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Self-supervised learning has become the cornerstone of building generalizable and transferable artificial intelligence systems in medical imaging. In particular, contrastive representation learning techniques trained on large multi-modal datasets have demonstrated impressive capabilities of producing highly transferable representations for different downstream tasks. In ophthalmology, large multi-modal datasets are abundantly available and conveniently accessible as modern retinal imaging scanners acquire both 2D fundus images and 3D optical coherence tomography (OCT) scans to assess the eye. In this context, we introduce a novel multi-modal contrastive learning-based pipeline to facilitate learning joint representations for the two retinal imaging modalities. After self-supervised pre-training on 153,306 scan pairs, we show that such a pre-training framework can provide both a retrieval system and encoders that produce comprehensive OCT and fundus image representations that generalize well for various downstream tasks on three independent external datasets, explicitly focusing on clinically pertinent prediction tasks. In addition, we show that interchanging OCT with lower-cost fundus imaging can preserve the predictive power of the trained models., (© 2024. The Author(s).)

Background and Objective: Despite the promising capabilities of 3D transformer architectures in video analysis, their application to high-resolution 3D medical volumes encounters several challenges. One major limitation is the high number of 3D patches, which reduces the efficiency of the global self-attention mechanisms of transformers. Additionally, background information can distract vision transformers from focusing on crucial areas of the input image, thereby introducing noise into the final representation. Moreover, the variability in the number of slices per volume complicates the development of models capable of processing input volumes of any resolution while simple solutions like subsampling may risk losing essential diagnostic details., Methods: To address these challenges, we introduce an end-to-end transformer-based framework, variable length feature aggregator transformer rollout (VLFATRollout), to classify volumetric data. The proposed VLFATRollout enjoys several merits. First, the proposed VLFATRollout can effectively mine slice-level fore-background information with the help of transformer's attention matrices. Second, randomization of volume-wise resolution (i.e. the number of slices) during training enhances the learning capacity of the learnable positional embedding (PE) assigned to each volume slice. This technique allows the PEs to generalize across neighboring slices, facilitating the handling of high-resolution volumes at the test time., Results: VLFATRollout was thoroughly tested on the retinal optical coherence tomography (OCT) volume classification task, demonstrating a notable average improvement of 5.47% in balanced accuracy over the leading convolutional models for a 5-class diagnostic task. These results emphasize the effectiveness of our framework in enhancing slice-level representation and its adaptability across different volume resolutions, paving the way for advanced transformer applications in medical image analysis. The code is available at https://github.com/marziehoghbaie/VLFATRollout/., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Deep learning has potential to automate screening, monitoring and grading of disease in medical images. Pretraining with contrastive learning enables models to extract robust and generalisable features from natural image datasets, facilitating label-efficient downstream image analysis. However, the direct application of conventional contrastive methods to medical datasets introduces two domain-specific issues. Firstly, several image transformations which have been shown to be crucial for effective contrastive learning do not translate from the natural image to the medical image domain. Secondly, the assumption made by conventional methods, that any two images are dissimilar, is systematically misleading in medical datasets depicting the same anatomy and disease. This is exacerbated in longitudinal image datasets that repeatedly image the same patient cohort to monitor their disease progression over time. In this paper we tackle these issues by extending conventional contrastive frameworks with a novel metadata-enhanced strategy. Our approach employs widely available patient metadata to approximate the true set of inter-image contrastive relationships. To this end we employ records for patient identity, eye position (i.e. left or right) and time series information. In experiments using two large longitudinal datasets containing 170,427 retinal optical coherence tomography (OCT) images of 7912 patients with age-related macular degeneration (AMD), we evaluate the utility of using metadata to incorporate the temporal dynamics of disease progression into pretraining. Our metadata-enhanced approach outperforms both standard contrastive methods and a retinal image foundation model in five out of six image-level downstream tasks related to AMD. We find benefits in both a low-data and high-data regime across tasks ranging from AMD stage and type classification to prediction of visual acuity. Due to its modularity, our method can be quickly and cost-effectively tested to establish the potential benefits of including available metadata in contrastive pretraining., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Deep learning algorithms have allowed the automation of segmentation for many biomarkers in retinal OCTs, enabling comprehensive clinical research and precise patient monitoring. These segmentation algorithms predominantly rely on supervised training and specialised segmentation networks, such as U-Nets. However, they require segmentation annotations, which are challenging to collect and require specialized expertise. In this paper, we explore leveraging 3D self-supervised learning based on image restoration techniques, that allow to pretrain 3D networks with the aim of improving segmentation performance. We test two methods, based on image restoration and denoising. After pretraining on a large 3D OCT dataset, we evaluate our weights by fine-tuning them on two challenging fluid segmentation datasets utilising different amount of training data. The chosen methods are easy to set up while providing large improvements for fluid segmentation, enabling the reduction of the amount of required annotation or an increase in the performance. Overall, the best results were obtained for denoising-based SSL methods, with higher results on both fluid segmentation datasets as well as faster pretraining durations., Competing Interests: Ursula Schmidt-Erfurth: Genentech (F), Kodiak (F), Novartis (F), Apellis (F,C), RetinSight (F,P). Hrvoje Bogunović: Heidelberg Engineering (F), Apellis (F)., (© 2024 Optica Publishing Group.)

Optical coherence tomography angiography (OCTA) provides detailed information on retinal blood flow and perfusion. Abnormal retinal perfusion indicates possible ocular or systemic disease. We propose a deep learning-based anomaly detection model to identify such anomalies in OCTA. It utilizes two deep learning approaches. First, a representation learning with a Vector-Quantized Variational Auto-Encoder (VQ-VAE) followed by Auto-Regressive (AR) modeling. Second, it exploits epistemic uncertainty estimates from Bayesian U-Net employed to segment the vasculature on OCTA en face images. Evaluation on two large public datasets, DRAC and OCTA-500, demonstrates effective anomaly detection (an AUROC of 0.92 for the DRAC and an AUROC of 0.75 for the OCTA-500) and localization (a mean Dice score of 0.61 for the DRAC) on this challenging task. To our knowledge, this is the first work that addresses anomaly detection in OCTA.

