Atherosclerosis through Hierarchical Explainable Neural Network Analysis

TL;DR

This paper introduces ATHENA, a hierarchical explainable neural network that integrates clinical and molecular data to improve personalized classification and understanding of atherosclerosis, enabling better patient subtyping and disease management.

Contribution

The paper presents a novel hierarchical graph neural network framework that combines clinical features with molecular data for improved disease classification and interpretability in atherosclerosis.

Findings

Up to 13% improvement in AUC for classification

Up to 20% improvement in F1 score

Enables mechanistic patient subtype discovery

Abstract

In this work, we study the problem pertaining to personalized classification of subclinical atherosclerosis by developing a hierarchical graph neural network framework to leverage two characteristic modalities of a patient: clinical features within the context of the cohort, and molecular data unique to individual patients. Current graph-based methods for disease classification detect patient-specific molecular fingerprints, but lack consistency and comprehension regarding cohort-wide features, which are an essential requirement for understanding pathogenic phenotypes across diverse atherosclerotic trajectories. Furthermore, understanding patient subtypes often considers clinical feature similarity in isolation, without integration of shared pathogenic interdependencies among patients. To address these challenges, we introduce ATHENA: Atherosclerosis Through Hierarchical Explainable Neural Network Analysis, which constructs a novel hierarchical network representation through integrated modality learning; subsequently, it optimizes learned patient-specific molecular fingerprints that reflect individual omics data, enforcing consistency with cohort-wide patterns. With a primary clinical dataset of 391 patients, we demonstrate that this heterogeneous alignment of clinical features with molecular interaction patterns has significantly boosted subclinical atherosclerosis classification performance across various baselines by up to 13% in area under the receiver operating curve (AUC) and 20% in F1 score. Taken together, ATHENA enables mechanistically-informed patient subtype discovery through explainable AI (XAI)-driven subnetwork clustering; this novel integration framework strengthens personalized intervention strategies, thereby improving the prediction of atherosclerotic disease progression and management of their clinical actionable outcomes.