RESUMEN
Primary open angle glaucoma (POAG) is a complex disease with a major genetic contribution. Its prevalence varies greatly among ethnic groups, and is up to five times more frequent in black African populations compared to Europeans. So far, worldwide efforts to elucidate the genetic complexity of POAG in African populations has been limited. We conducted a genome-wide association study in 1113 POAG cases and 1826 controls from Tanzanian, South African and African American study samples. Apart from confirming evidence of association at TXNRD2 (rs16984299; OR[T] 1.20; P = 0.003), we found that a genetic risk score combining the effects of the 15 previously reported POAG loci was significantly associated with POAG in our samples (OR 1.56; 95% CI 1.26-1.93; P = 4.79 × 10-5). By genome-wide association testing we identified a novel candidate locus, rs141186647, harboring EXOC4 (OR[A] 0.48; P = 3.75 × 10-8), a gene transcribing a component of the exocyst complex involved in vesicle transport. The low frequency and high degree of genetic heterogeneity at this region hampered validation of this finding in predominantly West-African replication sets. Our results suggest that established genetic risk factors play a role in African POAG, however, they do not explain the higher disease load. The high heterogeneity within Africans remains a challenge to identify the genetic commonalities for POAG in this ethnicity, and demands studies of extremely large size.
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Población Negra/genética , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Glaucoma de Ángulo Abierto/genética , Tiorredoxina Reductasa 2/genética , Proteínas de Transporte Vesicular/genética , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Primary open-angle glaucoma (POAG) is a blinding disease. Two important risk factors for this disease are a positive family history and elevated intraocular pressure (IOP), which is also highly heritable. Genes found to date associated with IOP and POAG are ABCA1, CAV1/CAV2, GAS7 and TMCO1. However, these genes explain only a small part of the heritability of IOP and POAG. We performed a genome-wide association study of IOP in the population-based Rotterdam Study I and Rotterdam Study II using single nucleotide polymorphisms (SNPs) imputed to 1000 Genomes. In this discovery cohort (n = 8105), we identified a new locus associated with IOP. The most significantly associated SNP was rs58073046 (ß = 0.44, P-value = 1.87 × 10(-8), minor allele frequency = 0.12), within the gene ARHGEF12. Independent replication in five population-based studies (n = 7471) resulted in an effect size in the same direction that was significantly associated (ß = 0.16, P-value = 0.04). The SNP was also significantly associated with POAG in two independent case-control studies [n = 1225 cases and n = 4117 controls; odds ratio (OR) = 1.53, P-value = 1.99 × 10(-8)], especially with high-tension glaucoma (OR = 1.66, P-value = 2.81 × 10(-9); for normal-tension glaucoma OR = 1.29, P-value = 4.23 × 10(-2)). ARHGEF12 plays an important role in the RhoA/RhoA kinase pathway, which has been implicated in IOP regulation. Furthermore, it binds to ABCA1 and links the ABCA1, CAV1/CAV2 and GAS7 pathway to Mendelian POAG genes (MYOC, OPTN, WDR36). In conclusion, this study identified a novel association between IOP and ARHGEF12.
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Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Glaucoma/genética , Glaucoma/fisiopatología , Presión Intraocular/genética , Factores de Intercambio de Guanina Nucleótido Rho/genética , Anciano , Femenino , Expresión Génica , Estudio de Asociación del Genoma Completo , Glaucoma/epidemiología , Glaucoma de Ángulo Abierto/genética , Glaucoma de Ángulo Abierto/fisiopatología , Humanos , Masculino , Metaanálisis como Asunto , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Mapeo de Interacción de Proteínas , Mapas de Interacción de Proteínas , Factores de Intercambio de Guanina Nucleótido Rho/metabolismoRESUMEN
The Bayesian approach has become increasingly popular because it allows to fit quite complex models to data via Markov chain Monte Carlo sampling. However, it is also recognized nowadays that Markov chain Monte Carlo sampling can become computationally prohibitive when applied to a large data set. We encountered serious computational difficulties when fitting an hierarchical model to longitudinal glaucoma data of patients who participate in an ongoing Dutch study. To overcome this problem, we applied and extended a recently proposed two-stage approach to model these data. Glaucoma is one of the leading causes of blindness in the world. In order to detect deterioration at an early stage, a model for predicting visual fields (VFs) in time is needed. Hence, the true underlying VF progression can be determined, and treatment strategies can then be optimized to prevent further VF loss. Because we were unable to fit these data with the classical one-stage approach upon which the current popular Bayesian software is based, we made use of the two-stage Bayesian approach. The considered hierarchical longitudinal model involves estimating a large number of random effects and deals with censoring and high measurement variability. In addition, we extended the approach with tools for model evaluation. Copyright © 2017 John Wiley & Sons, Ltd.
