Yih Chung Tham

Ehsan Misaghi, Sean T Berkowitz, Bing Yu Chen et al.

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 38.5%; RD: -16.50 [-22.27, -10.73]). Coverage analysis revealed net positive gains for accuracy (ΔCoverage: 4.4-9.8 percentage points) and safety (ΔCoverage: 13.6-20.6), indicating councils recovered correct diagnoses and averted harm. Councils elevated correct diagnoses to higher rank positions; and produced more complete differentials and management plans (all P<.05). Harmful council responses showed reduced combined commission-and-omission errors and tended to be less severe. Structured deliberation via multi-agent LLM councils may enhance the reliability of LLM-assisted ophthalmic clinical reasoning.

Jianing Qiu, Jian Wu, Hao Wei et al.

We present VisionFM, a foundation model pre-trained with 3.4 million ophthalmic images from 560,457 individuals, covering a broad range of ophthalmic diseases, modalities, imaging devices, and demography. After pre-training, VisionFM provides a foundation to foster multiple ophthalmic artificial intelligence (AI) applications, such as disease screening and diagnosis, disease prognosis, subclassification of disease phenotype, and systemic biomarker and disease prediction, with each application enhanced with expert-level intelligence and accuracy. The generalist intelligence of VisionFM outperformed ophthalmologists with basic and intermediate levels in jointly diagnosing 12 common ophthalmic diseases. Evaluated on a new large-scale ophthalmic disease diagnosis benchmark database, as well as a new large-scale segmentation and detection benchmark database, VisionFM outperformed strong baseline deep neural networks. The ophthalmic image representations learned by VisionFM exhibited noteworthy explainability, and demonstrated strong generalizability to new ophthalmic modalities, disease spectrum, and imaging devices. As a foundation model, VisionFM has a large capacity to learn from diverse ophthalmic imaging data and disparate datasets. To be commensurate with this capacity, in addition to the real data used for pre-training, we also generated and leveraged synthetic ophthalmic imaging data. Experimental results revealed that synthetic data that passed visual Turing tests, can also enhance the representation learning capability of VisionFM, leading to substantial performance gains on downstream ophthalmic AI tasks. Beyond the ophthalmic AI applications developed, validated, and demonstrated in this work, substantial further applications can be achieved in an efficient and cost-effective manner using VisionFM as the foundation.

Jay Zoellin, Colin Merk, Mischa Buob et al.

Integrating deep learning into medical imaging is poised to greatly advance diagnostic methods but it faces challenges with generalizability. Foundation models, based on self-supervised learning, address these issues and improve data efficiency. Natural domain foundation models show promise for medical imaging, but systematic research evaluating domain adaptation, especially using self-supervised learning and parameter-efficient fine-tuning, remains underexplored. Additionally, little research addresses the issue of catastrophic forgetting during fine-tuning of foundation models. We adapted the DINOv2 vision transformer for retinal imaging classification tasks using self-supervised learning and generated two novel foundation models termed DINORET and BE DINORET. Publicly available color fundus photographs were employed for model development and subsequent fine-tuning for diabetic retinopathy staging and glaucoma detection. We introduced block expansion as a novel domain adaptation strategy and assessed the models for catastrophic forgetting. Models were benchmarked to RETFound, a state-of-the-art foundation model in ophthalmology. DINORET and BE DINORET demonstrated competitive performance on retinal imaging tasks, with the block expanded model achieving the highest scores on most datasets. Block expansion successfully mitigated catastrophic forgetting. Our few-shot learning studies indicated that DINORET and BE DINORET outperform RETFound in terms of data-efficiency. This study highlights the potential of adapting natural domain vision models to retinal imaging using self-supervised learning and block expansion. BE DINORET offers robust performance without sacrificing previously acquired capabilities. Our findings suggest that these methods could enable healthcare institutions to develop tailored vision models for their patient populations, enhancing global healthcare inclusivity.

Ziyu Gao, Xinyuan Wu, Xiaolan Chen et al.

