Ching-Yu Cheng

Xiaofeng Lei, Shaohua Li, Xinxing Xu et al.

Localizing anatomical landmarks are important tasks in medical image analysis. However, the landmarks to be localized often lack prominent visual features. Their locations are elusive and easily confused with the background, and thus precise localization highly depends on the context formed by their surrounding areas. In addition, the required precision is usually higher than segmentation and object detection tasks. Therefore, localization has its unique challenges different from segmentation or detection. In this paper, we propose a zoom-in attentive network (ZIAN) for anatomical landmark localization in ocular images. First, a coarse-to-fine, or "zoom-in" strategy is utilized to learn the contextualized features in different scales. Then, an attentive fusion module is adopted to aggregate multi-scale features, which consists of 1) a co-attention network with a multiple regions-of-interest (ROIs) scheme that learns complementary features from the multiple ROIs, 2) an attention-based fusion module which integrates the multi-ROIs features and non-ROI features. We evaluated ZIAN on two open challenge tasks, i.e., the fovea localization in fundus images and scleral spur localization in AS-OCT images. Experiments show that ZIAN achieves promising performances and outperforms state-of-the-art localization methods. The source code and trained models of ZIAN are available at https://github.com/leixiaofeng-astar/OMIA9-ZIAN.

Kai Yu, Yang Zhou, Yang Bai et al.

Retinal foundation models aim to learn generalizable representations from diverse retinal images, facilitating label-efficient model adaptation across various ophthalmic tasks. Despite their success, current retinal foundation models are generally restricted to a single imaging modality, such as Color Fundus Photography (CFP) or Optical Coherence Tomography (OCT), limiting their versatility. Moreover, these models may struggle to fully leverage expert annotations and overlook the valuable domain knowledge essential for domain-specific representation learning. To overcome these limitations, we introduce UrFound, a retinal foundation model designed to learn universal representations from both multimodal retinal images and domain knowledge. UrFound is equipped with a modality-agnostic image encoder and accepts either CFP or OCT images as inputs. To integrate domain knowledge into representation learning, we encode expert annotation in text supervision and propose a knowledge-guided masked modeling strategy for model pre-training. It involves reconstructing randomly masked patches of retinal images while predicting masked text tokens conditioned on the corresponding retinal image. This approach aligns multimodal images and textual expert annotations within a unified latent space, facilitating generalizable and domain-specific representation learning. Experimental results demonstrate that UrFound exhibits strong generalization ability and data efficiency when adapting to various tasks in retinal image analysis. By training on ~180k retinal images, UrFound significantly outperforms the state-of-the-art retinal foundation model trained on up to 1.6 million unlabelled images across 8 public retinal datasets. Our code and data are available at https://github.com/yukkai/UrFound.

Qingyu Chen, Tiarnan D L Keenan, Elvira Agron et al.

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.

Xiaoye Wang, Nicole Xi Zhang, Hongyu He et al.

Recent advancements in artificial intelligence (AI), particularly in large language models (LLMs), have unlocked significant potential to enhance the quality and efficiency of medical care. By introducing a novel way to interact with AI and data through natural language, LLMs offer new opportunities for medical practitioners, patients, and researchers. However, as AI and LLMs become more powerful and especially achieve superhuman performance in some medical tasks, public concerns over their safety have intensified. These concerns about AI safety have emerged as the most significant obstacles to the adoption of AI in medicine. In response, this review examines emerging risks in AI utilization during the LLM era. First, we explore LLM-specific safety challenges from functional and communication perspectives, addressing issues across data collection, model training, and real-world application. We then consider inherent safety problems shared by all AI systems, along with additional complications introduced by LLMs. Last, we discussed how safety issues of using AI in clinical practice and healthcare system operation would undermine trust among patient, clinicians and the public, and how to build confidence in these systems. By emphasizing the development of safe AI, we believe these technologies can be more rapidly and reliably integrated into everyday medical practice to benefit both patients and clinicians.

Peisong Zhang, Manqiang Peng, Yuxuan Wu et al.

