Review and comparison of retinal vessel calibre and geometry software and their application to diabetes, cardiovascular disease, and dementia.

Developments in retinal imaging technologies have enabled the quantitative evaluation of the retinal vasculature. Changes in retinal calibre and/or geometry have been reported in systemic vascular diseases, including diabetes mellitus (DM), cardiovascular disease (CVD), and more recently in neurodegenerative diseases, such as dementia. Several retinal vessel analysis softwares exist, some being disease-specific, others for a broader context. In the research setting, retinal vasculature analysis using semi-automated software has identified associations between retinal vessel calibre and geometry and the presence of or risk of DM and its chronic complications, and of CVD and dementia, including in the general population. In this article, we review and compare the most widely used semi-automated retinal vessel analysis softwares and their associations with ocular imaging findings in common systemic diseases, including DM and its chronic complications, CVD, and dementia. We also provide original data comparing retinal calibre grading in people with Type 1 DM using two softwares, with good concordance.

Automatic Detection of Abnormalities and Grading of Diabetic Retinopathy in 6-Field Retinal Images: Integration of Segmentation Into Classification.

Purpose: Classification of diabetic retinopathy (DR) is traditionally based on severity grading, given by the most advanced lesion, but potentially leaving out relevant information for risk stratification. In this study, we aimed to develop a deep learning model able to individually segment seven different DR-lesions, in order to test if this would improve a subsequently developed classification model. Methods: First, manual segmentation of 34,075 different DR-lesions was used to construct a segmentation model, with performance subsequently compared to another retinal specialist. Second, we constructed a 5-step classification model using a data set of 31,325 expert-annotated retinal 6-field images and evaluated if performance was improved with the integration of presegmentation given by the segmentation model. Results: The segmentation model had higher average sensitivity across all abnormalities compared to the retinal expert (0.68 and 0.62) at a comparable average F1-score (0.60 and 0.62). Model sensitivity for microaneurysms, retinal hemorrhages and intraretinal microvascular abnormalities was higher by 42.5%, 8.8%, and 67.5% and F1-scores by 15.8%, 6.5%, and 12.5%, respectively. When presegmentation was included, grading performance increased by 29.7%, 6.0%, and 4.5% for average per class accuracy, quadratic weighted kappa, and multiclass macro area under the curve, with values of 70.4%, 0.90, and 0.92, respectively. Conclusions: The segmentation model matched an expert in detecting retinal abnormalities, and presegmentation substantially improved accuracy of the automated classification model. Translational Relevance: Presegmentation may yield more accurate automated DR grading models and increase interpretability and trust in model decisions.

A digital online platform for education and certification of diabetic retinopathy health care professionals in the Region of Southern Denmark.

PURPOSE: The incidence of diabetes continues to increase across the world. As the number of patients rises, so does the need for educated health care professionals. Diabetic retinopathy (DR) remains one of the primary complications in diabetes, and screening has proved to be a cost-effective measure to avoid DR-related blindness. Denmark has an established screening programme, but no formal training of the people responsible for analysing retinal images. METHODS: We here present an online learning platform that offers a diabetic eye screening course for health care professionals undertaking screening responsibility in the Region of Southern Denmark. The course is divided into lectures, each focussed on identifying different levels of DR or detecting related lesions. The course is free to use on-demand, contains instructional videos, interactive tests and exercises, and it is concluded with a certification test. The tools on the platform can in addition be used to generate data for research purposes, such as comparing users or experts in detection of lesions or annotating data for the development of machine learning models. RESULTS: More than 150 participants have so far completed the course, and the platform is being adopted for education in other regions of Denmark.

Risk of eye diseases in osteogenesis imperfecta - A nationwide, register-based cohort study.

