Multimodal Outer Arithmetic Block Dual Fusion of Whole Slide Images and Omics Data for Precision Oncology

Developing a central nervous system (CNS) tumor classifier by integrating DNA methylation data with Whole Slide Images (WSI) offers significant potential for enhancing diagnostic precision in neuropathology. Existing approaches typically integrate encoded omic data with histology only once - either at an early or late fusion stage - while reintroducing encoded omic data to create a dual fusion variant remains unexplored. Nevertheless, reintroduction of omic embeddings during early and late fusion enables the capture of complementary information from localized patch-level and holistic slide-level interactions, allowing boosted performance through advanced multimodal integration. To achieve this, we propose a dual fusion framework that integrates omic data at both early and late stages, fully leveraging its diagnostic strength. In the early fusion stage, omic embeddings are projected into a patch-wise latent space, generating omic-WSI embeddings that encapsulate per-patch molecular and morphological insights, effectively incorporating this information into the spatial representation of histology. These embeddings are refined with a multiple instance learning gated attention mechanism to attend to critical patches. In the late fusion stage, we reintroduce the omic data by fusing it with slide-level omic-WSI embeddings using a Multimodal Outer Arithmetic Block (MOAB), which richly intermingles features from both modalities, capturing their global correlations and complementarity. We demonstrate accurate CNS tumor subtyping across 20 fine-grained subtypes and validate our approach on benchmark datasets, achieving improved survival prediction on TCGA-BLCA and competitive performance on TCGA-BRCA compared to state-of-the-art methods. This dual fusion strategy enhances interpretability and classification performance, highlighting its potential for clinical diagnostics.