Cross-modality Labeling Enables Noninvasive Capillary Quantification as a Sensitive Biomarker for Assessing Cardiovascular Risk

Danli Shi, Yukun Zhou, Shuang He, Siegfried K. Wagner, Yu Huang, Pearse A. Keane, Daniel S.W. Ting, Lei Zhang, Yingfeng Zheng, Mingguang He

Research output: Contribution to journalArticleResearchpeer-review


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.

Original languageEnglish
Article number100441
Number of pages11
JournalOphthalmology Science
Issue number3
Publication statusPublished - 1 May 2024


  • Cardiovascular disease
  • Cross-modality labeling
  • Retinal capillary quantification

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