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Aim: The aim of our research was to evaluate the effectiveness of treating patients with Long COVID Syndrome in health-resort conditions. Materials and Methods: 33 patients were qualified for the research. They have all suffered virus infection confirmed by PCR test and met the criteria of Long COVID Syndrome. Course of the acute phase of infection varied among these patients: 22% had mild, 60% moderate and 18% severe symptoms. Patients were treated with our own program including: dietary treatment, kinesiotherapy, balneotherapy, physical therapy and Oxygen therapy. Each patient underwent 5 individually selected therapeutic procedures per day for the period of 14 to 28 days. Each day body temperature, saturation, blood pressure, weight and general clinical condition were monitored. Before and after treatment there was a clinical assessment of physical capacity based on indirect stress test on cycle ergometer, determining general physical capacity level and the maximum capacity of Oxygen absorption (VO2max/l/min.) according to Astrand-Ryhming normogram. Results: statistically significant improvement in clinical condition has been achieved. In case of 10 patients (1/3 of all researched) all syndromes resolved, other patients’ symptoms became fewer and less severe. Differences between average values before and after treatment were statistically significant. In terms of physical capacity a general improvement determined by capacity level was ascertained. 46% of patients researched had initially low or very low capacity level, and after treatment none of them presented the symptoms of low physical capacity. Those patients reached the average physical capacity level. Differences between the average values of VO2max before and after treatment were not statistically significant, which is probably due to little number of patients capable of taking the stress test with the use of cycle ergometer. Conclusions: 1/ Treating patients with Long COVID Syndrome in health-resort conditions is very effective and beneficial, and provides comprehensive therapy of patients with multi-morbidity. 2/ Properly prepared program of treating Long COVID Syndrome allows not only to improve patients’ life quality, but also increases their non-specific immunity, regulates gut microbiome and may help in preventing future infections.

Mean sensitivity (MS) derived from a standard test grid using microperimetry is a sensitive outcome measure in clinical trials investigating new treatments for degenerative retinal diseases. This study hypothesizes that the functional decline is faster at the edge of the dense scotoma (eMS) than by using the overall MS.Multicenter, international, prospective cohort study: ProgStar Study.Stargardt disease type 1 patients (carrying at least 1 mutation in the ABCA4 gene) were followed over 12 months using microperimetry with a Humphrey 10-2 test grid. Customized software was developed to automatically define and selectively follow the test points directly adjacent to the dense scotoma points and to calculate their mean sensitivity (eMS).Among 361 eyes (185 patients), the mean age was 32.9 ± 15.1 years old. At baseline, MS was 10.4 ± 5.2 dB (n = 361), and the eMS was 9.3 ± 3.3 dB (n = 335). The yearly progression rate of MS (1.5 ± 2.1 dB/year) was significantly lower (β = -1.33; P.001) than that for eMS (2.9 ± 2.9 dB/year). There were no differences between progression rates using automated grading and those using manual grading (β = .09; P = .461).In Stargardt disease type 1, macular sensitivity declines significantly faster at the edge of the dense scotoma than in the overall test grid. An automated, time-efficient approach for extracting and grading eMS is possible and appears valid. Thus, eMS offers a valuable tool and sensitive outcome parameter with which to follow Stargardt patients in clinical trials, allowing clinical trial designs with shorter duration and/or smaller cohorts.

Refractive errors, particularly myopia, are the most common eye conditions, often leading to serious visual impairment. The age of onset is correlated with the severity of refractive error in adulthood observed in epidemiological and genetic studies and can be used as a proxy in refractive error genetic studies. To further elucidate genetic factors that influence refractive error, we analysed self-reported age of refractive error correction data from the UK Biobank European and perform genome-wide time-to-event analyses on the age of first spectacle wear (AFSW). Genome-wide proportional hazards ratio analyses were conducted in 340 318 European subjects. We subsequently assessed the similarities and differences in the genetic architectures of refractive error correction from different causes. All-cause AFSW was genetically strongly correlated (rg = −0.68) with spherical equivalent (the measured strength of spectacle lens required to correct the refractive error) and was used as a proxy for refractive error. Time-to-event analyses found genome-wide significant associations at 44 independent genomic loci, many of which (GJD2, LAMA2, etc.) were previously associated with refractive error. We also identified six novel regions associated with AFSW, the most significant of which was on chromosome 17q (P = 3.06 × 10−09 for rs55882072), replicating in an independent dataset. We found that genes associated with AFSW were significantly enriched for expression in central nervous system tissues and were involved in neurogenesis. This work demonstrates the merits of time-to-event study design in the genetic investigation of refractive error and contributes additional knowledge on its genetic risk factors in the general population.

We summarize IEEE Big Data Cup: Predicting Escalations in Customer Support – a data mining competition organized jointly by companies Information Builders and QED Software at the KnowledgePit platform, in the frame of the 2020 IEEE International Conference on Big Data. We discuss the motivation for organizing this event and highlight the factors that make it such a challenging topic. We describe the data provided to participants and formulate the competition task. We also provide an overview of competition results with a detailed analysis of a few selected solutions. Finally, we present a novel functionality of the KnowledgePit platform – an analytic module that allows organizers to investigate selected solutions using a convenient GUI and provides in-depth insights about their quality.

Contains fulltext : 218893.pdf (Publisher’s version ) (Closed access) Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P = 0.004) and surgical intervention in advanced disease (P = 3.6 x 10(-)(6)). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups.

Purpose To investigate the natural history of Stargardt disease (STGD1) using fixation location and fixation stability. Design Multicenter, international, prospective cohort study. Methods Fixation testing was performed using the Nidek MP-1 microperimeter as part of the prospective, multicenter, natural history study on the Prog ression of Star gardt disease (ProgStar). A total of 238 patients with ABCA4-related STGD1 were enrolled at baseline (bilateral enrollment in 86.6%) and underwent repeat testing at months 6 and 12. Results Outcome measures included the distance of the preferred retinal locus from the fovea (PRL) and the bivariate contour ellipse area (BCEA). After 12 months of follow-up, the change in the eccentricity of the PRL from the anatomic fovea was −0.0014 degrees (95% confidence interval [CI], −0.27 degrees, 0.27 degrees; P = .99). The deterioration in the stability of fixation as expressed by a larger BCEA encompassing 1 standard deviation of all fixation points was 1.21 degrees squared (deg2) (95% CI, −1.23 deg2, 3.65 deg2; P = .33). Eyes with increases and decreases in PRL eccentricity and/or BCEA values were observed. Conclusions Our observations point to the complexity of fixation parameters. The association of increasingly eccentric and unstable fixation with longer disease duration that is typically found in cross-sectional studies may be countered within individual patients by poorly understood processes like neuronal adaptation. Nevertheless, fixation parameters may serve as useful secondary outcome parameters in selected cases and for counseling patients to explain changes to their visual functionality.

BACKGROUND Postoperative nausea and vomiting (PONV) is a common complication after anesthesia and surgery. Ondansetron is one of the most widely used drugs in the prophylaxis of PONV and is extensively metabolized in humans. In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic cytochrome P450 enzymes. The cytochrome P450 (human hepatic cytochrome [CYP]) 2D6 inhibitor quinidine reduced in vitro hydroxylation of ondansetron, which indicates the important role of CYP2D6 in ondansetron metabolism. Genotyping these alleles allows the prediction of the extensive metabolizer (EM) and poor metabolizer (PM) phenotypes with approx. 90-96% accuracy. OBJECTIVES The aim of our study was to evaluate whether the pharmacological prevention of PONV with ondansetron depends on the most common CYP2D6 alleles (CYP2D6*1, *3, *4, *5, and NxN [multiplication gene]). MATERIAL AND METHODS Genotyping for the defective CYP2D6*3, CYP2D6*4 and CYP2D6*5 alleles among 93 surgical female patients was performed by polymerase chain reaction amplification and restriction fragment length polymorphism (PCR-RFLP). RESULTS The genetically defined EMs and ultrarapid metabolizers (UMs) of CYP2D6 had a statistically significant (p < 0.02) higher frequency of nausea and vomiting after strumectomy (33.3%) than intermediate metabolizers (IMs) (10.3%) and PMs (0%). The relative risk (odds ratio [OR]) of PONV occurrence was 5 times higher for EMs/UMs than IMs/PMs. CONCLUSIONS Our results suggest that PONV treatment with ondansetron could be improved by basic, widely available and inexpensive PCR-RFLP genetic tests.

