Hrvoje Bogunović

Coen de Vente, Koenraad A. Vermeer, Nicolas Jaccard et al.

The early detection of glaucoma is essential in preventing visual impairment. Artificial intelligence (AI) can be used to analyze color fundus photographs (CFPs) in a cost-effective manner, making glaucoma screening more accessible. While AI models for glaucoma screening from CFPs have shown promising results in laboratory settings, their performance decreases significantly in real-world scenarios due to the presence of out-of-distribution and low-quality images. To address this issue, we propose the Artificial Intelligence for Robust Glaucoma Screening (AIROGS) challenge. This challenge includes a large dataset of around 113,000 images from about 60,000 patients and 500 different screening centers, and encourages the development of algorithms that are robust to ungradable and unexpected input data. We evaluated solutions from 14 teams in this paper, and found that the best teams performed similarly to a set of 20 expert ophthalmologists and optometrists. The highest-scoring team achieved an area under the receiver operating characteristic curve of 0.99 (95% CI: 0.98-0.99) for detecting ungradable images on-the-fly. Additionally, many of the algorithms showed robust performance when tested on three other publicly available datasets. These results demonstrate the feasibility of robust AI-enabled glaucoma screening.

Robbie Holland, Oliver Leingang, Hrvoje Bogunović et al.

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 OCT images of 7,912 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. 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.

Taha Emre, Marzieh Oghbaie, Arunava Chakravarty et al.

In the field of medical imaging, 3D deep learning models play a crucial role in building powerful predictive models of disease progression. However, the size of these models presents significant challenges, both in terms of computational resources and data requirements. Moreover, achieving high-quality pretraining of 3D models proves to be even more challenging. To address these issues, hybrid 2.5D approaches provide an effective solution for utilizing 3D volumetric data efficiently using 2D models. Combining 2D and 3D techniques offers a promising avenue for optimizing performance while minimizing memory requirements. In this paper, we explore 2.5D architectures based on a combination of convolutional neural networks (CNNs), long short-term memory (LSTM), and Transformers. In addition, leveraging the benefits of recent non-contrastive pretraining approaches in 2D, we enhanced the performance and data efficiency of 2.5D techniques even further. We demonstrate the effectiveness of architectures and associated pretraining on a task of predicting progression to wet age-related macular degeneration (AMD) within a six-month period on two large longitudinal OCT datasets.

Robbie Holland, Oliver Leingang, Christopher Holmes et al.

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Current grading systems based on imaging biomarkers only coarsely group disease stages into broad categories and are unable to predict future disease progression. It is widely believed that this is due to their focus on a single point in time, disregarding the dynamic nature of the disease. In this work, we present the first method to automatically discover biomarkers that capture temporal dynamics of disease progression. Our method represents patient time series as trajectories in a latent feature space built with contrastive learning. Then, individual trajectories are partitioned into atomic sub-sequences that encode transitions between disease states. These are clustered using a newly introduced distance metric. In quantitative experiments we found our method yields temporal biomarkers that are predictive of conversion to late AMD. Furthermore, these clusters were highly interpretable to ophthalmologists who confirmed that many of the clusters represent dynamics that have previously been linked to the progression of AMD, even though they are currently not included in any clinical grading system.

Arunava Chakravarty, Taha Emre, Oliver Leingang et al.

The lack of reliable biomarkers makes predicting the conversion from intermediate to neovascular age-related macular degeneration (iAMD, nAMD) a challenging task. We develop a Deep Learning (DL) model to predict the future risk of conversion of an eye from iAMD to nAMD from its current OCT scan. Although eye clinics generate vast amounts of longitudinal OCT scans to monitor AMD progression, only a small subset can be manually labeled for supervised DL. To address this issue, we propose Morph-SSL, a novel Self-supervised Learning (SSL) method for longitudinal data. It uses pairs of unlabelled OCT scans from different visits and involves morphing the scan from the previous visit to the next. The Decoder predicts the transformation for morphing and ensures a smooth feature manifold that can generate intermediate scans between visits through linear interpolation. Next, the Morph-SSL trained features are input to a Classifier which is trained in a supervised manner to model the cumulative probability distribution of the time to conversion with a sigmoidal function. Morph-SSL was trained on unlabelled scans of 399 eyes (3570 visits). The Classifier was evaluated with a five-fold cross-validation on 2418 scans from 343 eyes with clinical labels of the conversion date. The Morph-SSL features achieved an AUC of 0.766 in predicting the conversion to nAMD within the next 6 months, outperforming the same network when trained end-to-end from scratch or pre-trained with popular SSL methods. Automated prediction of the future risk of nAMD onset can enable timely treatment and individualized AMD management.

Dmitrii Lachinov, Arunava Chakravarty, Christoph Grechenig et al.