Purpose: We introduce a deep learning-based biomarker proposal system for the purpose of accelerating biomarker discovery in age-related macular degeneration (AMD)., Design: Retrospective analysis of a large data set of retinal OCT images., Participants: A total of 3456 adults aged between 51 and 102 years whose OCT images were collected under the PINNACLE project., Methods: Our system proposes candidates for novel AMD imaging biomarkers in OCT. It works by first training a neural network using self-supervised contrastive learning to discover, without any clinical annotations, features relating to both known and unknown AMD biomarkers present in 46 496 retinal OCT images. To interpret the learned biomarkers, we partition the images into 30 subsets, termed clusters, that contain similar features. We conduct 2 parallel 1.5-hour semistructured interviews with 2 independent teams of retinal specialists to assign descriptions in clinical language to each cluster. Descriptions of clusters achieving consensus can potentially inform new biomarker candidates., Main Outcome Measures: We checked if each cluster showed clear features comprehensible to retinal specialists, if they related to AMD, and how many described established biomarkers used in grading systems as opposed to recently proposed or potentially new biomarkers. We also compared their prognostic value for late-stage wet and dry AMD against an established clinical grading system and a demographic baseline model., Results: Overall, both teams independently identified clearly distinct characteristics in 27 of 30 clusters, of which 23 were related to AMD. Seven were recognized as known biomarkers used in established grading systems, and 16 depicted biomarker combinations or subtypes that are either not yet used in grading systems, were only recently proposed, or were unknown. Clusters separated incomplete from complete retinal atrophy, intraretinal from subretinal fluid, and thick from thin choroids, and, in simulation, outperformed clinically used grading systems in prognostic value., Conclusions: Using self-supervised deep learning, we were able to automatically propose AMD biomarkers going beyond the set used in clinically established grading systems. Without any clinical annotations, contrastive learning discovered subtle differences between fine-grained biomarkers. Ultimately, we envision that equipping clinicians with discovery-oriented deep learning tools can accelerate the discovery of novel prognostic biomarkers., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2024 by the American Academy of Ophthalmology.)

Automated lesion detection in retinal optical coherence tomography (OCT) scans has shown promise for several clinical applications, including diagnosis, monitoring and guidance of treatment decisions. However, segmentation models still struggle to achieve the desired results for some complex lesions or datasets that commonly occur in real-world, e.g. due to variability of lesion phenotypes, image quality or disease appearance. While several techniques have been proposed to improve them, one line of research that has not yet been investigated is the incorporation of additional semantic context through the application of anomaly detection models. In this study we experimentally show that incorporating weak anomaly labels to standard segmentation models consistently improves lesion segmentation results. This can be done relatively easy by detecting anomalies with a separate model and then adding these output masks as an extra class for training the segmentation model. This provides additional semantic context without requiring extra manual labels. We empirically validated this strategy using two in-house and two publicly available retinal OCT datasets for multiple lesion targets, demonstrating the potential of this generic anomaly guided segmentation approach to be used as an extra tool for improving lesion detection models., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hrvoje Bogunovic reports financial support was provided by FWF Austrian Science Fund (grant number FG 9-N). Hrvoje Bogunovic reports a relationship with Heidelberg Engineering Inc that includes: funding grants. Ursula Schmidt-Erfurth reports a relationship with Genentech, Novartis, Roche, Heidelberg Engineering, Kodiak, RetInSight that includes: consulting or advisory. Hrvoje Bogunovic is editorial board member of the Medical Image Analysis journal., (Copyright © 2024. Published by Elsevier B.V.)

Pathologic myopia (PM) is a common blinding retinal degeneration suffered by highly myopic population. Early screening of this condition can reduce the damage caused by the associated fundus lesions and therefore prevent vision loss. Automated diagnostic tools based on artificial intelligence methods can benefit this process by aiding clinicians to identify disease signs or to screen mass populations using color fundus photographs as inputs. This paper provides insights about PALM, our open fundus imaging dataset for pathological myopia recognition and anatomical structure annotation. Our databases comprises 1200 images with associated labels for the pathologic myopia category and manual annotations of the optic disc, the position of the fovea and delineations of lesions such as patchy retinal atrophy (including peripapillary atrophy) and retinal detachment. In addition, this paper elaborates on other details such as the labeling process used to construct the database, the quality and characteristics of the samples and provides other relevant usage notes., (© 2024. The Author(s).)

Glaucoma is a chronic neuro-degenerative condition that is one of the world's leading causes of irreversible but preventable blindness. The blindness is generally caused by the lack of timely detection and treatment. Early screening is thus essential for early treatment to preserve vision and maintain life quality. Colour fundus photography and Optical Coherence Tomography (OCT) are the two most cost-effective tools for glaucoma screening. Both imaging modalities have prominent biomarkers to indicate glaucoma suspects, such as the vertical cup-to-disc ratio (vCDR) on fundus images and retinal nerve fiber layer (RNFL) thickness on OCT volume. In clinical practice, it is often recommended to take both of the screenings for a more accurate and reliable diagnosis. However, although numerous algorithms are proposed based on fundus images or OCT volumes for the automated glaucoma detection, there are few methods that leverage both of the modalities to achieve the target. To fulfil the research gap, we set up the Glaucoma grAding from Multi-Modality imAges (GAMMA) Challenge to encourage the development of fundus & OCT-based glaucoma grading. The primary task of the challenge is to grade glaucoma from both the 2D fundus images and 3D OCT scanning volumes. As part of GAMMA, we have publicly released a glaucoma annotated dataset with both 2D fundus colour photography and 3D OCT volumes, which is the first multi-modality dataset for machine learning based glaucoma grading. In addition, an evaluation framework is also established to evaluate the performance of the submitted methods. During the challenge, 1272 results were submitted, and finally, ten best performing teams were selected for the final stage. We analyse their results and summarize their methods in the paper. Since all the teams submitted their source code in the challenge, we conducted a detailed ablation study to verify the effectiveness of the particular modules proposed. Finally, we identify the proposed techniques and strategies that could be of practical value for the clinical diagnosis of glaucoma. As the first in-depth study of fundus & OCT multi-modality glaucoma grading, we believe the GAMMA Challenge will serve as an essential guideline and benchmark for future research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Real-world retinal optical coherence tomography (OCT) scans are available in abundance in primary and secondary eye care centres. They contain a wealth of information to be analyzed in retrospective studies. The associated electronic health records alone are often not enough to generate a high-quality dataset for clinical, statistical, and machine learning analysis. We have developed a deep learning-based age-related macular degeneration (AMD) stage classifier, to efficiently identify the first onset of early/intermediate (iAMD), atrophic (GA), and neovascular (nAMD) stage of AMD in retrospective data. We trained a two-stage convolutional neural network to classify macula-centered 3D volumes from Topcon OCT images into 4 classes: Normal, iAMD, GA and nAMD. In the first stage, a 2D ResNet50 is trained to identify the disease categories on the individual OCT B-scans while in the second stage, four smaller models (ResNets) use the concatenated B-scan-wise output from the first stage to classify the entire OCT volume. Classification uncertainty estimates are generated with Monte-Carlo dropout at inference time. The model was trained on a real-world OCT dataset, 3765 scans of 1849 eyes, and extensively evaluated, where it reached an average ROC-AUC of 0.94 in a real-world test set., (© 2023. The Author(s).)

