Eye Disease Study Research Articles

DeepLensNet: Deep Learning Automated Diagnosis and Quantitative Classification of Cataract Type and Severity

To develop deep learning models to perform automated diagnosis and quantitative classification of age-related cataract from anterior segment photographs. DeepLensNet was trained by applying deep learning models to the Age-Related Eye Disease Study (AREDS) dataset. A total of 18 999 photographs (6333 triplets) from longitudinal follow-up of 1137 eyes (576 AREDS participants). Deep learning models were trained to detect and quantify nuclear sclerosis (NS; scale 0.9-7.1) from 45-degree slit-lamp photographs and cortical lens opacity (CLO; scale 0%-100%) and posterior subcapsular cataract (PSC; scale 0%-100%) from retroillumination photographs. DeepLensNet performance was compared with that of 14 ophthalmologists and 24 medical students. Mean squared error (MSE). On the full test set, mean MSE for DeepLensNet was 0.23 (standard deviation [SD], 0.01) for NS, 13.1 (SD, 1.6) for CLO, and 16.6 (SD, 2.4) for PSC. On a subset of the test set (substantially enriched for positive cases of CLO and PSC), for NS, mean MSE for DeepLensNet was 0.23 (SD, 0.02), compared with 0.98 (SD, 0.24; P= 0.000001) for the ophthalmologists and 1.24 (SD, 0.34; P= 0.000005) for the medical students. For CLO, mean MSE was 53.5 (SD, 14.8), compared with 134.9 (SD, 89.9; P= 0.003) for the ophthalmologists and 433.6 (SD, 962.1; P= 0.0007) for the medical students. For PSC, mean MSE was 171.9 (SD, 38.9), compared with 176.8 (SD, 98.0; P= 0.67) for the ophthalmologists and 398.2 (SD, 645.4; P=0.18) for the medical students. In external validation on the Singapore Malay Eye Study (sampled to reflect the cataract severity distribution in AREDS), the MSE for DeepSeeNet was 1.27 for NS and 25.5 for PSC. DeepLensNet performed automated and quantitative classification of cataract severity for all 3 types of age-related cataract. For the 2 most common types (NS and CLO), the accuracy was significantly superior to that of ophthalmologists; for the least common type (PSC), it was similar. DeepLensNet may have wide potential applications in both clinical and research domains. In the future, such approaches may increase the accessibility of cataract assessment globally. The code and models are available at https://github.com/ncbi/deeplensnet.

Эпидемиология наследственных болезней органа зрения в популяциях Российской Федерации

Aim: genetic epidemiological study of hereditary eye diseases in various populations of the Russian Federation and comparative analysis of these findings. Patients and Methods: the sample included 12 ethnic groups from 14 regions of European Russia. The entire population irrespective of gender or age was examined. To confirm a certain type of inheritance of diseases from heterogeneous groups, the material was subjected to the multicomponent analysis used in multiple family registration. The rate of segregation was evaluated using the Weinberg proband method. Molecular genetic tests (Sanger sequencing, MLPA, AFLP, RFLP, whole exome sequencing) were applied. To identify the cases of hereditary disease accumulation in individual populations and/or ethnic groups, the prevalence of certain diseases in this population was calculated using F-distribution to compare the samples of rare diseases. Results: more than 46,000 patients and their relatives with presumably hereditary conditions were examined and data were collected. 554 clinically diverse hereditary diseases in 9,979 individuals were identified. Isolated hereditary eye disease (60 clinical variants) was identifie in 1,407 patients (14.56%). The mean prevalence of isolated hereditary eye disease was 1:2,272 (or 44.01 per 100,000). When assessing patterns of nosological spectrum and prevalence of isolated hereditary eye disease in each population/ethnic group using principal component analysis, 2 clusters were isolated. The first cluster includes 6 Russian populations and the second cluster includes 5 ethnic Volga Region groups, which are more similar to Russian populations than the North Caucasus people. In general, 57 hereditary syndromes (affecting anterior and posterior eye segments) in 1,051 patients were discovered. The mean prevalence of syndromic hereditary eye disease was 1:3,040 (or 32.89 per 100,000). Keywords: ophthalmogenetics, genetic epidemiological study, spectrum, ethnic group, type of inheritance, segregation, accumulation, isolated and syndromic hereditary eye diseases, prevalence, retinal degeneration. For citation: Kadyshev V.V., Ginter E.K., Kutsev S.I. et al. Epidemiology of hereditary eye disease in the populations of Russian Federation. Russian Journal of Clinical Ophthalmology. 2022;22(2):69–79 (in Russ.). DOI: 10.32364/2311-7729-2022-22-2-69-79.