Ophthalmic decision-making depends on subtle lesion-scale cues interpreted across multimodal imaging and over time, yet most medical foundation models remain static and degrade under modality and acquisition shifts. Here we introduce EyeWorld, a generative world model that conceptualizes the eye as a partially observed dynamical system grounded in clinical imaging. EyeWorld learns an observation-stable latent ocular state shared across modalities, unifying fine-grained parsing, structure-preserving cross-modality translation and quality-robust enhancement within a single framework. Longitudinal supervision further enables time-conditioned state transitions, supporting forecasting of clinically meaningful progression while preserving stable anatomy. By moving from static representation learning to explicit dynamical modeling, EyeWorld provides a unified approach to robust multimodal interpretation and prognosis-oriented simulation in medicine.

Qingshan Hou, Yukun Zhou, Jocelyn Hui Lin Goh et al.

The advent of foundation models (FMs) is transforming medical domain. In ophthalmology, RETFound, a retina-specific FM pre-trained sequentially on 1.4 million natural images and 1.6 million retinal images, has demonstrated high adaptability across clinical applications. Conversely, DINOv2, a general-purpose vision FM pre-trained on 142 million natural images, has shown promise in non-medical domains. However, its applicability to clinical tasks remains underexplored. To address this, we conducted head-to-head evaluations by fine-tuning RETFound and three DINOv2 models (large, base, small) for ocular disease detection and systemic disease prediction tasks, across eight standardized open-source ocular datasets, as well as the Moorfields AlzEye and the UK Biobank datasets. DINOv2-large model outperformed RETFound in detecting diabetic retinopathy (AUROC=0.850-0.952 vs 0.823-0.944, across three datasets, all P<=0.007) and multi-class eye diseases (AUROC=0.892 vs. 0.846, P<0.001). In glaucoma, DINOv2-base model outperformed RETFound (AUROC=0.958 vs 0.940, P<0.001). Conversely, RETFound achieved superior performance over all DINOv2 models in predicting heart failure, myocardial infarction, and ischaemic stroke (AUROC=0.732-0.796 vs 0.663-0.771, all P<0.001). These trends persisted even with 10% of the fine-tuning data. These findings showcase the distinct scenarios where general-purpose and domain-specific FMs excel, highlighting the importance of aligning FM selection with task-specific requirements to optimise clinical performance.

Danli Shi, Weiyi Zhang, Xiaolan Chen et al.

Artificial intelligence (AI) is vital in ophthalmology, tackling tasks like diagnosis, classification, and visual question answering (VQA). However, existing AI models in this domain often require extensive annotation and are task-specific, limiting their clinical utility. While recent developments have brought about foundation models for ophthalmology, they are limited by the need to train separate weights for each imaging modality, preventing a comprehensive representation of multi-modal features. This highlights the need for versatile foundation models capable of handling various tasks and modalities in ophthalmology. To address this gap, we present EyeFound, a multimodal foundation model for ophthalmic images. Unlike existing models, EyeFound learns generalizable representations from unlabeled multimodal retinal images, enabling efficient model adaptation across multiple applications. Trained on 2.78 million images from 227 hospitals across 11 ophthalmic modalities, EyeFound facilitates generalist representations and diverse multimodal downstream tasks, even for detecting challenging rare diseases. It outperforms previous work RETFound in diagnosing eye diseases, predicting systemic disease incidents, and zero-shot multimodal VQA. EyeFound provides a generalizable solution to improve model performance and lessen the annotation burden on experts, facilitating widespread clinical AI applications for retinal imaging.

Ke Zou, Yang Bai, Bo Liu et al.

Medical phrase grounding is crucial for identifying relevant regions in medical images based on phrase queries, facilitating accurate image analysis and diagnosis. However, current methods rely on manual extraction of key phrases from medical reports, reducing efficiency and increasing the workload for clinicians. Additionally, the lack of model confidence estimation limits clinical trust and usability. In this paper, we introduce a novel task called Medical Report Grounding (MRG), which aims to directly identify diagnostic phrases and their corresponding grounding boxes from medical reports in an end-to-end manner. To address this challenge, we propose uMedGround, a robust and reliable framework that leverages a multimodal large language model to predict diagnostic phrases by embedding a unique token, <BOX>, into the vocabulary to enhance detection capabilities. A vision encoder-decoder processes the embedded token and input image to generate grounding boxes. Critically, uMedGround incorporates an uncertainty-aware prediction model, significantly improving the robustness and reliability of grounding predictions. Experimental results demonstrate that uMedGround outperforms state-of-the-art medical phrase grounding methods and fine-tuned large visual-language models, validating its effectiveness and reliability. This study represents a pioneering exploration of the MRG task, marking the first-ever endeavor in this domain. Additionally, we demonstrate the applicability of uMedGround in medical visual question answering and class-based localization tasks, where it highlights visual evidence aligned with key diagnostic phrases, supporting clinicians in interpreting various types of textual inputs, including free-text reports, visual question answering queries, and class labels.

