular examination at the base hospital which included log MAR visual acuity, refraction, applanation tonometry and a dilated fundus examination. Fundus photography, optical coherence tomography and fundus fluorescein angiography were performed where indicated. RESULTS: Complete data was available for 3966 (82.62%) out of the total of 4800 enumerated subjects. The mean age was 55.08 years (SD 11.51). The overall prevalence of vitreo-retinal disorders was 5.35% (95% CI, 4.67 - 6.09). Increasing age was associated with a higher prevalence of vitreo-retinal disorders (P < 0.001). The prevalence of diabetes mellitus was 7.69% (95% CI, 6.88 - 8.56). Age-related macular degeneration (AMD) was the most common vitreo-retinal disorder with a prevalence of 1.50% (95% CI, 1.15 - 1.94), increasing significantly with age. The prevalence of diabetic retinopathy among the study population was 0.78% (95% CI, 0.53 - 1.11) and among the diabetic population 10.16% (95% CI, 7.01 - 14.12). The population prevalence of other retinal disorders were hypertensive retinopathy 0.88%, macular scar 0.37%, retinal vein occlusion 0.50%, macular hole 0.20%, retinitis pigmentosa 0.12%. and retinal detachment 0.10%.The prevalence of low vision and blindness due to vitreo-retinal disorders was 1.53% (95% CI, 1.18 - 1.97) and 0.65% (95% CI, 0.43 - 0.96), respectively. The prevalence of low vision and blindness was 28.77% (95% CI, 22.78-35.37) and 12.26% (95% CI, 8.17-17.45), respectively among cases with vitreo-retinal disorders. Blindness was observed to be unilateral in 19 cases (73%), and bilateral in 7 cases (27%). CONCLUSIONS: The prevalence of vitreo-retinal disorders in this Nepalese population was 5.35%, which increased significantly with age. AMD was the predominant retinal condition followed by diabetic retinopathy. One fourth of the subjects with vitreo-retinal disorder had low vision. Taking into consideration the aging population and emerging systemic diseases such as diabetes mellitus and hypertension, vitreo-retinal disorders could be of future public health importance.

Association of eNOS polymorphisms with primary angle-closure glaucoma.

PURPOSE: Recently, several studies have investigated genetic associations between Cytochrome P450 (CYP1B1), Endothelial nitric oxide synthase (eNOS), and Neurotrophin-4 (NTF4) with primary angle-closure glaucoma (PACG) in various ethnic groups. We investigated the association of these candidate genes with PACG in samples from Australia and Nepal. METHODS: A total of 235 patients with PACG (106 Nepalese and 129 Australian) and 492 controls (204 Nepalese and 288 Australian) was included. Tag single nucleotide polymorphisms (SNPs) were selected to cover the majority of common variation within the candidate genes and genotyped in DNA extracted from peripheral whole blood. Allele and haplotype analyses were conducted in PLINK. Bonferroni correction was applied for the total number of SNPs in this study (P = 0.05/15 = 0.003). RESULTS: In the Australian cohort, one eNOS SNP rs3793342 showed significance association with PACG after Bonferroni correction (P value of 0.003, odds ratio [OR] 0.5, 95% confidence interval [CI] 0.3-0.8). After adjusting the results for sex and age, SNPs rs3793342 and rs7830 showed significance after Bonferroni correction (P value of 0.001 and 0.003, respectively). The eNOS haplotype of all 7 typed SNPs showed significant association with a global P value of 0.019, with the CGCAATC haplotype giving a specific P value of 0.008 and OR of 1.5 (95% CI 0.9-2.4). In the Nepalese cohort, SNPs in CYP1B1 and NTF4 genes showed borderline association with PACG, but did not survive Bonferroni correction. CONCLUSIONS: Our data support the involvement of common variations in eNOS with PACG pathogenesis. Differences were observed in the two populations studied, and additional replication studies in other populations are necessary to confirm these associations.

A cross-ethnicity investigation of genes previously implicated in primary angle closure glaucoma.