Background/aimsTo describe the genetic characteristics of the cohort enrolled in the international multicentre progression of Stargardt disease 1 (STGD1) studies (ProgStar) and to determine geographic differences based on the allele frequency.Methods345 participants with a clinical diagnosis of STGD1 and harbouring at least one disease-causing ABCA4 variant were enrolled from 9 centres in the USA and Europe. All variants were reviewed and in silico analysis was performed including allele frequency in public databases and pathogenicity predictions. Participants with multiple likely pathogenic variants were classified into four national subgroups (USA, UK, France, Germany), with subsequent comparison analysis of the allele frequency for each prevalent allele.Results211 likely pathogenic variants were identified in the total cohort, including missense (63%), splice site alteration (18%), stop (9%) and others. 50 variants were novel. Exclusively missense variants were detected in 139 (50%) of 279 patients with multiple pathogenic variants. The three most prevalent variants of these patients with multiple pathogenic variants were p.G1961E (15%), p.G863A (7%) and c.5461-10 T>C (5%). Subgroup analysis revealed a statistically significant difference between the four recruiting nations in the allele frequency of nine variants.ConclusionsThere is a large spectrum of ABCA4 sequence variants, including 50 novel variants, in a well-characterised cohort thereby further adding to the unique allelic heterogeneity in STGD1. Approximately half of the cohort harbours missense variants only, indicating a relatively mild phenotype of the ProgStar cohort. There are significant differences in allele frequencies between nations, although the three most prevalent variants are shared as frequent variants.

The prevalence of myopia has increased dramatically worldwide within the last three decades, and has reached epidemic proportions in some parts of East Asia. Recent experimental and epidemiological studies have shown that refractive development is influenced by environmental, behavioral, and inherited factors. Large epidemiological studies (mainly genome-wide association studies) have increased our understanding of the genetics involved in refractive error and myopia. Affordable sequencing has enabled investigation of the human exome for rare mutations causing extreme myopia. These studies have identified interesting candidate genes, and will no doubt continue to discover many more. All the genetic loci discovered to date indicate that refractive development is a complex heterogeneous process mediated by a number of often overlapping biological processes. The exact mechanisms by which these biological networks regulate eye growth are poorly understood. Although several individual genes and/or molecular pathways have been investigated in animal models, a systematic network-based approach in modeling human refractive development and experimental myopia is necessary to understand the complex interplay between genes and environment in refractive error. New biomedical technologies and better-designed studies will continue to refine our understanding of refractive error, and may lead to preventative and therapeutic measures to combat the myopia epidemic.

212 Background: The 2006 ASCO and the ESMO consensus statement on quality cancer care defined the delivery of multimodality treatment by a multidisciplinary team of appropriately skilled health professionals as an essential component of quality cancer care. Furthermore, MDCs have demonstrated improved survival in breast, head and neck, ovarian and colorectal cancers. Despite these advantages, health care systems struggle to implement and sustain MDCs due to the heavy burden imposed by the required work processes. We report on the large-scale utilization of a propriety quality measurement platform OncoLens to run MDCs across the country. Methods: Technology quality metrics were collected from the ongoing daily usage of the platform including cancer characteristics, care team utilization metrics, average attendance, quality metrics collected for accreditation and clinical trials matching on the OncoLens platform. Results: The virtual platform was accessible to around 8000 providers across the United States. In 2020, 13771 cases were discussed. Attendance of the required specialties for high quality care of Medical Oncology, Radiation Oncology, Surgery, Pathology and Radiology was attained, with the average conference attendance being 14. Race/ethnicity data on the cases revealed White (9197, 67%), Black (1817,13%), Hispanic (363,3%) and Other (2356,17%). Optional quality metrics were collected during discussions for CoC, NAPBC and NAPRC accreditation. These included NCCN guidelines discussed, Staging discussed, clinical trials discussed, Genetics discussion, palliative care discussion, rehabilitation services, reproductive counselling discussed, psychosocial counselling discussed, nutritional counselling discussed, reconstructive surgery discussion, tobacco cessation discussion across General and Site-specific conferences. Most of the case presentations were prospective. This format does enable cancer programs to collect quality metrics around Cancer program accreditation by the American College of Surgeons. 66% of patients discussed potentially matched to clinical trials during the discussion. Conclusions: A technology platform can assist cancer programs to collect quality metrics around cancer care. This gives them the ability to run data driven quality programs targeting specific quality metrics. Hispanics have a lower percentage of cases presented at MDC compared to other race/ethnicities. It is possible to have high quality discussions and attain metrics for Commission on Cancer accreditation utilizing a virtual platform.

Background: Myopia prevalence has increased in the past 20 years, with many studies linking the increase to reduced time spent outdoors. A number of recent observational studies have shown an inverse association between vitamin D [25(OH)D] serum levels and myopia. However, in such studies it is difficult to separate the effects of time outdoors and vitamin D levels. In this work we use Mendelian randomization (MR) to assess if genetically determined 25(OH)D levels contribute to the degree of myopia.Methods: We performed MR using results from a meta-analysis of refractive error (RE) genome-wide association study (GWAS) that included 37 382 and 8 376 adult participants of European and Asian ancestry, respectively, published by the Consortium for Refractive Error And Myopia (CREAM). We used single nucleotide polymorphisms (SNPs) in the DHCR7 , CYP2R1, GC and CYP24A1 genes with known effects on 25(OH)D concentration as instrumental variables (IV). We estimated the effect of 25(OH)D on myopia level using a Wald-type ratio estimator based on the effect estimates from the CREAM GWAS.Results: Using the combined effect attributed to the four SNPs, the estimate for the effect of 25(OH)D on refractive error was -0.02 [95% confidence interval (CI) -0.09, 0.04] dioptres (D) per 10 nmol/l increase in 25(OH)D concentration in Caucasians and 0.01 (95% CI -0.17, 0.19) D per 10 nmol/l increase in Asians.Conclusions: The tight confidence intervals on our estimates suggest the true contribution of vitamin D levels to degree of myopia is very small and indistinguishable from zero. Previous findings from observational studies linking vitamin D levels to myopia were likely attributable to the effects of confounding by time spent outdoors.

e13561 Background: Cancer centers in the US are required to discuss a minimum of 15% analytic cases and prospective presentation (minimum 80%) in the multidisciplinary case conference (tumor board, MDCC), per the Commission on Cancer accrediting standards. Tumor board discussion have been shown to improve treatment decision making and patient outcomes. These meetings were in person meetings in the Pre-COVID era. The COVID 19 pandemic and the subsequent requirements for social distancing forced hospitals to move most MDCCs to a virtual format. We report on the large scale utilization of a propriety Care-Coordination platform OncoLens to run MDCCs across the country. Methods: Technology quality metrics were collected from the ongoing daily usage of the platform including time characteristics, care team utilization metrics, average attendance, quality metrics collected for accreditation and clinical trials matching on the OncoLens platform. Results: The virtual platform was accessible to around 8000 providers across the United States. On average per month there were 250 virtual meetings with over 290,000 meeting minutes. Conferences ranged from 30 minutes to 4 hours. 75% of users used the web application 25% of users utilized their smart phones .System uptime was 99.99%. Hospitals were able to conduct General and Site specific conferences. Virtual attendance of the required specialties of Medical Oncology, Radiation Oncology, Surgery, Pathology and Radiology was attained, with the average conference attendance being 14. On average hospitals required 2 administrative training sessions. Most of the case presentations were prospective. This format does enable cancer programs to collect quality metrics around Cancer program accreditation by the American College of Surgeons. A wide variety of common and rare cancer types were discussed in the virtual format. 66% of patients discussed potentially matched to clinical trials during the discussion. Conclusions: The shift of MDCCs to a mostly virtual environment occurred quickly in response to the COVID 19 pandemic. It took an average of 2 training classes to get the cancer care team on board with the use of new technology. It is possible to have high quality discussions and attain metrics for Commission On Cancer accreditation utilizing a virtual platform.