Estimating individualized treatment effects from longitudinal observational data is central to data-driven medicine, yet existing methods face a fundamental limitation: reducing confounding bias often suppresses clinically informative heterogeneity, degrading patient-specific predictions. Here, we identify this tension as a bias-precision paradox in causal representation learning and introduce sampling-based maximum mean discrepancy (sMMD), a stochastic alignment strategy that replaces global adversarial balancing with subset-level matching. We instantiate this approach in a framework for counterfactual outcome prediction with attribution-grounded interpretability. Across two large-scale ICU cohorts (n = 27,783), our framework improves accuracy under distribution shift, reducing error by up to 11.5% and substantially increasing recall in high-risk tasks. Mechanistic analyses show that sMMD selectively preserves clinically decisive variables. In human-AI evaluation, our method outperforms clinicians-in-training and large language models, and improves clinician accuracy by 14.7% while reducing decision time, enabling interpretable, real-time clinical decision support.

Samantha Min Er Yew, Xiaofeng Lei, Jocelyn Hui Lin Goh et al.

Background: RETFound, a self-supervised, retina-specific foundation model (FM), showed potential in downstream applications. However, its comparative performance with traditional deep learning (DL) models remains incompletely understood. This study aimed to evaluate RETFound against three ImageNet-pretrained supervised DL models (ResNet50, ViT-base, SwinV2) in detecting ocular and systemic diseases. Methods: We fine-tuned/trained RETFound and three DL models on full datasets, 50%, 20%, and fixed sample sizes (400, 200, 100 images, with half comprising disease cases; for each DR severity class, 100 and 50 cases were used. Fine-tuned models were tested internally using the SEED (53,090 images) and APTOS-2019 (3,672 images) datasets and externally validated on population-based (BES, CIEMS, SP2, UKBB) and open-source datasets (ODIR-5k, PAPILA, GAMMA, IDRiD, MESSIDOR-2). Model performance was compared using area under the receiver operating characteristic curve (AUC) and Z-tests with Bonferroni correction (P<0.05/3). Interpretation: Traditional DL models are mostly comparable to RETFound for ocular disease detection with large datasets. However, RETFound is superior in systemic disease detection with smaller datasets. These findings offer valuable insights into the respective merits and limitation of traditional models and FMs.

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.

Hongyu He, Shaowen Xiang, Ye Zhang et al.

Generative artificial intelligence (AI) is rapidly populating medical records with synthetic content, creating a feedback loop where future models are increasingly at risk of training on uncurated AI-generated data. However, the clinical consequences of this AI-generated data contamination remain unexplored. Here, we show that in the absence of mandatory human verification, this self-referential cycle drives a rapid erosion of pathological variability and diagnostic reliability. By analysing more than 800,000 synthetic data points across clinical text generation, vision-language reporting, and medical image synthesis, we find that models progressively converge toward generic phenotypes regardless of the model architecture. Specifically, rare but critical findings, including pneumothorax and effusions, vanish from the synthetic content generated by AI models, while demographic representations skew heavily toward middle-aged male phenotypes. Crucially, this degradation is masked by false diagnostic confidence; models continue to issue reassuring reports while failing to detect life-threatening pathology, with false reassurance rates tripling to 40%. Blinded physician evaluation confirms that this decoupling of confidence and accuracy renders AI-generated documentation clinically useless after just two generations. We systematically evaluate three mitigation strategies, finding that while synthetic volume scaling fails to prevent collapse, mixing real data with quality-aware filtering effectively preserves diversity. Ultimately, our results suggest that without policy-mandated human oversight, the deployment of generative AI threatens to degrade the very healthcare data ecosystems it relies upon.

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.

Yiming Tang, Arash Lagzian, Srinivas Anumasa et al.

The rapid development of generative AI has transformed content creation, communication, and human development. However, this technology raises profound concerns in high-stakes domains, demanding rigorous methods to analyze and evaluate AI-generated content. While existing analytic methods often treat images as indivisible wholes, real-world AI failures generally manifest as specific visual patterns that can evade holistic detection and suit more granular and decomposed analysis. Here we introduce a content analysis tool, Language-Grounded Sparse Encoders (LanSE), which decompose images into interpretable visual patterns with natural language descriptions. Utilizing interpretability modules and large multimodal models, LanSE can automatically identify visual patterns within data modalities. Our method discovers more than 5,000 visual patterns with 93\% human agreement, provides decomposed evaluation outperforming existing methods, establishes the first systematic evaluation of physical plausibility, and extends to medical imaging settings. Our method's capability to extract language-grounded patterns can be naturally adapted to numerous fields, including biology and geography, as well as other data modalities such as protein structures and time series, thereby advancing content analysis for generative AI.

Yue Wu, Yibo Guo, Yulong Yan et al.