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Teorema de Bayes , Glaucoma/patología , Campos Visuales , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Interpretación Estadística de Datos , Progresión de la Enfermedad , Femenino , Humanos , Estudios Longitudinales , Masculino , Cadenas de Markov , Persona de Mediana Edad , Modelos Estadísticos , Método de Montecarlo , Estudios Prospectivos , Adulto JovenRESUMEN
Primary open-angle glaucoma is the most common optic neuropathy and an important cause of irreversible blindness worldwide. The optic nerve head or optic disc is divided in two parts: a central cup (without nerve fibers) surrounded by the neuroretinal rim (containing axons of the retinal ganglion cells). The International Glaucoma Genetics Consortium conducted a meta-analysis of genome-wide association studies consisting of 17,248 individuals of European ancestry and 6,841 individuals of Asian ancestry. The outcomes of the genome-wide association studies were disc area and cup area. These specific measurements describe optic nerve morphology in another way than the vertical cup-disc ratio, which is a clinically used measurement, and may shed light on new glaucoma mechanisms. We identified 10 new loci associated with disc area (CDC42BPA, F5, DIRC3, RARB, ABI3BP, DCAF4L2, ELP4, TMTC2, NR2F2, and HORMAD2) and another 10 new loci associated with cup area (DHRS3, TRIB2, EFEMP1, FLNB, FAM101, DDHD1, ASB7, KPNB1, BCAS3, and TRIOBP). The new genes participate in a number of pathways and future work is likely to identify more functions related to the pathogenesis of glaucoma.
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Estudio de Asociación del Genoma Completo , Glaucoma/genética , Disco Óptico/patología , Enfermedades del Nervio Óptico/genética , Sitios de Carácter Cuantitativo/genética , Pueblo Asiatico/genética , Glaucoma/etnología , Glaucoma/patología , Humanos , Enfermedades del Nervio Óptico/etnología , Enfermedades del Nervio Óptico/patología , Población Blanca/genéticaRESUMEN
Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p=1.4×10(-8)), and with rs7555523, located in TMCO1 at 1q24.1 (p=1.6×10(-8)). In a meta-analysis of 4 case-control studies (total Nâ=â1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p=2.4×10(-2) for rs11656696 and p=9.1×10(-4) for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation.
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Estudio de Asociación del Genoma Completo , Glaucoma de Ángulo Abierto/genética , Presión Intraocular/genética , Proteínas del Tejido Nervioso/genética , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Cuerpo Ciliar/metabolismo , Cuerpo Ciliar/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nervio Óptico/metabolismo , Nervio Óptico/patología , Polimorfismo de Nucleótido Simple , Malla Trabecular/metabolismo , Malla Trabecular/patologíaRESUMEN
Eye movement perimetry (EMP) expresses the decline in visual field (VF) responsiveness based on the deviation in saccadic reaction times (SRTs) from their expected age-similar responses (normative database). Since ethnic dissimilarities tend to affect saccade parameters, we evaluated the effect of such a factor on SRT and its interaction with age, stimulus eccentricity, and intensity. 149 healthy adults, spread into five age groups, drawn from Indian and Dutch ethnicities underwent a customized EMP protocol integrated with a saccade task from which the SRTs to 'seen' visual stimuli were computed. The EMP test had a total of 54 coordinates (five stimulus eccentricities) tested using Goldmann size III visual stimuli presented at four stimulus intensity (SI) levels against a constant background. Considering SRT as a dependent variable, a Generalized Linear Mixed Model analysis was conducted that revealed a statistically significant (p < 0.001) influence of ethnicity and interaction between the tested factors (ethnicity × age × stimulus eccentricity × intensity). However, during the post hoc analysis, out of the 100 possible pair-wise comparisons, only 6% (minor proportion) of the estimates showed statistical significance. Hence, the ethnic-specific differences need not be accounted for while implementing EMP in a diverse set of populations instead a collective database might serve the purpose.
