Age-related Macular Degeneration (AMD) is a prevalent eye condition affecting visual acuity. Anti-vascular endothelial growth factor (anti-VEGF) treatments have been effective in slowing the progression of neovascular AMD, with better outcomes achieved through timely diagnosis and consistent monitoring. Tracking the progression of neovascular activity in OCT scans of patients with exudative AMD allows for the development of more personalized and effective treatment plans. This was the focus of the Monitoring Age-related Macular Degeneration Progression in Optical Coherence Tomography (MARIO) challenge, in which we participated. In Task 1, which involved classifying the evolution between two pairs of 2D slices from consecutive OCT acquisitions, we employed a fusion CNN network with model ensembling to further enhance the model's performance. For Task 2, which focused on predicting progression over the next three months based on current exam data, we proposed the Patch Progression Masked Autoencoder that generates an OCT for the next exam and then classifies the evolution between the current OCT and the one generated using our solution from Task 1. The results we achieved allowed us to place in the Top 10 for both tasks. Some team members are part of the same organization as the challenge organizers; therefore, we are not eligible to compete for the prize.

Visual impairment represents a major global health challenge, with multimodal imaging providing complementary information that is essential for accurate ophthalmic diagnosis. This comprehensive survey systematically reviews the latest advances in multimodal deep learning methods in ophthalmology up to the year 2025. The review focuses on two main categories: task-specific multimodal approaches and large-scale multimodal foundation models. Task-specific approaches are designed for particular clinical applications such as lesion detection, disease diagnosis, and image synthesis. These methods utilize a variety of imaging modalities including color fundus photography, optical coherence tomography, and angiography. On the other hand, foundation models combine sophisticated vision-language architectures and large language models pretrained on diverse ophthalmic datasets. These models enable robust cross-modal understanding, automated clinical report generation, and decision support. The survey critically examines important datasets, evaluation metrics, and methodological innovations including self-supervised learning, attention-based fusion, and contrastive alignment. It also discusses ongoing challenges such as variability in data, limited annotations, lack of interpretability, and issues with generalizability across different patient populations. Finally, the survey outlines promising future directions that emphasize the use of ultra-widefield imaging and reinforcement learning-based reasoning frameworks to create intelligent, interpretable, and clinically applicable AI systems for ophthalmology.

Machine Learning (ML) is used to tackle various tasks, such as disease classification and prediction. The effectiveness of ML models relies heavily on having large amounts of complete data. However, healthcare data is often limited or incomplete, which can hinder model performance. Additionally, issues like the trustworthiness of solutions vary with the datasets used. The lack of transparency in some ML models further complicates their understanding and use. In healthcare, particularly in the case of Age-related Macular Degeneration (AMD), which affects millions of older adults, early diagnosis is crucial due to the absence of effective treatments for reversing progression. Diagnosing AMD involves assessing retinal images along with patients' symptom reports. There is a need for classification approaches that consider genetic, dietary, clinical, and demographic factors. Recently, we introduced the -Comprehensive Abstraction and Classification Tool for Uncovering Structures-(CACTUS), aimed at improving AMD stage classification. CACTUS offers explainability and flexibility, outperforming standard ML models. It enhances decision-making by identifying key factors and providing confidence in its results. The important features identified by CACTUS allow us to compare with existing medical knowledge. By eliminating less relevant or biased data, we created a clinical scenario for clinicians to offer feedback and address biases.

Self-supervised learning (SSL) has enabled Vision Transformers (ViTs) to learn robust representations from large-scale natural image datasets, enhancing their generalization across domains. In retinal imaging, foundation models pretrained on either natural or ophthalmic data have shown promise, but the benefits of in-domain pretraining remain uncertain. To investigate this, we benchmark six SSL-pretrained ViTs on seven digital fundus image (DFI) datasets totaling 70,000 expert-annotated images for the task of moderate-to-late age-related macular degeneration (AMD) identification. Our results show that iBOT pretrained on natural images achieves the highest out-of-distribution generalization, with AUROCs of 0.80-0.97, outperforming domain-specific models, which achieved AUROCs of 0.78-0.96 and a baseline ViT-L with no pretraining, which achieved AUROCs of 0.68-0.91. These findings highlight the value of foundation models in improving AMD identification and challenge the assumption that in-domain pretraining is necessary. Furthermore, we release BRAMD, an open-access dataset (n=587) of DFIs with AMD labels from Brazil.

