# ProtoPathway: Biologically Structured Prototype-Pathway Fusion for Multimodal Cancer Survival Prediction

arXiv: https://arxiv.org/abs/2605.21454 · HTML: https://mlsanity.com/paper/2605.21454/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 27 of its 53 references that are in the map.
- First posted on arXiv 20 May 2026.

## Builds on (most cited first, 27 of 27)

- [Graph Attention Networks](https://mlsanity.com/paper/1710.10903/) (2017)
- [A Unified Approach to Interpreting Model Predictions](https://mlsanity.com/paper/1705.07874/) (2017)
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- ["Why Should I Trust You?": Explaining the Predictions of Any Classifier](https://mlsanity.com/paper/1602.04938/) (2016)
- [Interpretability Beyond Feature Attribution: Quantitative Testing with Concept Activation Vectors (TCAV)](https://mlsanity.com/paper/1711.11279/) (2017)
- [Attention-based Deep Multiple Instance Learning](https://mlsanity.com/paper/1802.04712/) (2018)
- [Concept Bottleneck Models](https://mlsanity.com/paper/2007.04612/) (2020)
- [Attention is not Explanation](https://mlsanity.com/paper/1902.10186/) (2019)
- [Object-Centric Learning with Slot Attention](https://mlsanity.com/paper/2006.15055/) (2020)
- [How Attentive are Graph Attention Networks?](https://mlsanity.com/paper/2105.14491/) (2021)
- [This Looks Like That: Deep Learning for Interpretable Image Recognition](https://mlsanity.com/paper/1806.10574/) (2018)
- [Self-Normalizing Neural Networks](https://mlsanity.com/paper/1706.02515/) (2017)
- [TransMIL: Transformer based Correlated Multiple Instance Learning for Whole Slide Image Classification](https://mlsanity.com/paper/2106.00908/) (2021)
- [Dual-stream Multiple Instance Learning Network for Whole Slide Image Classification with Self-supervised Contrastive Learning](https://mlsanity.com/paper/2011.08939/) (2020)
- [Fooling LIME and SHAP: Adversarial Attacks on Post hoc Explanation Methods](https://mlsanity.com/paper/1911.02508/) (2019)
- [On Completeness-aware Concept-Based Explanations in Deep Neural Networks](https://mlsanity.com/paper/1910.07969/) (2019)
- [Pathomic Fusion: An Integrated Framework for Fusing Histopathology and Genomic Features for Cancer Diagnosis and Prognosis](https://mlsanity.com/paper/1912.08937/) (2019)
- [Modeling Dense Multimodal Interactions Between Biological Pathways and Histology for Survival Prediction](https://mlsanity.com/paper/2304.06819/) (2023)
- [Multimodal Optimal Transport-based Co-Attention Transformer with Global Structure Consistency for Survival Prediction](https://mlsanity.com/paper/2306.08330/) (2023)
- [Morphological Prototyping for Unsupervised Slide Representation Learning in Computational Pathology](https://mlsanity.com/paper/2405.11643/) (2024)
- [Multimodal Prototyping for cancer survival prediction](https://mlsanity.com/paper/2407.00224/) (2024)
- [Prototypical Information Bottlenecking and Disentangling for Multimodal Cancer Survival Prediction](https://mlsanity.com/paper/2401.01646/) (2024)
- [Interpretable by Design: Learning Predictors by Composing Interpretable Queries](https://mlsanity.com/paper/2207.00938/) (2022)
- [ProtoMIL: Multiple Instance Learning with Prototypical Parts for Whole-Slide Image Classification](https://mlsanity.com/paper/2108.10612/) (2021)
- [Predicting molecular phenotypes from histopathology images: a transcriptome-wide expression-morphology analysis in breast cancer](https://mlsanity.com/paper/2009.08917/) (2020)
- [TPMIL: Trainable Prototype Enhanced Multiple Instance Learning for Whole Slide Image Classification](https://mlsanity.com/paper/2305.00696/) (2023)
- [Slot-Mixup with Subsampling: A Simple Regularization for WSI Classification](https://mlsanity.com/paper/2311.17466/) (2023)

## Abstract (arXiv)

We introduce ProtoPathway, an interpretable-by-design multimodal framework for cancer survival prediction that unifies whole slide imaging and transcriptomics through encoders producing biologically grounded representations on both sides of the fusion. On the histopathology side, K learnable morphological prototypes, trained end-to-end with the survival objective, serve as the slide representation itself: patches flow into prototype tokens via soft assignment, compressing variable-length patch sets into fixed task-adaptive tokens. On the genomic side, a bipartite graph neural network encodes gene expression within the Reactome pathway hierarchy, producing pathway embeddings that reflect both constituent genes and their broader biological context through bidirectional message passing over a shared gene--pathway graph. Cross-modal attention then operates over a compact prototype × pathway matrix in which prototypes query pathways, modeling the biological direction in which molecular programs give rise to tissue morphology. Because both axes carry stable task-learned identity, the attention matrix is itself an interpretability output, yielding native inference-time attribution across the full biological hierarchy, from genes through pathways and prototypes to spatial tissue maps. We evaluate on five TCGA cancer cohorts, demonstrating competitive or superior survival prediction with substantially improved biological interpretability and reduced computational cost, with interpretability claims validated through fold-stratified rank-based population-level analysis. Our source code, model weights, and Reactome pathways, together with a unified codebase reimplementing all multimodal survival baselines under identical preprocessing and evaluation, are available at: https://github.com/AmayaGS/ProtoPathway.