Robust forecasting of the future anatomical changes inflicted by an ongoing disease is an extremely challenging task that is out of grasp even for experienced healthcare professionals. Such a capability, however, is of great importance since it can improve patient management by providing information on the speed of disease progression already at the admission stage, or it can enrich the clinical trials with fast progressors and avoid the need for control arms by the means of digital twins. In this work, we develop a deep learning method that models the evolution of age-related disease by processing a single medical scan and providing a segmentation of the target anatomy at a requested future point in time. Our method represents a time-invariant physical process and solves a large-scale problem of modeling temporal pixel-level changes utilizing NeuralODEs. In addition, we demonstrate the approaches to incorporate the prior domain-specific constraints into our method and define temporal Dice loss for learning temporal objectives. To evaluate the applicability of our approach across different age-related diseases and imaging modalities, we developed and tested the proposed method on the datasets with 967 retinal OCT volumes of 100 patients with Geographic Atrophy, and 2823 brain MRI volumes of 633 patients with Alzheimer's Disease. For Geographic Atrophy, the proposed method outperformed the related baseline models in the atrophy growth prediction. For Alzheimer's Disease, the proposed method demonstrated remarkable performance in predicting the brain ventricle changes induced by the disease, achieving the state-of-the-art result on TADPOLE challenge.

Botond Fazekas, Dmitrii Lachinov, Guilherme Aresta et al.

Bruch's membrane (BM) segmentation on optical coherence tomography (OCT) is a pivotal step for the diagnosis and follow-up of age-related macular degeneration (AMD), one of the leading causes of blindness in the developed world. Automated BM segmentation methods exist, but they usually do not account for the anatomical coherence of the results, neither provide feedback on the confidence of the prediction. These factors limit the applicability of these systems in real-world scenarios. With this in mind, we propose an end-to-end deep learning method for automated BM segmentation in AMD patients. An Attention U-Net is trained to output a probability density function of the BM position, while taking into account the natural curvature of the surface. Besides the surface position, the method also estimates an A-scan wise uncertainty measure of the segmentation output. Subsequently, the A-scans with high uncertainty are interpolated using thin plate splines (TPS). We tested our method with ablation studies on an internal dataset with 138 patients covering all three AMD stages, and achieved a mean absolute localization error of 4.10 um. In addition, the proposed segmentation method was compared against the state-of-the-art methods and showed a superior performance on an external publicly available dataset from a different patient cohort and OCT device, demonstrating strong generalization ability.

Botond Fazekas, Guilherme Aresta, Dmitrii Lachinov et al.

Optical coherence tomography (OCT) is a non-invasive 3D modality widely used in ophthalmology for imaging the retina. Achieving automated, anatomically coherent retinal layer segmentation on OCT is important for the detection and monitoring of different retinal diseases, like Age-related Macular Disease (AMD) or Diabetic Retinopathy. However, the majority of state-of-the-art layer segmentation methods are based on purely supervised deep-learning, requiring a large amount of pixel-level annotated data that is expensive and hard to obtain. With this in mind, we introduce a semi-supervised paradigm into the retinal layer segmentation task that makes use of the information present in large-scale unlabeled datasets as well as anatomical priors. In particular, a novel fully differentiable approach is used for converting surface position regression into a pixel-wise structured segmentation, allowing to use both 1D surface and 2D layer representations in a coupled fashion to train the model. In particular, these 2D segmentations are used as anatomical factors that, together with learned style factors, compose disentangled representations used for reconstructing the input image. In parallel, we propose a set of anatomical priors to improve network training when a limited amount of labeled data is available. We demonstrate on the real-world dataset of scans with intermediate and wet-AMD that our method outperforms state-of-the-art when using our full training set, but more importantly largely exceeds state-of-the-art when it is trained with a fraction of the labeled data.

Robbie Holland, Thomas R. P. Taylor, Christopher Holmes et al.

Clinicians spend a significant amount of time reviewing medical images and transcribing their findings regarding patient diagnosis, referral and treatment in text form. Vision-language models (VLMs), which automatically interpret images and summarize their findings as text, have enormous potential to alleviate clinical workloads and increase patient access to high-quality medical care. While foundational models have stirred considerable interest in the medical community, it is unclear whether their general capabilities translate to real-world clinical utility. In this work, we demonstrate that OpenAI's ChatGPT-4o model, in addition to two foundation VLMs designed for medical use, markedly underperform compared to practicing ophthalmologists on specialist tasks crucial to the care of patients with age-related macular degeneration (AMD). To address this, we initially identified the essential capabilities required for image-based clinical decision-making, and then developed a curriculum to selectively train VLMs in these skills. The resulting model, RetinaVLM, can be instructed to write reports that significantly outperform those written by leading foundation medical VLMs and ChatGPT-4o in disease staging (F1 score of 0.63 vs. 0.33) and patient referral (0.67 vs. 0.50), and approaches the diagnostic performance of junior ophthalmologists (who achieve 0.77 and 0.78 on the respective tasks). Furthermore, in a single-blind reader study two senior ophthalmologists with up to 32 years of experience found RetinaVLM's reports were found to be substantially more accurate than those by ChatGPT-4o (64.3% vs. 14.3%). These results reinforce that our curriculum-based approach provides a blueprint towards specializing foundation medical VLMs for real-world clinical tasks.

Marzieh Oghbaie, Teresa Araujo, Taha Emre et al.

