The advent of foundation models has heralded a new era in medical artificial intelligence (AI), enabling the extraction of generalizable representations from large-scale unlabeled datasets. However, current ophthalmic AI paradigms are predominantly constrained to single-modality inference, thereby creating a dissonance with clinical practice where diagnosis relies on the synthesis of complementary imaging modalities. Furthermore, the deployment of high-performance AI in resource-limited settings is frequently impeded by the unavailability of advanced three-dimensional imaging hardware. Here, we present the Ophthalmic multimodal Masked Autoencoder (OphMAE), a multi-imaging foundation model engineered to synergize the volumetric depth of 3D Optical Coherence Tomography (OCT) with the planar context of 2D en face OCT. By implementing a novel cross-modal fusion architecture and a unique adaptive inference mechanism, OphMAE was pre-trained on a massive dataset with of 183,875 paired OCT images derived from 32,765 patients. In a rigorous benchmark encompassing 17 diverse diagnostic tasks with 48,340 paired OCT images from 8,191 patients, the model demonstrated state-of-the-art performanc
Diabetic retinopathy (DR) is a leading cause of vision loss in working-age adults. While screening reduces the risk of blindness, traditional imaging is often costly and inaccessible. Artificial intelligence (AI) algorithms present a scalable diagnostic solution, but concerns regarding fairness and generalization persist. This work evaluates the fairness and performance of image-trained models in DR prediction, as well as the impact of disentanglement as a bias mitigation technique, using the diverse mBRSET fundus dataset. Three models, ConvNeXt V2, DINOv2, and Swin V2, were trained on macula images to predict DR and sensitive attributes (SAs) (e.g., age and gender/sex). Fairness was assessed between subgroups of SAs, and disentanglement was applied to reduce bias. All models achieved high DR prediction performance in diagnosing (up to 94% AUROC) and could reasonably predict age and gender/sex (91% and 77% AUROC, respectively). Fairness assessment suggests disparities, such as a 10% AUROC gap between age groups in DINOv2. Disentangling SAs from DR prediction had varying results, depending on the model selected. Disentanglement improved DINOv2 performance (2% AUROC gain), but led to
Current benchmarks evaluating large language models (LLMs) in ophthalmology are limited in scope and disproportionately prioritise accuracy. We introduce BELO (BEnchmarking LLMs for Ophthalmology), a standardized and comprehensive evaluation benchmark developed through multiple rounds of expert checking by 13 ophthalmologists. BELO assesses ophthalmology-related clinical accuracy and reasoning quality. Using keyword matching and a fine-tuned PubMedBERT model, we curated ophthalmology-specific multiple-choice-questions (MCQs) from diverse medical datasets (BCSC, MedMCQA, MedQA, BioASQ, and PubMedQA). The dataset underwent multiple rounds of expert checking. Duplicate and substandard questions were systematically removed. Ten ophthalmologists refined the explanations of each MCQ's correct answer. This was further adjudicated by three senior ophthalmologists. To illustrate BELO's utility, we evaluated six LLMs (OpenAI o1, o3-mini, GPT-4o, DeepSeek-R1, Llama-3-8B, and Gemini 1.5 Pro) using accuracy, macro-F1, and five text-generation metrics (ROUGE-L, BERTScore, BARTScore, METEOR, and AlignScore). In a further evaluation involving human experts, two ophthalmologists qualitatively revie
Current ophthalmology clinical workflows are plagued by over-referrals, long waits, and complex and heterogeneous medical records. Large language models (LLMs) present a promising solution to automate various procedures such as triaging, preliminary tests like visual acuity assessment, and report summaries. However, LLMs have demonstrated significantly varied performance across different languages in natural language question-answering tasks, potentially exacerbating healthcare disparities in Low and Middle-Income Countries (LMICs). This study introduces the first multilingual ophthalmological question-answering benchmark with manually curated questions parallel across languages, allowing for direct cross-lingual comparisons. Our evaluation of 6 popular LLMs across 7 different languages reveals substantial bias across different languages, highlighting risks for clinical deployment of LLMs in LMICs. Existing debiasing methods such as Translation Chain-of-Thought or Retrieval-augmented generation (RAG) by themselves fall short of closing this performance gap, often failing to improve performance across all languages and lacking specificity for the medical domain. To address this issu