Deep neural networks have been increasingly proposed for automated screening and diagnosis of retinal diseases from optical coherence tomography (OCT), but often provide high-confidence predictions on out-of-distribution (OOD) cases, compromising their clinical usage. With this in mind, we performed an in-depth comparative analysis of the state-of-the-art uncertainty estimation methods for OOD detection in retinal OCT imaging. The analysis was performed within the use-case of automated screening and staging of age-related macular degeneration (AMD), one of the leading causes of blindness worldwide, where we achieved a macro-average area under the curve (AUC) of 0.981 for AMD classification. We focus on a few-shot Outlier Exposure (OE) method and the detection of near-OOD cases that share pathomorphological characteristics with the inlier AMD classes. Scoring the OOD case based on the Cosine distance in the feature space from the penultimate network layer proved to be a robust approach for OOD detection, especially in combination with the OE. Using Cosine distance and only 8 outliers exposed per class, we were able to improve the near-OOD detection performance of the OE with Reject Bucket method by [Formula: see text] 10% compared to without OE, reaching an AUC of 0.937. The Cosine distance served as a robust metric for OOD detection of both known and unknown classes and should thus be considered as an alternative to the reject bucket class probability in OE approaches, especially in the few-shot scenario. The inclusion of these methodologies did not come at the expense of classification performance, and can substantially improve the reliability and trustworthiness of the resulting deep learning-based diagnostic systems in the context of retinal OCT., (© 2023. Springer Nature Limited.)

Optical coherence tomography (OCT) is the most widely used imaging modality in ophthalmology. There are multiple variations of OCT imaging capable of producing complementary information. Thus, registering these complementary volumes is desirable in order to combine their information. In this work, we propose a novel automated pipeline to register OCT images produced by different devices. This pipeline is based on two steps: a multi-modal 2D en-face registration based on deep learning, and a Z-axis (axial axis) registration based on the retinal layer segmentation. We evaluate our method using data from a Heidelberg Spectralis and an experimental PS-OCT device. The empirical results demonstrated high-quality registrations, with mean errors of approximately 46 µm for the 2D registration and 9.59 µm for the Z-axis registration. These registrations may help in multiple clinical applications such as the validation of layer segmentations among others., Competing Interests: U. Schmidt-Erfurth: Genentech (F), Kodiak (F), Novartis (F), Apellis (F,C), RetinSight (F,P). H. Bogunović: Heidelberg Engineering (F), Apellis (F). The other authors declare no conflict of interest., (Published by Optica Publishing Group under the terms of the Creative Commons Attribution 4.0 License. Further distribution of this work must maintain attribution to the author(s) and the published article’s title, journal citation, and DOI.)

Using conventional optical coherence tomography (OCT), it is difficult to image Henle fibers (HF) due to their low backscattering potential. However, fibrous structures exhibit form birefringence, which can be exploited to visualize the presence of HF by polarization-sensitive (PS) OCT. We found a slight asymmetry in the retardation pattern of HF in the fovea region that can be associated with the asymmetric decrease of cone density with eccentricity from the fovea. We introduce a new measure based on a PS-OCT assessment of optic axis orientation to estimate the presence of HF at various eccentricities from the fovea in a large cohort of 150 healthy subjects. By comparing a healthy age-matched sub-group (N = 87) to a cohort of 64 early-stage glaucoma patients, we found no significant difference in HF extension but a slightly decreased retardation at about 2° to 7.5° eccentricity from the fovea in the glaucoma patients. This potentially indicates that glaucoma affects this neuronal tissue at an early state., Competing Interests: The authors declare no conflicts of interest., (Published by Optica Publishing Group under the terms of the Creative Commons Attribution 4.0 License. Further distribution of this work must maintain attribution to the author(s) and the published article’s title, journal citation, and DOI.)

In patients with age-related macular degeneration (AMD), the risk of progression to late stages is highly heterogeneous, and the prognostic imaging biomarkers remain unclear. We propose a deep survival model to predict the progression towards the late atrophic stage of AMD. The model combines the advantages of survival modelling, accounting for time-to-event and censoring, and the advantages of deep learning, generating prediction from raw 3D OCT scans, without the need for extracting a predefined set of quantitative biomarkers. We demonstrate, in an extensive set of evaluations, based on two large longitudinal datasets with 231 eyes from 121 patients for internal evaluation, and 280 eyes from 140 patients for the external evaluation, that this model improves the risk estimation performance over standard deep learning classification models., Competing Interests: Gregor Reiter: RetInSight (F). Robyn H. Guymer: Bayer (C), Novartis (C), Roche Genentech (C), Apellis (C). Ursula Schmidt-Erfurth: Genentech (F), Kodiak (F), Novartis (F), Apellis (F,C), RetinSight (F,P). Hrvoje Bogunović: Heidelberg Engineering (F), Apellis (F)., (© 2023 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement.)

Aims: Age-related macular degeneration (AMD) is characterised by a progressive loss of central vision. Intermediate AMD is a risk factor for progression to advanced stages categorised as geographic atrophy (GA) and neovascular AMD. However, rates of progression to advanced stages vary between individuals. Recent advances in imaging and computing technologies have enabled deep phenotyping of intermediate AMD. The aim of this project is to utilise machine learning (ML) and advanced statistical modelling as an innovative approach to discover novel features and accurately quantify markers of pathological retinal ageing that can individualise progression to advanced AMD., Methods: The PINNACLE study consists of both retrospective and prospective parts. In the retrospective part, more than 400,000 optical coherent tomography (OCT) images collected from four University Teaching Hospitals and the UK Biobank Population Study are being pooled, centrally stored and pre-processed. With this large dataset featuring eyes with AMD at various stages and healthy controls, we aim to identify imaging biomarkers for disease progression for intermediate AMD via supervised and unsupervised ML. The prospective study part will firstly characterise the progression of intermediate AMD in patients followed between one and three years; secondly, it will validate the utility of biomarkers identified in the retrospective cohort as predictors of progression towards late AMD. Patients aged 55-90 years old with intermediate AMD in at least one eye will be recruited across multiple sites in UK, Austria and Switzerland for visual function tests, multimodal retinal imaging and genotyping. Imaging will be repeated every four months to identify early focal signs of deterioration on spectral-domain optical coherence tomography (OCT) by human graders. A focal event triggers more frequent follow-up with visual function and imaging tests. The primary outcome is the sensitivity and specificity of the OCT imaging biomarkers. Secondary outcomes include sensitivity and specificity of novel multimodal imaging characteristics at predicting disease progression, ROC curves, time from development of imaging change to development of these endpoints, structure-function correlations, structure-genotype correlation and predictive risk models., Conclusions: This is one of the first studies in intermediate AMD to combine both ML, retrospective and prospective AMD patient data with the goal of identifying biomarkers of progression and to report the natural history of progression of intermediate AMD with multimodal retinal imaging., (© 2022. The Author(s).)