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Etnicidad , Movimientos Sacádicos , Adulto , Humanos , Tiempo de Reacción/fisiología , Movimientos Oculares , Campos VisualesRESUMEN
The early detection of glaucoma is essential in preventing visual impairment. Artificial intelligence (AI) can be used to analyze color fundus photographs (CFPs) in a cost-effective manner, making glaucoma screening more accessible. While AI models for glaucoma screening from CFPs have shown promising results in laboratory settings, their performance decreases significantly in real-world scenarios due to the presence of out-of-distribution and low-quality images. To address this issue, we propose the Artificial Intelligence for Robust Glaucoma Screening (AIROGS) challenge. This challenge includes a large dataset of around 113,000 images from about 60,000 patients and 500 different screening centers, and encourages the development of algorithms that are robust to ungradable and unexpected input data. We evaluated solutions from 14 teams in this paper and found that the best teams performed similarly to a set of 20 expert ophthalmologists and optometrists. The highest-scoring team achieved an area under the receiver operating characteristic curve of 0.99 (95% CI: 0.98-0.99) for detecting ungradable images on-the-fly. Additionally, many of the algorithms showed robust performance when tested on three other publicly available datasets. These results demonstrate the feasibility of robust AI-enabled glaucoma screening.
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Inteligencia Artificial , Glaucoma , Humanos , Glaucoma/diagnóstico por imagen , Fondo de Ojo , Técnicas de Diagnóstico Oftalmológico , AlgoritmosRESUMEN
Open-angle glaucoma (glaucoma) is a major eye disorder characterized by optic disc pathology. Recent genome-wide association studies identified new loci associated with clinically relevant optic disc parameters, such as the optic disc area and vertical cup-disc ratio (VCDR). We examined to what extent these loci are involved in glaucoma. The loci studied include ATOH7, CDC7/TGFBR3 and SALL1 for optic disc area, and CDKN2B, SIX1, SCYL1/LTBP3, CHEK2, ATOH7 and DCLK1 for VCDR. We performed a meta-analysis using data from six independent studies including: the Rotterdam Study (n= 5736), Genetic Research in Isolated Populations combined with Erasmus Rucphen Family study (n= 1750), Amsterdam Glaucoma Study (n= 296) and cohorts from Erlangen and Tübingen (n= 1363), Southampton (n= 702) and deCODE (n= 36 151) resulting in a total of 3161 glaucoma cases and 42 837 controls. Of the eight loci, we found significant evidence (P= 1.41 × 10(-8)) for the association of CDKN2B with glaucoma [odds ratio (OR) for those homozygous for the risk allele: 0.76; 95% confidence interval (CI): 0.70-0.84], for the role of ATOH7 (OR: 1.28; 95% CI: 1.12-1.47) and for SIX1 (OR: 1.20; 95% CI: 1.10-1.31) when adjusting for the number of tested loci. Furthermore, there was a borderline significant association of CDC7/TGFBR3 and SALL1 (both P= 0.04) with glaucoma. In conclusion, we found consistent evidence for three common variants (CDKN2B, ATOH7 and SIX1) significantly associated with glaucoma. These findings may shed new light on the pathophysiological protein pathways leading to glaucoma, and point to pathways involved in the growth and development of the optic nerve.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Predisposición Genética a la Enfermedad/genética , Glaucoma de Ángulo Abierto/genética , Proteínas de Homeodominio/genética , Disco Óptico/metabolismo , Estudios de Cohortes , Glaucoma de Ángulo Abierto/metabolismo , Humanos , Modelos Logísticos , Oportunidad Relativa , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
PURPOSE: To determine the ability of ophthalmologists across Europe to match stereoscopic optic disc photographs to visual fields of varying severity. DESIGN: Evaluation and comparison of 2 diagnostic tests. PARTICIPANTS: A total of 109 of 260 invited ophthalmologists in 11 European countries. These had participated in the previous European Optic Disc Assessment Trial (EODAT), a trial on glaucoma diagnostic accuracy based on optic discs only. METHODS: Each participant matched stereo optic disc photographs of 40 healthy and 48 glaucomatous eyes to a visual field chosen from 4 options per disc. The 4 presented visual fields included the corresponding one and 3 other visual fields, varying in severity. The matching accuracy and any inaccuracy per disease severity were calculated. Classification accuracy (as glaucomatous or healthy) was compared with EODAT data. Duplicate slides allowed for the assessment of intraobserver agreement. MAIN OUTCOME MEASURES: Accuracy of matching optic discs with their corresponding visual field and of classifying them as healthy or glaucomatous; intraobserver agreement (κ). RESULTS: The overall accuracy of ophthalmologists for correctly matching stereoscopic optic disc photographs to their visual fields was 58.7%. When incorrectly matched, the observers generally overestimated the visual field severity (P<0.001), notably in eyes with early glaucoma. The intraobserver agreement was, on average, moderate (0.52). CONCLUSIONS: European ophthalmologists correctly matched stereoscopic optic disc photographs to their corresponding visual field in only approximately 59% of cases. In most mismatches, the clinicians overestimated the visual field damage.