Vision-language models hold considerable promise for ophthalmology, but their development depends on large-scale, high-quality image-text datasets that remain scarce. We present PubMed-Ophtha, a hierarchical dataset of 102,023 ophthalmological image-caption pairs extracted from 15,842 open-access articles in PubMed Central. Unlike existing datasets, figures are extracted directly from article PDFs at full resolution and decomposed into their constituent panels, panel identifiers, and individual images. Each image is annotated with its imaging modality -- color fundus photography, optical coherence tomography, retinal imaging, or other -- and a mark status indicating the presence of annotation marks such as arrows. Figure captions are split into panel-level subcaptions using a two-step LLM approach, achieving a mean average sentence BLEU score of 0.913 on human-annotated data. Panel and image detection models reach a mAP@0.50 of 0.909 and 0.892, respectively, and figure extraction achieves a median IoU of 0.997. To support reproducibility, we additionally release the human-annotated ground-truth data, all trained models, and the full dataset generation pipeline.
Training vision-language models (VLMs) for medical report generation is often hindered by the scarcity of high-quality annotated data. This work evaluates the use of a weighted loss function to improve data efficiency. Compared to standard cross-entropy loss, which treats all token prediction errors equally, the reweighted loss shifts the focus to semantically salient tokens with outsized clinical importance. In experiments on ophthalmological report generation, we show that this simple method improves efficiency across multiple data scales, achieving similar report quality with up to ten times less training data.
Subject of research: is the study of methods for analyzing perimetric images for the diagnosis and control of glaucoma diseases. Objects of research: is a dataset collected on the ophthalmological perimeter with the results of various patient pathologies, since the ophthalmological community is acutely aware of the issue of disease control and import substitution. [5]. Purpose of research: is to consider various machine learning methods that can classify glaucoma. This is possible thanks to the classifier built after labeling the dataset. It is able to determine from the image whether the visual fields depicted on it are the results of the impact of glaucoma on the eyes or other visual diseases. Earlier in the work [3], a dataset was described that was collected on the Tomey perimeter. The average age of the examined patients ranged from 30 to 85 years. Methods of research: machine learning methods for classifying image results (stochastic gradient descent, logistic regression, random forest, naive Bayes). Main results of research: the result of the study is computer modeling that can determine from the image whether the result is glaucoma or another disease (binary classification)
Large language models (LLMs) show potential for ophthalmic clinical reasoning, yet individual models risk introducing harm. We evaluated whether multi-agent LLM deliberative councils improve diagnostic performance and mitigate harm compared to individual LLMs. In a comparative cross-sectional study, we assessed 12 individual LLMs and three multi-agent councils on 100 ophthalmology clinical vignettes. Each council comprised four models assembled by type: proprietary flagship, proprietary fast, and open-source. Models independently answered a vignette, anonymously ranked one another's responses, and a designated chair synthesized all responses and peer reviews into a final answer. Councils consistently outperformed pooled individual models across all three tiers. Accuracy improved for proprietary flagship (95.0% vs 90.8%; risk difference [RD]: 4.25 [95% CI: 0.45, 8.05]), proprietary fast (96.0% vs 86.5%; RD: 9.50 [5.31, 13.59]), and open-source councils (91.0% vs 83.2%; RD: 7.75 [4.17, 11.33]). Harm rates declined for proprietary flagship (10.0% vs 22.5%; RD: -12.50 [-16.86, -8.14]), proprietary fast (16.0% vs 31.8%; RD: -15.75 [-21.49, -10.01]), and open-source councils (22.0% vs 38
