Department of Radiology, Case Western Reserve University, Cleveland, OH, 44106, USA Abstract Background: Recent studies have used basic epicardial adipose tissue (EAT) assessments (e.g., volume and mean HU) to predict risk of atherosclerosis-related, major adverse cardiovascular events (MACE). Objectives: Create novel, hand-crafted EAT features, "fat-omics", to capture the pathophysiology of EAT and improve MACE prediction. We extracted 148 radiomic features (morphological, spatial, and intensity) and used Cox elastic-net for feature reduction and prediction of MACE. Results: Traditional fat features gave marginal prediction (EAT-volume/EAT-mean-HU/ BMI gave C-index 0.53/0.55/0.57, Significant improvement was obtained with 15 fat-omics features (C-index=0.69, Other high-risk features include kurtosis-of-EAT-thickness, reflecting the heterogeneity of thicknesses, and EATvolume-in-the-top-25%-of-the-heart, emphasizing adipose near the proximal coronary arteries. Kaplan-Meyer plots of Cox-identified, high-and low-risk patients were well separated with the median of the fat-omics risk, while high-risk group having HR 2.4 times that of the low-risk group (P<0.001). Conclusion: Preliminary findings indicate an opportunity to use more finely tuned, explainable assessments on EAT for improved cardiovascular risk prediction. Introduction Cardiovascular disease is a major cause of morbidity and mortality worldwide (1), leading to 17.9 million deaths globally each year (2). Numerous risk score methodologies have been developed to predict risks from cardiovascular disease, but these methods often lack sufficient discrimination (3). Accurate explainable risk prediction models will provide useful information to patients and physicians for more personalized medications and interventions. Previous studies have determined the usefulness of coronary calcification Agatston score as obtained from CT calcium score (CTCS) images for cardiovascular risk prediction.

Background. Coronary artery calcium (CAC) is a powerful predictor of major adverse cardiovascular events (MACE). Traditional Agatston score simply sums the calcium, albeit in a non-linear way, leaving room for improved calcification assessments that will more fully capture the extent of disease. Objective. To determine if AI methods using detailed calcification features (i.e., calcium-omics) can improve MACE prediction. Methods. We investigated additional features of calcification including assessment of mass, volume, density, spatial distribution, territory, etc. We used a Cox model with elastic-net regularization on 2457 CT calcium score (CTCS) enriched for MACE events obtained from a large no-cost CLARIFY program (ClinicalTri-als.gov Identifier: NCT04075162). We employed sampling techniques to enhance model training. We also investigated Cox models with selected features to identify explainable high-risk characteristics. Results. Our proposed calcium-omics model with modified synthetic down sampling and up sampling gave C-index (80.5%/71.6%) and two-year AUC (82.4%/74.8%) for (80:20, training/testing), respectively (sampling was applied to the training set only). Results compared favorably to Agatston which gave C-index (71.3%/70.3%) and AUC (71.8%/68.8%), respectively. Among calcium-omics features, numbers of calcifications, LAD mass, and diffusivity (a measure of spatial distribution) were important determinants of increased risk, with dense calcification (>1000HU) associated with lower risk. The calcium-omics model reclassified 63% of MACE patients to the high risk group in a held-out test. The categorical net-reclassification index was NRI=0.153. Conclusions. AI analysis of coronary calcification can lead to improved results as compared to Agatston scoring. Our findings suggest the utility of calcium-omics in improved prediction of risk.