A Clinical Study of Intensity-Modulated Radiotherapy-Induced Dry Eye Disease in Head and Neck Malignancies

Context: Dry Eye Disease is a multifaceted disorder caused by a variety of factors ranging from age to demographic profile. Radiation-induced dry eye disease is a relatively unexplored domain of this disease. Aim: To explore the various factors contributing to dry eye disease in patients receiving radiation therapy for head and neck malignancies with a fixed dose and duration of radiotherapy. Settings and design: A cross-sectional study conducted at a tertiary healthcare centre during a period of 1 year. Method and material: The study included 101 patients with head and neck malignancies who received a 60-Gray (Gy) dose of radiotherapy over a duration of 30 weeks. Patients were evaluated for signs and symptoms of dry eye on day 30 after completing their radiotherapy cycles using slit lamp biomicroscopy and various other tests for dry eye and compared with age, gender, location of malignancy, and adjunctive chemotherapy. Results: Out of a total of 101 patients, 45% had mild dry eye disease. 44–45% of mild dry eye disease was seen in the age groups of 20–50 and 51–80 years. The incidence of mild-to-moderate dry eye disease was almost similar (47% and 50 %) in both genders. The incidence of severe dry eye was seen in only 1% of patients. Dry eye disease was more severe in malignancies located closer to the orbit. The use of cisplatin as an adjunctive chemotherapy agent proved to be a risk factor for dry eye disease. Conclusion: Intensity-modulated radiotherapy is not enough to prevent the development of dry eye disease. A close and strict follow-up with an opthalmologist is essential for its prevention and early management.

A Clinical Study of Intensity-Modulated Radiotherapy-Induced Dry Eye Disease in Head and Neck Malignancies

Context: Dry Eye Disease is a multifaceted disorder caused by a variety of factors ranging from age to demographic profile. Radiation-induced dry eye disease is a relatively unexplored domain of this disease. Aim: To explore the various factors contributing to dry eye disease in patients receiving radiation therapy for head and neck malignancies with a fixed dose and duration of radiotherapy. Settings and design: A cross-sectional study conducted at a tertiary healthcare centre during a period of 1 year. Method and material: The study included 101 patients with head and neck malignancies who received a 60-Gray (Gy) dose of radiotherapy over a duration of 30 weeks. Patients were evaluated for signs and symptoms of dry eye on day 30 after completing their radiotherapy cycles using slit lamp biomicroscopy and various other tests for dry eye and compared with age, gender, location of malignancy, and adjunctive chemotherapy. Results: Out of a total of 101 patients, 45% had mild dry eye disease. 44–45% of mild dry eye disease was seen in the age groups of 20–50 and 51–80 years. The incidence of mild-to-moderate dry eye disease was almost similar (47% and 50 %) in both genders. The incidence of severe dry eye was seen in only 1% of patients. Dry eye disease was more severe in malignancies located closer to the orbit. The use of cisplatin as an adjunctive chemotherapy agent proved to be a risk factor for dry eye disease. Conclusion: Intensity-modulated radiotherapy is not enough to prevent the development of dry eye disease. A close and strict follow-up with an opthalmologist is essential for its prevention and early management.

Predicting Age-related Macular Degeneration Progression with Longitudinal Fundus Images Using Deep Learning.