BACKGROUND: Osteogenesis imperfecta (OI) is a hereditary disease caused by affected collagen type 1. Collagen type 1 is an important structural component of the eye. Ocular manifestations in OI are described in literature, but little is known about the risk of eye diseases in OI. OBJECTIVE: To investigate the risk of eye diseases in OI. DESIGN: A Danish nationwide register-based cohort study based on data from the Danish National Patient Register. PARTICIPANTS: All patients registered with an OI diagnosis between January 1977 and December 2018 matched 1:5 with a reference population on gender and birth month and birth year. MEASUREMENTS: Incidence rates (IR) per 1000 patient years and sub-hazard ratio (SHR) for any eye disease, corneal diseases, cataract, refraction disorders, vitreous haemorrhage, retinal detachment, retinopathy, angiopathy, retinal haemorrhage, retinal degeneration, retinal changes, optic nerve disorders, and traumatic eye lesions. RESULTS: We identified 907 OI patients (493 women) and 4535 persons (2465 women) in the reference population. The IR for any eye disease was 4.07 [95% CI 3.41-4.85] in the OI cohort and 1.96 [95% CI 1.89-2.12] in the reference cohort. The two diseases with highest incidence was cataract (2.41 [95%CI 1.93-3.03] vs 1.29 [95% CI 1.12-1.47], SHR 1.76 [95% CI 1.34-2.33]) and glaucoma (1.08 [95% CI 0.77-1.51] vs 0.42 [95% CI 0.33-0.54], SHR 2.33 [95% CI 1.55-3.53]). The absolute risk of most other eye diseases was low, but the SHR indicated a higher risk in the OI cohort compared to the reference group showing statistically increased risk of refractive disorders, vitreous haemorrhage, retinal detachment or ruptures, other retinal diseases (i.e., retinopathy, angiopathy, retinal haemorrhage, degeneration, retinal changes), and optic nerve disorders. Corneal diseases and traumatic eye lesions were not statistically significantly increased in OI-patients. CONCLUSION: Patients with OI have a higher risk of cataract, refractive disorders, glaucoma, vitreous haemorrhages, retinal detachment/ruptures, retinal diseases, and optic nerve disorders.

Comparison of different methods of retinal imaging for the screening of diabetic retinopathy: a systematic review.

BACKGROUND: Screening for diabetic retinopathy (DR) is recommended to detect sight-threatening complications prior to visual loss. Early Treatment Diabetic Retinopathy Study (ETDRS) seven standard field (7SF) retinal imaging has traditionally been regarded the gold standard for DR classification, but other methods are often preferred clinically. The purpose of this systematic review was to determine whether 7SF is the most optimal screening method for DR grading, or if similar results can be achieved by other methods using a smaller field of view (<7SF) or ultra-wide field (UWF) imaging. METHODS: Based on Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, two independent reviewers initially identified 7167 publications in PubMed, Cochrane and Embase databases. Of these, 16 publications were included based on predefined inclusion criteria. RESULTS: 7SF was used as reference standard in 12 studies (compared with < 7SF in five studies and UWF in seven studies), and four studies compared other reference standards. Compared to 7SF, studies using < 7SF and UWF images both reported of similar agreement. A lower rate of ungradable images was reported for mydriatic and non-mydriatic UWF as compared to non-mydriatic < 7SF modalities. CONCLUSION: Retinal imaging of <7SF and UWF both provide acceptable performance compared to 7SF. Given the time-consuming nature of the latter, these methods could be reasonable options in DR screening, even though a high number of ungradable images in non-mydriatic < 7SF may pose a clinical challenge.

Clinicopathologic characteristics of Burkitt lymphoma of the head and neck in a non-endemic region-a Danish nationwide study.

BACKGROUND: Burkitt lymphoma rarely presents in head and neck (H&N) in Western countries. AIMS/OBJECTIVES: We aimed to characterise clinicopathological features of H&N Burkitt lymphoma in Denmark representing a non-endemic region. MATERIAL AND METHODS: Clinical records were reviewed for a nationwide cohort of patients diagnosed with H&N Burkitt lymphoma in Denmark between 1980 and 2018. The diagnosis was histologically validated. RESULTS: Thirty-four patients with H&N Burkitt lymphoma (highest incidence in age group 0-9 years, male-to-female ratio 4.7:1) were included. Thirty-three lymphomas (97%) were extranodal. The tumour was visible at the clinical examination in 81% (n = 22) of the cases. The palatine tonsils were the most frequent location (n = 13, 38%) and 52% (n = 17) of the patients were diagnosed in advanced stage. Lymphoma was the tentative clinical diagnosis in 23% of the cases. The 5-year overall- and disease-specific survival was 78% and 81%, respectively. CONCLUSIONS: Due to the rarity of Burkitt lymphoma of the H&N, there is a high risk of clinical misdiagnosis. Our findings suggest which symptoms and clinical presentations to be aware of in the diagnostics work up that could lead to the diagnosis of Burkitt lymphoma.

