EAGLE: Efficient Alignment of Generalized Latent Embeddings for Multimodal Survival Prediction with Interpretable Attribution Analysis

Abstract: Accurate cancer survival prediction requires integration of diverse data modalities that reflect the complex interplay between imaging, clinical parameters, and textual reports. However, existing multimodal approaches suffer from simplistic fusion strategies, massive computational requirements, and lack of interpretability-critical barriers to clinical adoption. We present EAGLE (Efficient Alignment of Generalized Latent Embeddings), a novel deep learning framework that addresses these limitations through attention-based multimodal fusion with comprehensive attribution analysis. EAGLE introduces four key innovations: (1) dynamic cross-modal attention mechanisms that learn hierarchical relationships between modalities, (2) massive dimensionality reduction (99.96%) while maintaining predictive performance, (3) three complementary attribution methods providing patient-level interpretability, and (4) a unified pipeline enabling seamless adaptation across cancer types. We evaluated EAGLE on 911 patients across three distinct malignancies: glioblastoma (GBM, n=160), intraductal papillary mucinous neoplasms (IPMN, n=171), and non-small cell lung cancer (NSCLC, n=580). Patient-level analysis showed high-risk individuals relied more heavily on adverse imaging features, while low-risk patients demonstrated balanced modality contributions. Risk stratification identified clinically meaningful groups with 4-fold (GBM) to 5-fold (NSCLC) differences in median survival, directly informing treatment intensity decisions. By combining state-of-the-art performance with clinical interpretability, EAGLE bridges the gap between advanced AI capabilities and practical healthcare deployment, offering a scalable solution for multimodal survival prediction that enhances both prognostic accuracy and physician trust in automated predictions.