Vision impairment affects millions globally, and early detection is critical to preventing irreversible vision loss. Ophthalmology workflows require clinicians to integrate medical images, structured clinical data, and free-text notes to determine disease severity and management, which is time-consuming and burdensome. Recent multimodal large language models (MLLMs) show promise, but existing general and medical MLLMs perform poorly in ophthalmology, and few ophthalmology-specific MLLMs are openly available. We present VOLMO (Versatile and Open Large Models for Ophthalmology), a model-agnostic, data-open framework for developing ophthalmology-specific MLLMs. VOLMO includes three stages: ophthalmology knowledge pretraining on 86,965 image-text pairs from 26,569 articles across 82 journals; domain task fine-tuning on 26,929 annotated instances spanning 12 eye conditions for disease screening and severity classification; and multi-step clinical reasoning on 913 patient case reports for assessment, planning, and follow-up care. Using this framework, we trained a compact 2B-parameter MLLM and compared it with strong baselines, including InternVL-2B, LLaVA-Med-7B, MedGemma-4B, MedGemma-2
The advancement of general medical Multimodal Large Language Models (MLLMs) has shown great potential for building conversational assistants to support clinical diagnosis. However, their adaptation to highly specialized domains such as ophthalmology remains underexplored, primarily due to the scarcity of large-scale, domain-specific instruction-tuning data. Existing ophthalmic datasets for conversational agents are often limited in scale and largely rely on images from established public benchmarks, limiting the scalability of ophthalmic MLLMs and their ability to capture real-world clinical complexity. To address this gap, we propose $\textbf{OphIn-Engine}$, an ophthalmology-specific instruction data curation pipeline that constructs high-quality instruction data from open-access ophthalmology web-scale videos. The pipeline integrates multimodal transcription for extracting image-transcript pairs, visual cue separation and scoring for identifying clinically relevant visual descriptions, and instruction synthesis with quality control for generating accurate and diverse clinical dialogues. Using this engine, we introduce $\textbf{OphIn-500K}$, a large-scale multimodal ophthalmology
Precision medicine in ophthalmology requires accurate longitudinal predictions, but the fragmented nature of multimodal clinical data remains a barrier to forecasting. We introduce OphthaDT, an LLM-based digital twin for ophthalmology that serializes longitudinal patient histories from 3,220 patients across four Phase III clinical trials into structured narratives to forecast best corrected visual acuity (BCVA). In benchmarks spanning up to 100 weeks, OphthaDT demonstrated the lowest prediction error in neovascular age-related macular degeneration (nAMD), achieving an average mean absolute error (MAE) reduction of 6.0% compared to all baselines. In diabetic macular edema (DME), OphthaDT demonstrated competitive performance against all baselines while outperforming Random Forest and XGBoost by an average MAE reduction of 2.6% and 6.9%, respectively. Results reveal that OphthaDT's predictive advantage scales with trajectory complexity: whereas linear models remain effective for the more stable treatment responses of DME, OphthaDT's capacity is better suited for capturing the high longitudinal variability of nAMD. Finally, OphthaDT handles irregular sampling without imputation, positi