The automatic classification of 3D medical data is memory-intensive. Also, variations in the number of slices between samples is common. Naïve solutions such as subsampling can solve these problems, but at the cost of potentially eliminating relevant diagnosis information. Transformers have shown promising performance for sequential data analysis. However, their application for long sequences is data, computationally, and memory demanding. In this paper, we propose an end-to-end Transformer-based framework that allows to classify volumetric data of variable length in an efficient fashion. Particularly, by randomizing the input volume-wise resolution(#slices) during training, we enhance the capacity of the learnable positional embedding assigned to each volume slice. Consequently, the accumulated positional information in each positional embedding can be generalized to the neighbouring slices, even for high-resolution volumes at the test time. By doing so, the model will be more robust to variable volume length and amenable to different computational budgets. We evaluated the proposed approach in retinal OCT volume classification and achieved 21.96% average improvement in balanced accuracy on a 9-class diagnostic task, compared to state-of-the-art video transformers. Our findings show that varying the volume-wise resolution of the input during training results in more informative volume representation as compared to training with fixed number of slices per volume.

Arunava Chakravarty, Taha Emre, Dmitrii Lachinov et al.

Predicting future disease progression risk from medical images is challenging due to patient heterogeneity, and subtle or unknown imaging biomarkers. Moreover, deep learning (DL) methods for survival analysis are susceptible to image domain shifts across scanners. We tackle these issues in the task of predicting late dry Age-related Macular Degeneration (dAMD) onset from retinal OCT scans. We propose a novel DL method for survival prediction to jointly predict from the current scan a risk score, inversely related to time-to-conversion, and the probability of conversion within a time interval $t$. It uses a family of parallel hyperplanes generated by parameterizing the bias term as a function of $t$. In addition, we develop unsupervised losses based on intra-subject image pairs to ensure that risk scores increase over time and that future conversion predictions are consistent with AMD stage prediction using actual scans of future visits. Such losses enable data-efficient fine-tuning of the trained model on new unlabeled datasets acquired with a different scanner. Extensive evaluation on two large datasets acquired with different scanners resulted in a mean AUROCs of 0.82 for Dataset-1 and 0.83 for Dataset-2, across prediction intervals of 6,12 and 24 months.

Taha Emre, Arunava Chakravarty, Antoine Rivail et al.

Recent contrastive learning methods achieved state-of-the-art in low label regimes. However, the training requires large batch sizes and heavy augmentations to create multiple views of an image. With non-contrastive methods, the negatives are implicitly incorporated in the loss, allowing different images and modalities as pairs. Although the meta-information (i.e., age, sex) in medical imaging is abundant, the annotations are noisy and prone to class imbalance. In this work, we exploited already existing temporal information (different visits from a patient) in a longitudinal optical coherence tomography (OCT) dataset using temporally informed non-contrastive loss (TINC) without increasing complexity and need for negative pairs. Moreover, our novel pair-forming scheme can avoid heavy augmentations and implicitly incorporates the temporal information in the pairs. Finally, these representations learned from the pretraining are more successful in predicting disease progression where the temporal information is crucial for the downstream task. More specifically, our model outperforms existing models in predicting the risk of conversion within a time frame from intermediate age-related macular degeneration (AMD) to the late wet-AMD stage.

José Morano, Guilherme Aresta, Dmitrii Lachinov et al.

Deep learning has become a valuable tool for the automation of certain medical image segmentation tasks, significantly relieving the workload of medical specialists. Some of these tasks require segmentation to be performed on a subset of the input dimensions, the most common case being 3D-to-2D. However, the performance of existing methods is strongly conditioned by the amount of labeled data available, as there is currently no data efficient method, e.g. transfer learning, that has been validated on these tasks. In this work, we propose a novel convolutional neural network (CNN) and self-supervised learning (SSL) method for label-efficient 3D-to-2D segmentation. The CNN is composed of a 3D encoder and a 2D decoder connected by novel 3D-to-2D blocks. The SSL method consists of reconstructing image pairs of modalities with different dimensionality. The approach has been validated in two tasks with clinical relevance: the en-face segmentation of geographic atrophy and reticular pseudodrusen in optical coherence tomography. Results on different datasets demonstrate that the proposed CNN significantly improves the state of the art in scenarios with limited labeled data by up to 8% in Dice score. Moreover, the proposed SSL method allows further improvement of this performance by up to 23%, and we show that the SSL is beneficial regardless of the network architecture.

Botond Fazekas, José Morano, Dmitrii Lachinov et al.

The Segment Anything Model (SAM) has gained significant attention in the field of image segmentation due to its impressive capabilities and prompt-based interface. While SAM has already been extensively evaluated in various domains, its adaptation to retinal OCT scans remains unexplored. To bridge this research gap, we conduct a comprehensive evaluation of SAM and its adaptations on a large-scale public dataset of OCTs from RETOUCH challenge. Our evaluation covers diverse retinal diseases, fluid compartments, and device vendors, comparing SAM against state-of-the-art retinal fluid segmentation methods. Through our analysis, we showcase adapted SAM's efficacy as a powerful segmentation model in retinal OCT scans, although still lagging behind established methods in some circumstances. The findings highlight SAM's adaptability and robustness, showcasing its utility as a valuable tool in retinal OCT image analysis and paving the way for further advancements in this domain.