Accurately predicting a patient's risk of progressing to late age-related macular degeneration (AMD) is difficult but crucial for personalized medicine. While existing risk prediction models for progression to late AMD are useful for triaging patients, none utilizes longitudinal color fundus photographs (CFPs) in a patient's history to estimate the risk of late AMD in a given subsequent time interval. In this work, we seek to evaluate how deep neural networks capture the sequential information in longitudinal CFPs and improve the prediction of 2-year and 5-year risk of progression to late AMD. Specifically, we proposed two deep learning models, CNN-LSTM and CNN-Transformer, which use a Long-Short Term Memory (LSTM) and a Transformer, respectively with convolutional neural networks (CNN), to capture the sequential information in longitudinal CFPs. We evaluated our models in comparison to baselines on the Age-Related Eye Disease Study, one of the largest longitudinal AMD cohorts with CFPs. The proposed models outperformed the baseline models that utilized only single-visit CFPs to predict the risk of late AMD (0.879 vs 0.868 in AUC for 2-year prediction, and 0.879 vs 0.862 for 5-year prediction). Further experiments showed that utilizing longitudinal CFPs over a longer time period was helpful for deep learning models to predict the risk of late AMD. We made the source code available at https://github.com/bionlplab/AMD_prognosis_mlmi2022 to catalyze future works that seek to develop deep learning models for late AMD prediction.

Association between age-related macular degeneration and 25(OH) vitamin D levels in the Turkish population.

Age-related macular degeneration is the most common cause of blindness in developed countries, and several factors have been attributed for its etiology. This study was conducted to explore the relationship between serum vitamin D levels and age-related macular degeneration. We retrospectively analyzed the data of 114 patients with age-related macular degeneration. A total of 102 patients who did not have any other diseases than refractive error were allocated to the control group. The best-corrected visual acuity, fundus findings, and spectral domain optical coherence tomography findings were analyzed. Patients were allocated to groups based on the Age-related Eye Disease Study classification. Serum 25(OH) vitamin D levels were measured. The central foveal thickness and the subfoveal choroidal thickness were measured by optical coherence tomography. The 25(OH) vitamin D levels in age- and gender-matched patients with age-related macular degeneration and in healthy subjects were 14.6 ± 9.8 and 29.14 ± 15.1 ng/ml, respectively. The age-related macular degeneration group had significantly lower vitamin D levels than the control group (p>0.001). The subfoveal choroidal thickness was lower in patients with age-related macular degeneration (p>0.001). The 25(OH) vitamin D level showed a weak positive correlation with choroidal thickness (r=0.357, p=0.01). When the level of 25(OH) vitamin D was evaluated according to the stages of age-related macular degeneration, it was found to be lower in the advanced-stage disease (p=0.01). The risk for the development of choroid neovascular membrane and subretinal fibrosis was found to increase with decreased vitamin D levels. Significantly decreased levels of 25(OH) vitamin D in advanced-stage age-related macular degeneration suggest a significant correlation existing between vitamin D deficiency and age-related macular degeneration development. Further studies are required to examine whether vitamin D supplementation has an effect on the development and progression of age-related macular degeneration.

Are macular drusen in midlife a marker of accelerated biological ageing?

ABSTRACT Clinical relevance Macular drusen are associated with age-related maculopathy but are not an ocular manifestation or biomarker of systemic ageing. Background Macular drusen are the first sign of age-related maculopathy, an eye disease for which age is the strongest risk factor. The aim of this cohort study was to investigate whether macular drusen in midlife – a sign of the earliest stages of age-related macular degeneration (AMD) – are associated with accelerated biological ageing more generally. Methods Members of the long-running Dunedin Multidisciplinary Health and Development Study (hereafter the Dunedin Study, n = 1037) underwent retinal photography at their most recent assessment at the age of 45 years. Images were graded for the presence of AMD using a simplified scale from the Age-Related Eye Disease Study (AREDS). Accelerated ageing was assessed by (i) a measure of Pace of Ageing defined from a combination of clinical and serum biomarkers obtained at ages 26, 32, 38, and 45 years and (ii) Facial Ageing, defined from photographs obtained at age 38 and 45 years. Results Of the 938 participants who participated at the age 45 assessments, 834 had gradable retinal photographs, and of these 165 (19.8%) had macular drusen. There was no significant difference in Pace of Ageing (p = .743) or Facial Ageing (p = .945) among participants with and without macular drusen. Conclusions In this representative general population sample, macular drusen in midlife were not associated with accelerated ageing. Future studies tracking longitudinal changes in drusen number and severity at older ages may reveal whether drusen are a biomarker of accelerated ageing.

