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Purpose: We aim to use fundus fluorescein angiography (FFA) to label the capillaries on color fundus (CF) photographs and train a deep learning model to quantify retinal capillaries noninvasively from CF and apply it to cardiovascular disease (CVD) risk assessment. Design: Cross-sectional and longitudinal study. Participants: A total of 90732 pairs of CF-FFA images from 3893 participants for segmentation model development, and 49229 participants in the UK Biobank for association analysis. Methods: We matched the vessels extracted from FFA and CF, and used vessels from FFA as labels to train a deep learning model (RMHAS-FA) to segment retinal capillaries using CF. We tested the model's accuracy on a manually labeled internal test set (FundusCapi). For external validation, we tested the segmentation model on 7 vessel segmentation datasets, and investigated the clinical value of the segmented vessels in predicting CVD events in the UK Biobank. Main Outcome Measures: Area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity for segmentation. Hazard ratio (HR; 95% confidence interval [CI]) for Cox regression analysis. Results: On the FundusCapi dataset, the segmentation performance was AUC = 0.95, accuracy = 0.94, sensitivity = 0.90, and specificity = 0.93. Smaller vessel skeleton density had a stronger correlation with CVD risk factors and incidence (P < 0.01). Reduced density of small vessel skeletons was strongly associated with an increased risk of CVD incidence and mortality for women (HR [95% CI] = 0.91 [0.84-0.98] and 0.68 [0.54-0.86], respectively). Conclusions: Using paired CF-FFA images, we automated the laborious manual labeling process and enabled noninvasive capillary quantification from CF, supporting its potential as a sensitive screening method for identifying individuals at high risk of future CVD events. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Purpose: To perform one-shot retinal artery and vein segmentation with cross-modality artery-vein (AV) soft-label pretraining. Design: Cross-sectional study. Subjects: The study included 6479 color fundus photography (CFP) and arterial-venous fundus fluorescein angiography (FFA) pairs from 1964 participants for pretraining and 6 AV segmentation data sets with various image sources, including RITE, HRF, LES-AV, AV-WIDE, PortableAV, and DRSplusAV for one-shot finetuning and testing. Methods: We structurally matched the arterial and venous phase of FFA with CFP, the AV soft labels were automatically generated by utilizing the fluorescein intensity difference of the arterial and venous-phase FFA images, and the soft labels were then used to train a generative adversarial network to learn to generate AV soft segmentations using CFP images as input. We then finetuned the pretrained model to perform AV segmentation using only one image from each of the AV segmentation data sets and test on the remainder. To investigate the effect and reliability of one-shot finetuning, we conducted experiments without finetuning and by finetuning the pretrained model on an iteratively different single image for each data set under the same experimental setting and tested the models on the remaining images. Main Outcome Measures: The AV segmentation was assessed by area under the receiver operating characteristic curve (AUC), accuracy, Dice score, sensitivity, and specificity. Results: After the FFA-AV soft label pretraining, our method required only one exemplar image from each camera or modality and achieved similar performance with full-data training, with AUC ranging from 0.901 to 0.971, accuracy from 0.959 to 0.980, Dice score from 0.585 to 0.773, sensitivity from 0.574 to 0.763, and specificity from 0.981 to 0.991. Compared with no finetuning, the segmentation performance improved after one-shot finetuning. When finetuned on different images in each data set, the standard deviation of the segmentation results across models ranged from 0.001 to 0.10. Conclusions: This study presents the first one-shot approach to retinal artery and vein segmentation. The proposed labeling method is time-saving and efficient, demonstrating a promising direction for retinal-vessel segmentation and enabling the potential for widespread application. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Purpose: To develop and validate a deep learning model that can transform color fundus (CF) photography into corresponding venous and late-phase fundus fluorescein angiography (FFA) images. Design: Cross-sectional study. Participants: We included 51 370 CF-venous FFA pairs and 14 644 CF-late FFA pairs from 4438 patients for model development. External testing involved 50 eyes with CF-FFA pairs and 2 public datasets for diabetic retinopathy (DR) classification, with 86 952 CF from EyePACs, and 1744 CF from MESSIDOR2. Methods: We trained a deep-learning model to transform CF into corresponding venous and late-phase FFA images. The translated FFA images’ quality was evaluated quantitatively on the internal test set and subjectively on 100 eyes with CF-FFA paired images (50 from external), based on the realisticity of the global image, anatomical landmarks (macula, optic disc, and vessels), and lesions. Moreover, we validated the clinical utility of the translated FFA for classifying 5-class DR and diabetic macular edema (DME) in the EyePACs and MESSIDOR2 datasets. Main Outcome Measures: Image generation was quantitatively assessed by structural similarity measures (SSIM), and subjectively by 2 clinical experts on a 5-point scale (1 refers real FFA); intragrader agreement was assessed by kappa. The DR classification accuracy was assessed by area under the receiver operating characteristic curve. Results: The SSIM of the translated FFA images were > 0.6, and the subjective quality scores ranged from 1.37 to 2.60. Both experts reported similar quality scores with substantial agreement (all kappas > 0.8). Adding the generated FFA on top of CF improved DR classification in the EyePACs and MESSIDOR2 datasets, with the area under the receiver operating characteristic curve increased from 0.912 to 0.939 on the EyePACs dataset and from 0.952 to 0.972 on the MESSIDOR2 dataset. The DME area under the receiver operating characteristic curve also increased from 0.927 to 0.974 in the MESSIDOR2 dataset. Conclusions: Our CF-to-FFA framework produced realistic FFA images. Moreover, adding the translated FFA images on top of CF improved the accuracy of DR screening. These results suggest that CF-to-FFA translation could be used as a surrogate method when FFA examination is not feasible and as a simple add-on to improve DR screening. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.