José Morano, Guilherme Aresta, Hrvoje Bogunović

The caliber and configuration of retinal blood vessels serve as important biomarkers for various diseases and medical conditions. A thorough analysis of the retinal vasculature requires the segmentation of the blood vessels and their classification into arteries and veins, typically performed on color fundus images obtained by retinography. However, manually performing these tasks is labor-intensive and prone to human error. While several automated methods have been proposed to address this task, the current state of art faces challenges due to manifest classification errors affecting the topological consistency of segmentation maps. In this work, we introduce RRWNet, a novel end-to-end deep learning framework that addresses this limitation. The framework consists of a fully convolutional neural network that recursively refines semantic segmentation maps, correcting manifest classification errors and thus improving topological consistency. In particular, RRWNet is composed of two specialized subnetworks: a Base subnetwork that generates base segmentation maps from the input images, and a Recursive Refinement subnetwork that iteratively and recursively improves these maps. Evaluation on three different public datasets demonstrates the state-of-the-art performance of the proposed method, yielding more topologically consistent segmentation maps with fewer manifest classification errors than existing approaches. In addition, the Recursive Refinement module within RRWNet proves effective in post-processing segmentation maps from other methods, further demonstrating its potential. The model code, weights, and predictions will be publicly available at https://github.com/j-morano/rrwnet.

José Morano, Botond Fazekas, Emese Sükei et al.

Artificial intelligence (AI) has become a fundamental tool for assisting clinicians in analyzing ophthalmic images, such as optical coherence tomography (OCT). However, developing AI models often requires extensive annotation, and existing models tend to underperform on independent, unseen data. Foundation models (FMs), large AI models trained on vast unlabeled datasets, have shown promise in overcoming these challenges. Nonetheless, available FMs for ophthalmology lack extensive validation, especially for segmentation tasks, and focus on a single imaging modality. In this context, we propose MIRAGE, a novel multimodal FM for the analysis of OCT and scanning laser ophthalmoscopy (SLO) images. Additionally, we propose a new evaluation benchmark with OCT/SLO classification and segmentation tasks. The comparison with general and specialized FMs and segmentation methods shows the superiority of MIRAGE in both types of tasks, highlighting its suitability as a basis for the development of robust AI systems for retinal OCT image analysis. Both MIRAGE and the evaluation benchmark are publicly available: https://github.com/j-morano/MIRAGE.

Ronald Fecso, José Morano, Ursula Schmidt-Erfurth et al.

The rise of imaging techniques such as optical coherence tomography (OCT) and advances in deep learning (DL) have enabled clinicians and researchers to streamline retinal disease staging. A popular DL approach is self-supervised learning (SSL), where models learn from vast amounts of unlabeled data, avoiding costly annotation. SSL has allowed the development of foundation models (FMs), large models that can be used for a variety of downstream tasks. However, existing FMs for OCT, trained solely on image data, lack a comprehensive and robust semantic understanding of images, as evidenced by their downstream performance (especially for complex tasks), and thus require supervised fine-tuning (which may be unfeasible) to better adapt to specific applications and populations. To address this, we propose RetFiner, an SSL vision-language refinement scheme that improves the representations of existing FMs and enables their efficient and direct adaptation to specific populations for improved downstream performance. Our method uses a diverse set of training objectives which take advantage of the rich supervisory signal found in textual data. We tested RetFiner on the retinal FMs RETFound, UrFound, and VisionFM, showing significant improvements in linear probing performance on seven highly diverse OCT classification tasks, with an average increase of 5.8, 3.9, and 2.1 percentage points over their baselines, respectively. Our code and model weights are publicly available at https://github.com/ronnief1/RetFiner.

Marzieh Oghbaie, Teresa Araújo, Hrvoje Bogunović

Background and Objective: Prototype-based methods improve interpretability by learning fine-grained part-prototypes; however, their visualization in the input pixel space is not always consistent with human-understandable biomarkers. In addition, well-known prototype-based approaches typically learn extremely granular prototypes that are less interpretable in medical imaging, where both the presence and extent of biomarkers and lesions are critical. Methods: To address these challenges, we propose PiPViT (Patch-based Visual Interpretable Prototypes), an inherently interpretable prototypical model for image recognition. Leveraging a vision transformer (ViT), PiPViT captures long-range dependencies among patches to learn robust, human-interpretable prototypes that approximate lesion extent only using image-level labels. Additionally, PiPViT benefits from contrastive learning and multi-resolution input processing, which enables effective localization of biomarkers across scales. Results: We evaluated PiPViT on retinal OCT image classification across four datasets, where it achieved competitive quantitative performance compared to state-of-the-art methods while delivering more meaningful explanations. Moreover, quantitative evaluation on a hold-out test set confirms that the learned prototypes are semantically and clinically relevant. We believe PiPViT can transparently explain its decisions and assist clinicians in understanding diagnostic outcomes. Github page: https://github.com/marziehoghbaie/PiPViT

Huihui Fang, Fei Li, Junde Wu et al.