Myopia is the largest cause of uncorrected visual impairments globally and its recent dramatic increase in the population has made it a major public health problem. In observational studies, educational attainment has been consistently reported to be correlated to myopia. Nonetheless, correlation does not imply causation. Observational studies do not tell us if education causes myopia or if instead there are confounding factors underlying the association. In this work, we use a two-step least squares instrumental-variable (IV) approach to estimate the causal effect of education on refractive error, specifically myopia. We used the results from the educational attainment GWAS from the Social Science Genetic Association Consortium to define a polygenic risk score (PGRS) in three cohorts of late middle age and elderly Caucasian individuals (N = 5,649). In a meta-analysis of the three cohorts, using the PGRS as an IV, we estimated that each z-score increase in education (approximately 2 years of education) results in a reduction of 0.92 ± 0.29 diopters (P = 1.04 × 10(-3) ). Our estimate of the effect of education on myopia was higher (P = 0.01) than the observed estimate (0.25 ± 0.03 diopters reduction per education z-score [∼2 years] increase). This suggests that observational studies may actually underestimate the true effect. Our Mendelian Randomization (MR) analysis provides new evidence for a causal role of educational attainment on refractive error.

Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene (P = 4.19 x 10(-8) for rs6445055), two on chromosome 9 (P = 2.80 x 10(-11) for rs2472493 near ABCA1 and P = 6.39 x 10(-11) for rs8176693 within ABO) and one on chromosome 11p11.2 (best P = 1.04 x 10(-11) for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG.

Refractive error is a complex ocular trait governed by both genetic and environmental factors and possibly their interplay. Thus far, data on the interaction between genetic variants and environmental risk factors for refractive errors are largely lacking. By using findings from recent genome-wide association studies, we investigated whether the main environmental factor, education, modifies the effect of 40 single nucleotide polymorphisms on refractive error among 8461 adults from five studies including ethnic Chinese, Malay and Indian residents of Singapore. Three genetic loci SHISA6-DNAH9, GJD2 and ZMAT4-SFRP1 exhibited a strong association with myopic refractive error in individuals with higher secondary or university education (SHISA6-DNAH9: rs2969180 A allele, beta = -0.33 D, P = 3.6 x 10(-6); GJD2: rs524952 A allele, beta = -0.31 D, P = 1.68 x 10(-5); ZMAT4-SFRP1: rs2137277 A allele, beta = 20.47 D, P = 1.68 x 10(-4)), whereas the association at these loci was non-significant or of borderline significance in those with lower secondary education or below (P for interaction: 3.82 x 10(-3)-4.78 x 10(-4)). The evidence for interaction was strengthened when combining the genetic effects of these three loci (P for interaction = 4.40 x 10(-8)), and significant interactions with education were also observed for axial length and myopia. Our study shows that low level of education may attenuate the effect of risk alleles on myopia. These findings further underline the role of gene-environment interactions in the pathophysiology of myopia.

Purpose A previous study of Old Order Amish families showed an association of ocular refraction with markers proximal to matrix metalloproteinase (MMP) genes MMP1 and MMP10 and intragenic to MMP2 . A candidate gene replication study of association between refraction and single nucleotide polymorphisms (SNPs) within these genomic regions was conducted. Design Candidate gene genetic association study. Participants Two thousand participants drawn from the Age-Related Eye Disease Study (AREDS) were chosen for genotyping. After quality-control filtering, 1912 individuals were available for analysis. Methods Microarray genotyping was performed using the HumanOmni 2.5 bead array (Illumina, Inc., San Diego, CA). Single nucleotide polymorphisms originally typed in the previous Amish association study were extracted for analysis. In addition, haplotype tagging SNPs were genotyped using TaqMan assays. Quantitative trait association analyses of mean spherical equivalent refraction were performed on 30 markers using linear regression models and an additive genetic risk model while adjusting for age, sex, education, and population substructure. Post hoc analyses were performed after stratifying on a dichotomous education variable. Pointwise ( P emp ) and multiple-test study-wise ( P multi ) significance levels were calculated empirically through permutation. Main Outcome Measures Mean spherical equivalent refraction was used as a quantitative measure of ocular refraction. Results The mean age and ocular refraction were 68 years (standard deviation [SD], 4.7 years) and +0.55 diopters (D; SD, 2.14 D), respectively. Pointwise statistical significance was obtained for rs1939008 ( P emp = 0.0326). No SNP attained statistical significance after correcting for multiple testing. In stratified analyses, multiple SNPs reached pointwise significance in the lower-education group: 2 of these were statistically significant after multiple testing correction. The 2 highest-ranking SNPs in Amish families (rs1939008 and rs9928731) showed pointwise P emp Conclusions This study showed suggestive evidence of replication of an association signal for ocular refraction to a marker between MMP1 and MMP10 . Evidence of a gene–environment interaction between previously reported markers and education on refractive error also was shown. Variants in MMP1 through MMP10 and MMP2 regions seem to affect population variation in ocular refraction in environmental conditions less favorable for myopia development. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Author version made available in accordance with the publisher's policy., Refractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European ancestry and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in individuals of European ancestry, of which 8 were shared with Asians. Combined analysis identified 8 additional associated loci. The new loci include candidate genes with functions in neurotransmission (GRIA4), ion transport (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2 and BMP2) and eye development (SIX6 and PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for individuals carrying the highest genetic load. Our results, based on a large meta-analysis across independent multiancestry studies, considerably advance understanding of the mechanisms involved in refractive error and myopia., Australian National Health and Medical Research Council.

To examine the association between characteristics of Stargardt disease and visual acuity (VA), to estimate the longitudinal rate of VA loss, and to identify risk factors for VA loss.Retrospective, multicenter cohort study.A total of 176 patients (332 eyes) with molecularly and clinically confirmed Stargardt disease enrolled from the United States and Europe.Standardized data report forms were used to collect retrospective data on participants' characteristics and best-corrected or presenting VA from medical charts. Linear models with generalized estimating equations were used to estimate the cross-sectional associations, and linear mixed effects models were used to estimate the longitudinal VA loss.Yearly change in VA.The median duration of observation was 3.6 years. At baseline, older age of symptom onset was associated with better VA, and a longer duration of symptoms was associated with worse VA. Longitudinal analysis estimated an average of 0.3 lines loss (P0.0001) per year overall, but the rate varied according to baseline VA: (1) eyes with baseline VA ≥20/25 (N = 53) declined at a rate of approximately 1.0 line per year; (2) eyes with VA between 20/25 and 20/70 (N = 65) declined at a rate of approximately 0.9 lines per year; (3) eyes with VA between 20/70 and 20/200 (N = 163) declined at a rate of 0.2 lines per year; and (4) eyes with VA worse than 20/200 (n = 49) improved at a rate of 0.5 lines per year. Older age of onset was associated with slower VA loss: Patients with onset age30 years showed 0.4 lines slower change of VA per year (P = 0.01) compared with patients with onset age ≤14 years.Given the overall slow rate of VA loss, VA is unlikely to be a sensitive outcome measure for treatment trials of Stargardt disease. However, given the faster decline in younger patients and those with no or mild visual impairment, VA may be a potential outcome measure for trials targeting such subgroups of patients. These observations will need to be assessed in a prospective study bearing in mind the inherent limitations of retrospective datasets.

The refractive errors, myopia and hyperopia, are optical defects of the visual system that can cause blurred vision. Uncorrected refractive errors are the most common causes of visual impairment worldwide. It is estimated that 2.5 billion people will be affected by myopia alone within the next decade. Experimental, epidemiological and clinical research has shown that refractive development is influenced by both environmental and genetic factors. Animal models have showed that eye growth and refractive maturation during infancy are tightly regulated by visually guided mechanisms. Observational data in human populations provide compelling evidence that environmental influences and individual behavioral factors play crucial roles in myopia susceptibility. Nevertheless, the majority of the variance of refractive error within populations is thought to be because of hereditary factors. Genetic linkage studies have mapped two dozen loci, while association studies have implicated more than 25 different genes in refractive variation. Many of these genes are involved in common biological pathways known to mediate extracellular matrix (ECM) composition and regulate connective tissue remodeling. Other associated genomic regions suggest novel mechanisms in the etiology of human myopia, such as mitochondrial-mediated cell death or photoreceptor-mediated visual signal transmission. Taken together, observational and experimental studies have revealed the complex nature of human refractive variation, which likely involves variants in several genes and functional pathways. Multiway interactions between genes and/or environmental factors may also be important in determining individual risks of myopia, and may help explain the complex pattern of refractive error in human populations.