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Glaucoma/diagnóstico , Oftalmología/estadística & datos numéricos , Disco Óptico/patología , Enfermedades del Nervio Óptico/diagnóstico , Trastornos de la Visión/fisiopatología , Campos Visuales/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Presión Intraocular , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Hipertensión Ocular/diagnóstico , Oftalmología/normas , Oftalmoscopía , Fotograbar , Reproducibilidad de los Resultados , Pruebas del Campo Visual , Población BlancaRESUMEN
PURPOSE: To assess the ability of UK optometrists to accurately discriminate between stereoscopic photographs of healthy and glaucomatous optic discs. METHODS: An online survey, including questions relating to qualification, practice environment, and diagnostic methods was completed by 1256 optometrists. Based on their responses, 208 (17%) were selected to undertake an online disc assessment exercise. Optometrists evaluated the same disc images previously assessed by European ophthalmologists as part of the European Optic Disc Assessment Trial (EODAT); the task was to state if the disc appeared healthy or glaucomatous. There were 110 stereoscopic disc images, of which 40 were healthy, 48 glaucomatous, and six ocular hypertensive, with 16 duplicates images. Sensitivity, specificity and overall accuracy were calculated and compared between optometrist groups and with the EODAT ophthalmologists using permutation analysis. RESULTS: Median sensitivity was 0.92 (95% CI: 0.70, 1.00) and median specificity was 0.74 (95% CI: 0.62, 0.88). Median overall accuracy was 80% (95% CI: 67%, 88%). Agreement between optometrists was moderate (Fleiss' κ: 0.57). Optometrists with higher qualifications did not have overall higher sensitivity than those without (p = 0.23), but had higher specificity (p = 0.001) and higher overall accuracy (p < 0.001). Optometrists displayed higher sensitivity but lower specificity than the EODAT ophthalmologists. CONCLUSION: UK optometrists displayed a high sensitivity and moderate specificity when assessing optic discs for the presence of glaucoma, in the context of this study.
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Competencia Clínica/normas , Técnicas de Diagnóstico Oftalmológico , Glaucoma/diagnóstico , Disco Óptico/patología , Optometría/normas , Fotograbar/normas , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Sensibilidad y Especificidad , Encuestas y Cuestionarios , Reino UnidoRESUMEN
The optic nerve head is involved in many ophthalmic disorders, including common diseases such as myopia and open-angle glaucoma. Two of the most important parameters are the size of the optic disc area and the vertical cup-disc ratio (VCDR). Both are highly heritable but genetically largely undetermined. We performed a meta-analysis of genome-wide association (GWA) data to identify genetic variants associated with optic disc area and VCDR. The gene discovery included 7,360 unrelated individuals from the population-based Rotterdam Study I and Rotterdam Study II cohorts. These cohorts revealed two genome-wide significant loci for optic disc area, rs1192415 on chromosome 1p22 (p = 6.72x10(-19)) within 117 kb of the CDC7 gene and rs1900004 on chromosome 10q21.3-q22.1 (p = 2.67x10(-33)) within 10 kb of the ATOH7 gene. They revealed two genome-wide significant loci for VCDR, rs1063192 on chromosome 9p21 (p = 6.15x10(-11)) in the CDKN2B gene and rs10483727 on chromosome 14q22.3-q23 (p = 2.93x10(-10)) within 40 kbp of the SIX1 gene. Findings were replicated in two independent Dutch cohorts (Rotterdam Study III and Erasmus Rucphen Family study; N = 3,612), and the TwinsUK cohort (N = 843). Meta-analysis with the replication cohorts confirmed the four loci and revealed a third locus at 16q12.1 associated with optic disc area, and four other loci at 11q13, 13q13, 17q23 (borderline significant), and 22q12.1 for VCDR. ATOH7 was also associated with VCDR independent of optic disc area. Three of the loci were marginally associated with open-angle glaucoma. The protein pathways in which the loci of optic disc area are involved overlap with those identified for VCDR, suggesting a common genetic origin.