Objectives: To assess the therapeutic response to brolucizumab and aflibercept by deep learning/OCT-based analysis of macular fluid volumes in neovascular age-related macular degeneration., Methods: In this post-hoc analysis of two phase III, randomised, multi-centre studies (HAWK/HARRIER), 1078 and 739 treatment-naive eyes receiving brolucizumab or aflibercept according to protocol-specified criteria in HAWK and HARRIER, respectively, were included. Macular fluid on 41,840 OCT scans was localised and quantified using a validated deep learning-based algorithm. Volumes of intraretinal fluid (IRF), subretinal fluid (SRF), pigment epithelial detachment (PED) for all central macular areas (1, 3 and 6 mm) in nanolitres (nL) and best corrected visual acuity (BCVA) change in ETDRS letters were associated using mixed models for repeated measures., Results: Baseline IRF volumes decreased by >92% following the first intravitreal injection and consistently remained low during follow-up. Baseline SRF volumes decreased by >74% following the first injection, while PED volume resolved by 68-79% of its baseline volume. Resolution of SRF and PED was dependent on the substance and regimen used. Larger residual post-loading IRF, SRF and PED volumes were all independently associated with progressive vision loss during maintenance, where the differences in mean BCVA change between high and low fluid volume subgroups for IRF, SRF and PED were 3.4 letters (p < 0.0001), 1.7 letters (p < 0.001) and 2.5 letters (p < 0.0001), respectively., Conclusions: Deep-learning methods allow an accurate assessment of substance and regimen efficacy. Irrespectively, all fluid compartments were found to be important markers of disease activity and were relevant for visual outcomes., (© 2022. The Author(s).)

Purpose: To study the individual course of retinal changes caused by healthy aging using deep learning., Design: Retrospective analysis of a large data set of retinal OCT images., Participants: A total of 85 709 adults between the age of 40 and 75 years of whom OCT images were acquired in the scope of the UK Biobank population study., Methods: We created a counterfactual generative adversarial network (GAN), a type of neural network that learns from cross-sectional, retrospective data. It then synthesizes high-resolution counterfactual OCT images and longitudinal time series. These counterfactuals allow visualization and analysis of hypothetical scenarios in which certain characteristics of the imaged subject, such as age or sex, are altered, whereas other attributes, crucially the subject's identity and image acquisition settings, remain fixed., Main Outcome Measures: Using our counterfactual GAN, we investigated subject-specific changes in the retinal layer structure as a function of age and sex. In particular, we measured changes in the retinal nerve fiber layer (RNFL), combined ganglion cell layer plus inner plexiform layer (GCIPL), inner nuclear layer to the inner boundary of the retinal pigment epithelium (INL-RPE), and retinal pigment epithelium (RPE)., Results: Our counterfactual GAN is able to smoothly visualize the individual course of retinal aging. Across all counterfactual images, the RNFL, GCIPL, INL-RPE, and RPE changed by -0.1 μm ± 0.1 μm, -0.5 μm ± 0.2 μm, -0.2 μm ± 0.1 μm, and 0.1 μm ± 0.1 μm, respectively, per decade of age. These results agree well with previous studies based on the same cohort from the UK Biobank population study. Beyond population-wide average measures, our counterfactual GAN allows us to explore whether the retinal layers of a given eye will increase in thickness, decrease in thickness, or stagnate as a subject ages., Conclusion: This study demonstrates how counterfactual GANs can aid research into retinal aging by generating high-resolution, high-fidelity OCT images, and longitudinal time series. Ultimately, we envision that they will enable clinical experts to derive and explore hypotheses for potential imaging biomarkers for healthy and pathologic aging that can be refined and tested in prospective clinical trials., Financial Disclosures: Proprietary or commercial disclosure may be found after the references., (© 2023 Published by Elsevier Inc. on behalf of American Academy of Ophthalmology.)

Purpose: To identify disease activity and effects of intravitreal pegcetacoplan treatment on the topographic progression of geographic atrophy (GA) secondary to age-related macular degeneration quantified in spectral-domain OCT (SD-OCT) by automated deep learning assessment., Design: Retrospective analysis of a phase II clinical trial study evaluating pegcetacoplan in GA patients (FILLY, NCT02503332)., Subjects: SD-OCT scans of 57 eyes with monthly treatment, 46 eyes with every-other-month (EOM) treatment, and 53 eyes with sham injection from baseline and 12-month follow-ups were included, in a total of 312 scans., Methods: Retinal pigment epithelium loss, photoreceptor (PR) integrity, and hyperreflective foci (HRF) were automatically segmented using validated deep learning algorithms. Local progression rate (LPR) was determined from a growth model measuring the local expansion of GA margins between baseline and 1 year. For each individual margin point, the eccentricity to the foveal center, the progression direction, mean PR thickness, and HRF concentration in the junctional zone were computed. Mean LPR in disease activity and treatment effect conditioned on these properties were estimated by spatial generalized additive mixed-effect models., Main Outcome Measures: LPR of GA, PR thickness, and HRF concentration in μm., Results: A total of 31,527 local GA margin locations were analyzed. LPR was higher for areas with low eccentricity to the fovea, thinner PR layer thickness, or higher HRF concentration in the GA junctional zone. When controlling for topographic and structural risk factors, we report on average a significantly lower LPR by -28.0% (95% confidence interval [CI], -42.8 to -9.4; P = 0.0051) and -23.9% (95% CI, -40.2 to -3.0; P = 0.027) for monthly and EOM-treated eyes, respectively, compared with sham., Conclusions: Assessing GA progression on a topographic level is essential to capture the pathognomonic heterogeneity in individual lesion growth and therapeutic response. Pegcetacoplan-treated eyes showed a significantly slower GA lesion progression rate compared with sham, and an even slower growth rate toward the fovea. This study may help to identify patient cohorts with faster progressing lesions, in which pegcetacoplan treatment would be particularly beneficial. Automated artificial intelligence-based tools will provide reliable guidance for the management of GA in clinical practice., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