PURPOSE: To identify genetic risk factors contributing to central corneal thickness (CCT) in individuals from South India, a population with a high prevalence of ocular disorders. METHODS: One hundred ninety-five individuals from 15 large South Indian pedigrees were genotyped using the Omni2.5 bead array. Family-based association for CCT was conducted using the score test in MERLIN. RESULTS: Genome-wide association study (GWAS) identified strongest association for single nucleotide polymorphisms (SNPs) in the first intron of WNT7B and CCT (top SNP rs9330813; β = −0.57, 95% confidence interval CI: −0.78 to −0.36; P = 1.7 × 10−7). We further investigated rs9330813 in a Latino cohort and four independent European cohorts. A meta-analysis of these data sets demonstrated statistically significant association between rs9330813 and CCT (β = −3.94, 95% CI: −5.23 to −2.66; P = 1.7 × 10−9). WNT7B SNPs located in the same genomic region that includes rs9330813 have previously been associated with CCT in Latinos but with other ocular quantitative traits related to myopia (corneal curvature and axial length) in a Japanese population (rs10453441 and rs200329677). To evaluate the specificity of the observed WNT7B association with CCT in the South Indian families, we completed an ocular phenome-wide association study (PheWAS) for the top WNT7B SNPs using 45 ocular traits measured in these same families including corneal curvature and axial length. The ocular PheWAS results indicate that in the South Indian families WNT7B SNPs are primarily associated with CCT. CONCLUSIONS: The results indicate robust evidence for association between WNT7B SNPs and CCT in South Indian pedigrees, and suggest that WNT7B SNPs can have population-specific effects on ocular quantitative traits.

Refractive development is influenced by environmental and genetic factors. Genetic studies have identified several regions of linkage to ocular refraction, but none have been carried out in African-derived populations. We performed quantitative trait locus linkage analyses in African-American (AA) families to identify genomic regions responsible for refraction. We recruited 493 AA individuals in 96 families to participate in the Myopia Family Study. Genotyping of 387 microsatellite markers was performed on 398 participants. The mean refraction among genotyped individuals was -2.87 D (SD=3.58) and myopia of at least 1 D was present in 267 (68%) participants. Multipoint, regression-based, linkage analyses were carried out on a logarithmic transformation of ocular refraction using the statistical package MERLIN-REGRESS. Empirical significance levels were determined via 4,898 whole-genome gene-dropping simulations. Linkage analyses were repeated after clustering families into two subgroups based on admixture proportions as determined by the software package STRUCTURE. Genomewide significant linkage was seen at 47 cM on chromosome 7 (logarithm of the odds ratio (LOD)=5.87, P=0.00005). In addition, three regions on chromosomes 2p, 3p and 10p showed suggestive evidence of linkage (LOD>2, P

Myopia is the largest cause of uncorrected visual impairments globally and its recent dramatic increase in the population has made it a major public health problem. In observational studies, educational attainment has been consistently reported to be correlated to myopia. Nonetheless, correlation does not imply causation. Observational studies do not tell us if education causes myopia or if instead there are confounding factors underlying the association. In this work, we use a two-step least squares instrumental-variable (IV) approach to estimate the causal effect of education on refractive error, specifically myopia. We used the results from the educational attainment GWAS from the Social Science Genetic Association Consortium to define a polygenic risk score (PGRS) in three cohorts of late middle age and elderly Caucasian individuals (N = 5,649). In a meta-analysis of the three cohorts, using the PGRS as an IV, we estimated that each z-score increase in education (approximately 2 years of education) results in a reduction of 0.92 ± 0.29 diopters (P = 1.04 × 10(-3) ). Our estimate of the effect of education on myopia was higher (P = 0.01) than the observed estimate (0.25 ± 0.03 diopters reduction per education z-score [∼2 years] increase). This suggests that observational studies may actually underestimate the true effect. Our Mendelian Randomization (MR) analysis provides new evidence for a causal role of educational attainment on refractive error.

The development of refractive error is mediated by both environmental and genetic factors. We performed regression-based quantitative trait locus (QTL) linkage analysis on Ashkenazi Jewish families to identify regions in the genome responsible for ocular refraction. We measured refractive error on individuals in 49 multi-generational American families of Ashkenazi Jewish descent. The average family size was 11.1 individuals and was composed of 2.7 generations. Recruitment criteria specified that each family contain at least two myopic members. The mean spherical equivalent refractive error in the sample was −3.46D (SD=3.29) and 87% of individuals were myopic. Microsatellite genotyping with 387 markers was performed on 411 individuals. We performed multipoint regression-based linkage analysis for ocular refraction and a log transformation of the trait using the statistical package Merlin-Regress. Empirical genomewide significance levels were estimated through gene-dropping simulations by generating random genotypes at each of the 387 markers in 200 replicates of our pedigrees. Maximum LOD scores of 9.5 for ocular refraction and 8.7 for log-transformed refraction (LTR) were observed at 49.1 cM on chromosome 1p36 between markers D1S552 and D1S1622. The empirical genomewide significance levels were P=0.065 for ocular refraction and P

Purpose To investigate the heritability of intraocular pressure (IOP) and cup-to-disc ratio (CDR) in an older well-defined population. Design Family-based cohort study. Participants Through the population-based Salisbury Eye Evaluation study, we recruited 726 siblings (mean age, 74.7 years) in 284 sibships. Methods Intraocular pressure and CDR were measured bilaterally for all participants. The presence or absence of glaucoma was determined by a glacuoma specialist for all probands on the basis of visual field, optic nerve appearance, and history. The heritability of IOP was calculated as twice the residual between-sibling correlation of IOP using linear regression and generalized estimating equations after adjusting for age, gender, mean arterial pressure, race, self-reported diabetes status, and history of systemic steroid use. The heritability of CDR was calculated using the same model and adjustments as above, while also adjusting for IOP. Main Outcome Measures Heritability and determinants of IOP and CDR, and impact of siblings' glaucoma status on IOP and CDR. Results We estimated the heritability to be 0.29 (95% confidence interval [CI], 0.12–0.46) for IOP and 0.56 (95% CI, 0.35–0.76) for CDR in this population. Mean IOP in siblings of glaucomatous probands was statistically significantly higher than in siblings of normal probands (mean difference, 1.02 mmHg; P = 0.017). The mean CDR in siblings of glaucomatous probands was 0.07 (or 19%) larger than in siblings of glaucoma suspect referrals ( P = 0.045) and siblings of normal probands ( P = 0.004). Conclusions In this elderly population, we found CDR to be highly heritable and IOP to be moderately heritable. On average, siblings of glaucoma patients had higher IOPs and larger CDRs than siblings of nonglaucomatous probands.

Purpose To determine whether hyperopia aggregates in families in an older mixed-race population. Design Cross-sectional familial aggregation study using sibships. Methods We recruited 759 subjects (mean age, 73.4 years) in 241 families through the population-based Salisbury Eye Evaluation study. Subjects underwent noncycloplegic refraction if best-corrected visual acuity (BCVA) was ≤20/40, had lensometry to measure their currently worn spectacles if BCVA was >20/40 with spectacles, or were considered to be plano (refraction of zero) if the BCVA was >20/40 without spectacles. Preoperative refraction from medical records was used for bilaterally pseudophakic subjects. Results Utilizing hyperopia cutoffs from 1.00 to 2.50 diopters, age-, race-, and gender-adjusted odds ratios for hyperopia with an affected sibling ranged from 2.72 (95% confidence interval [CI], 1.84–4.01) to 4.87 (95% CI, 2.54–9.30). The odds of hyperopia increased with age until 75 years, after which they remained relatively constant. Black men were significantly less likely to be hyperopic than white men, white women, or black women. Conclusions Hyperopia appears to be under strong genetic control in this older population.