PURPOSE: To investigate the underlying genetic variation between candidate genes and primary angle closure glaucoma (PACG) in both Nepalese and Australian populations. METHODS: A total of 213 patients with PACG (106 Nepalese and 107 Australian) and 492 age and sex matched controls (204 Nepalese and 288 Australian) were included in the current study. Three candidate genes were selected; methyl-tetrahydrofolate reductase (MTHFR), calcitonin receptor-like receptor gene (CALCRL), and membrane frizzled-related protein (MFRP). Tag single nucleotide polymorphisms (SNPs) were selected and genotyped to capture the majority of common variation across each locus. Allele and haplotype analyses were conducted using PLINK. RESULTS: SNPs in the nanophthalmos gene MFRP were found to be nominally associated with PACG under the allelic model. Two SNPs were associated in the Australian cohort (rs948414; p=0.02 and rs36015759; p=0.02), and a single SNP in the Nepalese cohort (rs10790289; p=0.03), however these SNPs failed to remain significant after adjustment for sex and age. A haplotype at the CALCRL gene (AATACAGAT) was associated in the Australian cohort (corrected p-value=0.024). No association was observed in either cohort for MTHFR. CONCLUSIONS: This study implicates genetic variation at the CALCRL gene in the pathogenesis of PACG in an Australian Caucasian cohort. Additionally, the MFRP gene shows tendency to be associated with PACG in both the Australian and Nepalese cohorts. Further investigation in a larger cohort is warranted to confirm these findings. No statistically significant associations were identified between MTHFR and PACG in either population.

A population-based survey of the prevalence and types of glaucoma in Nepal: the Bhaktapur Glaucoma Study.

OBJECTIVE: To determine the prevalence and types of glaucoma in a Nepalese population. DESIGN: Cross-sectional, population-based survey. PARTICIPANTS: A total of 4800 subjects aged 40 years or older from the Bhaktapur district of Kathmandu valley. METHODS: Subjects aged 40 years or older were selected using a cluster sampling procedure and door-to-door enumeration for a population-based, cross-sectional study. All subjects underwent a detailed ocular examination at the base hospital, which included logarithm of minimal angle of resolution visual acuity, refraction, applanation tonometry, gonioscopy, Lens Opacities Classification System II cataract grading, retinal examination, and Swedish Interactive Thresholding Algorithm standard perimetry when indicated. MAIN OUTCOME MEASURES: Diagnosis of glaucoma was based on criteria described by the International Society for Geographic and Epidemiological Ophthalmology. RESULTS: A total of 4003 subjects underwent a comprehensive eye examination (response rate 83.4%), and complete data were available in 3991 subjects. The mean intraocular pressure was 13.3 mmHg (97.5th and 99.5th percentiles, 18 and 20 mmHg, respectively), and the mean vertical cup-to-disc ratio was 0.26 (97.5th and 99.5th percentiles, 0.6 and 0.8 mmHg, respectively). There were 75 subjects with glaucoma, an age- and sex-standardized prevalence of 1.80 (95% confidence interval [CI], 1.68-1.92). Age- and sex-standardized prevalence was 1.24% (95% CI, 1.14-1.34) for primary open-angle glaucoma (POAG), 0.39% (95% CI, 0.34-0.45) for primary angle-closure glaucoma (PACG), and 0.15% (95% CI, 0.07-0.36) for secondary glaucoma. The prevalence of glaucoma increased with an increase in age with no significant difference in gender. Primary angle-closure glaucoma was 3 times more common in women. Nine eyes were blind, and 2 subjects were bilaterally blind from glaucoma. CONCLUSIONS: The overall prevalence of glaucoma was 1.9%. Of all glaucoma cases, POAG accounted for 68%, PACG accounted for 22.67%, and secondary glaucoma accounted for 9.33%. Among the subjects with POAG, 96.08% had not been previously diagnosed.

Central corneal thickness and intraocular pressure in a Nepalese population: the Bhaktapur Glaucoma Study.

PURPOSE: The purpose of the study was to evaluate the characteristics of central corneal thickness and its association with age, sex, and intraocular pressure in a Nepalese population. PATIENTS AND METHODS: The study design was a cross-sectional, population-based survey. Two thousand three hundred thirty patients aged 40 years and older were examined at Tilganga Institute of Ophthalmology, a tertiary referral eye centre in Kathmandu, Nepal. All patients underwent a complete ophthalmic examination that included measurements of central corneal thickness with an ultrasonic pachymeter and intraocular pressure with a Goldman type applanation tonometer. RESULTS: The main outcome measures were central corneal thickness and intraocular pressure. Mean age of the 2330 patients examined was 51.3 years (SD±9.56). The mean central corneal thickness and mean intraocular pressure was 539.10 µm (SD±33.73) and 13.33 mm Hg (SD±2.26), respectively. Central corneal thickness showed an average decrease of 2.67 µm (95% confidence interval, 2.21-4.1) per decade increase in age. A 100 µm increase in central corneal thickness was associated with a 1.03 mm Hg (95% confidence interval, 0.79-1.26) increase in intraocular pressure after adjusting for age and sex. CONCLUSIONS: The changes in central corneal thickness values cause a significant variation in intraocular pressure in this population, suggesting that measurement of central corneal thickness will have implications in the diagnosis and management of glaucoma.