With the rapid development of artificial intelligence (AI) in medical image processing, deep learning in color fundus photography (CFP) analysis is also evolving. Although there are some open-source, labeled datasets of CFPs in the ophthalmology community, large-scale datasets for screening only have labels of disease categories, and datasets with annotations of fundus structures are usually small in size. In addition, labeling standards are not uniform across datasets, and there is no clear information on the acquisition device. Here we release a multi-annotation, multi-quality, and multi-device color fundus image dataset for glaucoma analysis on an original challenge -- Retinal Fundus Glaucoma Challenge 2nd Edition (REFUGE2). The REFUGE2 dataset contains 2000 color fundus images with annotations of glaucoma classification, optic disc/cup segmentation, as well as fovea localization. Meanwhile, the REFUGE2 challenge sets three sub-tasks of automatic glaucoma diagnosis and fundus structure analysis and provides an online evaluation framework. Based on the characteristics of multi-device and multi-quality data, some methods with strong generalizations are provided in the challenge to make the predictions more robust. This shows that REFUGE2 brings attention to the characteristics of real-world multi-domain data, bridging the gap between scientific research and clinical application.

Robbie Holland, Rebecca Kaye, Ahmed M. Hagag et al.

Diseases are currently managed by grading systems, where patients are stratified by grading systems into stages that indicate patient risk and guide clinical management. However, these broad categories typically lack prognostic value, and proposals for new biomarkers are currently limited to anecdotal observations. In this work, we introduce a deep-learning-based biomarker proposal system for the purpose of accelerating biomarker discovery in age-related macular degeneration (AMD). 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 optical coherence tomography (OCT) images. To interpret the discovered biomarkers, we partition the images into 30 subsets, termed clusters, that contain similar features. We then conduct two parallel 1.5-hour semi-structured interviews with two independent teams of retinal specialists that describe each cluster in clinical language. Overall, both teams independently identified clearly distinct characteristics in 27 of 30 clusters, of which 23 were related to AMD. Seven were recognised as known biomarkers already 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. Overall, contrastive learning enabled the automatic proposal of AMD biomarkers that go beyond the set used by clinically established grading systems. Ultimately, we envision that equipping clinicians with discovery-oriented deep-learning tools can accelerate discovery of novel prognostic biomarkers.

José Morano, Guilherme Aresta, Christoph Grechenig et al.

The use of multimodal imaging has led to significant improvements in the diagnosis and treatment of many diseases. Similar to clinical practice, some works have demonstrated the benefits of multimodal fusion for automatic segmentation and classification using deep learning-based methods. However, current segmentation methods are limited to fusion of modalities with the same dimensionality (e.g., 3D+3D, 2D+2D), which is not always possible, and the fusion strategies implemented by classification methods are incompatible with localization tasks. In this work, we propose a novel deep learning-based framework for the fusion of multimodal data with heterogeneous dimensionality (e.g., 3D+2D) that is compatible with localization tasks. The proposed framework extracts the features of the different modalities and projects them into the common feature subspace. The projected features are then fused and further processed to obtain the final prediction. The framework was validated on the following tasks: segmentation of geographic atrophy (GA), a late-stage manifestation of age-related macular degeneration, and segmentation of retinal blood vessels (RBV) in multimodal retinal imaging. Our results show that the proposed method outperforms the state-of-the-art monomodal methods on GA and RBV segmentation by up to 3.10% and 4.64% Dice, respectively.

Taha Emre, Arunava Chakravarty, Antoine Rivail et al.

Self-supervised learning (SSL) has emerged as a powerful technique for improving the efficiency and effectiveness of deep learning models. Contrastive methods are a prominent family of SSL that extract similar representations of two augmented views of an image while pushing away others in the representation space as negatives. However, the state-of-the-art contrastive methods require large batch sizes and augmentations designed for natural images that are impractical for 3D medical images. To address these limitations, we propose a new longitudinal SSL method, 3DTINC, based on non-contrastive learning. It is designed to learn perturbation-invariant features for 3D optical coherence tomography (OCT) volumes, using augmentations specifically designed for OCT. We introduce a new non-contrastive similarity loss term that learns temporal information implicitly from intra-patient scans acquired at different times. Our experiments show that this temporal information is crucial for predicting progression of retinal diseases, such as age-related macular degeneration (AMD). After pretraining with 3DTINC, we evaluated the learned representations and the prognostic models on two large-scale longitudinal datasets of retinal OCTs where we predict the conversion to wet-AMD within a six months interval. Our results demonstrate that each component of our contributions is crucial for learning meaningful representations useful in predicting disease progression from longitudinal volumetric scans.

Chengzhi Shen, Martin J. Menten, Hrvoje Bogunović et al.

Analyzing temporal developments is crucial for the accurate prognosis of many medical conditions. Temporal changes that occur over short time scales are key to assessing the health of physiological functions, such as the cardiac cycle. Moreover, tracking longer term developments that occur over months or years in evolving processes, such as age-related macular degeneration (AMD), is essential for accurate prognosis. Despite the importance of both short and long term analysis to clinical decision making, they remain understudied in medical deep learning. State of the art methods for spatiotemporal representation learning, developed for short natural videos, prioritize the detection of temporal constants rather than temporal developments. Moreover, they do not account for varying time intervals between acquisitions, which are essential for contextualizing observed changes. To address these issues, we propose two approaches. First, we combine clip-level contrastive learning with a novel temporal embedding to adapt to irregular time series. Second, we propose masking and predicting latent frame representations of the temporal sequence. Our two approaches outperform all prior methods on temporally-dependent tasks including cardiac output estimation and three prognostic AMD tasks. Overall, this enables the automated analysis of temporal patterns which are typically overlooked in applications of deep learning to medicine.