Inverse Cross-sectional and Longitudinal Relationships between Diabetic Retinopathy and Obstructive Sleep Apnea in Type 2 Diabetes: Results from a National Screening Program.

Purpose: In previous smaller studies, associations were demonstrated between diabetic retinopathy (DR) and obstructive sleep apnea (OSA), but longitudinal relationships have not been evaluated in larger cohorts. The aim of the present study was to assess the cross-sectional and prospective associations between DR and OSA in a national cohort of patients with type 2 diabetes. Design: Cross-sectional and 5-year longitudinal registry-based cohort study. Participants: For cases, we included 153 238 patients with type 2 diabetes who had attended diabetic eye screening and were registered in the Danish Registry of Diabetic Retinopathy (DiaBase). Each of these were matched by 5 control participants without diabetes of the same age and gender (n = 746 148). Methods: Exposure and outcome data as well as systemic morbidity and use of medications were identified in national registers, including the DiaBase, the Danish National Patient Register, the Danish National Prescription Registry, and the Danish Civil Registration System. The index date was defined as the date of the first DR screening registered in DiaBase. Main Outcome Measures: Exposure was defined as present and level-specific DR, and main outcomes were crude, age- and gender-adjusted, and multivariable adjusted odds ratios (ORs) for prevalent OSA as well as hazard ratios (HR) for 5-year incident OSA and DR. Results: Patients with type 2 diabetes independently were more likely to have prevalent OSA (OR, 2.01; 95% confidence interval [CI], 1.95-2.08) and to develop OSA within 5 years (HR, 1.55; 95% CI, 1.46-1.64). Patients with type 2 diabetes and DR at baseline were less likely to have prevalent OSA (OR, 0.57; 95% CI, 0.52-0.62) or to demonstrate incident OSA (HR, 0.86; 95% CI, 0.74-0.99). Likewise, patients with OSA had a lower risk to develop DR (HR, 0.83; 95% CI, 0.74-0.92). Conclusions: In a registry-based national cohort study, patients with type 2 diabetes had a higher risk of OSA. However, a 43% decreased risk of prevalent OSA was demonstrated in patients with DR, and prospectively, OSA and DR both were related inversely with each other.

Noninvasive Retinal Markers in Diabetic Retinopathy: Advancing from Bench towards Bedside.

The retinal vascular system is the only part of the human body available for direct, in vivo inspection. Noninvasive retinal markers are important to identity patients in risk of sight-threatening diabetic retinopathy. Studies have correlated structural features like retinal vascular caliber and fractals with micro- and macrovascular dysfunction in diabetes. Likewise, the retinal metabolism can be evaluated by retinal oximetry, and higher retinal venular oxygen saturation has been demonstrated in patients with diabetic retinopathy. So far, most studies have been cross-sectional, but these can only disclose associations and are not able to separate cause from effect or to establish the predictive value of retinal vascular dysfunction with respect to long-term complications. Likewise, retinal markers have not been investigated as markers of treatment outcome in patients with proliferative diabetic retinopathy and diabetic macular edema. The Department of Ophthalmology at Odense University Hospital, Denmark, has a strong tradition of studying the retinal microvasculature in diabetic retinopathy. In the present paper, we demonstrate the importance of the retinal vasculature not only as predictors of long-term microvasculopathy but also as markers of treatment outcome in sight-threatening diabetic retinopathy in well-established population-based cohorts of patients with diabetes.

Polymorphisms in the CTSH gene may influence the progression of diabetic retinopathy: a candidate-gene study in the Danish Cohort of Pediatric Diabetes 1987 (DCPD1987).