Purpose To quantify the risk for age-related cortical cataract and posterior subcapsular cataract (PSC) associated with having an affected sibling after adjusting for known environmental and personal risk factors. Design Sibling cohort study. Participants Participants in the ongoing Salisbury Eye Evaluation (SEE) study (n = 321; mean age, 78.1±4.2 years) and their locally resident siblings (n = 453; mean age, 72.6±7.4 years) were recruited at the time of Rounds 3 and 4 of the SEE study. Intervention/testing methods Retroillumination photographs of the lens were graded for the presence of cortical cataract and PSC with the Wilmer grading system. The residual correlation between siblings' cataract grades was estimated after adjustment for a number of factors (age; gender; race; lifetime exposure to ultraviolet-B light; cigarette, alcohol, estrogen, and steroid use; serum antioxidants; history of diabetes; blood pressure; and body mass index) suspected to be associated with the presence of cataract. Results The average sibship size was 2.7 per family. Multivariate analysis revealed the magnitude of heritability (h 2 ) for cortical cataract to be 24% (95% CI, 6%–42%), whereas that for PSC was not statistically significant (h 2 4%; 95% CI, 0%–11%) after adjustment for the covariates. The model revealed that increasing age, female gender, a history of diabetes, and black race increased the odds of cortical cataract, whereas higher levels of provitamin A were protective. A history of diabetes and steroid use increased the odds for PSC. Conclusions This study is consistent with a significant genetic effect for age-related cortical cataract but not PSC.

The prevalence of angle-closure glaucoma (ACG) is greater for Eskimos/Inuit than it is for any other ethnic group in the world. Although it has been suggested that this prevalence may be due to a population tendency toward shallower anterior chamber angles, available evidence for other populations such as Chinese with high rates of ACG has not consistently demonstrated such a tendency.A reticule, slit-lamp, and standard Goldmann one-mirror goniolens were used to make measurements in the anterior chamber (AC) angle according to a previously reported protocol for biometric gonioscopy (BG) (Ophthalmology 1999;106:2161-7). Measurements were made in all four quadrants of one eye among 133 phakic Alaskan Eskimos aged 40 years and older. Automatic refraction, dilated examination of the anterior segment and optic nerve, and A-scan measurements of AC depth, lens thickness, and axial length were also carried out for all subjects.Both central and peripheral AC measurements for the Eskimo subjects were significantly lower than those previously reported by us for Chinese, blacks, and whites under the identical protocol. Eskimos also seemed to have somewhat more hyperopia. There were no differences in biometric measurements between men and women in this Eskimo population. Angle measurements by BG seemed to decline more rapidly over life among Eskimos and Chinese than blacks or whites. Although there was a significant apparent decrease in AC depth, increase in lens thickness, and increase in hyperopia with age among Eskimos, all of these trends seemed to reverse in the seventh decade and beyond.Eskimos do seem to have shallower ACs than do other racial groups. Measurements of the AC angle seem to decline more rapidly over life among Eskimos than among blacks or whites, a phenomenon also observed by us among Chinese, another group with high ACG prevalence. This apparent more rapid decline may be due to a cohort effect with higher prevalence of myopia and resulting wider angles among younger Eskimos and Chinese.

To compare the prevalence of angle closure among siblings of patients with open angles (OAs), suspect angle closure (PACS), and either primary angle closure (PAC) or PAC glaucoma (PACG).Cross-sectional, clinical study.A total of 303 South Indian sibling pairs, including 81 OA probands, 143 PACS probands, and 79 PAC/PACG probands.Probands and siblings underwent a clinical examination, including gonioscopy by a masked grader, applanation tonometry, slit-lamp biomicroscopy, optic nerve evaluation, and A-scan ultrasonography. Probands and siblings were classified into 1 of 3 groups based on the phenotype of the more severely affected eye: OA, PACS, or PAC/PACG. Multivariable regression models were used to estimate the odds of prevalent angle closure in PACS or PAC/PACG siblings compared with OA siblings.Prevalence and relative prevalence of angle closure and PAC/PACG among OA, PACS, and PAC/PACG siblings.Mean sibling age was 49.7 ± 8.7 years, and 56.6% of siblings were females. Angle closure was more prevalent in both PACS siblings (35.0%) and PAC/PACG siblings (36.7%) compared with OA siblings (3.7%; P0.001). There was PAC/PACG present in 11.4% of PAC/PACG siblings compared with 4.9% of PACS siblings (P = 0.07) and 0% of OA siblings (P = 0.002). In multivariable models adjusting for sibling age and sex, the odds of angle closure was 13.6 times greater in angle closure (PACS or PAC/PACG) siblings compared with OA siblings (95% confidence interval [CI], 4.1-45.0; P0.001). Sibling angle-closure risk was also greater in female (odds ratio [OR], 2.3; 95% CI, 1.3-4.0; P = 0.005) and older siblings (OR, 1.5 per 10-year increment; 95% CI, 1.1-2.0; P = 0.02). Siblings of PAC/PACG probands had a 2.3-fold greater odds (95% CI, 0.8-6.5) of having PAC/PACG compared with siblings of PACS probands, although the association was not significant (P = 0.13).In the South Indian population screened, siblings of angle-closure patients had a1 in 3 risk of prevalent angle closure, whereas siblings of PAC/PACG patients had a10% risk of prevalent PAC/PACG. Screening siblings of angle-closure patients is likely to be of high yield in finding undetected angle closure.

In this paper we propose Generalized Momentum Asset Allocation Model (GMAA). GMAA is a new approach to construct optimal portfolio and is based on close examination of asset’s returns distribution. GMAA tries to capture certain market phenomena and use information they contain as predictors for future returns. Our model is validated using MSCI Indexes with MSCI World Index set as a benchmark. We find results rather promising as we managed to significantly reduce portfolio volatility and obtain stable path of cumulative returns of portfolio. Our model outperforms benchmark in terms of Information Ratio or Maximum Drawdown. Detailed sensitivity analysis was conducted at the end of this paper and it shows that our strategy is sensitive to a few optimization parameters thus further research may be required.

PURPOSE. Three loci defined by single nucleotide polymorphisms (SNPs) rs11024102 in PLEKHA7, rs3753841 in COL11A1, and rs1015213 between the PCMTD1 and ST18 genes, recently have been associated with primary angle closure glaucoma (PACG). We explored the genetic association of these SNPs with subtypes of primary angle closure in a South Indian population. METHODS. The study included three case definitions: primary angle closure/primary angle closure glaucoma (PAC/PACG, N ¼ 180); primary angle closure suspect (PACS, N ¼ 171), and a combined any-angle closure group. Controls consisted of 411 individuals from South India. Genotyping for all three SNPs was performed using the TaqMan allelic discrimination assay. Genetic association was estimated using a v 2 test statistics and logistic regression. RESULTS. Among the three studied SNPs, significant genetic association was identified for rs1015213 in the PAC/PACG (P ¼ 0.002) and any-angle closure (P ¼ 0.003) analyses. However, no significant genetic association was seen when in PACS subjects (P ¼ 0.052). SNPs rs3753841 and rs11024102 showed no evidence of genetic association with angleclosure phenotypes (P > 0.05) in South Indian participants. CONCLUSIONS. In our study, rs1015213 (located in the intergenic region between PCMTD1 and ST18) was associated significantly with PAC/PACG, confirming prior reports of an association between this region and angle closure glaucoma. Further work with a larger sample size is necessary to confirm the importance of COL11A1 and PLEKHA7 in the pathogenesis of glaucoma.

Purpose Refractive error is a complex trait with multiple genetic and environmental risk factors, and is the most common cause of preventable blindness worldwide. The common nature of the trait suggests the presence of many genetic factors that individually may have modest effects. To achieve an adequate sample size to detect these common variants, large, international collaborations have formed. These consortia typically use meta-analysis to combine multiple studies from many different populations. This approach is robust to differences between populations; however, it does not compensate for the different haplotypes in each genetic background evidenced by different alleles in linkage disequilibrium with the causative variant. We used the Age-Related Eye Disease Study (AREDS) cohort to replicate published significant associations at two loci on chromosome 15 from two genome-wide association studies (GWASs). The single nucleotide polymorphisms (SNPs) that exhibited association on chromosome 15 in the original studies did not show evidence of association with refractive error in the AREDS cohort. This paper seeks to determine whether the non-replication in this AREDS sample may be due to the limited number of SNPs chosen for replication. Methods We selected all SNPs genotyped on the Illumina Omni2.5v1_B array or custom TaqMan assays or imputed from the GWAS data, in the region surrounding the SNPs from the Consortium for Refractive Error and Myopia study. We analyzed the SNPs for association with refractive error using standard regression methods in PLINK. The effective number of tests was calculated using the Genetic Type I Error Calculator. Results Although use of the same SNPs used in the Consortium for Refractive Error and Myopia study did not show any evidence of association with refractive error in this AREDS sample, other SNPs within the candidate regions demonstrated an association with refractive error. Significant evidence of association was found using the hyperopia categorical trait, with the most significant SNPs rs1357179 on 15q14 (p=1.69×10−3) and rs7164400 on 15q25 (p=8.39×10−4), which passed the replication thresholds. Conclusions This study adds to the growing body of evidence that attempting to replicate the most significant SNPs found in one population may not be significant in another population due to differences in the linkage disequilibrium structure and/or allele frequency. This suggests that replication studies should include less significant SNPs in an associated region rather than only a few selected SNPs chosen by a significance threshold.

Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P, This report by the Consortium for Refractive Error and Myopia uses gene-environment-wide interaction study (GEWIS) to identify genetic loci that affect environmental influence in myopia development, and identifies ethnic specific genetic loci that attribute to eye refractive errors.

A previous study of Old Order Amish families showed an association of ocular refraction with markers proximal to matrix metalloproteinase (MMP) genes MMP1 and MMP10 and intragenic to MMP2. A candidate gene replication study of association between refraction and single nucleotide polymorphisms (SNPs) within these genomic regions was conducted.Candidate gene genetic association study.Two thousand participants drawn from the Age-Related Eye Disease Study (AREDS) were chosen for genotyping. After quality-control filtering, 1912 individuals were available for analysis.Microarray genotyping was performed using the HumanOmni 2.5 bead array (Illumina, Inc., San Diego, CA). Single nucleotide polymorphisms originally typed in the previous Amish association study were extracted for analysis. In addition, haplotype tagging SNPs were genotyped using TaqMan assays. Quantitative trait association analyses of mean spherical equivalent refraction were performed on 30 markers using linear regression models and an additive genetic risk model while adjusting for age, sex, education, and population substructure. Post hoc analyses were performed after stratifying on a dichotomous education variable. Pointwise (P(emp)) and multiple-test study-wise (P(multi)) significance levels were calculated empirically through permutation.Mean spherical equivalent refraction was used as a quantitative measure of ocular refraction.The mean age and ocular refraction were 68 years (standard deviation [SD], 4.7 years) and +0.55 diopters (D; SD, 2.14 D), respectively. Pointwise statistical significance was obtained for rs1939008 (P(emp) = 0.0326). No SNP attained statistical significance after correcting for multiple testing. In stratified analyses, multiple SNPs reached pointwise significance in the lower-education group: 2 of these were statistically significant after multiple testing correction. The 2 highest-ranking SNPs in Amish families (rs1939008 and rs9928731) showed pointwise P(emp)0.01 in the lower-education stratum of AREDS participants.This study showed suggestive evidence of replication of an association signal for ocular refraction to a marker between MMP1 and MMP10. Evidence of a gene-environment interaction between previously reported markers and education on refractive error also was shown. Variants in MMP1 through MMP10 and MMP2 regions seem to affect population variation in ocular refraction in environmental conditions less favorable for myopia development.

Family-based study designs are again becoming popular as new next-generation sequencing technologies make whole-exome and whole-genome sequencing projects economically and temporally feasible. Here we evaluate the statistical properties of linkage analyses and family-based tests of association for the Genetic Analysis Workshop 17 mini-exome sequence data. Based on our results, the linkage methods using relative pairs or nuclear families had low power, with the best results coming from variance components linkage analysis in nuclear families and Elston-Stewart model-based linkage analysis in extended pedigrees. For family-based tests of association, both ASSOC and ROMP performed well for genes with large effects, but ROMP had the advantage of not requiring parental genotypes in the analysis. For the linkage analyses we conclude that genome-wide significance levels appear to control type I error well but that “suggestive” significance levels do not. Methods that make use of the extended pedigrees are well powered to detect major loci segregating in the families even when there is substantial genetic heterogeneity and the trait is mainly polygenic. However, large numbers of such pedigrees will be necessary to detect all major loci. The family-based tests of association found the same major loci as the linkage analyses and detected low-frequency loci with moderate effect sizes, but control of type I error was not as stringent.

A previous genome-wide study in Orthodox Ashkenazi Jewish pedigrees showed significant linkage of ocular refraction to a Quantitative Trait Locus (QTL) on 1p34-36.1. We carried out a fine-mapping study of this region in Orthodox Ashkenazi Jewish (ASHK) and Old Order Amish (OOA) families to confirm linkage and narrow the candidate region.Families were recruited from ASHK and OOA American communities. The samples included: 402 individuals in 53 OOA families; and 596 members in 68 ASHK families. Families were ascertained to contain multiple myopic individuals. Genotyping of 1,367 SNPs was carried out within a 35cM (approximately 23.9 Mb) candidate QTL region on 1p34-36. Multipoint variance components (VC) and regression-based (REG) linkage analyses were carried out separately in OOA and ASHK groups, and in a combined analysis that included all families.Evidence of linkage of refractive error was found in both OOA (VC LOD=3.45, REG LOD=3.38 at approximately 59 cM) and ASHK families (VC LOD=3.12, REG LOD=4.263 at ~66 cM). Combined analyses showed three highly significant linkage peaks, separated by approximately 11cM (or 10 Mb), within the candidate region.In a fine-mapping linkage study of OOA and ASHK families, we have confirmed linkage of refractive error to a QTL on 1p. The area of linkage has been narrowed down to a gene-rich region at 1p34.2-35.1 containing ~124 genes.

To assess the correlations between retinal nerve fiber layer (RNFL) thickness measured with scanning laser polarimetry and visual field (VF) sensitivity in primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG).Prospective, comparative, observational cases series.Fifty patients with POAG and 56 patients with PACG were examined using scanning laser polarimetry with variable corneal compensation (GDx VCC; Laser Diagnostic Technologies, Inc.) and Humphrey VF analyzer (Carl Zeiss Meditec, Inc.) between August 2005 and July 2006 at Taipei Veterans General Hospital. Correlations between RNFL thickness and VF sensitivity, expressed as mean sensitivity in both decibel and 1/Lambert scales, were estimated by the Spearman rank correlation coefficient (r(s)) and multivariate median regression models (pseudo R(2)). The correlations were determined globally and for 6 RNFL sectors and their corresponding VF regions.The correlation between RNFL thickness and mean sensitivity (in decibels) was weaker in the PACG group (r(s) = 0.38; P = .004; pseudo R(2) = 0.17) than in the POAG group (r(s) = 0.51; P.001; pseudo R(2) = .31), but the difference in the magnitude of correlation was not significant (P = .42). With Bonferroni correction, the structure-function correlation was significant in the superotemporal (r(s) = 0.62), superonasal (r(s) = 0.56), inferonasal (r(s) = 0.53), and inferotemporal (r(s) = 0.50) sectors in the POAG group (all P.001), whereas it was significant only in the superotemporal (r(s) = 0.53) and inferotemporal (r(s) = 0.48) sectors in the PACG group (both P.001). The results were similar when mean sensitivity was expressed as 1/Lambert scale.Both POAG and PACG eyes had moderate structure-function correlations using scanning laser polarimetry. Compared with eyes with POAG, fewer RNFL sectors have significant structure-function correlations in eyes with PACG.

Purpose To identify myopia susceptibility genes influencing common myopia in 94 African-American and 36 White families. Design A prospective study of families with myopia consisting of a minimum of two individuals affected with myopia. Methods Extended families consisting of at least two siblings affected with myopia were ascertained. A genome-wide linkage scan using 387 markers was conducted by the Center for Inherited Disease Research. Linkage analyses were conducted with parametric and nonparametric methods. Model-free linkage analysis was performed maximizing over penetrance and over dominance (that is, fitting a wide range of both dominant and recessive models). Results Under the model-free analysis, the maximum two point heterogeneity logarithm of the odds score (MALOD) was 2.87 at D6S1009 in the White cohort and the maximum multipoint MALOD was 2.42 at D12S373-D12S1042 in the same cohort. The nonparametric linkage (NPL) maximum multipoint at D6S1035 had a P value of .005. An overall multipoint NPL score was obtained by combining NPL scores from both populations. The highest combined NPL score was observed at D20S478 with a significant P value of .008. Suggestive evidence of linkage in the White cohort mapped to a previously mapped locus on chromosome 11 at D11S1981 (NPL = 2.14; P = .02). Conclusions Suggestive evidence of linkage to myopia in both African Americans and Whites was seen on chromosome 20 and became more significant when the scores were combined for both groups. The locus on chromosome 11 independently confirms a report by Hammond and associates mapping a myopia quantitative trait locus to this region.