Qingshan Hou, Shuai Cheng, Peng Cao et al.

Representation learning offers a conduit to elucidate distinctive features within the latent space and interpret the deep models. However, the randomness of lesion distribution and the complexity of low-quality factors in medical images pose great challenges for models to extract key lesion features. Disease diagnosis methods guided by contrastive learning (CL) have shown significant advantages in lesion feature representation. Nevertheless, the effectiveness of CL is highly dependent on the quality of the positive and negative sample pairs. In this work, we propose a clinical-oriented multi-level CL framework that aims to enhance the model's capacity to extract lesion features and discriminate between lesion and low-quality factors, thereby enabling more accurate disease diagnosis from low-quality medical images. Specifically, we first construct multi-level positive and negative pairs to enhance the model's comprehensive recognition capability of lesion features by integrating information from different levels and qualities of medical images. Moreover, to improve the quality of the learned lesion embeddings, we introduce a dynamic hard sample mining method based on self-paced learning. The proposed CL framework is validated on two public medical image datasets, EyeQ and Chest X-ray, demonstrating superior performance compared to other state-of-the-art disease diagnostic methods.

Sahana Srinivasan, Xuguang Ai, Minjie Zou et al.

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.

Zhi Da Soh, Yang Bai, Kai Yu et al.

Current deep learning models are mostly task specific and lack a user-friendly interface to operate. We present Meta-EyeFM, a multi-function foundation model that integrates a large language model (LLM) with vision foundation models (VFMs) for ocular disease assessment. Meta-EyeFM leverages a routing mechanism to enable accurate task-specific analysis based on text queries. Using Low Rank Adaptation, we fine-tuned our VFMs to detect ocular and systemic diseases, differentiate ocular disease severity, and identify common ocular signs. The model achieved 100% accuracy in routing fundus images to appropriate VFMs, which achieved $\ge$ 82.2% accuracy in disease detection, $\ge$ 89% in severity differentiation, $\ge$ 76% in sign identification. Meta-EyeFM was 11% to 43% more accurate than Gemini-1.5-flash and ChatGPT-4o LMMs in detecting various eye diseases and comparable to an ophthalmologist. This system offers enhanced usability and diagnostic performance, making it a valuable decision support tool for primary eye care or an online LLM for fundus evaluation.

Minjie Zou, Sahana Srinivasan, Thaddaeus Wai Soon Lo et al.

Recent advances in reasoning-focused large language models (LLMs) mark a shift from general LLMs toward models designed for complex decision-making, a crucial aspect in medicine. However, their performance in specialized domains like ophthalmology remains underexplored. This study comprehensively evaluated and compared the accuracy and reasoning capabilities of four newly developed reasoning-focused LLMs, namely DeepSeek-R1, OpenAI o1, o3-mini, and Gemini 2.0 Flash-Thinking. Each model was assessed using 5,888 multiple-choice ophthalmology exam questions from the MedMCQA dataset in zero-shot setting. Quantitative evaluation included accuracy, Macro-F1, and five text-generation metrics (ROUGE-L, METEOR, BERTScore, BARTScore, and AlignScore), computed against ground-truth reasonings. Average inference time was recorded for a subset of 100 randomly selected questions. Additionally, two board-certified ophthalmologists qualitatively assessed clarity, completeness, and reasoning structure of responses to differential diagnosis questions.O1 (0.902) and DeepSeek-R1 (0.888) achieved the highest accuracy, with o1 also leading in Macro-F1 (0.900). The performance of models across the text-generation metrics varied: O3-mini excelled in ROUGE-L (0.151), o1 in METEOR (0.232), DeepSeek-R1 and o3-mini tied for BERTScore (0.673), DeepSeek-R1 (-4.105) and Gemini 2.0 Flash-Thinking (-4.127) performed best in BARTScore, while o3-mini (0.181) and o1 (0.176) led AlignScore. Inference time across the models varied, with DeepSeek-R1 being slowest (40.4 seconds) and Gemini 2.0 Flash-Thinking fastest (6.7 seconds). Qualitative evaluation revealed that DeepSeek-R1 and Gemini 2.0 Flash-Thinking tended to provide detailed and comprehensive intermediate reasoning, whereas o1 and o3-mini displayed concise and summarized justifications.