Botond Fazekas, Thomas Pinetz, Guilherme Aresta et al.

Optical Coherence Tomography (OCT) is a vital imaging modality for diagnosing and monitoring retinal diseases. However, OCT images are inherently degraded by speckle noise, which obscures fine details and hinders accurate interpretation. While numerous denoising methods exist, many struggle to balance noise reduction with the preservation of crucial anatomical structures. This paper introduces GARD (Gamma-based Anatomical Restoration and Denoising), a novel deep learning approach for OCT image despeckling that leverages the strengths of diffusion probabilistic models. Unlike conventional diffusion models that assume Gaussian noise, GARD employs a Denoising Diffusion Gamma Model to more accurately reflect the statistical properties of speckle. Furthermore, we introduce a Noise-Reduced Fidelity Term that utilizes a pre-processed, less-noisy image to guide the denoising process. This crucial addition prevents the reintroduction of high-frequency noise. We accelerate the inference process by adapting the Denoising Diffusion Implicit Model framework to our Gamma-based model. Experiments on a dataset with paired noisy and less-noisy OCT B-scans demonstrate that GARD significantly outperforms traditional denoising methods and state-of-the-art deep learning models in terms of PSNR, SSIM, and MSE. Qualitative results confirm that GARD produces sharper edges and better preserves fine anatomical details.

Rachid Zeghlache, Ikram Brahim, Pierre-Henri Conze et al.

The MARIO challenge, held at MICCAI 2024, focused on advancing the automated detection and monitoring of age-related macular degeneration (AMD) through the analysis of optical coherence tomography (OCT) images. Designed to evaluate algorithmic performance in detecting neovascular activity changes within AMD, the challenge incorporated unique multi-modal datasets. The primary dataset, sourced from Brest, France, was used by participating teams to train and test their models. The final ranking was determined based on performance on this dataset. An auxiliary dataset from Algeria was used post-challenge to evaluate population and device shifts from submitted solutions. Two tasks were involved in the MARIO challenge. The first one was the classification of evolution between two consecutive 2D OCT B-scans. The second one was the prediction of future AMD evolution over three months for patients undergoing anti-vascular endothelial growth factor (VEGF) therapy. Thirty-five teams participated, with the top 12 finalists presenting their methods. This paper outlines the challenge's structure, tasks, data characteristics, and winning methodologies, setting a benchmark for AMD monitoring using OCT, infrared imaging, and clinical data (such as the number of visits, age, gender, etc.). The results of this challenge indicate that artificial intelligence (AI) performs as well as a physician in measuring AMD progression (Task 1) but is not yet able of predicting future evolution (Task 2).

Taha Emre, Teresa Araújo, Marzieh Oghbaie et al.

Neovascular age-related macular degeneration (nAMD) is a leading cause of vision loss among older adults, where disease activity detection and progression prediction are critical for nAMD management in terms of timely drug administration and improving patient outcomes. Recent advancements in deep learning offer a promising solution for predicting changes in AMD from optical coherence tomography (OCT) retinal volumes. In this work, we proposed deep learning models for the two tasks of the public MARIO Challenge at MICCAI 2024, designed to detect and forecast changes in nAMD severity with longitudinal retinal OCT. For the first task, we employ a Vision Transformer (ViT) based Siamese Network to detect changes in AMD severity by comparing scan embeddings of a patient from different time points. To train a model to forecast the change after 3 months, we exploit, for the first time, an Earth Mover (Wasserstein) Distance-based loss to harness the ordinal relation within the severity change classes. Both models ranked high on the preliminary leaderboard, demonstrating that their predictive capabilities could facilitate nAMD treatment management.

Taha Emre, Arunava Chakravarty, Dmitrii Lachinov et al.

Contrastive pretraining provides robust representations by ensuring their invariance to different image transformations while simultaneously preventing representational collapse. Equivariant contrastive learning, on the other hand, provides representations sensitive to specific image transformations while remaining invariant to others. By introducing equivariance to time-induced transformations, such as disease-related anatomical changes in longitudinal imaging, the model can effectively capture such changes in the representation space. In this work, we propose a Time-equivariant Contrastive Learning (TC) method. First, an encoder embeds two unlabeled scans from different time points of the same patient into the representation space. Next, a temporal equivariance module is trained to predict the representation of a later visit based on the representation from one of the previous visits and the corresponding time interval with a novel regularization loss term while preserving the invariance property to irrelevant image transformations. On a large longitudinal dataset, our model clearly outperforms existing equivariant contrastive methods in predicting progression from intermediate age-related macular degeneration (AMD) to advanced wet-AMD within a specified time-window.

Huihui Fang, Fei Li, Junde Wu et al.

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.