Diabetic retinopathy (DR) is a leading cause of preventable blindness worldwide, demanding accurate automated diagnostic systems. While general-domain vision-language models like Contrastive Language-Image Pre-Training (CLIP) perform well on natural image tasks, they struggle in medical domain applications, particularly in cross-modal retrieval for ophthalmological images. We propose a novel knowledge-enhanced joint embedding framework that integrates retinal fundus images, clinical text, and structured patient data through a multimodal transformer architecture to address the critical gap in medical image-text alignment. Our approach employs separate encoders for each modality: a Vision Transformer (ViT-B/16) for retinal images, Bio-ClinicalBERT for clinical narratives, and a multilayer perceptron for structured demographic and clinical features. These modalities are fused through a joint transformer with modality-specific embeddings, trained using multiple objectives including contrastive losses between modality pairs, reconstruction losses for images and text, and classification losses for DR severity grading according to ICDR and SDRG schemes. Experimental results on the Brazili
This paper introduces an innovative software system for fundus image analysis that deliberately diverges from the conventional screening approach, opting not to predict specific diagnoses. Instead, our methodology mimics the diagnostic process by thoroughly analyzing both normal and pathological features of fundus structures, leaving the ultimate decision-making authority in the hands of healthcare professionals. Our initiative addresses the need for objective clinical analysis and seeks to automate and enhance the clinical workflow of fundus image examination. The system, from its overarching architecture to the modular analysis design powered by artificial intelligence (AI) models, aligns seamlessly with ophthalmological practices. Our unique approach utilizes a combination of state-of-the-art deep learning methods and traditional computer vision algorithms to provide a comprehensive and nuanced analysis of fundus structures. We present a distinctive methodology for designing medical applications, using our system as an illustrative example. Comprehensive verification and validation results demonstrate the efficacy of our approach in revolutionizing fundus image analysis, with po
Quantum technologies are rapidly advancing across multiple research domains, with a growing impact on biomedical imaging and sensing. We examine their emerging role in ophthalmology through four complementary directions: photon-limited retinal imaging, correlation based imaging, nanoscale optical probes, and quantum-limited visual perception. Advances in optical coherence tomography and single-photon detection enable imaging under strict photon budget constraints, reducing phototoxicity while preserving image quality. Correlation-based approaches, including ghost imaging, offer alternative strategies for image formation in low-light and scattering environments, although practical implementation remains limited by detection efficiency and acquisition time. In parallel, nanoscale optical platforms such as quantum dots provide tunable and photostable probes for enhanced contrast and targeted delivery, with ongoing challenges related to biocompatibility and clinical translation. Finally, experiments at the single-photon level and with structured light fields demonstrate how the visual system itself operates near physical detection limits and can be probed using controlled optical state
Question: What is the performance and reasoning ability of OpenAI o1 compared to other large language models in addressing ophthalmology-specific questions? Findings: This study evaluated OpenAI o1 and five LLMs using 6,990 ophthalmological questions from MedMCQA. O1 achieved the highest accuracy (0.88) and macro-F1 score but ranked third in reasoning capabilities based on text-generation metrics. Across subtopics, o1 ranked first in ``Lens'' and ``Glaucoma'' but second to GPT-4o in ``Corneal and External Diseases'', ``Vitreous and Retina'' and ``Oculoplastic and Orbital Diseases''. Subgroup analyses showed o1 performed better on queries with longer ground truth explanations. Meaning: O1's reasoning enhancements may not fully extend to ophthalmology, underscoring the need for domain-specific refinements to optimize performance in specialized fields like ophthalmology.