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Disco Óptico/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Variación Genética , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Purpose: Significant visual impairment due to glaucoma is largely caused by the disease being detected too late. Objective: To build a labeled data set for training artificial intelligence (AI) algorithms for glaucoma screening by fundus photography, to assess the accuracy of the graders, and to characterize the features of all eyes with referable glaucoma (RG). Design: Cross-sectional study. Subjects: Color fundus photographs (CFPs) of 113 893 eyes of 60 357 individuals were obtained from EyePACS, California, United States, from a population screening program for diabetic retinopathy. Methods: Carefully selected graders (ophthalmologists and optometrists) graded the images. To qualify, they had to pass the European Optic Disc Assessment Trial optic disc assessment with ≥ 85% accuracy and 92% specificity. Of 90 candidates, 30 passed. Each image of the EyePACS set was then scored by varying random pairs of graders as "RG," "no referable glaucoma (NRG)," or "ungradable (UG)." In case of disagreement, a glaucoma specialist made the final grading. Referable glaucoma was scored if visual field damage was expected. In case of RG, graders were instructed to mark up to 10 relevant glaucomatous features. Main Outcome Measures: Qualitative features in eyes with RG. Results: The performance of each grader was monitored; if the sensitivity and specificity dropped below 80% and 95%, respectively (the final grade served as reference), they exited the study and their gradings were redone by other graders. In all, 20 graders qualified; their mean sensitivity and specificity (standard deviation [SD]) were 85.6% (5.7) and 96.1% (2.8), respectively. The 2 graders agreed in 92.45% of the images (Gwet's AC2, expressing the inter-rater reliability, was 0.917). Of all gradings, the sensitivity and specificity (95% confidence interval) were 86.0 (85.2-86.7)% and 96.4 (96.3-96.5)%, respectively. Of all gradable eyes (n = 111 183; 97.62%) the prevalence of RG was 4.38%. The most common features of RG were the appearance of the neuroretinal rim (NRR) inferiorly and superiorly. Conclusions: A large data set of CFPs was put together of sufficient quality to develop AI screening solutions for glaucoma. The most common features of RG were the appearance of the NRR inferiorly and superiorly. Disc hemorrhages were a rare feature of RG. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.
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PRCIS: Irregular visual field test frequency at relatively short intervals initially and longer intervals later on in the disease provided acceptable results in detecting glaucoma progression. PURPOSE: It is challenging to maintain a balance between the frequency of visual field testing and the long-term costs that may result from insufficient treatment of glaucoma patients. This study aims to simulate real-world circumstances of visual field data to determine the optimum follow-up scheme for the timely detection of glaucoma progression using a linear mixed effects model (LMM). MATERIALS AND METHODS: An LMM with random intercept and slope was used to simulate the series of mean deviation sensitivities over time. A cohort study including 277 glaucoma eyes that were followed for 9.0±1.2 years was used to derive residuals. Data were generated from patients with early-stage glaucoma having various regular and irregular follow-up scenarios and different rates of visual field loss. For each condition, 10,000 series of eyes were simulated, and one confirmatory test was conducted to identify progression. RESULTS: By doing one confirmatory test, the percentage of incorrect progression detection decreased considerably. The time to detect progression was shorter for eyes with an evenly spaced 4-monthly schedule, particularly in the first 2 years. From then onward, results from twice-a-year testing were similar to results from examinations scheduled 3 times per year. CONCLUSIONS: Irregular visual field test frequency at relatively short intervals initially and longer intervals later on in the disease provided acceptable results in detecting glaucoma progression. This approach could be considered for improving glaucoma monitoring. Moreover, simulating data using LMM may provide a better estimate of the disease progression time.