Epidemiological study of dry eye disease and its influencing factors among soldiers on an island in South China Sea

Epidemiological study of dry eye disease and its influencing factors among soldiers on an island in South China Sea

Evidence-based vitamin supplements for age-related macular degeneration: an analysis of available products

ABSTRACT Clinical Relevance A wide range of supplements are available for age-related macular degeneration (AMD); however, clinicians may not be aware of which supplements contain an evidence-based formula. Background Vitamin and antioxidant supplementation has been shown to be effective in slowing the progression of AMD. The Age-Related Eye Disease Studies (AREDS) group reported an evidence-based formula in the AREDS 2 trials. Commercially available products carry varying degrees of resemblance to this formula. Methods A review of commercially available supplements in pharmacies and websites across Australasia, the United States, the United Kingdom, and Canada was undertaken. Supplements containing all the ingredients of the AREDS 2 recipe were included. The dose, formulation, and cost of the supplements were reviewed. Results Sixty-six products were reviewed. Forty-three products contained all the AREDS 2 ingredients and were therefore included for analysis. Twenty products contained all ingredients at 100% or more of the recommended dose, and 23 products contained some ingredients at a lower dose. The cost of the products varied from Australian dollar (AUD) $0.12 to AUD $6.72 per day. Seven (35%) products were available online only and 13 (65%) products were available both online and in pharmacies. Eight products were available in the United States pharmacies, five products were available in Canadian pharmacies, three products were available in the United Kingdom pharmacies, and one product was available in Australasian pharmacies. Conclusions Commercially available AMD supplements vary widely in price and resemblance to the AREDS 2 formulation. Clinician awareness of this information is important when counselling patients on which supplement is most suitable. The categorisation of products in Table 1 may assist with patient counselling of vitamin supplementation for AMD.

Cataract Surgery and the Risk of Developing Late Age-Related Macular Degeneration: The Age-Related Eye Disease Study 2 Report Number 27

To evaluate the risk of developing late age-related macular degeneration (AMD) after incident cataract surgery. A prospective cohort study within a randomized controlled clinical trial of oral supplementation for the treatment of AMD, the Age-Related Eye Disease Study 2 (AREDS2). AREDS2 participants aged 50 to 85 years with bilateral large drusen or unilateral late AMD. In eyes free of cataract surgery and late AMD at baseline, 2 groups were compared for incident late AMD: (1) eyes that received cataract surgery after the baseline visit and before any evidence of late AMD and (2) eyes that remained phakic until study completion. Eyes with at least 2 years of follow-up after cataract surgery were included in the analysis. We used Cox regression models, matched-pairs analysis, and logistic regression models that were adjusted for age, sex, smoking, education, study treatment group, and AMD severity. Late AMD was defined as the presence of geographic atrophy or neovascular AMD detected on annual stereoscopic fundus photographs or as documented by medical records, including intravitreous injections of anti-vascular endothelial growth factor medication. A total of 1767 eligible eyes (1195 participants) received cataract surgery; 1981 eyes (1524 participants) developed late AMD during a mean (range) follow-up of 9 (1-12) years. The Cox regression model showed no increased risk of developing late AMD after cataract surgery: hazard ratio, 0.96; 95% confidence interval (CI), 0.81-1.13 (P= 0.60) for right eyes and hazard ratio, 1.05; 95% CI, 0.89-1.25 (P= 0.56) for left eyes. Of the matched pairs, late AMD was identified in 408 eyes that received cataract surgery and in 429 phakic controls: odds ratio (OR) 0.92 (95% CI, 0.77-1.10; P= 0.34). The risk of late AMD after cataract surgery from the logistic regression model was not statistically significant (risk ratio, 0.92; 95% CI, 0.56-1.49; P= 0.73). Cataract surgery did not increase the risk of developing late AMD among AREDS2 participants with up to 10 years of follow-up. This study provides data for counseling AMD patients who might benefit from cataract surgery.

