Bridging the gap between Performance and Interpretability: An Explainable Disentangled Multimodal Framework for Cancer Survival Prediction

While multimodal survival prediction models are increasingly more accurate, their complexity often reduces interpretability, limiting insight into how different data sources influence predictions. To address this, we introduce DIMAFx, an explainable multimodal framework for cancer survival prediction that produces disentangled, interpretable modality-specific and modality-shared representations from histopathology whole-slide images and transcriptomics data. Across multiple cancer cohorts, DIMAFx achieves state-of-the-art performance and improved representation disentanglement. Leveraging its interpretable design and SHapley Additive exPlanations, DIMAFx systematically reveals key multimodal interactions and the biological information encoded in the disentangled representations. In breast cancer survival prediction, the most predictive features contain modality-shared information, including one capturing solid tumor morphology contextualized primarily by late estrogen response, where higher-grade morphology aligned with pathway upregulation and increased risk, consistent with known breast cancer biology. Key modality-specific features capture microenvironmental signals from interacting adipose and stromal morphologies. These results show that multimodal models can overcome the traditional trade-off between performance and explainability, supporting their application in precision medicine.

Disentangled and Interpretable Multimodal Attention Fusion for Cancer Survival Prediction

To improve the prediction of cancer survival using whole-slide images and transcriptomics data, it is crucial to capture both modality-shared and modality-specific information. However, multimodal frameworks often entangle these representations, limiting interpretability and potentially suppressing discriminative features. To address this, we propose Disentangled and Interpretable Multimodal Attention Fusion (DIMAF), a multimodal framework that separates the intra- and inter-modal interactions within an attention-based fusion mechanism to learn distinct modality-specific and modality-shared representations. We introduce a loss based on Distance Correlation to promote disentanglement between these representations and integrate Shapley additive explanations to assess their relative contributions to survival prediction. We evaluate DIMAF on four public cancer survival datasets, achieving a relative average improvement of 1.85% in performance and 23.7% in disentanglement compared to current state-of-the-art multimodal models. Beyond improved performance, our interpretable framework enables a deeper exploration of the underlying interactions between and within modalities in cancer biology.

A CAD System for Colorectal Cancer from WSI: A Clinically Validated Interpretable ML-based Prototype

The integration of Artificial Intelligence (AI) and Digital Pathology has been increasing over the past years. Nowadays, applications of deep learning (DL) methods to diagnose cancer from whole-slide images (WSI) are, more than ever, a reality within different research groups. Nonetheless, the development of these systems was limited by a myriad of constraints regarding the lack of training samples, the scaling difficulties, the opaqueness of DL methods, and, more importantly, the lack of clinical validation. As such, we propose a system designed specifically for the diagnosis of colorectal samples. The construction of such a system consisted of four stages: (1) a careful data collection and annotation process, which resulted in one of the largest WSI colorectal samples datasets; (2) the design of an interpretable mixed-supervision scheme to leverage the domain knowledge introduced by pathologists through spatial annotations; (3) the development of an effective sampling approach based on the expected severeness of each tile, which decreased the computation cost by a factor of almost 6x; (4) the creation of a prototype that integrates the full set of features of the model to be evaluated in clinical practice. During these stages, the proposed method was evaluated in four separate test sets, two of them are external and completely independent. On the largest of those sets, the proposed approach achieved an accuracy of 93.44%. DL for colorectal samples is a few steps closer to stop being research exclusive and to become fully integrated in clinical practice.