We present measurements of depolarization introduced by the retinal pigment epithelium (RPE) over a 45° field of view using polarization sensitive optical coherence tomography. A detailed spatial distribution analysis of depolarization caused by the RPE is presented in a total of 153 subjects including both healthy and diseased eyes. Age and sex related differences in the depolarizing character of the RPE are investigated., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Motschi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: To investigate the therapeutic effect of intravitreal pegcetacoplan on the inhibition of photoreceptor (PR) loss and thinning in geographic atrophy (GA) on conventional spectral-domain OCT (SD-OCT) imaging by deep learning-based automated PR quantification., Design: Post hoc analysis of a prospective, multicenter, randomized, sham (SM)-controlled, masked phase II trial investigating the safety and efficacy of pegcetacoplan for the treatment of GA because of age-related macular degeneration., Participants: Study eyes of 246 patients, randomized 1:1:1 to monthly (AM), bimonthly (AEOM), and SM treatment., Methods: We performed fully automated, deep learning-based segmentation of retinal pigment epithelium (RPE) loss and PR thickness on SD-OCT volumes acquired at baseline and months 2, 6, and 12. The difference in the change of PR loss area was compared among the treatment arms. Change in PR thickness adjacent to the GA borders and the entire 20° scanning area was compared between treatment arms., Main Outcome Measures: Square-root transformed PR loss area in μm or mm, PR thickness in μm, and PR loss/RPE loss ratio., Results: A total of 31 556 B-scans of 644 SD-OCT volumes of 161 study eyes (AM 52, AEOM 54, SM 56) were evaluated from baseline to month 12. Comparison of the mean change in PR loss area revealed statistically significantly less growth in the AM group at months 2, 6, and 12 than in the SM group (-41 μm ± 219 vs. 77 μm ± 126; P = 0.0004; -5 μm ± 221 vs. 156 μm ± 139; P < 0.0001; 106 μm ± 400 vs. 283 μm ± 226; P = 0.0014). Photoreceptor thinning was significantly reduced under AM treatment compared with SM within the GA junctional zone, as well as throughout the 20° area. A trend toward greater inhibition of PR loss than RPE loss was observed under therapy., Conclusions: Distinct and reliable quantification of PR loss using deep learning-based algorithms offers an essential tool to evaluate therapeutic efficacy in slowing disease progression. Photoreceptor loss and thinning are reduced by intravitreal complement C3 inhibition. Automated quantification of PR loss/maintenance based on OCT images is an ideal approach to reliably monitor disease activity and therapeutic efficacy in GA management in clinical routine and regulatory trials., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To predict visual outcomes and treatment needs in a treat & extend (T&E) regimen in neovascular age-related macular degeneration (nAMD) using a machine learning model based on quantitative optical coherence tomography (OCT) imaging biomarkers., Materials and Methods: Study eyes of 270 treatment-naïve subjects, randomized to receiving ranibizumab therapy in the T&E arm of a randomized clinical trial were considered. OCT volume scans were processed at baseline and at the first follow-up visit 4 weeks later. Automated image segmentation was performed, where intraretinal (IRF), subretinal (SRF) fluid, pigment epithelial detachment (PED), hyperreflective foci, and the photoreceptor layer were delineated using a convolutional neural network (CNN). A set of respective quantitative imaging biomarkers were computed across an Early Treatment Diabetic Retinopathy Study (ETDRS) grid to describe the retinal pathomorphology spatially and its change after the first injection. Lastly, using the computed set of OCT features and available clinical and demographic information, predictive models of outcomes and retreatment intervals were built using machine learning and their performance evaluated with a 10-fold cross-validation., Results: Data of 228 evaluable patients were included, as some had missing scans or were lost to follow-up. Of those patients, 55% reached and maintained long (8, 10, 12 weeks) and another 45% stayed at short (4, 6 weeks) treatment intervals. This provides further evidence for a high disease activity in a major proportion of patients. The model predicted the extendable treatment interval group with an AUROC of 0.71, and the visual outcome with an AUROC of up to 0.87 when utilizing both, clinical and imaging features. The volume of SRF and the volume of IRF, remaining at the first follow-up visit, were found to be the most important predictive markers for treatment intervals and visual outcomes, respectively, supporting the important role of quantitative fluid parameters on OCT., Conclusion: The proposed Artificial intelligence (AI) methodology was able to predict visual outcomes and retreatment intervals of a T&E regimen from a single injection. The result of this study is an urgently needed step toward AI-supported management of patients with active and progressive nAMD., (Copyright © 2022 Bogunović, Mares, Reiter and Schmidt-Erfurth.)