Genome-wide linkage analysis using microsatellite markers has been successful in the identification of numerous Mendelian and complex disease loci. The recent availability of high-density single-nucleotide polymorphism (SNP) maps provides a potentially more powerful option. Using the simulated and Collaborative Study on the Genetics of Alcoholism (COGA) datasets from the Genetics Analysis Workshop 14 (GAW14), we examined how altering the density of SNP marker sets impacted the overall information content, the power to detect trait loci, and the number of false positive results. For the simulated data we used SNP maps with density of 0.3 cM, 1 cM, 2 cM, and 3 cM. For the COGA data we combined the marker sets from Illumina and Affymetrix to create a map with average density of 0.25 cM and then, using a sub-sample of these markers, created maps with density of 0.3 cM, 0.6 cM, 1 cM, 2 cM, and 3 cM. For each marker set, multipoint linkage analysis using MERLIN was performed for both dominant and recessive traits derived from marker loci. Our results showed that information content increased with increased map density. For the homogeneous, completely penetrant traits we created, there was only a modest difference in ability to detect trait loci. Additionally, as map density increased there was only a slight increase in the number of false positive results when there was linkage disequilibrium (LD) between markers. The presence of LD between markers may have led to an increased number of false positive regions but no clear relationship between regions of high LD and locations of false positive linkage signals was observed.

The study was conducted on full-families of Black-and-White cattle obtained as 25 AI sire families and 355 cows, as well as their progenies, mostly heifers at the age of 1-3 months. The sire group was composed by the casual qualification of 10 PRNP 6/6 and 15 PRNP 6/5 individuals on the basis of accessible young progenies. The randomly selected group of cows is characterised by a very high frequency of PRNP 6/6 (74.9%), followed by lower frequency of PRNP 6/5 (24.5%) and a very low frequency of PRNP 5/5 genotype (0.6%). The progenies represent all expected genotypes, such as: PRNP 6/6 (60.5%), PRNP 6/5 (35.8%) and PRNP 5/5 (3.7%), respectively. Taking into consideration the genotypes of parents and progenies, the segregation of PRNP 6 and PRNP 5 alleles was analysed. Results of the non-informative mating variant of male symbol PRNP 6/6 x female symbol PRNP 6/6 (n = 87) are affected by the PRNP 6/6 progeny genotype in all cases. Subsequently, the results of mating variants male symbol PRNP 6/6 x female symbol PRNP 6/5 (n = 29) and male symbol PRNP 6/5 female symbol PRNP 6/6 (n = 179) showed statistically non-significant differences in both above-mentioned alternations. The progeny group related from male symbol PRNP 6/5 x female symbol PRNP 6/5 parental mating obtained fully informative and most valuable results based on the presented research concept. In the common group of 58 calves, the genotype PRNP 6/6 is represented by 26 individuals (44.8%), PRNP 6/5 - by 19 individuals (32.8%) and PRNP 5/5 - by 13 individuals (22.4%). Therefore, the theoretical genotype rate (25% : 50% : 25%) is drastically deformed and the differentiation between the observed and expected numbers of animals is statistically highly significant (chi(2) = 12.72; 2 df.). These differences are affected by two times higher PRNP 6/6 homozygous (chi(2) = 9.12; 1 df.) and responsively by the low number of PRNP 6/5 heterozygous animals (chi(2) = 3.45; 1 df.). Further investigations are carried out to explain the genetic determination of abnormal PRNP octa-peptide repeat allele segregation, which suggests possible lethal cis-trans linkage effects.

The investigation of the genetic basis of refractive error and myopia entered a new stage with the introduction of genome-wide association studies (GWAS). Multiple GWAS on many ethnic groups have been published over the years, providing new insight into the genetic architecture and pathophysiology of refractive error. This is a review of the GWAS published to date, the main lessons learned, and future possible directions of genetic studies of myopia and refractive error.

PURPOSE: We examined whether the decline in motion sensitivity in the elderly is equivalent for different visual field locations. METHODS: High velocity (28 degrees/s) random dot kinematograms (RDK's) were used to measure direction discrimination thresholds for 5 locations in the visual field (1 position centered on fixation and 4 locations each centered 18 degrees from fixation in the nasal, temporal, superior, and inferior quadrants). Differential luminance sensitivity was assessed by automated perimetry. Younger (N = 15, mean age = 22.9 +/- 1.3 years) and older (N = 13, mean age = 66.6 +/- 4.5 years) subjects were studied. RESULTS: Motion sensitivity varied with test location for both younger and older subjects, but sensitivity was significantly lower in older individuals. The largest age-related reduction in sensitivity was in the central location, whereas the smallest decline was in the superior position. No significant correlations between motion and differential luminance sensitivity were evident. CONCLUSIONS: There is a significant age-related deterioration in visual sensitivity to motion which is more pronounced in the central visual field than in some regions of the more peripheral field. Although both motion and differential luminance sensitivity decrease with age, the rate and the magnitude of the loss differ for these two visual functions.

The attrition of nerve fibers in the peripapillary area and the optic nerve head (ONH) in glaucoma has been attributed to mechanical compression of, or aberrant blood flow to the ganglion cell axons comprising the optic nerve1. Recently, greater attention has been focussed on the vascular factors in glaucoma2. Much of the delay in understanding the pathophysiology of glaucoma has been the absence of clinically usable instruments for reliably quantifying subtle structural changes in the ONH, and blood flow in the optic nerve. Fortunately, Petrig and Riva recently demonstrated the applicability of laser doppler principles for measuring blood flow in the ONH in man3, and confocal imaging principles have been adapted for computer reconstruction of serial laser scanned planes of the ophthalmoscopically visible ONH to provide highly accurate and reliable three-dimensional images4 for fundamental/clinical research.

PURPOSE: To investigate age-related trends in refractive, corneal, and internal astigmatism and to assess the association between internal astigmatism and lens opacity in an elderly Chinese population. METHODS: A population-based study was conducted among 1360 inhabitants aged 65 years and older in Taipei, Taiwan. Participants underwent measurements of refraction, corneal dioptric power, and slit lamp biomicroscopy with lens grading. A total of 2084 eyes were included in power vector analyses of Cartesian astigmatism (J(0)) and oblique astigmatism (J(45)) components of refractive, corneal, and internal astigmatism. RESULTS: The crude prevalence of refractive astigmatism (defined as ≥0.75 diopters) was 73.0% based on the right eyes and 76.4% based on the left eyes. The vector values in both refractive J(0) and corneal J(0) tended to be more negative with increasing age (P < 0.001), indicating the trend toward against-the-rule (ATR) astigmatism. Corneal J(0) alone accounted for 54% of the variability in refractive J(0). Refractive J(45) increased with age in the right eyes (P < 0.001) and decreased slightly with age in the left eyes (P = 0.012). Cortical opacity was associated with internal J(0) (P = 0.025), but the association was weak. CONCLUSIONS: Astigmatism affects approximately three quarters of the Chinese population aged 65 years and older in Taiwan. With increasing age, the prevalence of astigmatism increases, and refractive and corneal astigmatism shift toward ATR. Continuous corneal changes appear to be responsible for the age trend in refractive astigmatism. The severity of lens opacity plays only a minor role in the change of internal astigmatism.