Meeting the challenges of retention and enrollment of study participants in clinical trials during the COVID-19 pandemic from the study leadership perspective: Experience from the Zoster Eye Disease Study (ZEDS)

PurposeTo describe steps taken that enabled a high rate of retention and early resumption of enrollment in the Zoster Eye Disease Study (ZEDS), a randomized controlled trial funded by the National Eye Institute, during the first 13 months (3/1/2020–3/31/2021) of the COVID–19 pandemic. MethodsA number of responses were implemented in ZEDS when the focus shifted to retention of study participants at the beginning of the pandemic including frequent communication with the participating clinical centers (PCCs) about remote visits, local lab work, shipping study medication, and completion of revised case report forms. Additional payments were provided to the PCCs. Remote activation of PCCs continued. Screening and enrollment visits gradually resumed when allowed. ResultsCommunication with PCCs increased, and average attendance at monthly coordinator teleconferences went up from 17 to 47. Remote visits peaked in April 2020, accounting for 75% (33/44) of study visits, then declined to less than 10% of study visits beginning August 2020. Overall, 97% (590/609) of study visits were completed. Only 5.5% (9/165) of study participants withdrew consent, and 2.4% (4/165) were lost to follow-up. Enrollment returned to pre-pandemic levels by September 2020. DiscussionStrong communication and unwavering commitment, combined with the technological capability for remote work, visits, and shipment of study medication, were key to the successful retention of study participants and resumption of enrollment. ConclusionsRapid responses to challenges to trials caused by the COVID-19 pandemic can enable them to continue successfully and provide insights into the planning of future trials.

Assessing bidirectional associations between cognitive impairment and late age-related macular degeneration in the Age-Related Eye Disease Study 2.

We aimed to investigate bidirectional associations between cognitive impairment and late age-related macular degeneration (AMD). Participants in the Age-Related Eye Disease Study 2 (AREDS2) received annual eye examinations and cognitive function testing (e.g., Modified Telephone Interview for Cognitive Status [TICS-M]). We examined bidirectional associations between cognitive impairment (e.g., a TICS-M score<30) and late AMD at 5 and 10 years. Five thousand one hundred eighty-nine eyes (3157 participants; mean age 72.7 years) were analyzed and followed for a median of 10.4 years. Eyes of participants with cognitive impairment at baseline were more likely to progress to late AMD at 5 years (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.08-1.43) and 10 years (HR, 1.20; 95% CI, 1.05-1.37) than eyes of participants without cognitive impairment. Worse baseline AMD severity was not associated with developing cognitive impairment. Cognitive impairment is associated with late AMD progression in AREDS2. Our finding highlights the importance of eyecare for people with cognitive impairment.

Optimized Prediction Models from Fundus Imaging and Genetics for Late Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a leading cause of blindness in the developed world. In this study, we compare the performance of retinal fundus images and genetic-information-based machine learning models for the prediction of late AMD. Using data from the Age-related Eye Disease Study, we built machine learning models with various combinations of genetic, socio-demographic/clinical, and retinal image data to predict late AMD using its severity and category in a single visit, in 2, 5, and 10 years. We compared their performance in sensitivity, specificity, accuracy, and unweighted kappa. The 2-year model based on retinal image and socio-demographic (S-D) parameters achieved a sensitivity of 91.34%, specificity of 84.49% while the same for genetic and S-D-parameters-based model was 79.79% and 66.84%. For the 5-year model, the retinal image and S-D-parameters-based model also outperformed the genetic and S-D parameters-based model. The two 10-year models achieved similar sensitivities of 74.24% and 75.79%, respectively, but the retinal image and S-D-parameters-based model was otherwise superior. The retinal-image-based models were not further improved by adding genetic data. Retinal imaging and S-D data can build an excellent machine learning predictor of developing late AMD over 2–5 years; the retinal imaging model appears to be the preferred prognostic tool for efficient patient management.

