Diabetic Retinopathy (DR) is a common complication of diabetes and a leading cause of blindness worldwide. Early and accurate grading of its severity is crucial for disease management. Although deep learning has shown great potential for automated DR grading, its real-world deployment is still challenging due to distribution shifts among source and target domains, known as the domain generalization problem. Existing works have mainly attributed the performance degradation to limited domain shifts caused by simple visual discrepancies, which cannot handle complex real-world scenarios. Instead, we present preliminary evidence suggesting the existence of three-fold generalization issues: visual and degradation style shifts, diagnostic pattern diversity, and data imbalance. To tackle these issues, we propose a novel unified framework named Generalizable Diabetic Retinopathy Grading Network (GDRNet). GDRNet consists of three vital components: fundus visual-artifact augmentation (FundusAug), dynamic hybrid-supervised loss (DahLoss), and domain-class-aware re-balancing (DCR). FundusAug generates realistic augmented images via visual transformation and image degradation, while DahLoss jointly leverages pixel-level consistency and image-level semantics to capture the diverse diagnostic patterns and build generalizable feature representations. Moreover, DCR mitigates the data imbalance from a domain-class view and avoids undesired over-emphasis on rare domain-class pairs. Finally, we design a publicly available benchmark for fair evaluations. Extensive comparison experiments against advanced methods and exhaustive ablation studies demonstrate the effectiveness and generalization ability of GDRNet.

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