Purpose: The currently used measures of retinal function are limited by being subjective, nonlocalized, or taxing for patients. To address these limitations, we sought to develop and evaluate a deep learning (DL) method to automatically predict the functional end point (retinal sensitivity) based on structural OCT images., Design: Retrospective, cross-sectional study., Subjects: In total, 714 volumes of 289 patients were used in this study., Methods: A DL algorithm was developed to automatically predict a comprehensive retinal sensitivity map from an OCT volume. Four hundred sixty-three spectral-domain OCT volumes from 174 patients and their corresponding microperimetry examinations (Nidek MP-1) were used for development and internal validation, with a total of 15 563 retinal sensitivity measurements. The patients presented with a healthy macula, early or intermediate age-related macular degeneration, choroidal neovascularization, or geographic atrophy. In addition, an external validation was performed using 251 volumes of 115 patients, comprising 3 different patient populations: those with diabetic macular edema, retinal vein occlusion, or epiretinal membrane., Main Outcome Measures: We evaluated the performance of the algorithm using the mean absolute error (MAE), limits of agreement (LoA), and correlation coefficients of point-wise sensitivity (PWS) and mean sensitivity (MS)., Results: The algorithm achieved an MAE of 2.34 dB and 1.30 dB, an LoA of 5.70 and 3.07, a Pearson correlation coefficient of 0.66 and 0.84, and a Spearman correlation coefficient of 0.68 and 0.83 for PWS and MS, respectively. In the external test set, the method achieved an MAE of 2.73 dB and 1.66 dB for PWS and MS, respectively., Conclusions: The proposed approach allows the prediction of retinal function at each measured location directly based on an OCT scan, demonstrating how structural imaging can serve as a surrogate of visual function. Prospectively, the approach may help to complement retinal function measures, explore the association between image-based information and retinal functionality, improve disease progression monitoring, and provide objective surrogate measures for future clinical trials., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the functional associations of intraretinal fluid (IRF) and subretinal fluid (SRF) volumes at baseline and after the loading dose as well as fluid change after the first injection with best-corrected visual acuity (BCVA) in patients with neovascular age-related macular degeneration (nAMD) who received an anti-VEGF treatment over 24 months., Design: Post hoc analysis of a phase III, randomized, multicenter trial in which ranibizumab was administered monthly or in a pro re nata regimen (HARBOR)., Participants: Study eyes of 1094 treatment-naïve patients with nAMD., Methods: IRF and SRF volumes were segmented automatically on monthly spectral domain OCT images. Fluid volumes and changes thereof were included as covariates into longitudinal mixed-effects models, which modeled BCVA trajectories., Main Outcome Measures: BCVA estimates corresponding to baseline, follow-up, and persistent IRF/SRF volumes after the loading dose; BCVA estimates of change in fluid volumes after the first injection; and marginal and conditional R 2 ., Results: Analysis of 22 494 volumetric scans revealed that foveal IRF consistently shows a negative correlation with BCVA at baseline and subsequent visits (-3.23 and -4.32 letters/100 nL, respectively). After the first injection, BCVA increased by +2.13 letters/100 nL decrease in foveal IRF. Persistent IRF was associated with lower baseline BCVA and less improvement. Foveal SRF correlated with better BCVA at baseline and subsequent visits (+6.52 and +1.42 letters/100 nL, respectively). After the first injection, SRF decrease was associated with significant vision gain (+5.88 letters/100 nL). Foveal fluid correlated more with BCVA than parafoveal IRF/SRF., Conclusions: Although IRF consistently correlates with decreased function and recovery throughout therapy, SRF is associated with a more pronounced functional improvement. Moreover, SRF resolution provides increased benefit. Fluid-function correlation represents an essential base for the development of personalized treatment regimens, optimizing functional outcomes, and reducing treatment burden., (Copyright © 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Retinal fluid as the major biomarker in exudative macular disease is accurately visualized by high-resolution three-dimensional optical coherence tomography (OCT), which is used world-wide as a diagnostic gold standard largely replacing clinical examination. Artificial intelligence (AI) with its capability to objectively identify, localize and quantify fluid introduces fully automated tools into OCT imaging for personalized disease management. Deep learning performance has already proven superior to human experts, including physicians and certified readers, in terms of accuracy and speed. Reproducible measurement of retinal fluid relies on precise AI-based segmentation methods that assign a label to each OCT voxel denoting its fluid type such as intraretinal fluid (IRF) and subretinal fluid (SRF) or pigment epithelial detachment (PED) and its location within the central 1-, 3- and 6-mm macular area. Such reliable analysis is most relevant to reflect differences in pathophysiological mechanisms and impacts on retinal function, and the dynamics of fluid resolution during therapy with different regimens and substances. Yet, an in-depth understanding of the mode of action of supervised and unsupervised learning, the functionality of a convolutional neural net (CNN) and various network architectures is needed. Greater insight regarding adequate methods for performance, validation assessment, and device- and scanning-pattern-dependent variations is necessary to empower ophthalmologists to become qualified AI users. Fluid/function correlation can lead to a better definition of valid fluid variables relevant for optimal outcomes on an individual and a population level. AI-based fluid analysis opens the way for precision medicine in real-world practice of the leading retinal diseases of modern times., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To investigate associations between residual subretinal fluid (rSRF) volumes, quantified using artificial intelligence and treatment outcomes in a subretinal fluid (SRF)-tolerant treat-and-extend (T&E) regimen in neovascular age-related macular degeneration., Methods: Patients enrolled in the prospective, multicenter FLUID study randomized in an SRF-tolerant T&E regimen were examined by spectral-domain optical coherence tomography and tested for best-corrected visual acuity (BCVA). Intraretinal fluid and SRF volumes were quantified using artificial intelligence tools. In total, 375 visits of 98 patients were divided into subgroups: extended intervals despite rSRF and extended intervals without fluid. Associations between BCVA change, SRF volume, subgroups, and treatment intervals were estimated using linear mixed models., Results: In extended intervals despite rSRF, increased SRF was associated with reduced BCVA at the next visit in the central 1 mm (-0.138 letters per nL; P = 0.014) and 6 mm (-0.024 letters per nL; P = 0.049). A negative association between increased interval and BCVA change was found for rSRF in 1 mm and 6 mm (-0.250 and -0.233 letter per week interval, respectively; both P < 0.001). Extended intervals despite rSRF had significantly higher SRF volumes in the central 6 mm at the following visit (P = 0.002)., Conclusion: Artificial intelligence-based analysis of extended visits despite rSRF demonstrated increasing SRF volumes associated with BCVA loss at the consecutive visit. This negative association contributes to the understanding of rSRF volumes on treatment outcomes in neovascular age-related macular degeneration.

Subretinal fibrosis is one of the most prevalent causes of blindness in the elderly population, but a true gold standard to objectively diagnose fibrosis is still lacking. Since fibrotic tissue is birefringent, it can be detected by polarization-sensitive optical coherence tomography (PS-OCT). We present a new algorithm to automatically detect, segment, and quantify fibrotic lesions within 3D data sets recorded by PS-OCT. The algorithm first compensates for the birefringence of anterior ocular tissues and then uses the uniformity of the birefringent optic axis as an indicator to identify fibrotic tissue, which is then segmented and quantified. The algorithm was applied to 3D volumes recorded in 57 eyes of 57 patients with neovascular age-related macular degeneration using a spectral domain PS-OCT system. The results of fibrosis detection were compared to the clinical diagnosis based on color fundus photography (CFP), and the precision of fibrotic area measurement was assessed by three repeated measurements in a sub-set of 15 eyes. The average standard deviation of the fibrotic area obtained in eyes with a lesion area > 0.7 mm 2 was 15%. Fibrosis detection by CFP and PS-OCT agreed in 48 cases, discrepancies were only observed in cases of lesion area < 0.7 mm 2 . These remaining discrepancies are discussed, and a new method to treat ambiguous cases is presented., Competing Interests: The authors declare no conflicts of interest., (Published by The Optical Society under the terms of the Creative Commons Attribution 4.0 License. Further distribution of this work must maintain attribution to the author(s) and the published article’s title, journal citation, and DOI.)