Choroidal melanocytic lesions in children: focal aggregates and melanocytosis

To investigate prevalence and age of onset of choroidal melanocytic lesions (other than nevi) in pediatric patients. The pooled data of participants 6 months to 18 years of age in the Sydney Paediatric Eye Disease Study, the Sydney Myopia Study, and the Sydney Adolescent Vascular Eye Disease Study were reviewed retrospectively to identify children with choroidal melanocytic lesions. The clinical features and prevalence by age were assessed. From the pooled sample of 5,533 unique children, 39 cases of focal melanocytic aggregates and 22 cases of choroidal melanocytosis were identified, with overall prevalence of 0.70% and 0.40%, respectively. There was a statistically significant trend toward increased prevalence with increasing age. Both focal melanocytic aggregates and choroidal melanocytosis tended to be bilateral (100% and 86% respectively), brown in color, and temporally located in all cases. Amelanotic variants were not identified. Focal melanocytic aggregates were small (0.15-0.5 mm), whereas choroidal melanocytosis varied in size (5.0-20 mm). All focal melanocytic aggregates were characteristically located 4-5 mm temporal to the center ofthe fovea and were associated with linear nervelike (11 [28%]) or tortuous vessel like structures (10 [26%]). In this study, pooled data from large population studies revealed morphologic patterns of choroidal melanocytic lesions, other than nevus, that correlate with described clinicalappearance in adults. The association of focal melanocytic aggregates with nervelike structures supports their embryologic origin along the migration path of uveal melanocytes.

Local Progression Kinetics of Geographic Atrophy Depends Upon the Border Location.

PurposeTo assess the influence of lesion morphology and location on geographic atrophy (GA) growth rate.MethodsWe manually delineated GA on color fundus photographs of 237 eyes in the Age-Related Eye Disease Study. We calculated local border expansion rate (BER) as the linear distance that a point on the GA border traveled over 1 year based on a Euclidean distance map. Eye-specific BER was defined as the mean local BER of all points on the GA border in an eye. The percentage area affected by GA was defined as the GA area divided by the total retinal area in the region.ResultsGA enlarged 1.51 ± 1.96 mm2 in area and 0.13 ± 0.11 mm in distance over 1 year. The GA area growth rate (mm2/y) was associated with the baseline GA area (P < 0.001), perimeter (P < 0.001), lesion number (P < 0.001), and circularity index (P < 0.001); in contrast, eye-specific BER (mm/y) was not significantly associated with any of these factors. As the retinal eccentricity increased from 0 to 3.5 mm, the local BER increased from 0.10 to 0.24 mm/y (P < 0.001); in contrast, the percentage of area affected by GA decreased from 49.3% to 2.3%.ConclusionsUsing distance-based measurements allows GA progression evaluation without significant confounding effects from baseline GA morphology. Local GA progression rates increased as a function of retinal eccentricity within the macula which is opposite of the trend for GA distribution, suggesting that GA initiation and enlargement may be mediated by different biological processes.

Relationship between vision impairment and employment

AimsTo examine the relationship between vision impairment (VI) and employment outcomes in a multiethnic Asian population.MethodsWe included 7608 Asian individuals aged ≥40 years (mean (SD) age: 58.4 (10.3) years; 64.8%...

Delayed Diagnosis of Amblyopia in Children of Lower Socioeconomic Families: The Hong Kong Children Eye Study

ABSTRACT Aims To determine the prevalence of amblyopia and the factors associated with delayed diagnosis among school-aged children in Hong Kong. Methods Completed comprehensive ophthalmoscopic examinations were conducted among 4.273 children aged 6–8 years in the population-based Hong Kong Children Eye Study. New and previous diagnoses of amblyopia were identified. Socioeconomic status was surveyed through questionnaires. Results According to criteria from the Multi-Ethnic Pediatric Eye Disease Study (MEPEDS), amblyopia was present in 43 out of 4,273 children (1.01%; 95% CI, 0.71–1.31). Among them, 33 (0.77%) were newly detected cases that were more likely from families living in Public Rental Housing or subdivided flats (OR, 4.22; P = .012), with lower paternal (OR 6.68, P = .008) and maternal education levels (OR, 4.38; P = .039). Multivariate analysis revealed associations of amblyopia with hyperopia (≥+2.00D; OR, 6.23; 95% CI, 2.86–13.56, P < .001), astigmatism (≥+2.00D; OR, 24.88; 95% CI, 10.69–57.91, P < .001) and anisometropia (≥2.00D; OR, 14.49; 95% CI, 5.93–37.63, P < .001). Conclusion These children with delayed diagnoses of amblyopia were more likely to come from lower socioeconomic backgrounds. Public education aimed at increasing awareness and utilization of child vision screening among such families is needed.