Retinal blood vessel segmentation can extract clinically relevant information from fundus images. As manual tracing is cumbersome, algorithms based on Convolution Neural Networks have been developed. Such studies have used small publicly available datasets for training and measuring performance, running the risk of overfitting. Here, we provide a rigorous benchmark for various architectural and training choices commonly used in the literature on the largest dataset published to date. We train and evaluate five published models on the publicly available FIVES fundus image dataset, which exceeds previous ones in size and quality and which contains also images from common ophthalmological conditions (diabetic retinopathy, age-related macular degeneration, glaucoma). We compare the performance of different model architectures across different loss functions, levels of image qualitiy and ophthalmological conditions and assess their ability to perform well in the face of disease-induced domain shifts. Given sufficient training data, basic architectures such as U-Net perform just as well as more advanced ones, and transfer across disease-induced domain shifts typically works well for most
Large language models (LLMs) such as GPT-5 integrate advanced reasoning capabilities that may improve performance on complex medical question-answering tasks. For this latest generation of reasoning models, the configurations that maximize both accuracy and cost-efficiency have yet to be established. We evaluated 12 configurations of OpenAI's GPT-5 series (three model tiers across four reasoning effort settings) alongside o1-high, o3-high, and GPT-4o, using 260 closed-access multiple-choice questions from the American Academy of Ophthalmology Basic Clinical Science Course (BCSC) dataset. The primary outcome was multiple-choice accuracy; secondary outcomes included head-to-head ranking via a Bradley-Terry model, rationale quality assessment using a reference-anchored, pairwise LLM-as-a-judge framework, and analysis of accuracy-cost trade-offs using token-based cost estimates. GPT-5-high achieved the highest accuracy (0.965; 95% CI, 0.942-0.985), outperforming all GPT-5-nano variants (P < .001), o1-high (P = .04), and GPT-4o (P < .001), but not o3-high (0.958; 95% CI, 0.931-0.981). GPT-5-high ranked first in both accuracy (1.66x stronger than o3-high) and rationale quality (1.1
Large language models (LLMs) have shown significant promise across various medical applications, with ophthalmology being a notable area of focus. Many ophthalmic tasks have shown substantial improvement through the integration of LLMs. However, before these models can be widely adopted in clinical practice, evaluating their capabilities and identifying their limitations is crucial. To address this research gap and support the real-world application of LLMs, we introduce the OphthBench, a specialized benchmark designed to assess LLM performance within the context of Chinese ophthalmic practices. This benchmark systematically divides a typical ophthalmic clinical workflow into five key scenarios: Education, Triage, Diagnosis, Treatment, and Prognosis. For each scenario, we developed multiple tasks featuring diverse question types, resulting in a comprehensive benchmark comprising 9 tasks and 591 questions. This comprehensive framework allows for a thorough assessment of LLMs' capabilities and provides insights into their practical application in Chinese ophthalmology. Using this benchmark, we conducted extensive experiments and analyzed the results from 39 popular LLMs. Our evaluati
Vision-threatening eye diseases pose a major global health burden, with timely diagnosis limited by workforce shortages and restricted access to specialized care. While multimodal large language models (MLLMs) show promise for medical image interpretation, advancing MLLMs for ophthalmology is hindered by the lack of comprehensive benchmark datasets suitable for evaluating generative models. We present a large-scale multimodal ophthalmology benchmark comprising 32,633 instances with multi-granular annotations across 12 common ophthalmic conditions and 5 imaging modalities. The dataset integrates imaging, anatomical structures, demographics, and free-text annotations, supporting anatomical structure recognition, disease screening, disease staging, and demographic prediction for bias evaluation. This work extends our preliminary LMOD benchmark with three major enhancements: (1) nearly 50% dataset expansion with substantial enlargement of color fundus photography; (2) broadened task coverage including binary disease diagnosis, multi-class diagnosis, severity classification with international grading standards, and demographic prediction; and (3) systematic evaluation of 24 state-of-the
Recent advancements in ophthalmology foundation models such as RetFound have demonstrated remarkable diagnostic capabilities but require massive datasets for effective pre-training, creating significant barriers for development and deployment. To address this critical challenge, we propose FundusGAN, a novel hierarchical feature-aware generative framework specifically designed for high-fidelity fundus image synthesis. Our approach leverages a Feature Pyramid Network within its encoder to comprehensively extract multi-scale information, capturing both large anatomical structures and subtle pathological features. The framework incorporates a modified StyleGAN-based generator with dilated convolutions and strategic upsampling adjustments to preserve critical retinal structures while enhancing pathological detail representation. Comprehensive evaluations on the DDR, DRIVE, and IDRiD datasets demonstrate that FundusGAN consistently outperforms state-of-the-art methods across multiple metrics (SSIM: 0.8863, FID: 54.2, KID: 0.0436 on DDR). Furthermore, disease classification experiments reveal that augmenting training data with FundusGAN-generated images significantly improves diagnostic