Age-related macular degeneration (AMD) is the predominant cause of vision loss in the elderly with a major impact on ageing societies and healthcare systems. A major challenge in AMD management is the difficulty to determine the disease stage, the highly variable progression speed and the risk of conversion to advanced AMD, where irreversible functional loss occurs. In this study we developed an optical coherence tomography (OCT) imaging based spatio-temporal reference frame to characterize the morphologic progression of intermediate age-related macular degeneration (AMD) and to identify distinctive patterns of conversion to the advanced stages macular neovascularization (MNV) and macular atrophy (MA). We included 10,040 OCT volumes of 518 eyes with intermediate AMD acquired according to a standardized protocol in monthly intervals over two years. Two independent masked retina specialists determined the time of conversion to MNV or MA. All scans were aligned to a common reference frame by intra-patient and inter-patient registration. Automated segmentations of retinal layers and the choroid were computed and en-face maps were transformed into the common reference frame. Population maps were constructed in the subgroups converting to MNV (n=135), MA (n=50) and in non-progressors (n=333). Topographically resolved maps of changes were computed and tested for statistical significant differences. The development over time was analysed by a joint model accounting for longitudinal and right-censoring aspect. Significantly enhanced thinning of the outer nuclear layer (ONL) and retinal pigment epithelium (RPE)-photoreceptorinner segment/outer segment (PR-IS/OS) layers within the central 3 mm and a faster thinning speed preceding conversion was documented for MA progressors. Converters to MNV presented an accelerated thinning of the choroid and appearance changes in the choroid prior to MNV onset. The large-scale automated image analysis allowed us to distinctly assess the progression of morphologic changes in intermediate AMD based on conventional OCT imaging. Distinct topographic and temporal patterns allow to prospectively determine eyes with risk of progression and thereby greatly improving early detection, prevention and development of novel therapeutic strategies.

Purpose: To compare the performance of automatically quantified OCT imaging biomarkers and conventional risk factors manually graded on color fundus photographs for predicting progression to late age-related macular degeneration (AMD)., Design: Longitudinal observational study., Participants: Two hundred eighty eyes from 140 participants with bilateral large drusen., Methods: All participants underwent OCT and color fundus photography (CFP) at baseline and were then reviewed at 6-month intervals to determine progression to late AMD. Color fundus photographs were graded manually and OCT scans underwent automated image analyses to quantify risk factors and imaging biomarkers, respectively, based on drusen and AMD pigmentary abnormalities. Four predictive models for progression to late AMD or atrophic AMD were only developed (each including age) based on: (1) CFP only (2 parameters); (2) OCT biomarkers, minimal (3 parameters); (3) OCT biomarkers, extended (7 parameters); and (4) CFP and OCT combined (8 parameters)., Main Outcome Measures: Predictive performance for progression to late AMD, examined based on the area under the receiver operating characteristic curve (AUC) for correctly predicting progression., Results: The AUC for predicting late AMD development was similar for the models based on CFP alone (model 1; 0.80), OCT alone (models 2 and 3; 0.82 for both), and when using both methods together (model 4; 0.85). In addition, these models also performed similarly for predicting the end point of atrophic AMD only (AUC, 0.83, 0.84, 0.85, and 0.88 for models 1, 2, 3, and 4, respectively)., Conclusions: OCT imaging biomarkers could provide an automatic method of risk stratification for progression to vision-threatening late AMD as well as manual grading of CFP., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Angle closure glaucoma (ACG) is a more aggressive disease than open-angle glaucoma, where the abnormal anatomical structures of the anterior chamber angle (ACA) may cause an elevated intraocular pressure and gradually lead to glaucomatous optic neuropathy and eventually to visual impairment and blindness. Anterior Segment Optical Coherence Tomography (AS-OCT) imaging provides a fast and contactless way to discriminate angle closure from open angle. Although many medical image analysis algorithms have been developed for glaucoma diagnosis, only a few studies have focused on AS-OCT imaging. In particular, there is no public AS-OCT dataset available for evaluating the existing methods in a uniform way, which limits progress in the development of automated techniques for angle closure detection and assessment. To address this, we organized the Angle closure Glaucoma Evaluation challenge (AGE), held in conjunction with MICCAI 2019. The AGE challenge consisted of two tasks: scleral spur localization and angle closure classification. For this challenge, we released a large dataset of 4800 annotated AS-OCT images from 199 patients, and also proposed an evaluation framework to benchmark and compare different models. During the AGE challenge, over 200 teams registered online, and more than 1100 results were submitted for online evaluation. Finally, eight teams participated in the onsite challenge. In this paper, we summarize these eight onsite challenge methods and analyze their corresponding results for the two tasks. We further discuss limitations and future directions. In the AGE challenge, the top-performing approach had an average Euclidean Distance of 10 pixels (10 µm) in scleral spur localization, while in the task of angle closure classification, all the algorithms achieved satisfactory performances, with two best obtaining an accuracy rate of 100%. These artificial intelligence techniques have the potential to promote new developments in AS-OCT image analysis and image-based angle closure glaucoma assessment in particular., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Anti-vascular endothelial growth factor (VEGF) treatment of neovascular age-related macular degeneration (AMD) is a highly effective advance in the retinal armentarium. OCT offering 3-dimensional imaging of the retina is widely used to guide treatment. Although poor outcomes reported from clinical practice are multifactorial, availability of reliable, reproducible, and quantitative evaluation tools to accurately measure the fluid response, that is, a "VEGF meter," may be a better means of monitoring and treating than the current purely qualitative evaluation used in clinical practice., Design: Post hoc analysis of a phase III, randomized, multicenter study., Participants: Study eyes of 1095 treatment-naive subjects receiving pro re nata (PRN) or monthly ranibizumab therapy according to protocol-specified criteria in the HARBOR study., Methods: A deep learning method for localization and quantification of fluid in all retinal compartments was applied for automated segmentation of fluid with every voxel classified by a convolutional neural network (CNN). Three-dimensional volumes (nanoliters) for intraretinal fluid (IRF), subretinal fluid (SRF), and pigment epithelial detachment (PED) were determined in 24 362 volume scans obtained from 1095 patients treated over 24 months in a phase III clinical trial with randomization to 2 drug dosages (0.5 mg and 2.0 mg ranibizumab) and 2 regimens (monthly and PRN). A multivariable mixed-effects regression model was used to test for differences in fluid between the arms and for fluid/function correlation., Main Outcome Measures: Fluid volume in nanoliters, structure-function as Pearson's correlation coefficient, and as a coefficient of determination (R 2 )., Results: Fluid volumes were quantified in all visits of all patients. Automated segmentation demonstrated characteristic response patterns for each fluid compartment individually: Intraretinal fluid showed the greatest and most rapid resolution, followed by SRF and PED the least. The loading dose treatment achieved resolution of all fluid types close to the lowest levels attainable. Dosage and regimen parameters correlated directly with resulting fluid volumes. Fluid/function correlation showed a volume-dependent negative impact of IRF on vision and weak positive prognostic effect of SRF., Conclusions: Automated quantification of the fluid response may improve therapeutic management of neovascular AMD, avoid discrepancies between clinicians/investigators, and establish structure/function correlations., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Artificial intelligence has recently made a disruptive impact in medical imaging by successfully automatizing expert-level diagnostic tasks. However, replicating human-made decisions may inherently be biased by the fallible and dogmatic nature of human experts, in addition to requiring prohibitive amounts of training data. In this paper, we introduce an unsupervised deep learning architecture particularly designed for OCT representations for unbiased, purely data-driven biomarker discovery. We developed artificial intelligence technology that provides biomarker candidates without any restricting input or domain knowledge beyond raw images. Analyzing 54,900 retinal optical coherence tomography (OCT) volume scans of 1094 patients with age-related macular degeneration, we generated a vocabulary of 20 local and global markers capturing characteristic retinal patterns. The resulting markers were validated by linking them with clinical outcomes (visual acuity, lesion activity and retinal morphology) using correlation and machine learning regression. The newly identified features correlated well with specific biomarkers traditionally used in clinical practice (r up to 0.73), and outperformed them in correlating with visual acuity ([Formula: see text] compared to [Formula: see text] for conventional markers), despite representing an enormous compression of OCT imaging data (67 million voxels to 20 features). In addition, our method also discovered hitherto unknown, clinically relevant biomarker candidates. The presented deep learning approach identified known as well as novel medical imaging biomarkers without any prior domain knowledge. Similar approaches may be worthwhile across other medical imaging fields.