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Glaucoma , Campos Visuales , Humanos , Estudios de Cohortes , Simulación por Computador , Presión Intraocular , Glaucoma/diagnóstico , Pruebas del Campo Visual/métodos , Trastornos de la Visión/diagnóstico , Progresión de la Enfermedad , Estudios de SeguimientoRESUMEN
BACKGROUND: Although the vertical cup-disc ratio (VCDR) and intraocular pressure (IOP) are important determinants of open angle glaucoma (OAG), it is unclear to what extent the genetic origin of these traits overlap with those of OAG. We evaluated whether the same genes that determine VCDR and IOP also predict OAG. METHODS: Genetic risk scores were constructed from single nucleotide polymorphisms (SNPs) using genome wide association data of 9326 participants from the Rotterdam Study cohorts (mean ± SD age: 64.6 ± 9.1 years). These risk scores were used to calculate the explained variance of VCDR and IOP in an independent cohort (Erasmus Rucphen Family study) consisting of 1646 participants (mean ± SD age: 46.8 ± 14.1 years) and the OAG risk in a subset of the Rotterdam Study cohorts. To evaluate false positive findings, we generated two new variables containing randomly sampled values to serve as a negative control. RESULTS: The explained variance of VCDR increased when increasing the number of SNPs included in the risk score, suggesting a polygenic model. We found no clear evidence for a similar model for IOP, suggesting that a small number of SNPs determine the susceptibility to IOP. The SNPs related to IOP in terms of p values contributed little to VCDR. The risk scores associated with VCDR were also associated significantly with OAG. This suggests a common polygenic background for VCDR and OAG CONCLUSIONS: We found evidence for a polygenic model underlying one of the major traits of OAG, VCDR, and OAG itself. The IOP did not show any evidence for such a model.
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Glaucoma de Ángulo Abierto/genética , Glaucoma de Ángulo Abierto/metabolismo , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Estudios Transversales , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Presión Intraocular , Masculino , Persona de Mediana Edad , Filogenia , Estudios Prospectivos , Factores de Riesgo , Distribución por Sexo , Adulto JovenRESUMEN
BACKGROUND: Despite extensive research on the genetic determinants of glaucoma, the genes identified to date explain only a small proportion of cases in the general population. METHODS: Genome-wide linkage and association analyses of quantitative traits related to glaucoma were performed: intraocular pressure, size and morphology of the optic disc (individual and combined by method of principal components) and thickness of the retinal nerve fibre layer (RNFL), in a large pedigree from a genetically isolated Dutch population. RESULTS: For the size of the optic disc, the study demonstrated a significant linkage signal (logarithm of odds (LOD)=3.6) at the LRP1B region on chromosome 2q21.2-q22.2 and significant association (p=8.95×10(-12)) with the previously reported CDC7/TGFBR3 locus at 1p22. For parameters describing morphology of the optic disc, the study obtained significant linkage signal (LOD=4.6) at regions SIRPA and RNF24/PANK2 at 20p13 (false discovery rate (FDR) based q value <0.05) and genome-wide significant association (p=2.38×10(-9)) with a common variant in the RERE gene at 1p36. Suggestive linkage and association signals indicated loci for morphology of the optic disc at 2q31-q33 (IGFBP2 locus) and for RNFL thickness at 3p22.2 (DCLK3 locus) and 14q22-q23 (SIX1 locus). CONCLUSION: This study identified new linkage regions at 20p13 (SIRPA and RNF24/PANK2 loci) and 2q33-q34 (IGFBP2 locus) for parameters describing morphology of the optic disc. The results of the study also suggested common genetic control of these parameters and RNFL thickness by SIX1 and doublecotin family genes. Finally, association signals for the recently reported RERE and LRP1B loci and the well known CDC7, TGFBR3, and ATOH7 loci were replicated.