Teresa Araújo, Guilherme Aresta, Hrvoje Bogunovic

The development of automatic tools for early glaucoma diagnosis with color fundus photographs can significantly reduce the impact of this disease. However, current state-of-the-art solutions are not robust to real-world scenarios, providing over-confident predictions for out-of-distribution cases. With this in mind, we propose a model based on the Dirichlet distribution that allows to obtain class-wise probabilities together with an uncertainty estimation without exposure to out-of-distribution cases. We demonstrate our approach on the AIROGS challenge. At the start of the final test phase (8 Feb. 2022), our method had the highest average score among all submissions.

Huihui Fang, Fei Li, Huazhu Fu et al.

Age-related macular degeneration (AMD) is the leading cause of visual impairment among elderly in the world. Early detection of AMD is of great importance, as the vision loss caused by this disease is irreversible and permanent. Color fundus photography is the most cost-effective imaging modality to screen for retinal disorders. Cutting edge deep learning based algorithms have been recently developed for automatically detecting AMD from fundus images. However, there are still lack of a comprehensive annotated dataset and standard evaluation benchmarks. To deal with this issue, we set up the Automatic Detection challenge on Age-related Macular degeneration (ADAM), which was held as a satellite event of the ISBI 2020 conference. The ADAM challenge consisted of four tasks which cover the main aspects of detecting and characterizing AMD from fundus images, including detection of AMD, detection and segmentation of optic disc, localization of fovea, and detection and segmentation of lesions. As part of the challenge, we have released a comprehensive dataset of 1200 fundus images with AMD diagnostic labels, pixel-wise segmentation masks for both optic disc and AMD-related lesions (drusen, exudates, hemorrhages and scars, among others), as well as the coordinates corresponding to the location of the macular fovea. A uniform evaluation framework has been built to make a fair comparison of different models using this dataset. During the challenge, 610 results were submitted for online evaluation, with 11 teams finally participating in the onsite challenge. This paper introduces the challenge, the dataset and the evaluation methods, as well as summarizes the participating methods and analyzes their results for each task. In particular, we observed that the ensembling strategy and the incorporation of clinical domain knowledge were the key to improve the performance of the deep learning models.

Junde Wu, Huihui Fang, Fei Li et al.

Color fundus photography and Optical Coherence Tomography (OCT) are the two most cost-effective tools for glaucoma screening. Both two modalities of images have prominent biomarkers to indicate glaucoma suspected. Clinically, 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 in computer-aided diagnosis, there are still few methods leveraging both of the modalities for the glaucoma assessment. Inspired by the success of Retinal Fundus Glaucoma Challenge (REFUGE) we held previously, 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 color photography and 3D OCT volumes, which is the first multi-modality dataset for 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, top-10 teams were selected to the final stage. We analysis their results and summarize their methods in the paper. Since all these teams submitted their source code in the challenge, a detailed ablation study is also conducted to verify the effectiveness of the particular modules proposed. We find many of the proposed techniques are practical 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 be an essential starting point for future research.

Dmitrii Lachinov, Philipp Seeboeck, Julia Mai et al.

In medical imaging, there are clinically relevant segmentation tasks where the output mask is a projection to a subset of input image dimensions. In this work, we propose a novel convolutional neural network architecture that can effectively learn to produce a lower-dimensional segmentation mask than the input image. The network restores encoded representation only in a subset of input spatial dimensions and keeps the representation unchanged in the others. The newly proposed projective skip-connections allow linking the encoder and decoder in a UNet-like structure. We evaluated the proposed method on two clinically relevant tasks in retinal Optical Coherence Tomography (OCT): geographic atrophy and retinal blood vessel segmentation. The proposed method outperformed the current state-of-the-art approaches on all the OCT datasets used, consisting of 3D volumes and corresponding 2D en-face masks. The proposed architecture fills the methodological gap between image classification and ND image segmentation.

Huazhu Fu, Fei Li, Xu Sun et al.

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 (10um) 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%.

Rhona Asgari, Sebastian Waldstein, Ferdinand Schlanitz et al.

The presence of drusen is the main hallmark of early/intermediate age-related macular degeneration (AMD). Therefore, automated drusen segmentation is an important step in image-guided management of AMD. There are two common approaches to drusen segmentation. In the first, the drusen are segmented directly as a binary classification task. In the second approach, the surrounding retinal layers (outer boundary retinal pigment epithelium (OBRPE) and Bruch's membrane (BM)) are segmented and the remaining space between these two layers is extracted as drusen. In this work, we extend the standard U-Net architecture with spatial pyramid pooling components to introduce global feature context. We apply the model to the task of segmenting drusen together with BM and OBRPE. The proposed network was trained and evaluated on a longitudinal OCT dataset of 425 scans from 38 patients with early/intermediate AMD. This preliminary study showed that the proposed network consistently outperformed the standard U-net model.

Antoine Rivail, Ursula Schmidt-Erfurth, Wolf-Dieter Vogl et al.