The association of hepatocyte growth factor (HGF) gene with primary angle closure glaucoma in the Nepalese population.

PURPOSE: Genetic variation in the hepatocyte growth factor (HGF) gene has recently been associated with hyperopia, which is a known risk factor for primary angle closure glaucoma (PACG). This study aimed to investigate whether genetic variation in HGF is associated with primary angle closure glaucoma in the Nepalese population. METHODS: One hundred six Nepalese patients with primary angle closure glaucoma and 204 matched controls were recruited. Twelve tag single nucleotide polymorphisms (SNPs) were selected and genotyped to cover the majority of common variation within HGF. Genotype and haplotype analyses were conducted in PLINK. RESULTS: Four HGF SNPs were found to be significantly associated with PACG, rs5745718, rs12536657, rs12540393 and rs17427817 (p=0.002, 0.002, 0.0006, and 0.0006, respectively). In addition, haplotype analysis showed one common haplotype to be significantly associated with PACG (p=0.001) in this population. CONCLUSIONS: Genetic variation in HGF is associated with PACG in the Nepalese population. Additional replication studies in other populations are necessary to confirm this association and to further explore the role of HGF in the pathogenesis of this blinding disease.

Outcomes of cataract surgery: a population-based developing world study in the Bhaktapur district, Nepal.

BACKGROUND: To evaluate the visual outcome after cataract surgery in a population of Nepal. DESIGN: Population-based cross-sectional study. PARTICIPANTS: Forty years and above residing in Bhaktapur district. METHODS: Subjects were selected from 30 clusters using cluster sampling procedure. All underwent a detailed examination at the base hospital, including logarithm of minimal angle of resolution visual acuity, refraction, applanation tonometry, cataract grading, retinal examination and perimetry when indicated. MAIN OUTCOME MEASURES: Visual acuity after cataract surgery. RESULTS: Out of 4003 subjects examined, 151 had undergone cataract surgery. Pseudophakia was present in 142 (94.0%), aphakia in nine (6%). Presenting and best-corrected visual acuity ≥6/18 was achieved in 123 (54.4%) and 164 (72.4%) eyes, respectively. Among the pseudophakic eyes, at presentation 122 (57.5%), 72 (33.9%), 18 (8.5%) and after best correction 162 (76.2%), 33 (15.8%), 17 (8.0%) had visual acuity of ≥6/18, <6/18-≥6/60 and <6/60, respectively. Retinal disease (35.5%), surgical complications (27.4%) and posterior capsular opacification (14.5%) were the principle causes of visual impairment after best correction in all eyes. There was no significant association in visual outcome based on age, sex, literacy and the duration of surgery. CONCLUSION: Correction of refractive errors, preoperative screening of coincidental diseases, reduction in surgical complication rates and monitoring of postoperative follow-up care has to be addressed seriously in order to improve the outcome of cataract surgery to meet standards proposed by the World Health Organization. In the future, longitudinal studies need to be undertaken to provide specific information on the outcomes of cataract surgery in this community.

Prevalence of visual impairment, cataract surgery and awareness of cataract and glaucoma in Bhaktapur district of Nepal: the Bhaktapur Glaucoma Study.

BACKGROUND: Cataract and glaucoma are the major causes of blindness in Nepal. Bhaktapur is one of the three districts of Kathmandu valley which represents a metropolitan city with a predominantly agrarian rural periphery. This study was undertaken to determine the prevalence of visual impairment, cataract surgery and awareness of cataract and glaucoma among subjects residing in this district of Nepal. METHODS: Subjects aged 40 years and above was selected using a cluster sampling methodology and a door to door enumeration was conducted for a population based cross sectional study. During the community field work, 11499 subjects underwent a structured interview regarding awareness (heard of) and knowledge (understanding of the disease) of cataract and glaucoma. At the base hospital 4003 out of 4800 (83.39%) subjects underwent a detailed ocular examination including log MAR visual acuity, refraction, applanation tonometry, cataract grading (LOCSΙΙ), retinal examination and SITA standard perimetry when indicated. RESULTS: The age-sex adjusted prevalence of blindness (best corrected <3/60) and low vision (best corrected <6/18 ≥ 3/60) was 0.43% (95%C.I. 0.25 - 0.68) and 3.97% (95% C.I. 3.40 - 4.60) respectively. Cataract (53.3%) was the principal cause of blindness. The leading causes of low vision were cataract (60.8%) followed by refractive error (12%). The cataract surgical coverage was 90.36% and was higher in the younger age group, females and illiterate subjects. Pseudophakia was seen in 94%. Awareness of cataract (6.7%) and glaucoma (2.4%) was very low. Among subjects who were aware, 70.4% had knowledge of cataract and 45.5% of glaucoma. Cataract was commonly known to be a 'pearl like dot' white opacity in the eye while glaucoma was known to cause blindness. Awareness remained unchanged in different age groups for cataract while for glaucoma there was an increase in awareness with age. Women were significantly less aware (odds ratio (OR): 0.63; 95%, confidence interval (CI): 0.54 - 0.74) for cataract and (OR: 0.64; 95% CI: 0.50 - 0.81) for glaucoma. Literacy was also correlated with awareness. CONCLUSION: The low prevalence of visual impairment and the high cataract surgical coverage suggests that cataract intervention programs have been successful in Bhaktapur. Awareness and knowledge of cataract and glaucoma was very poor among this population. Eye care programs needs to be directed towards preventing visual impairment from refractive errors, screening for incurable chronic eye diseases and promoting health education in order to raise awareness on cataract and glaucoma among this population.