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Ligamiento Genético , Estudio de Asociación del Genoma Completo , Glaucoma/genética , Antígenos de Diferenciación/genética , Proteínas Portadoras/genética , Cromosomas Humanos/genética , Sitios Genéticos , Glaucoma/patología , Proteínas de Homeodominio/genética , Humanos , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Presión Intraocular/genética , Países Bajos , Disco Óptico/citología , Disco Óptico/patología , Linaje , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Polimorfismo de Nucleótido Simple , Análisis de Componente Principal , Carácter Cuantitativo Heredable , Receptores Inmunológicos/genética , Receptores de LDL/genética , Retina/citología , Retina/patologíaRESUMEN
Purpose: To determine the sensitivity of optical coherence tomography (OCT) and standard automated perimetry (SAP) for detecting glaucomatous progression in the superior and inferior hemiretina. Methods: We calculated contrast-to-noise ratios (CNRs) for OCT retinal nerve fiber layer (RNFL) thickness of hemiretinas and for SAP mean total deviation (MTD) of the corresponding hemifields from longitudinal data (205 eyes, 125 participants). The glaucoma stage for each hemiretina was based on the corresponding hemifield's MTD. Contrast was defined as the difference of the parameter between two consecutive glaucoma stages, whereas noise was the measurement variability of the parameter in those stages. The higher the CNR of a parameter, the more sensitive it is to detecting progression in the transition between successive stages. Results: There were no statistically significant differences for the RNFL CNR and MTD CNR between superior and inferior hemiretinas. As the glaucoma stage of the opposite hemiretina worsened, the MTD CNR in the transition from moderate to advanced glaucoma significantly increased. The RNFL CNR in the transition from mild to moderate glaucoma significantly decreased in case of advanced glaucoma in the opposite hemiretina. Conclusions: Similar to full retinas, detecting conversion to glaucoma in hemiretinas is more sensitive with OCT than SAP, whereas with more advanced disease, SAP is more sensitive for detecting progression. More importantly, the sensitivity for detecting progression in one hemiretina with either technique depends on the glaucoma severity in the opposite hemiretina. Translational Relevance: Monitoring glaucomatous progression with either OCT or SAP partly depends on the glaucoma severity in the opposite hemiretina.
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Glaucoma , Fibras Nerviosas , Glaucoma/diagnóstico , Humanos , Retina , Tomografía de Coherencia Óptica/métodos , Pruebas del Campo VisualRESUMEN
Purpose: Accurate assessment of visual field (VF) trend may help clinicians devise the optimum treatment regimen. This study was conducted to investigate the behavior of VF sequences using pointwise and region-wise linear, exponential, and sigmoid regression models. Materials and Methods: In a retrospective cohort study, 277 eyes of 139 patients with glaucoma who had been followed for at least 7 years were investigated. Linear, exponential, and sigmoid regression models were fitted for each VF test location and Glaucoma Hemifield Test (GHT) region to model the trend of VF loss. The model with the lowest root mean square error (RMSE) was selected as the best fit. Results: The mean age (standard deviation [SD]) of the patients was 59.9 years (9.8) with a mean follow-up time of 9.3 (0.7) years. The exponential regression had the best fit based on pointwise and region-wise approaches in 39.3% and 38.1% of eyes, respectively. The results showed a better performance based on sigmoid regression in patients with initial VF sensitivity threshold greater than 22 dB (71.6% in pointwise and 62.2% in region-wise approaches). The overall RMSE of the region-wise regression model was lower than the overall RMSE of the pointwise model. Conclusions: In the current study, nonlinear regression models showed a better fit compared to the linear regression models in tracking VF loss behavior. Moreover, findings suggest region-wise analysis may provide a more appropriate approach for assessing VF deterioration. Translational Relevance: Findings may confirm a nonlinear progression of VF deterioration in patients with glaucoma.
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Glaucoma , Campos Visuales , Progresión de la Enfermedad , Estudios de Seguimiento , Glaucoma/complicaciones , Glaucoma/diagnóstico , Humanos , Presión Intraocular , Persona de Mediana Edad , Estudios Retrospectivos , Trastornos de la Visión/diagnósticoRESUMEN
PURPOSE: To determine whether the postoperative corneal endothelial cell density (ECD) differs between glaucoma patients who underwent Baerveldt implant (BGI) surgery and patients who underwent a trabeculectomy (TE) over 5 years ago. METHODS: Cross-sectional, observational study including 34 patients who underwent TE and 36 patients who underwent BGI surgery 5-11 years ago, as part of a randomized clinical trial. None of the patients had a history of intraocular surgery prior to their glaucoma surgery. Central and peripheral ECD was measured by using a non-contact specular microscope. RESULTS: Central and peripheral ECD in the TE group was 2285 ± 371 cells/mm2 (mean ± SD) and 2463 ± 476 cells/mm2 , respectively. Central and peripheral ECD in the BGI group was 1813 ± 745 cells/mm2 and 1876 ± 764 cells/mm2 , respectively. The central and peripheral ECD was statistically significantly higher in the TE group than in the BGI group (p = 0.001 for both). Additional intraocular surgical interventions were more prevalent in the BGI group (23) than in the TE group (5) (p < 0.001). In a subanalysis, without eyes that had undergone additional surgical interventions, only the peripheral ECD was statistically significantly higher in the TE group compared with the BGI group (p = 0.011). For the BGI group, a longer postoperative period resulted in a lower central ECD (r = -0.614, p = 0.004). CONCLUSION: Long-term ECD in eyes that underwent a BGI was considerably lower compared with eyes that underwent a TE, mainly in the peripheral cornea. This suggests that BGI causes a larger decrease of ECD than TE. Additionally, the decrease after BGI appears to continue for a longer period than after TE.