Longitudinal imaging is capable of capturing the static ana\-to\-mi\-cal structures and the dynamic changes of the morphology resulting from aging or disease progression. Self-supervised learning allows to learn new representation from available large unlabelled data without any expert knowledge. We propose a deep learning self-supervised approach to model disease progression from longitudinal retinal optical coherence tomography (OCT). Our self-supervised model takes benefit from a generic time-related task, by learning to estimate the time interval between pairs of scans acquired from the same patient. This task is (i) easy to implement, (ii) allows to use irregularly sampled data, (iii) is tolerant to poor registration, and (iv) does not rely on additional annotations. This novel method learns a representation that focuses on progression specific information only, which can be transferred to other types of longitudinal problems. We transfer the learnt representation to a clinically highly relevant task of predicting the onset of an advanced stage of age-related macular degeneration within a given time interval based on a single OCT scan. The boost in prediction accuracy, in comparison to a network learned from scratch or transferred from traditional tasks, demonstrates that our pretrained self-supervised representation learns a clinically meaningful information.

José Ignacio Orlando, Huazhu Fu, João Barbossa Breda et al.

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 (\url{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.

Rhona Asgari, José Ignacio Orlando, Sebastian Waldstein et al.

Automated drusen segmentation in retinal optical coherence tomography (OCT) scans is relevant for understanding age-related macular degeneration (AMD) risk and progression. This task is usually performed by segmenting the top/bottom anatomical interfaces that define drusen, the outer boundary of the retinal pigment epithelium (OBRPE) and the Bruch's membrane (BM), respectively. In this paper we propose a novel multi-decoder architecture that tackles drusen segmentation as a multitask problem. Instead of training a multiclass model for OBRPE/BM segmentation, we use one decoder per target class and an extra one aiming for the area between the layers. We also introduce connections between each class-specific branch and the additional decoder to increase the regularization effect of this surrogate task. We validated our approach on private/public data sets with 166 early/intermediate AMD Spectralis, and 200 AMD and control Bioptigen OCT volumes, respectively. Our method consistently outperformed several baselines in both layer and drusen segmentation evaluations.

Philipp Seeböck, José Ignacio Orlando, Thomas Schlegl et al.

Diagnosis and treatment guidance are aided by detecting relevant biomarkers in medical images. Although supervised deep learning can perform accurate segmentation of pathological areas, it is limited by requiring a-priori definitions of these regions, large-scale annotations, and a representative patient cohort in the training set. In contrast, anomaly detection is not limited to specific definitions of pathologies and allows for training on healthy samples without annotation. Anomalous regions can then serve as candidates for biomarker discovery. Knowledge about normal anatomical structure brings implicit information for detecting anomalies. We propose to take advantage of this property using bayesian deep learning, based on the assumption that epistemic uncertainties will correlate with anatomical deviations from a normal training set. A Bayesian U-Net is trained on a well-defined healthy environment using weak labels of healthy anatomy produced by existing methods. At test time, we capture epistemic uncertainty estimates of our model using Monte Carlo dropout. A novel post-processing technique is then applied to exploit these estimates and transfer their layered appearance to smooth blob-shaped segmentations of the anomalies. We experimentally validated this approach in retinal optical coherence tomography (OCT) images, using weak labels of retinal layers. Our method achieved a Dice index of 0.789 in an independent anomaly test set of age-related macular degeneration (AMD) cases. The resulting segmentations allowed very high accuracy for separating healthy and diseased cases with late wet AMD, dry geographic atrophy (GA), diabetic macular edema (DME) and retinal vein occlusion (RVO). Finally, we qualitatively observed that our approach can also detect other deviations in normal scans such as cut edge artifacts.

Philipp Seeböck, David Romo-Bucheli, Sebastian Waldstein et al.

Optical coherence tomography (OCT) has become the most important imaging modality in ophthalmology. A substantial amount of research has recently been devoted to the development of machine learning (ML) models for the identification and quantification of pathological features in OCT images. Among the several sources of variability the ML models have to deal with, a major factor is the acquisition device, which can limit the ML model's generalizability. In this paper, we propose to reduce the image variability across different OCT devices (Spectralis and Cirrus) by using CycleGAN, an unsupervised unpaired image transformation algorithm. The usefulness of this approach is evaluated in the setting of retinal fluid segmentation, namely intraretinal cystoid fluid (IRC) and subretinal fluid (SRF). First, we train a segmentation model on images acquired with a source OCT device. Then we evaluate the model on (1) source, (2) target and (3) transformed versions of the target OCT images. The presented transformation strategy shows an F1 score of 0.4 (0.51) for IRC (SRF) segmentations. Compared with traditional transformation approaches, this means an F1 score gain of 0.2 (0.12).

Thomas Schlegl, Hrvoje Bogunovic, Sophie Klimscha et al.

The automatic detection of disease related entities in retinal imaging data is relevant for disease- and treatment monitoring. It enables the quantitative assessment of large amounts of data and the corresponding study of disease characteristics. The presence of hyperreflective foci (HRF) is related to disease progression in various retinal diseases. Manual identification of HRF in spectral-domain optical coherence tomography (SD-OCT) scans is error-prone and tedious. We present a fully automated machine learning approach for segmenting HRF in SD-OCT scans. Evaluation on annotated OCT images of the retina demonstrates that a residual U-Net allows to segment HRF with high accuracy. As our dataset comprised data from different retinal diseases including age-related macular degeneration, diabetic macular edema and retinal vein occlusion, the algorithm can safely be applied in all of them though different pathophysiological origins are known.