Clear vision requires that images formed by incident light are focused at the eye's retinal plane. The maintenance of clear, focused, vision (i.e., emmetropia) through adulthood depends on a precise and complex regulation of eye shape during ocular development. This regulation ensures that the eye's focal and anatomic lengths are aligned. Any discrepancy between the position of the retina and the eye's focal point results in the spherical refractive errors myopia and hyperopia. In myopia, images of distant objects formed by the eye's optical system focus anterior to the retinal plane, causing blurred distance vision. In its functional opposite, hyperopia, these images focus behind the retina (in the unaccommodating eye). Hyperopia is associated with blurred near vision. Myopia and hyperopia are fundamentally qualitative definitions. However, the degree of departure from perfect focus can be quantified as the refractive error. Typically, refractive error represents the dioptric power of optical lenses necessary to achieve proper distance correction. By convention, negative values of refractive error (in diopters, D) represent myopia, whereas positive values represent hyperopia. Although there is a broad scientific consensus that environmental and behavioral factors influence refractive development and the genesis of myopia, genetic epidemiologic studies have consistently shown that the distribution of ocular refraction within populations is largely determined by genetics. Heritability estimates for refraction are usually very high across a wide spectrum of ethnic groups despite various intraethnic prevalences of myopia and myopigenic environmental influences. For example, we reported the heritability of refractive error in an adult Old Order Amish (AMISH) population to be 70%.1 High heritabilities are remarkably consistent across studies with estimates reported for Caucasian Americans,1–3 Europeans,4–7 and African Americans,3 ranging between 60% and 90%. Structurally, myopia is caused by an excessive axial length of the eye relative to its optical power.8 Hence, myopic eyes tend to be longer than nonmyopic eyes.8 The converse is true of hyperopia (i.e., hyperopic eyes are comparatively shorter than emmetropic and myopic eyes). Anatomically, these variations in axial length are due primarily to differences within the posterior (or vitreous) chamber, which occupies the bulk of the eye's volume. Although the molecular signal for blur-induced differential eye growth is thought to originate from within the retina, ocular elongation must occur via the growth of the outer tunic of the eye: the sclera. In mammals, the sclera is a fibrous connective tissue composed mainly of extracellular collagen, which accounts for up to 90% of the sclera's dry weight (Zorn N, et al. IOVS 1992;33:ARVO Abstract 1811). The majority (i.e., up to 99%) of scleral collagen is of the type I variety, although low levels of other collagen subtypes have also been found (Norton TT, et al. IOVS 1995;36:ARVO Abstract 3517). The structural organization of the scleral extracellular matrix (ECM) depends largely on the cellular activity of fibroblasts, the main ECM-producing cells in the sclera. The degradation of the ECM that occurs during scleral remodeling in eye growth and myopization (i.e., myopia development) is partially regulated through members of a major family of zinc- and calcium-dependent endopeptidases: the matrix metalloproteinases (MMPs) (see Rada et al.9 for a review). In humans, the MMP gene family comprises 23 distinct genes distributed across the genome; 9 MMP genes are located in a cluster at 11q22.2. The MMPs play numerous important roles in regulating cell–matrix composition in connective tissue and have been implicated in normal developmental processes and the pathogenesis of a variety of diseases.10,11 The expression of MMPs is generally low in tissues and is induced during active ECM remodeling.12 MMP regulation is mostly achieved at the transcriptional level but can occur at multiple stages. Activation of latent zymogens must occur for the MMPs to gain their proteolytic activity. Once activated, MMPs can be inactivated by multiple mechanisms, including direct interactions with one of four tissue inhibitors of matrix metalloproteinases (TIMPs).12 Given the important role of MMPs in ECM composition and remodeling, genetic variations in MMP genes are potential candidates for refractive error heritability and susceptibility to myopia. Indeed, a recent candidate gene study of older British adults reported statistically significant genetic associations between MMP3 and MMP9 polymorphisms and common myopia.13 We hypothesize that genetic polymorphisms in MMP and/or TIMP genes contribute to intrapopulation variations of refractive error measured as a quantitative trait. In the present study, we conducted family-based association analyses of genetic polymorphisms within MMP and TIMP candidate regions that included: MMP1, -2, -3, -7, -8, -9, -10, -12, -13, -14, -20, and -27, as well as TIMP1, -2, -3, and -4. These candidate regions were chosen to include genes whose homologs have shown differential expression in animal myopia models,14–17 as well as polymorphisms within a cluster of nine MMP genes situated at 11q22.2. Analyses were conducted on a subset of individuals from 63 Orthodox Ashkenazi Jewish (ASHK) and 55 Old Order Amish (AMISH) American families participating in the Myopia Family Study. We found statistically significant genetic associations between two single-nucleotide polymorphisms (SNPs), rs1939008 and rs9928731, and refractive error in the AMISH, but not the ASHK; rs1939008 is located between MMP1 and MMP10, and rs9928731 is located within MMP2.

To determine the heritability of refractive error and familial aggregation of myopia and hyperopia in an elderly Old Order Amish (OOA) population.Nine hundred sixty-seven siblings (mean age, 64.2 years) in 269 families were recruited for the Amish Eye Study in the Lancaster County area of Pennsylvania. Refractive error was determined by noncycloplegic manifest refraction. Heritability of refractive error was estimated with multivariate linear regression as twice the residual sibling-sibling correlation after adjustment for age and gender. Logistic regression models were used to estimate the sibling recurrence odds ratio (OR(s)). Myopia and hyperopia were defined with five different thresholds.The age- and gender-adjusted heritability of refractive error was 70% (95% CI: 48%-92%) in the OOA. Age and gender-adjusted OR(s) and sibling recurrence risk (lambda(s)), with different thresholds defining myopia ranged from 3.03 (95% CI: 1.58-5.80) to 7.02 (95% CI: 3.41-14.46) and from 2.36 (95% CI: 1.65-3.19) to 5.61 (95% CI: 3.06-9.34). Age and gender-adjusted OR(s) and lambda(s) for different thresholds of hyperopia ranged from 2.31 (95% CI: 1.56-3.42) to 2.94 (95% CI: 2.04-4.22) and from 1.33 (95% CI: 1.22-1.43) to 1.85 (95% CI: 1.18-2.78), respectively. Women were significantly more likely than men to have hyperopia. There was no significant gender difference in the risk of myopia.In the OOA, refractive error is highly heritable. Hyperopia and myopia aggregate strongly in OOA families.

Age-related cataract is the leading cause of blindness in the world1 and the leading cause of low vision in the United States,2 where it consumes approximately 60% of the Medicare budget for vision.3 It has been suggested that any intervention that could delay cataract for even 10 years may reduce the number of cataract surgeries in the United States by 45%.4 The potential impact of cataract prevention may be appreciated when we remember that 1 in 20 Americans over the age of 40 years have undergone cataract surgery.2 In the face of current knowledge about cataract and its causes, smoking prevention has been suggested as the most effective prevention strategy.5 Still, the simple clinical observation that some individuals survive very late in life without visually significant lens opacity has recently prompted several investigations into the genetics of age-related cataract as an avenue of research for novel prevention strategies. Available evidence from population-based studies6–9 suggests that cataract does in fact aggregate in families. However, such associations might result either from shared genes or shared environment. Twin studies provide a potentially powerful tool to distinguish between “nature” and “nurture,” and have been consistent with the idea of a genetic influence on age-related cataract.10,11 However, such studies are dependent on assumptions about the shared environment of different types of twins, and such assumptions are inherent in the models used to analyze these data. A practical difficulty in studies of the genetics of cataract, as with all age-related diseases, is that unaffected status at the time of examination may mean that the individual is truly unaffected or that he or she has simply not manifested the phenotype yet. Misattribution can thus be a serious problem in all but the oldest populations. An additional difficulty in performing studies to ascertain the degree of heritability of age-related cataract in the United States is that general access to cataract surgical services leads to systematic censorship of the most affected persons in the population, with attendant loss of power and possible introduction of bias. In the current investigation, we studied the heritability of nuclear cataract in a cohort of older sibships recruited through the Salisbury Eye Examination (SEE) on Maryland's Eastern Shore. We attempted to overcome some of the mentioned difficulties in studying the genetics of age-related cataract. To distinguish between familial aggregation of cataract due to environmental and genetic causes, information was collected on major personal and environmental cataract risk factors, including cigarette, alcohol, exogenous estrogen and other medication use, lifetime ultraviolet-B light exposure, serum antioxidant levels, history of diabetes and other relevant medical conditions, and body mass index (BMI). To minimize misattribution due to as yet unaffected individuals who will eventually manifest the phenotype, we chose to work in an older population, with the minimum age for probands of 72 years. Finally, to reduce the impact of censored data from bilaterally pseudophakic individuals, we relied on previous study photographs and records from operating ophthalmologists to assign cataract grades for individuals without a native lens in either eye at the time of enrollment in the study.