We envision the "virtual eye" as a next-generation, AI-powered platform that uses interconnected foundation models to simulate the eye's intricate structure and biological function across all scales. Advances in AI, imaging, and multiomics provide a fertile ground for constructing a universal, high-fidelity digital replica of the human eye. This perspective traces the evolution from early mechanistic and rule-based models to contemporary AI-driven approaches, integrating in a unified model with multimodal, multiscale, dynamic predictive capabilities and embedded feedback mechanisms. We propose a development roadmap emphasizing the roles of large-scale multimodal datasets, generative AI, foundation models, agent-based architectures, and interactive interfaces. Despite challenges in interpretability, ethics, data processing and evaluation, the virtual eye holds the potential to revolutionize personalized ophthalmic care and accelerate research into ocular health and disease.

Xiaofeng Lei, Yih-Chung Tham, Jocelyn Hui Lin Goh et al.

Community vision screening plays a crucial role in identifying individuals with vision loss and preventing avoidable blindness, particularly in rural communities where access to eye care services is limited. Currently, there is a pressing need for a simple and efficient process to screen and refer individuals with significant eye disease-related vision loss to tertiary eye care centers for further care. An ideal solution should seamlessly and readily integrate with existing workflows, providing comprehensive initial screening results to service providers, thereby enabling precise patient referrals for timely treatment. This paper introduces the Enhancing Community Vision Screening (ECVS) solution, which addresses the aforementioned concerns with a novel and feasible solution based on simple, non-invasive retinal photography for the detection of pathology-based visual impairment. Our study employs four distinct deep learning models: RETinal photo Quality Assessment (RETQA), Pathology Visual Impairment detection (PVI), Eye Disease Diagnosis (EDD) and Visualization of Lesion Regions of the eye (VLR). We conducted experiments on over 10 datasets, totaling more than 80,000 fundus photos collected from various sources. The models integrated into ECVS achieved impressive AUC scores of 0.98 for RETQA, 0.95 for PVI, and 0.90 for EDD, along with a DICE coefficient of 0.48 for VLR. These results underscore the promising capabilities of ECVS as a straightforward and scalable method for community-based vision screening.

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.

Anirudh Prabhakaran, YeKun Xiao, Ching-Yu Cheng et al.

Ocular diseases, including diabetic retinopathy and glaucoma, present a significant public health challenge due to their high prevalence and potential for causing vision impairment. Early and accurate diagnosis is crucial for effective treatment and management. In recent years, deep learning models have emerged as powerful tools for analysing medical images, such as retina imaging. However, challenges persist in model relibability and uncertainty estimation, which are critical for clinical decision-making. This study leverages the probabilistic framework of Generative Flow Networks (GFlowNets) to learn the posterior distribution over latent discrete dropout masks for the classification and analysis of ocular diseases using fundus images. We develop a robust and generalizable method that utilizes GFlowOut integrated with ResNet18 and ViT models as the backbone in identifying various ocular conditions. This study employs a unique set of dropout masks - none, random, bottomup, and topdown - to enhance model performance in analyzing these fundus images. Our results demonstrate that our learnable probablistic latents significantly improves accuracy, outperforming the traditional dropout approach. We utilize a gradient map calculation method, Grad-CAM, to assess model explainability, observing that the model accurately focuses on critical image regions for predictions. The integration of GFlowOut in neural networks presents a promising advancement in the automated diagnosis of ocular diseases, with implications for improving clinical workflows and patient outcomes.

Satish K. Panda, Haris Cheong, Tin A. Tun et al.

Purpose: To assess whether the three-dimensional (3D) structural configuration of the central retinal vessel trunk and its branches (CRVT&B) could be used as a diagnostic marker for glaucoma. Method: We trained a deep learning network to automatically segment the CRVT&B from the B-scans of the optical coherence tomography (OCT) volume of the optic nerve head (ONH). Subsequently, two different approaches were used for glaucoma diagnosis using the structural configuration of the CRVT&B as extracted from the OCT volumes. In the first approach, we aimed to provide a diagnosis using only 3D CNN and the 3D structure of the CRVT&B. For the second approach, we projected the 3D structure of the CRVT&B orthographically onto three planes to obtain 2D images, and then a 2D CNN was used for diagnosis. The segmentation accuracy was evaluated using the Dice coefficient, whereas the diagnostic accuracy was assessed using the area under the receiver operating characteristic curves (AUC). The diagnostic performance of the CRVT&B was also compared with that of retinal nerve fiber layer (RNFL) thickness. Results: Our segmentation network was able to efficiently segment retinal blood vessels from OCT scans. On a test set, we achieved a Dice coefficient of 0.81\pm0.07. The 3D and 2D diagnostic networks were able to differentiate glaucoma from non-glaucoma subjects with accuracies of 82.7% and 83.3%, respectively. The corresponding AUCs for CRVT&B were 0.89 and 0.90, higher than those obtained with RNFL thickness alone. Conclusions: Our work demonstrated that the diagnostic power of the CRVT&B is superior to that of a gold-standard glaucoma parameter, i.e., RNFL thickness. Our work also suggested that the major retinal blood vessels form a skeleton -- the configuration of which may be representative of major ONH structural changes as typically observed with the development and progression of glaucoma.