Diabetic macular edema (DME) and retina vein occlusion (RVO) are macular diseases in which central photoreceptors are affected due to pathological accumulation of fluid. Optical coherence tomography allows to visually assess and evaluate photoreceptor integrity, whose alteration has been observed as an important biomarker of both diseases. However, the manual quantification of this layered structure is challenging, tedious and time-consuming. In this paper we introduce a deep learning approach for automatically segmenting and characterising photoreceptor alteration. The photoreceptor layer is segmented using an ensemble of four different convolutional neural networks. En-face representations of the layer thickness are produced to characterize the photoreceptors. The pixel-wise standard deviation of the score maps produced by the individual models is also taken to indicate areas of photoreceptor abnormality or ambiguous results. Experimental results showed that our ensemble is able to produce results in pair with a human expert, outperforming each of its constitutive models. No statistically significant differences were observed between mean thickness estimates obtained from automated and manually generated annotations. Therefore, our model is able to reliable quantify photoreceptors, which can be used to improve prognosis and managment of macular diseases.

Glaucoma is one of the leading causes of irreversible but preventable blindness in working age populations. Color fundus photography (CFP) is the most cost-effective imaging modality to screen for retinal disorders. However, its application to glaucoma has been limited to the computation of a few related biomarkers such as the vertical cup-to-disc ratio. Deep learning approaches, although widely applied for medical image analysis, have not been extensively used for glaucoma assessment due to the limited size of the available data sets. Furthermore, the lack of a standardize benchmark strategy makes difficult to compare existing methods in a uniform way. In order to overcome these issues we set up the Retinal Fundus Glaucoma Challenge, REFUGE (https://refuge.grand-challenge.org), held in conjunction with MICCAI 2018. The challenge consisted of two primary tasks, namely optic disc/cup segmentation and glaucoma classification. As part of REFUGE, we have publicly released a data set of 1200 fundus images with ground truth segmentations and clinical glaucoma labels, currently the largest existing one. We have also built an evaluation framework to ease and ensure fairness in the comparison of different models, encouraging the development of novel techniques in the field. 12 teams qualified and participated in the online challenge. This paper summarizes their methods and analyzes their corresponding results. In particular, we observed that two of the top-ranked teams outperformed two human experts in the glaucoma classification task. Furthermore, the segmentation results were in general consistent with the ground truth annotations, with complementary outcomes that can be further exploited by ensembling the results., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Diagnosis and treatment in ophthalmology depend on modern retinal imaging by optical coherence tomography (OCT). The recent staggering results of machine learning in medical imaging have inspired the development of automated segmentation methods to identify and quantify pathological features in OCT scans. These models need to be sensitive to image features defining patterns of interest, while remaining robust to differences in imaging protocols. A dominant factor for such image differences is the type of OCT acquisition device. In this paper, we analyze the ability of recently developed unsupervised unpaired image translations based on cycle consistency losses (cycleGANs) to deal with image variability across different OCT devices (Spectralis and Cirrus). This evaluation was performed on two clinically relevant segmentation tasks in retinal OCT imaging: fluid and photoreceptor layer segmentation. Additionally, a visual Turing test designed to assess the quality of the learned translation models was carried out by a group of 18 participants with different background expertise. Results show that the learned translation models improve the generalization ability of segmentation models to other OCT-vendors/domains not seen during training. Moreover, relationships between model hyper-parameters and the realism as well as the morphological consistency of the generated images could be identified., Competing Interests: DRB, PS, JIO and HB declare no conflicts of interest. SMW: Bayer (C,F), Novartis (C) and Genentech (F). BSG: Roche (C), Novartis (C,F), Kinarus (F) and IDx (F). US-E: Böhringer Ingelheim (C), Genentech (C), Novartis (C) and Roche (C)., (© 2019 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

Major advances in diagnostic technologies are offering unprecedented insight into the condition of the retina and beyond ocular disease. Digital images providing millions of morphological datasets can fast and non-invasively be analyzed in a comprehensive manner using artificial intelligence (AI). Methods based on machine learning (ML) and particularly deep learning (DL) are able to identify, localize and quantify pathological features in almost every macular and retinal disease. Convolutional neural networks thereby mimic the path of the human brain for object recognition through learning of pathological features from training sets, supervised ML, or even extrapolation from patterns recognized independently, unsupervised ML. The methods of AI-based retinal analyses are diverse and differ widely in their applicability, interpretability and reliability in different datasets and diseases. Fully automated AI-based systems have recently been approved for screening of diabetic retinopathy (DR). The overall potential of ML/DL includes screening, diagnostic grading as well as guidance of therapy with automated detection of disease activity, recurrences, quantification of therapeutic effects and identification of relevant targets for novel therapeutic approaches. Prediction and prognostic conclusions further expand the potential benefit of AI in retina which will enable personalized health care as well as large scale management and will empower the ophthalmologist to provide high quality diagnosis/therapy and successfully deal with the complexity of 21st century ophthalmology., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)