BACKGROUND: The incidence of type 1 diabetes mellitus (T1DM) is increasing globally, and as a consequence, more patients are affected by microvascular complications such as diabetic retinopathy (DR). The aim of this study was to elucidate possible associations between diabetes-related single-nucleotide polymorphisms (SNP) and the development of DR. METHODS: Three hundred and thirty-nine patients with T1DM from the Danish Cohort of Pediatric Diabetes 1987 (DCPD1987) went through an ophthalmic examination in 1995; 185 of these were reexamined in 2011. The development of DR was assessed by comparison of overall DR level between baseline and follow-up in the worst eye at baseline. Patients were graded on a modified version of the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, and 20 SNPs were genotyped in 130 of the 185 patients. RESULTS: We found the CTSH/rs3825932 variant (C > T) was associated with reduced risk of progression to proliferative diabetic retinopathy (PDR) (OR [95 % CI] = 0.20 [0.07-0.56], p = 2.4 × 10(-3), padjust = 0.048) and ERBB3/rs2292239 variant (G > T) associated with increased risk of two-step progression (OR [95 % CI] = 2.76 [1.31-5.80], p = 7.5 × 10(-3), padjust = 0.15). The associations were independent of other known risk factors, such as HbA1c, sex, and diastolic blood pressure. CONCLUSION: In conclusion, CTSH/rs3825932 and ERBB3/rs2292239 SNPs were associated with reduced risk of progression to PDR and two-step progression of DR on the ETDRS scale accordingly. The variant CTSH remained statistically significant after adjusting for multiple testing. Our results suggest an overlap between genetic variants that confer risk of T1DM and progression of DR.

Comparison between Early Treatment Diabetic Retinopathy Study 7-field retinal photos and non-mydriatic, mydriatic and mydriatic steered widefield scanning laser ophthalmoscopy for assessment of diabetic retinopathy.

AIMS: To compare non-mydriatic, mydriatic and steered mydriatic widefield retinal images with mydriatic 7-field Early Treatment Diabetic Retinopathy Study (ETDRS)-standards in grading diabetic retinopathy (DR). METHODS: We examined 95 patients (190 eyes) with type 1 diabetes. A non-mydriatic, a mydriatic and four steered mydriatic 200° widefield retinal images were captured (Optos 200Tx, Optos plc, Dunfermline, Scotland) and compared to mydriatic 7-field 45° ETDRS images (Topcon 3D OCT-2000, Topcon, Tokyo, Japan). Images were graded for DR according to ETDRS-protocol by a trained and certified grader masked to the results of the corresponding grading. For agreement kappa-statistics were used. RESULTS: Exact level agreement with 7-field images was found in 76.3%, 76.1% and 70.7% for non-mydriatic, mydriatic and steered mydriatic widefield images, respectively. Corresponding values for one-level agreement were 99.0%, 98.9% and 99.5%, respectively. Non-mydriatic matched mydriatic widefield images almost fully with exact and one-level agreement of 96.8% and 100.0%, respectively. Mydriatic steered images resulted in higher grading in 24 eyes. CONCLUSIONS: Widefield images matched 7-field images favorably. Widefield images can be captured without pupil-dilation and only one image is needed. However, because of overlapping eyelashes and distortion some lesion might be missed. Mydriatic steered images in selected cases may solve some of these problems.

Retinal vascular fractals predict long-term microvascular complications in type 1 diabetes mellitus: the Danish Cohort of Pediatric Diabetes 1987 (DCPD1987).

AIMS/HYPOTHESIS: Fractal analysis of the retinal vasculature provides a global measure of the complexity and density of retinal vessels summarised as a single variable: the fractal dimension. We investigated fractal dimensions as long-term predictors of microvasculopathy in type 1 diabetes. METHODS: We included 180 patients with type 1 diabetes in a 16 year follow-up study. In baseline retinal photographs (from 1995), all vessels in a zone 0.5-2.0 disc diameters from the disc margin were traced using Singapore Institute Vessel Assessment-Fractal image analysis software. Artefacts were removed by a certified grader, and fractal dimensions were calculated using the box-counting method. At follow-up (in 2011), diabetic neuropathy, nephropathy and proliferative retinopathy were assessed and related to baseline fractal dimensions in multiple regressions adjusted for sex and baseline age, diabetes duration, HbA1c, BP, BMI, vibration perception threshold, albuminuria, retinopathy and vessel diameters. RESULTS: Mean baseline age and diabetes duration were 21.0 and 13.4 years, respectively, and of patients 50.0% were males. The mean fractal dimension was 1.3817. The 16 year incidences of neuropathy, nephropathy and proliferative retinopathy were 10.8%, 8.0% and 27.9%, respectively. Multiple regression analyses showed a lower fractal dimension to significantly predict incident neuropathy (OR 1.17 per 0.01 fractal dimension decrease [95% CI 1.01, 1.36]), nephropathy (OR 1.40 per 0.01 fractal dimension decrease [95% CI 1.10, 1.79]) and proliferative retinopathy (OR 1.22 per 0.01 fractal dimension decrease [95% CI 1.09, 1.37]). CONCLUSIONS/INTERPRETATION: The retinal vascular fractal dimension is a shared biomarker of diabetic microvasculopathy, thus indicating a possible common pathogenic pathway. Retinal fractal analysis therefore is a potential tool for risk stratification in type 1 diabetes.