High-Density Lipoprotein 3 Cholesterol and Primary Open-Angle Glaucoma: Metabolomics and Mendelian Randomization Analyses

We hypothesized that the effect of blood lipid-related metabolites on primary open-angle glaucoma (POAG) would differ according to specific lipoprotein particles and lipid sub-fractions. We investigated the associations of blood levels of lipoprotein particles and lipid sub-fractions with POAG. Cross-sectional study. Individuals recruited for the baseline visit of the population-based Singapore Epidemiology of Eye Disease study (n= 8503). All participants underwent detailed standardized ocular and systemic examinations. A total of 130 blood lipid-related metabolites were quantified using a nuclear magnetic resonance metabolomics platform. The analyses were conducted in 2 stages. First, we investigated whether and which lipid-related metabolites were directly associated with POAG using regression analyses followed by Bayesian network modeling. Second, we investigated if any causal relationship exists between the identified lipid-related metabolites, if any, and POAG using 2-sample Mendelian randomization (MR) analysis. We performed genome-wide association studies (GWAS) on high-density lipoprotein (HDL) 3 cholesterol (after inverse normal transformation) and used the top variants associated with HLD3 cholesterol as instrumental variables (IVs) in the MR analysis. Primary open-angle glaucoma. Of the participants, 175 (2.1%) had POAG. First, a logistic regression model showed that total HDL3 cholesterol (negatively) and phospholipids in very large HDL (positively) were associated with POAG. Further analyses using a Bayesian network analysis showed that only total HDL3 cholesterol was directly associated with POAG (odds ratio [OR], 0.72 per 1 standard deviation increase in HDL3 cholesterol; 95% confidence interval [CI], 0.61-0.84), independently of age, gender, intraocular pressure (IOP), body mass index (BMI), education level, systolic blood pressure, axial length, and statin medication. Using 5 IVs identified from the GWAS and with the inverse variance weighted MR method, we found that higher levels of HDL3 cholesterol were associated with a decreased odds of POAG (OR, 0.91; 95% CI, 0.84-0.99, P= 0.021). Other MR methods, including weighted median, mode-based estimator, and contamination mixture methods, derived consistent OR estimates. None of the routine lipids (blood total, HDL, or low-density lipoprotein [LDL] cholesterol) were associated with POAG. Overall, these results suggest that the relationship between HDL3 cholesterol and POAG might be causal and specific, and that dysregulation of cholesterol transport may play a role in the pathogenesis of POAG.

Identification and inference for subgroups with differential treatment efficacy from randomized controlled trials with survival outcomes through multiple testing.

With the uptake of targeted therapies, instead of the "one-fits-all" approach, modern randomized controlled trials (RCTs) often aim to develop treatments that target a subgroup of patients. Motivated by analyzing the Age-Related Eye Disease Study (AREDS) data, a large RCT to study the efficacy of nutritional supplements in delaying the progression of an eye disease, age-related macular degeneration (AMD), we develop a simultaneous inference procedure to identify and infer subgroups with differential treatment efficacy in RCTs with time-to-event outcomes. Specifically, we formulate the multiple testing problem through contrasts and construct their simultaneous confidence intervals, which appropriately control both within- and across-marker multiplicity. Realistic simulations are conducted using real genotype data to evaluate the method performance under various scenarios. The method is then applied to AREDS to assess the efficacy of antioxidants and zinc combination in delaying AMD progression. Multiple gene regions including ESRRB-VASH1 on chromosome 14 have been identified with subgroups showing differential efficacy. We further validate our findings in an independent subsequent RCT, AREDS2, by discovering consistent differential treatment responses in the targeted and non-targeted subgroups identified from AREDS. This multiple-testing-based simultaneous inference approach provides a step forward to confidently identify and infer subgroups in modern drug development.

Associations of systemic health and medication use with the enlargement rate of geographic atrophy in age-related macular degeneration

BackgroundThe associations of geographic atrophy (GA) progression with systemic health status and medication use are unclear.MethodsWe manually delineated GA in 318 eyes in the Age-Related Eye Disease Study. We calculated...