Comparison of axial lengths in occludable angle and angle-closure glaucoma--the Bhaktapur Glaucoma Study.

PURPOSE: To compare the anterior chamber depth (ACD) and axial length of eyes in a population-based sample among normal, occludable angle, and primary angle-closure glaucoma (PACG) groups. METHODS: Totally, 3979 subjects from a population-based glaucoma prevalence study underwent complete ocular examination including four mirror gonioscopy. An angle in which >270 degrees of the posterior trabecular meshwork could not be seen was considered occludable. PACG was considered when there were features of primary angle closure (eye with an occludable angle, peripheral anterior synechiae, increased intraocular pressure, iris whorling, lens opacities, or excessive pigment deposition on the trabecular surface) and optic disc with glaucomatous damage. A handheld ultrasonic biometer was used to measure the ACD and the axial length of subjects. The ACD and axial length were measured on all subjects with occludable angles (n = 86), PACG (n = 17) and a random subgroup of normal subjects (n = 685). The measurements were compared among the groups and statistically analyzed using independent t-test, one-way analysis of variance, χ2 test, and logistic regression. RESULTS: The mean age among occludable angle and angle-closure glaucoma groups was 59.64 ± 9.70 and 71.23 ± 8.5 years, respectively, which was significantly higher (p < 0.001) than the mean of 54.03 ± 10.90 years among normal subjects. In the occludable angle group, the ACD (2.55 ± 0.69) was significantly different (p < 0.001) than the normal group (2.85 ± 0.39). The axial length (22.08 ± 0.83) in the occludable angle group was also considerably different (p < 0.001) when compared with the normal group (22.62 ± 0.90). In PACG group, the ACD and axial length were 2.48 ± 0.22 and 22.02 ± 0.59, respectively. The risk of having an occludable angle decreased with per unit millimeter increase in ACD (odds ratio, 0.24; 95% confidence intervals, 0.12-0.50) and axial length (odds ratio, 0.49; 95% confidence intervals, 0.36-0.67) after adjusting the effect of age and sex. CONCLUSIONS: The eyes in Nepalese population with occludable angle and angle-closure glaucoma appear to have significantly shallower anterior chambers and shorter axial lengths when compared with the normal group.

Rationale, methods and baseline demographics of the Bhaktapur Glaucoma Study.

BACKGROUND: To describe the methodology and baseline data of a population-based study designed to determine the prevalence of glaucoma and to study the risk factors for glaucoma development in a Nepali population. DESIGN: Population-based cross-sectional study. PARTICIPANTS: Subjects 40 years and above residing in Bhaktapur District. PATIENTS AND METHODS: Power calculations suggest that a sample size of 4758 is required. Thirty clusters were randomly selected from the 2 municipalities and 16 Village Development Committees of Bhaktapur District in Nepal. A door-to-door census was conducted in the selected clusters to identify citizens 40 years of age and older. Demographic details were collected and a structured interview, regarding awareness for cataract and glaucoma was taken. All individuals fulfilling the eligibility criteria were recruited and referred to the Tilganga Institute of Ophthalmology in Kathmandu for a detailed clinical examination including glaucoma diagnostic procedures. Peripheral blood samples were taken to facilitate future genetic analysis. MAIN OUTCOME MEASURES: Prevalence of glaucoma, risk factors and genetic screening. RESULTS: A total of 4800 people were selected. The mean age of participants was 55.4 ± 12.3 years (range: 40-99) and 51.8% were female. In total, 64.8% of our cohort was aged less than 59 years and 60.5% were illiterate. Among the various ethnic races, 69.7% belonged to the Newar ethnic group. CONCLUSION: This study will determine the prevalence of glaucoma and allow for an increased understanding of the risk factors for glaucoma development in this region.