Retinal vessel calibers predict long-term microvascular complications in type 1 diabetes: the Danish Cohort of Pediatric Diabetes 1987 (DCPD1987).

Diabetic neuropathy, nephropathy, and retinopathy cause significant morbidity in patients with type 1 diabetes, even though improvements in treatment modalities delay the appearance and reduce the severity of these complications. To prevent or further delay the onset, it is necessary to better understand common underlying pathogenesis and to discover preclinical biomarkers of these complications. Retinal vessel calibers have been associated with the presence of microvascular complications, but their long-term predictive value has only been sparsely investigated. We examined retinal vessel calibers as 16-year predictors of diabetic nephropathy, neuropathy, and proliferative retinopathy in a young population-based Danish cohort with type 1 diabetes. We used semiautomated computer software to analyze vessel diameters on baseline retinal photos. Calibers of all vessels coursing through a zone 0.5-1 disc diameter from the disc margin were measured and summarized as the central artery and vein equivalents. In multiple regression analyses, we found wider venular diameters and smaller arteriolar diameters were both predictive of the 16-year development of nephropathy, neuropathy, and proliferative retinopathy. Early retinal vessel caliber changes are seemingly early markers of microvascular processes, precede the development of microvascular complications, and are a potential noninvasive predictive test on future risk of diabetic retinopathy, neuropathy, and nephropathy.

The 16-year incidence, progression and regression of diabetic retinopathy in a young population-based Danish cohort with type 1 diabetes mellitus: The Danish cohort of pediatric diabetes 1987 (DCPD1987).

The aim was to investigate the long-term incidence of proliferative diabetic retinopathy (PDR), and progression and regression of diabetic retinopathy (DR) and associated risk factors in young Danish patients with Type 1 diabetes mellitus. In 1987-89, a pediatric cohort involving approximately 75 % of all children with Type 1 diabetes in Denmark <19 years of age was identified (n = 720). In 1995, 339 (47.1 %) were re-studied with retinopathy graded and all relevant diabetic parameters assessed. Of those, 185 (54.6 %) were evaluated again in 2011 for the same clinical parameters. All retinal images were graded using modified early treatment of DR study for 1995 and 2011. In 1995, mean age was 21.0 years and mean diabetes duration 13.5 years. The 16-year incidence of proliferative retinopathy, 2-step progression and 2-step regression of DR was 31.0, 64.4 and 0.0 %, respectively, while the incidence of DR was 95.1 %. In a multivariate logistic regression model, progression to PDR was significantly associated with 1995 HbA1c (OR 2.61 per 1 % increase, 95 % CI 1.85-3.68) and 1995 diastolic blood pressure (OR 1.79 per 10 mmHg increase, 95 % CI 1.04-3.07). Two-step progression of DR was associated with male gender (OR 2.37 vs. female, 95 % CI 1.07-5.27), 1995 HbA1c (OR 3.02 per 1 % increase, 95 % CI 2.04-4.48) and 1995 vibration perception threshold (OR 1.19 per 1 Volt increase, 95 % CI 1.02-1.40). In conclusion, one in three progressed to PDR and two in three had 2-step progression despite young age and increased awareness of the importance of metabolic control. After 30 years duration of diabetes, the presence of DR is almost universal.