Asunto(s)
Pérdida de Celulas Endoteliales de la Córnea/etiología , Implantes de Drenaje de Glaucoma/efectos adversos , Trabeculectomía/efectos adversos , Anciano , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trabeculectomía/métodosRESUMEN
Corneal guttae, which are the abnormal growth of extracellular matrix in the corneal endothelium, are observed in specular images as black droplets that occlude the endothelial cells. To estimate the corneal parameters (endothelial cell density [ECD], coefficient of variation [CV], and hexagonality [HEX]), we propose a new deep learning method that includes a novel attention mechanism (named fNLA), which helps to infer the cell edges in the occluded areas. The approach first derives the cell edges, then infers the well-detected cells, and finally employs a postprocessing method to fix mistakes. This results in a binary segmentation from which the corneal parameters are estimated. We analyzed 1203 images (500 contained guttae) obtained with a Topcon SP-1P microscope. To generate the ground truth, we performed manual segmentation in all images. Several networks were evaluated (UNet, ResUNeXt, DenseUNets, UNet++, etc.) and we found that DenseUNets with fNLA provided the lowest error: a mean absolute error of 23.16 [cells/mm[Formula: see text]] in ECD, 1.28 [%] in CV, and 3.13 [%] in HEX. Compared with Topcon's built-in software, our error was 3-6 times smaller. Overall, our approach handled notably well the cells affected by guttae, detecting cell edges partially occluded by small guttae and discarding large areas covered by extensive guttae.
Asunto(s)
Endotelio Corneal , Microscopía , Recuento de Células , Células Endoteliales , Endotelio Corneal/diagnóstico por imagen , Retroalimentación , Microscopía/métodosRESUMEN
PURPOSE: To assess if ocular motility impairment, and the ensuing diplopia, after Baerveldt Glaucoma device (BGI) implantation, is related to the presence of a large fluid reservoir (bleb), using Magnetic Resonance Imaging (MRI). METHODS: In a masked observational study (CCMO-registry number: NL65633.058.18), the eyes of 30 glaucoma patients with (n = 12) or without diplopia (n = 18) who had previously undergone BGI implantation were scanned with a 7 Tesla MRI-scanner. The substructures of the BGI-complex, including both blebs and plate, were segmented in 3D. Primary outcomes were a comparison of volume and height of the BGI-complex between patients with and without diplopia. Comparisons were performed by using an unpaired t-test, Fisher's Exact or Mann-Whitney test. Correlations were determined by using Spearman correlation. RESULTS: The median volume and height of the BGI-complex was significantly higher in patients with compared to patients without diplopia (p = 0.007 and p = 0.025, respectively). Six patients had an excessively large total bleb volume (median of 1736.5mm3, interquartile range 1486.3-1933.9mm3), four of whom experienced diplopia (33% of the diplopia patients). Fibrotic strands through the BGI plate, intended to limit the height of the bleb, could be visualized but were not related to diplopia (75% versus 88%; p = 0.28). CONCLUSIONS: With MRI, we show that in a significant number of diplopia cases a large bleb is present in the orbit. Given the large volume of these blebs, they are a likely explanation of the development of diplopia in at least some of the patients with diplopia after BGI implantation. Additionally, the MR-images confirm the presence of fibrotic strands. As these strands are also visible in patients with a large bleb, they are apparently not sufficient to restrict the bleb height.