CRESTomics: Analyzing Carotid Plaques in the CREST-2 Trial with a New Additive Classification Model

Carotid atherosclerosis is a major contributor to ischemic stroke and transient ischemic attack. Conventional ultrasound assessment is commonly based on intima-media thickness, plaque appearance, stenosis degree, and peak systolic velocity, but these morphology- and velocity-based indicators may not fully capture patient-specific vascular risk. This study presents AtheroFlow-XNet, a CUBS-compatible ultrasound morphology and uncertainty-aware learning baseline for carotid intima-media segmentation and preliminary risk prediction. Using the Carotid Ultrasound Boundary Study dataset, manual lumen-intima and media-adventitia boundary annotations were converted into dense intima-media masks for supervised segmentation. Clinical variables were incorporated into an auxiliary risk-prediction branch, and Monte Carlo dropout was used for uncertainty-aware inference. The model was evaluated using a patient-level train-validation-test split with 1,522 training images, 326 validation images, and 328 testing images. The proposed model achieved a Dice coefficient of 0.7930 for LI-MA mask segmentation, a segmentation loss of 0.2359, and an area under the receiver operating characteristic curve of 0.6910 for preliminary risk prediction. Qualitative results showed that predicted masks were generally aligned with manual annotations, while uncertainty maps highlighted ambiguous wall-boundary regions. These results suggest that ultrasound-derived carotid morphology can support automated wall analysis and uncertainty-aware interpretation. Since CUBS does not provide Doppler waveforms or CFD-derived hemodynamic biomarkers, this work should be interpreted as a reproducible morphology-driven baseline. Future work will incorporate Doppler-derived flow profiles, patient-specific vascular reconstruction, and CFD-based wall shear biomarkers.

Cardiovascular risk prediction remains limited by incomplete clinical data and imaging biomarkers that reduce computed tomography (CT) to a small number of handcrafted features. We developed CARDINAL (Cardiovascular Assessment via Representation learning from Deep Imaging with Nested Anatomical Latent embeddings), a clinically grounded framework that learns compact representations from routine non-contrast cardiac CT for major adverse cardiovascular event (MACE) prediction. In 17,659 patients, CARDINAL was evaluated for 1-, 3-, 5-, and 10-year MACE prediction against American Heart Association (AHA) pooled cohort equations (PCE), AHA predicting risk of cardiovascular disease events (PREVENT), coronary artery calcium (CAC), segmentation-derived CT biomarkers, and 70-feature structural radiomics. Gains were largest at longer horizons. At 10 years, CARDINAL (joint) achieved an area under the receiver operating characteristic curve (AUROC) of 0.866 $\pm$ 0.020 and an area under the precision-recall curve (AUPRC) of 0.890 $\pm$ 0.015, compared with an AUROC of 0.826 $\pm$ 0.023 and an AUPRC of 0.826 $\pm$ 0.022 for structural radiomics, the strongest baseline. CARDINAL also achieved the highest survival concordance index (C-index), 0.753 $\pm$ 0.015, and high-versus-low risk-tertile hazard ratio, 10.78 $\pm$ 3.16, with favorable reclassification and exploratory calibration. These findings suggest that non-contrast cardiac CT contains prognostic information beyond conventional risk equations, CAC scoring, and engineered imaging biomarkers.

Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide, yet early risk detection is often limited by available diagnostics. Carotid ultrasound, a non-invasive and widely accessible modality, encodes rich structural and hemodynamic information that is largely untapped. Here, we present a machine learning (ML) framework that extracts clinically meaningful representations of vascular damage (VD) from carotid ultrasound videos, using hypertension as a weak proxy label. The model learns robust features that are biologically plausible, interpretable, and strongly associated with established cardiovascular risk factors, comorbidities, and laboratory measures. High VD stratifies individuals for myocardial infarction, cardiac death, and all-cause mortality, matching or outperforming conventional risk models such as SCORE2. Explainable AI analyses reveal that the model relies on vessel morphology and perivascular tissue characteristics, uncovering novel functional and anatomical signatures of vascular damage. This work demonstrates that routine carotid ultrasound contains far more prognostic information than previously recognized. Our approach provides a scalable, non-invasive, and cost-effective tool for population-wide cardiovascular risk assessment, enabling earlier and more personalized prevention strategies without reliance on laboratory tests or complex clinical inputs.