Satish K. Panda, Haris Cheong, Tin A. Tun et al.

The optic nerve head (ONH) typically experiences complex neural- and connective-tissue structural changes with the development and progression of glaucoma, and monitoring these changes could be critical for improved diagnosis and prognosis in the glaucoma clinic. The gold-standard technique to assess structural changes of the ONH clinically is optical coherence tomography (OCT). However, OCT is limited to the measurement of a few hand-engineered parameters, such as the thickness of the retinal nerve fiber layer (RNFL), and has not yet been qualified as a stand-alone device for glaucoma diagnosis and prognosis applications. We argue this is because the vast amount of information available in a 3D OCT scan of the ONH has not been fully exploited. In this study we propose a deep learning approach that can: \textbf{(1)} fully exploit information from an OCT scan of the ONH; \textbf{(2)} describe the structural phenotype of the glaucomatous ONH; and that can \textbf{(3)} be used as a robust glaucoma diagnosis tool. Specifically, the structural features identified by our algorithm were found to be related to clinical observations of glaucoma. The diagnostic accuracy from these structural features was $92.0 \pm 2.3 \%$ with a sensitivity of $90.0 \pm 2.4 \% $ (at $95 \%$ specificity). By changing their magnitudes in steps, we were able to reveal how the morphology of the ONH changes as one transitions from a `non-glaucoma' to a `glaucoma' condition. We believe our work may have strong clinical implication for our understanding of glaucoma pathogenesis, and could be improved in the future to also predict future loss of vision.

Sripad Krishna Devalla, Tan Hung Pham, Satish Kumar Panda et al.

Since the introduction of optical coherence tomography (OCT), it has been possible to study the complex 3D morphological changes of the optic nerve head (ONH) tissues that occur along with the progression of glaucoma. Although several deep learning (DL) techniques have been recently proposed for the automated extraction (segmentation) and quantification of these morphological changes, the device specific nature and the difficulty in preparing manual segmentations (training data) limit their clinical adoption. With several new manufacturers and next-generation OCT devices entering the market, the complexity in deploying DL algorithms clinically is only increasing. To address this, we propose a DL based 3D segmentation framework that is easily translatable across OCT devices in a label-free manner (i.e. without the need to manually re-segment data for each device). Specifically, we developed 2 sets of DL networks. The first (referred to as the enhancer) was able to enhance OCT image quality from 3 OCT devices, and harmonized image-characteristics across these devices. The second performed 3D segmentation of 6 important ONH tissue layers. We found that the use of the enhancer was critical for our segmentation network to achieve device independency. In other words, our 3D segmentation network trained on any of 3 devices successfully segmented ONH tissue layers from the other two devices with high performance (Dice coefficients > 0.92). With such an approach, we could automatically segment images from new OCT devices without ever needing manual segmentation data from such devices.

Tan Hung Pham, Sripad Krishna Devalla, Aloysius Ang et al.

Accurate isolation and quantification of intraocular dimensions in the anterior segment (AS) of the eye using optical coherence tomography (OCT) images is important in the diagnosis and treatment of many eye diseases, especially angle closure glaucoma. In this study, we developed a deep convolutional neural network (DCNN) for the localization of the scleral spur, and the segmentation of anterior segment structures (iris, corneo-sclera shell, anterior chamber). With limited training data, the DCNN was able to detect the scleral spur on unseen ASOCT images as accurately as an experienced ophthalmologist; and simultaneously isolated the anterior segment structures with a Dice coefficient of 95.7%. We then automatically extracted eight clinically relevant ASOCT parameters and proposed an automated quality check process that asserts the reliability of these parameters. When combined with an OCT machine capable of imaging multiple radial sections, the algorithms can provide a more complete objective assessment. This is an essential step toward providing a robust automated framework for reliable quantification of ASOCT scans, for applications in the diagnosis and management of angle closure glaucoma.