# Beyond Attention Heatmaps: How to Get Better Explanations for Multiple Instance Learning Models in Histopathology

arXiv: https://arxiv.org/abs/2603.08328 · HTML: https://mlsanity.com/paper/2603.08328/

## Key facts

- Cited by 2 papers in the map (data through 14 Oct 2026).
- Builds on 70 of its 146 references that are in the map.
- First posted on arXiv 9 Mar 2026.

## Builds on (most cited first, 30 of 70)

- [A Unified Approach to Interpreting Model Predictions](https://mlsanity.com/paper/1705.07874/) (2017)
- [Mamba: Linear-Time Sequence Modeling with Selective State Spaces](https://mlsanity.com/paper/2312.00752/) (2023)
- [Axiomatic Attribution for Deep Networks](https://mlsanity.com/paper/1703.01365/) (2017)
- [Learning Important Features Through Propagating Activation Differences](https://mlsanity.com/paper/1704.02685/) (2017)
- [Sanity Checks for Saliency Maps](https://mlsanity.com/paper/1810.03292/) (2018)
- [Attention-based Deep Multiple Instance Learning](https://mlsanity.com/paper/1802.04712/) (2018)
- [Attention is not Explanation](https://mlsanity.com/paper/1902.10186/) (2019)
- [Quantifying Attention Flow in Transformers](https://mlsanity.com/paper/2005.00928/) (2020)
- [Data Efficient and Weakly Supervised Computational Pathology on Whole Slide Images](https://mlsanity.com/paper/2004.09666/) (2020)
- [Attention is not not Explanation](https://mlsanity.com/paper/1908.04626/) (2019)
- [TransMIL: Transformer based Correlated Multiple Instance Learning for Whole Slide Image Classification](https://mlsanity.com/paper/2106.00908/) (2021)
- [Captum: A unified and generic model interpretability library for PyTorch](https://mlsanity.com/paper/2009.07896/) (2020)
- [Dual-stream Multiple Instance Learning Network for Whole Slide Image Classification with Self-supervised Contrastive Learning](https://mlsanity.com/paper/2011.08939/) (2020)
- [Evaluating the visualization of what a Deep Neural Network has learned](https://mlsanity.com/paper/1509.06321/) (2015)
- [Unmasking Clever Hans Predictors and Assessing What Machines Really Learn](https://mlsanity.com/paper/1902.10178/) (2019)
- [DeepSurv: Personalized Treatment Recommender System Using A Cox Proportional Hazards Deep Neural Network](https://mlsanity.com/paper/1606.00931/) (2016)
- [Methods for Interpreting and Understanding Deep Neural Networks](https://mlsanity.com/paper/1706.07979/) (2017)
- [From Anecdotal Evidence to Quantitative Evaluation Methods: A Systematic Review on Evaluating Explainable AI](https://mlsanity.com/paper/2201.08164/) (2022)
- [DTFD-MIL: Double-Tier Feature Distillation Multiple Instance Learning for Histopathology Whole Slide Image Classification](https://mlsanity.com/paper/2203.12081/) (2022)
- [Quantus: An Explainable AI Toolkit for Responsible Evaluation of Neural Network Explanations and Beyond](https://mlsanity.com/paper/2202.06861/) (2022)
- [Virchow2: Scaling Self-Supervised Mixed Magnification Models in Pathology](https://mlsanity.com/paper/2408.00738/) (2024)
- [Higher-Order Explanations of Graph Neural Networks via Relevant Walks](https://mlsanity.com/paper/2006.03589/) (2020)
- [Visual Language Pretrained Multiple Instance Zero-Shot Transfer for Histopathology Images](https://mlsanity.com/paper/2306.07831/) (2023)
- [CellViT: Vision Transformers for Precise Cell Segmentation and Classification](https://mlsanity.com/paper/2306.15350/) (2023)
- [HEST-1k: A Dataset for Spatial Transcriptomics and Histology Image Analysis](https://mlsanity.com/paper/2406.16192/) (2024)
- [XAI for Transformers: Better Explanations through Conservative Propagation](https://mlsanity.com/paper/2202.07304/) (2022)
- [Modeling Dense Multimodal Interactions Between Biological Pathways and Histology for Survival Prediction](https://mlsanity.com/paper/2304.06819/) (2023)
- [Deep Learning-based Computational Pathology Predicts Origins for Cancers of Unknown Primary](https://mlsanity.com/paper/2006.13932/) (2020)
- [MambaMIL: Enhancing Long Sequence Modeling with Sequence Reordering in Computational Pathology](https://mlsanity.com/paper/2403.06800/) (2024)
- [Feature Re-Embedding: Towards Foundation Model-Level Performance in Computational Pathology](https://mlsanity.com/paper/2402.17228/) (2024)

## Built on by (most cited first, 2 of 2)

- [Symb-xMIL: Symbolic Explanations for Multiple Instance Learning in Digital Pathology](https://mlsanity.com/paper/2606.06224/) (2026)
- [In-Context Multiple Instance Learning](https://mlsanity.com/paper/2606.06458/) (2026)

## Abstract (arXiv)

Multiple instance learning (MIL) has enabled substantial progress in computational histopathology, where a large amount of patches from gigapixel whole slide images are aggregated into slide-level predictions. Heatmaps are widely used to validate MIL models and to discover tissue biomarkers. Yet, the validity of these heatmaps has barely been investigated. In this work, we introduce a general framework for evaluating the quality of MIL heatmaps without requiring additional labels. We conduct a large-scale benchmark experiment to assess six explanation methods across histopathology task types (classification, regression, survival), MIL model architectures (Attention-, Transformer-, Mamba-based), and patch encoder backbones (UNI2, Virchow2). Our results show that explanation quality mostly depends on MIL model architecture and task type, with perturbation ("Single"), layer-wise relevance propagation (LRP), and integrated gradients (IG) consistently outperforming attention-based and gradient-based saliency heatmaps, which often fail to reflect model decision mechanisms. We further demonstrate the advanced capabilities of the best-performing explanation methods: (i) We provide a proof-of-concept that MIL heatmaps of a bulk gene expression prediction model can be correlated with spatial transcriptomics for biological validation, and (ii) showcase the discovery of distinct model strategies for predicting human papillomavirus (HPV) infection from head and neck cancer slides. Our work highlights the importance of validating MIL heatmaps and establishes that improved explainability can enable more reliable model validation and yield biological insights, making a case for a broader adoption of explainable AI in digital pathology. Our code is provided in a public GitHub repository: https://github.com/bifold-pathomics/xMIL/tree/xmil-journal