Applicability of Oculomics for Individual Risk Prediction: Repeatability and Robustness of Retinal Fractal Dimension Using DART and AutoMorph.

Purpose: To investigate whether fractal dimension (FD)-based oculomics could be used for individual risk prediction by evaluating repeatability and robustness. Methods: We used two datasets: "Caledonia," healthy adults imaged multiple times in quick succession for research (26 subjects, 39 eyes, 377 color fundus images), and GRAPE, glaucoma patients with baseline and follow-up visits (106 subjects, 196 eyes, 392 images). Mean follow-up time was 18.3 months in GRAPE; thus it provides a pessimistic lower bound because vasculature could change. FD was computed with DART and AutoMorph. Image quality was assessed with QuickQual, but no images were initially excluded. Pearson, Spearman, and intraclass correlation (ICC) were used for population-level repeatability. For individual-level repeatability, we introduce measurement noise parameter λ, which is within-eye standard deviation (SD) of FD measurements in units of between-eyes SD. Results: In Caledonia, ICC was 0.8153 for DART and 0.5779 for AutoMorph, Pearson/Spearman correlation (first and last image) 0.7857/0.7824 for DART, and 0.3933/0.6253 for AutoMorph. In GRAPE, Pearson/Spearman correlation (first and next visit) was 0.7479/0.7474 for DART, and 0.7109/0.7208 for AutoMorph (all P < 0.0001). Median λ in Caledonia without exclusions was 3.55% for DART and 12.65% for AutoMorph and improved to up to 1.67% and 6.64% with quality-based exclusions, respectively. Quality exclusions primarily mitigated large outliers. Worst quality in an eye correlated strongly with λ (Pearson 0.5350-0.7550, depending on dataset and method, all P < 0.0001). Conclusions: Repeatability was sufficient for individual-level predictions in heterogeneous populations. DART performed better on all metrics and might be able to detect small, longitudinal changes, highlighting the potential of robust methods.

Retinal Fractal Dimension Is a Potential Biomarker for Systemic Health-Evidence From a Mixed-Age, Primary-Care Population.

Purpose: To investigate whether fractal dimension (FD), a retinal trait relating to vascular complexity and a potential "oculomics" biomarker for systemic disease, is applicable to a mixed-age, primary-care population. Methods: We used cross-sectional data (96 individuals; 183 eyes; ages 18-81 years) from a university-based optometry clinic in Glasgow, Scotland, to study the association between FD and systemic health. We computed FD from color fundus images using Deep Approximation of Retinal Traits (DART), an artificial intelligence-based method designed to be more robust to poor image quality. Results: Despite DART being designed to be more robust, a significant association (P < 0.001) between image quality and FD remained. Consistent with previous literature, age was associated with lower FD (P < 0.001 univariate and when adjusting for image quality). However, FD variance was higher in older patients, and some patients over 60 had FD comparable to those of patients in their 20s. Prevalent systemic conditions were significantly (P = 0.037) associated with lower FD when adjusting for image quality and age. Conclusions: Our work suggests that FD as a biomarker for systemic health extends to mixed-age, primary-care populations. FD decreases with age but might not substantially decrease in everyone. This should be further investigated using longitudinal data. Finally, image quality was associated with FD, but it is unclear whether this finding is measurement error caused by image quality or confounded by age and health. Future work should investigate this to clarify whether adjusting for image quality is appropriate. Translational Relevance: FD could potentially be used in regular screening settings, but questions around image quality remain.

Using artificial intelligence to improve human performance: efficient retinal disease detection training with synthetic images.

BACKGROUND: Artificial intelligence (AI) in medical imaging diagnostics has huge potential, but human judgement is still indispensable. We propose an AI-aided teaching method that leverages generative AI to train students on many images while preserving patient privacy. METHODS: A web-based course was designed using 600 synthetic ultra-widefield (UWF) retinal images to teach students to detect disease in these images. The images were generated by stable diffusion, a large generative foundation model, which we fine-tuned with 6285 real UWF images from six categories: five retinal diseases (age-related macular degeneration, glaucoma, diabetic retinopathy, retinal detachment and retinal vein occlusion) and normal. 161 trainee orthoptists took the course. They were evaluated with two tests: one consisting of UWF images and another of standard field (SF) images, which the students had not encountered in the course. Both tests contained 120 real patient images, 20 per category. The students took both tests once before and after training, with a cool-off period in between. RESULTS: On average, students completed the course in 53 min, significantly improving their diagnostic accuracy. For UWF images, student accuracy increased from 43.6% to 74.1% (p<0.0001 by paired t-test), nearly matching the previously published state-of-the-art AI model's accuracy of 73.3%. For SF images, student accuracy rose from 42.7% to 68.7% (p<0.0001), surpassing the state-of-the-art AI model's 40%. CONCLUSION: Synthetic images can be used effectively in medical education. We also found that humans are more robust to novel situations than AI models, thus showcasing human judgement's essential role in medical diagnosis.

Choroidalyzer: An Open-Source, End-to-End Pipeline for Choroidal Analysis in Optical Coherence Tomography.