Ke Zou, Jocelyn Hui Lin Goh, Yukun Zhou et al.

Foundation models (FMs) have shown great promise in medical image analysis by improving generalization across diverse downstream tasks. In ophthalmology, several FMs have recently emerged, but there is still no clear answer to fundamental questions: Which FM performs the best? Are they equally good across different tasks? What if we combine all FMs together? To our knowledge, this is the first study to systematically evaluate both single and fused ophthalmic FMs. To address these questions, we propose FusionFM, a comprehensive evaluation suite, along with two fusion approaches to integrate different ophthalmic FMs. Our framework covers both ophthalmic disease detection (glaucoma, diabetic retinopathy, and age-related macular degeneration) and systemic disease prediction (diabetes and hypertension) based on retinal imaging. We benchmarked four state-of-the-art FMs (RETFound, VisionFM, RetiZero, and DINORET) using standardized datasets from multiple countries and evaluated their performance using AUC and F1 metrics. Our results show that DINORET and RetiZero achieve superior performance in both ophthalmic and systemic disease tasks, with RetiZero exhibiting stronger generalization on external datasets. Regarding fusion strategies, the Gating-based approach provides modest improvements in predicting glaucoma, AMD, and hypertension. Despite these advances, predicting systemic diseases, especially hypertension in external cohort remains challenging. These findings provide an evidence-based evaluation of ophthalmic FMs, highlight the benefits of model fusion, and point to strategies for enhancing their clinical applicability.

Meng Wang, Tian Lin, Qingshan Hou et al.

Artificial intelligence (AI) shows remarkable potential in medical imaging diagnostics, yet most current models require retraining when applied across different clinical settings, limiting their scalability. We introduce GlobeReady, a clinician-friendly AI platform that enables fundus disease diagnosis that operates without retraining, fine-tuning, or the needs for technical expertise. GlobeReady demonstrates high accuracy across imaging modalities: 93.9-98.5% for 11 fundus diseases using color fundus photographs (CPFs) and 87.2-92.7% for 15 fundus diseases using optic coherence tomography (OCT) scans. By leveraging training-free local feature augmentation, GlobeReady platform effectively mitigates domain shifts across centers and populations, achieving accuracies of 88.9-97.4% across five centers on average in China, 86.3-96.9% in Vietnam, and 73.4-91.0% in Singapore, and 90.2-98.9% in the UK. Incorporating a bulit-in confidence-quantifiable diagnostic mechanism further enhances the platform's accuracy to 94.9-99.4% with CFPs and 88.2-96.2% with OCT, while enabling identification of out-of-distribution cases with 86.3% accuracy across 49 common and rare fundus diseases using CFPs, and 90.6% accuracy across 13 diseases using OCT. Clinicians from countries rated GlobeReady highly for usability and clinical relevance (average score 4.6/5). These findings demonstrate GlobeReady's robustness, generalizability and potential to support global ophthalmic care without technical barriers.

Yang Bai, Haoran Cheng, Yang Zhou et al.