In recent years, large language models (LLMs) have demonstrated remarkable potential across various medical applications. Building on this foundation, multimodal large language models (MLLMs) integrate LLMs with visual models to process diverse inputs, including clinical data and medical images. In ophthalmology, LLMs have been explored for analyzing optical coherence tomography (OCT) reports, assisting in disease classification, and even predicting treatment outcomes. However, existing MLLM benchmarks often fail to capture the complexities of real-world clinical practice, particularly in the analysis of OCT images. Many suffer from limitations such as small sample sizes, a lack of diverse OCT datasets, and insufficient expert validation. These shortcomings hinder the accurate assessment of MLLMs' ability to interpret OCT scans and their broader applicability in ophthalmology. Our dataset, curated through rigorous quality control and expert annotation, consists of 439 fundus images and 75 OCT images. Using a standardized API-based framework, we assessed seven mainstream MLLMs and observed significant variability in diagnostic accuracy across different diseases. While some models performed well in diagnosing conditions such as diabetic retinopathy and age-related macular degeneration, they struggled with others, including choroidal neovascularization and myopia, highlighting inconsistencies in performance and the need for further refinement. Our findings emphasize the importance of developing clinically relevant benchmarks to provide a more accurate assessment of MLLMs' capabilities. By refining these models and expanding their scope, we can enhance their potential to transform ophthalmic diagnosis and treatment.

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.

Inherited retinal diseases (IRDs) are a diverse group of genetic disorders that lead to progressive vision loss and are a major cause of blindness in working-age adults. The complexity and heterogeneity of IRDs pose significant challenges in diagnosis, prognosis, and management. Recent advancements in artificial intelligence (AI) offer promising solutions to these challenges. However, the rapid development of AI techniques and their varied applications have led to fragmented knowledge in this field. This review consolidates existing studies, identifies gaps, and provides an overview of AI's potential in diagnosing and managing IRDs. It aims to structure pathways for advancing clinical applications by exploring AI techniques like machine learning and deep learning, particularly in disease detection, progression prediction, and personalized treatment planning. Special focus is placed on the effectiveness of convolutional neural networks in these areas. Additionally, the integration of explainable AI is discussed, emphasizing its importance in clinical settings to improve transparency and trust in AI-based systems. The review addresses the need to bridge existing gaps in focused studies on AI's role in IRDs, offering a structured analysis of current AI techniques and outlining future research directions. It concludes with an overview of the challenges and opportunities in deploying AI for IRDs, highlighting the need for interdisciplinary collaboration and the continuous development of robust, interpretable AI models to advance clinical applications.

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.

Timely disease diagnosis is challenging due to increasing disease burdens and limited clinician availability. AI shows promise in diagnosis accuracy but faces real-world application issues due to insufficient validation in clinical workflows and diverse populations. This study addresses gaps in medical AI downstream accountability through a case study on age-related macular degeneration (AMD) diagnosis and severity classification. We designed and implemented an AI-assisted diagnostic workflow for AMD, comparing diagnostic performance with and without AI assistance among 24 clinicians from 12 institutions with real patient data sampled from the Age-Related Eye Disease Study (AREDS). Additionally, we demonstrated continual enhancement of an existing AI model by incorporating approximately 40,000 additional medical images (named AREDS2 dataset). The improved model was then systematically evaluated using both AREDS and AREDS2 test sets, as well as an external test set from Singapore. AI assistance markedly enhanced diagnostic accuracy and classification for 23 out of 24 clinicians, with the average F1-score increasing by 20% from 37.71 (Manual) to 45.52 (Manual + AI) (P-value < 0.0001), achieving an improvement of over 50% in some cases. In terms of efficiency, AI assistance reduced diagnostic times for 17 out of the 19 clinicians tracked, with time savings of up to 40%. Furthermore, a model equipped with continual learning showed robust performance across three independent datasets, recording a 29% increase in accuracy, and elevating the F1-score from 42 to 54 in the Singapore population.

Age-related macular degeneration (AMD) is a major cause of blindness in older adults, severely affecting vision and quality of life. Despite advances in understanding AMD, the molecular factors driving the severity of subretinal scarring (fibrosis) remain elusive, hampering the development of effective therapies. This study introduces a machine learning-based framework to predict key genes that are strongly correlated with lesion severity and to identify potential therapeutic targets to prevent subretinal fibrosis in AMD. Using an original RNA sequencing (RNA-seq) dataset from the diseased retinas of JR5558 mice, we developed a novel and specific feature engineering technique, including pathway-based dimensionality reduction and gene-based feature expansion, to enhance prediction accuracy. Two iterative experiments were conducted by leveraging Ridge and ElasticNet regression models to assess biological relevance and gene impact. The results highlight the biological significance of several key genes and demonstrate the framework's effectiveness in identifying novel therapeutic targets. The key findings provide valuable insights for advancing drug discovery efforts and improving treatment strategies for AMD, with the potential to enhance patient outcomes by targeting the underlying genetic mechanisms of subretinal lesion development.