Purpose: To develop Choroidalyzer, an open-source, end-to-end pipeline for segmenting the choroid region, vessels, and fovea, and deriving choroidal thickness, area, and vascular index. Methods: We used 5600 OCT B-scans (233 subjects, six systemic disease cohorts, three device types, two manufacturers). To generate region and vessel ground-truths, we used state-of-the-art automatic methods following manual correction of inaccurate segmentations, with foveal positions manually annotated. We trained a U-Net deep learning model to detect the region, vessels, and fovea to calculate choroid thickness, area, and vascular index in a fovea-centered region of interest. We analyzed segmentation agreement (AUC, Dice) and choroid metrics agreement (Pearson, Spearman, mean absolute error [MAE]) in internal and external test sets. We compared Choroidalyzer to two manual graders on a small subset of external test images and examined cases of high error. Results: Choroidalyzer took 0.299 seconds per image on a standard laptop and achieved excellent region (Dice: internal 0.9789, external 0.9749), very good vessel segmentation performance (Dice: internal 0.8817, external 0.8703), and excellent fovea location prediction (MAE: internal 3.9 pixels, external 3.4 pixels). For thickness, area, and vascular index, Pearson correlations were 0.9754, 0.9815, and 0.8285 (internal)/0.9831, 0.9779, 0.7948 (external), respectively (all P < 0.0001). Choroidalyzer's agreement with graders was comparable to the intergrader agreement across all metrics. Conclusions: Choroidalyzer is an open-source, end-to-end pipeline that accurately segments the choroid and reliably extracts thickness, area, and vascular index. Especially choroidal vessel segmentation is a difficult and subjective task, and fully automatic methods like Choroidalyzer could provide objectivity and standardization.

An Open-Source Deep Learning Algorithm for Efficient and Fully Automatic Analysis of the Choroid in Optical Coherence Tomography.

Purpose: To develop an open-source, fully automatic deep learning algorithm, DeepGPET, for choroid region segmentation in optical coherence tomography (OCT) data. Methods: We used a dataset of 715 OCT B-scans (82 subjects, 115 eyes) from three clinical studies related to systemic disease. Ground-truth segmentations were generated using a clinically validated, semiautomatic choroid segmentation method, Gaussian Process Edge Tracing (GPET). We finetuned a U-Net with the MobileNetV3 backbone pretrained on ImageNet. Standard segmentation agreement metrics, as well as derived measures of choroidal thickness and area, were used to evaluate DeepGPET, alongside qualitative evaluation from a clinical ophthalmologist. Results: DeepGPET achieved excellent agreement with GPET on data from three clinical studies (AUC = 0.9994, Dice = 0.9664; Pearson correlation = 0.8908 for choroidal thickness and 0.9082 for choroidal area), while reducing the mean processing time per image on a standard laptop CPU from 34.49 ± 15.09 seconds using GPET to 1.25 ± 0.10 seconds using DeepGPET. Both methods performed similarly according to a clinical ophthalmologist who qualitatively judged a subset of segmentations by GPET and DeepGPET, based on smoothness and accuracy of segmentations. Conclusions: DeepGPET, a fully automatic, open-source algorithm for choroidal segmentation, will enable researchers to efficiently extract choroidal measurements, even for large datasets. As no manual interventions are required, DeepGPET is less subjective than semiautomatic methods and could be deployed in clinical practice without requiring a trained operator. Translational Relevance: DeepGPET addresses the lack of open-source, fully automatic, and clinically relevant choroid segmentation algorithms, and its subsequent public release will facilitate future choroidal research in both ophthalmology and wider systemic health.

Fine-mapping of retinal vascular complexity loci identifies Notch regulation as a shared mechanism with myocardial infarction outcomes.

There is increasing evidence that the complexity of the retinal vasculature measured as fractal dimension, Df, might offer earlier insights into the progression of coronary artery disease (CAD) before traditional biomarkers can be detected. This association could be partly explained by a common genetic basis; however, the genetic component of Df is poorly understood. We present a genome-wide association study (GWAS) of 38,000 individuals with white British ancestry from the UK Biobank aimed to comprehensively study the genetic component of Df and analyse its relationship with CAD. We replicated 5 Df loci and found 4 additional loci with suggestive significance (P < 1e-05) to contribute to Df variation, which previously were reported in retinal tortuosity and complexity, hypertension, and CAD studies. Significant negative genetic correlation estimates support the inverse relationship between Df and CAD, and between Df and myocardial infarction (MI), one of CAD's fatal outcomes. Fine-mapping of Df loci revealed Notch signalling regulatory variants supporting a shared mechanism with MI outcomes. We developed a predictive model for MI incident cases, recorded over a 10-year period following clinical and ophthalmic evaluation, combining clinical information, Df, and a CAD polygenic risk score. Internal cross-validation demonstrated a considerable improvement in the area under the curve (AUC) of our predictive model (AUC = 0.770 ± 0.001) when comparing with an established risk model, SCORE, (AUC = 0.741 ± 0.002) and extensions thereof leveraging the PRS (AUC = 0.728 ± 0.001). This evidences that Df provides risk information beyond demographic, lifestyle, and genetic risk factors. Our findings shed new light on the genetic basis of Df, unveiling a common control with MI, and highlighting the benefits of its application in individualised MI risk prediction.