Despite the promise of foundation models in medical AI, current systems remain limited - they are modality-specific and lack transparent reasoning processes, hindering clinical adoption. To address this gap, we present EVLF-FM, a multimodal vision-language foundation model (VLM) designed to unify broad diagnostic capability with fine-grain explainability. The development and testing of EVLF-FM encompassed over 1.3 million total samples from 23 global datasets across eleven imaging modalities related to six clinical specialties: dermatology, hepatology, ophthalmology, pathology, pulmonology, and radiology. External validation employed 8,884 independent test samples from 10 additional datasets across five imaging modalities. Technically, EVLF-FM is developed to assist with multiple disease diagnosis and visual question answering with pixel-level visual grounding and reasoning capabilities. In internal validation for disease diagnostics, EVLF-FM achieved the highest average accuracy (0.858) and F1-score (0.797), outperforming leading generalist and specialist models. In medical visual grounding, EVLF-FM also achieved stellar performance across nine modalities with average mIOU of 0.743 and Acc@0.5 of 0.837. External validations further confirmed strong zero-shot and few-shot performance, with competitive F1-scores despite a smaller model size. Through a hybrid training strategy combining supervised and visual reinforcement fine-tuning, EVLF-FM not only achieves state-of-the-art accuracy but also exhibits step-by-step reasoning, aligning outputs with visual evidence. EVLF-FM is an early multi-disease VLM model with explainability and reasoning capabilities that could advance adoption of and trust in foundation models for real-world clinical deployment.

Yukun Zhou, Paul Nderitu, Jocelyn Hui Lin Goh et al.

Medical foundation models, pre-trained with large-scale clinical data, demonstrate strong performance in diverse clinically relevant applications. RETFound, trained on nearly one million retinal images, exemplifies this approach in applications with retinal images. However, the emergence of increasingly powerful and multifold larger generalist foundation models such as DINOv2 and DINOv3 raises the question of whether domain-specific pre-training remains essential, and if so, what gap persists. To investigate this, we systematically evaluated the adaptability of DINOv2 and DINOv3 in retinal image applications, compared to two specialist RETFound models, RETFound-MAE and RETFound-DINOv2. We assessed performance on ocular disease detection and systemic disease prediction using two adaptation strategies: fine-tuning and linear probing. Data efficiency and adaptation efficiency were further analysed to characterise trade-offs between predictive performance and computational cost. Our results show that although scaling generalist models yields strong adaptability across diverse tasks, RETFound-DINOv2 consistently outperforms these generalist foundation models in ocular-disease detection and oculomics tasks, demonstrating stronger generalisability and data efficiency. These findings suggest that specialist retinal foundation models remain the most effective choice for clinical applications, while the narrowing gap with generalist foundation models suggests that continued data and model scaling can deliver domain-relevant gains and position them as strong foundations for future medical foundation models.

Fares Antaki, David Mikhail, Daniel Milad et al.

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 (1.11x stronger than o3-high). Cost-accuracy analysis identified several GPT-5 configurations on the Pareto frontier, with GPT-5-mini-low offering the most favorable low-cost, high-performance balance. These results benchmark GPT-5 on a high-quality ophthalmology dataset, demonstrate the influence of reasoning effort on accuracy, and introduce an autograder framework for scalable evaluation of LLM-generated answers against reference standards in ophthalmology.

Meng Wang, Tian Lin, Aidi Lin et al.

Previous foundation models for fundus images were pre-trained with limited disease categories and knowledge base. Here we introduce a knowledge-rich vision-language model (RetiZero) that leverages knowledge from more than 400 fundus diseases. For RetiZero's pretraining, we compiled 341,896 fundus images paired with texts, sourced from public datasets, ophthalmic literature, and online resources, encompassing a diverse range of diseases across multiple ethnicities and countries. RetiZero exhibits remarkable performance in several downstream tasks, including zero-shot disease recognition, image-to-image retrieval, AI-assisted clinical diagnosis,few-shot fine-tuning, and internal- and cross-domain disease identification. In zero-shot scenarios, RetiZero achieves Top-5 accuracies of 0.843 for 15 diseases and 0.756 for 52 diseases. For image retrieval, it achieves Top-5 scores of 0.950 and 0.886 for the same sets, respectively. AI-assisted clinical diagnosis results show that RetiZero's Top-3 zero-shot performance surpasses the average of 19 ophthalmologists from Singapore, China, and the United States. RetiZero substantially enhances clinicians' accuracy in diagnosing fundus diseases, in particularly rare ones. These findings underscore the value of integrating the RetiZero into clinical settings, where various fundus diseases are encountered.