# C2MIL: Synchronizing Semantic and Topological Causalities in Multiple Instance Learning for Robust and Interpretable Survival Analysis

arXiv: https://arxiv.org/abs/2509.20152 · HTML: https://mlsanity.com/paper/2509.20152/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 21 of its 45 references that are in the map.
- First posted on arXiv 24 Sep 2025.

## Builds on (most cited first, 21 of 21)

- [PyTorch: An Imperative Style, High-Performance Deep Learning Library](https://mlsanity.com/paper/1912.01703/) (2019)
- [Categorical Reparameterization with Gumbel-Softmax](https://mlsanity.com/paper/1611.01144/) (2016)
- [Fast Graph Representation Learning with PyTorch Geometric](https://mlsanity.com/paper/1903.02428/) (2019)
- [Estimating or Propagating Gradients Through Stochastic Neurons for Conditional Computation](https://mlsanity.com/paper/1308.3432/) (2013)
- [Attention-based Deep Multiple Instance Learning](https://mlsanity.com/paper/1802.04712/) (2018)
- [TransMIL: Transformer based Correlated Multiple Instance Learning for Whole Slide Image Classification](https://mlsanity.com/paper/2106.00908/) (2021)
- [Graph Transformer Networks](https://mlsanity.com/paper/1911.06455/) (2019)
- [Dual-stream Multiple Instance Learning Network for Whole Slide Image Classification with Self-supervised Contrastive Learning](https://mlsanity.com/paper/2011.08939/) (2020)
- [DTFD-MIL: Double-Tier Feature Distillation Multiple Instance Learning for Histopathology Whole Slide Image Classification](https://mlsanity.com/paper/2203.12081/) (2022)
- [Whole Slide Images based Cancer Survival Prediction using Attention Guided Deep Multiple Instance Learning Networks](https://mlsanity.com/paper/2009.11169/) (2020)
- [Whole Slide Images are 2D Point Clouds: Context-Aware Survival Prediction using Patch-based Graph Convolutional Networks](https://mlsanity.com/paper/2107.13048/) (2021)
- [Causal Attention for Interpretable and Generalizable Graph Classification](https://mlsanity.com/paper/2112.15089/) (2021)
- [Artificial Intelligence for Digital and Computational Pathology](https://mlsanity.com/paper/2401.06148/) (2023)
- [Interventional Bag Multi-Instance Learning On Whole-Slide Pathological Images](https://mlsanity.com/paper/2303.06873/) (2023)
- [Feature Re-Embedding: Towards Foundation Model-Level Performance in Computational Pathology](https://mlsanity.com/paper/2402.17228/) (2024)
- [Dynamic Graph Representation with Knowledge-aware Attention for Histopathology Whole Slide Image Analysis](https://mlsanity.com/paper/2403.07719/) (2024)
- [Deep Survival Analysis](https://mlsanity.com/paper/1608.02158/) (2016)
- [AdvMIL: Adversarial Multiple Instance Learning for the Survival Analysis on Whole-Slide Images](https://mlsanity.com/paper/2212.06515/) (2022)
- [A Topological Perspective on Causal Inference](https://mlsanity.com/paper/2107.08558/) (2021)
- [Bag Graph: Multiple Instance Learning using Bayesian Graph Neural Networks](https://mlsanity.com/paper/2202.11132/) (2022)
- [CIMIL-CRC: a clinically-informed multiple instance learning framework for patient-level colorectal cancer molecular subtypes classification from H&E stained images](https://mlsanity.com/paper/2401.16131/) (2024)

## Abstract (arXiv)

Graph-based Multiple Instance Learning (MIL) is widely used in survival analysis with Hematoxylin and Eosin (H&E)-stained whole slide images (WSIs) due to its ability to capture topological information. However, variations in staining and scanning can introduce semantic bias, while topological subgraphs that are not relevant to the causal relationships can create noise, resulting in biased slide-level representations. These issues can hinder both the interpretability and generalization of the analysis. To tackle this, we introduce a dual structural causal model as the theoretical foundation and propose a novel and interpretable dual causal graph-based MIL model, C2MIL. C2MIL incorporates a novel cross-scale adaptive feature disentangling module for semantic causal intervention and a new Bernoulli differentiable causal subgraph sampling method for topological causal discovery. A joint optimization strategy combining disentangling supervision and contrastive learning enables simultaneous refinement of both semantic and topological causalities. Experiments demonstrate that C2MIL consistently improves generalization and interpretability over existing methods and can serve as a causal enhancement for diverse MIL baselines. The code is available at https://github.com/mimic0127/C2MIL.