CAR-MIL: Counterfactual Attention Regularization for Multiple Instance Learning
Authors: Imane Chraki, Pierre Marza, Stergios Christodoulidis, Maria Vakalopoulou
Organizations: Université Paris-Saclay, CentraleSupélec, Gustave Roussy, INSERM, IHU PRISM, Cancer Data Science Unit, France · Université Paris-Saclay, CentraleSupélec, MICS Laboratory, France
Abstract
Multiple Instance Learning (MIL) is widely used for weakly supervised learning, particularly in digital pathology, where fine-grained annotations are costly. Most MIL methods aggregate instance features via attention mechanisms. However, attention weights do not always faithfully reflect instance importance and may focus on spuriously correlated regions. In this work, we propose CAR-MIL, a framework that explicitly guides attention learning through a counterfactual attention regularization objective inspired by counterfactual explanations. Built on a standard attention-based MIL architecture, our approach introduces a lightweight counterfactual attention branch trained to produce an alternative prediction while remaining close to the factual attention distribution. This encourages prediction changes to arise from minimal, structured redistributions of attention, leading to more informative evidence allocation. The resulting factual and counterfactual attention maps capture complementary evidence: the former highlights regions supporting the prediction, while the latter reveals regions whose reweighting would challenge it. We evaluate our method on synthetic MIL benchmarks with instance-level ground truth enabling controlled analysis of attention behavior and on five digital pathology datasets across four tasks. CAR-MIL maintains competitive classification performance, with the largest gains observed on more challenging tasks, while improving attention reliability, demonstrating the benefits of integrating counterfactual explainability reasoning into attention learning. Code is available at: https://github.com/ImaneCR/CAR-MIL/.
Existing computational pathology methods predominantly operate within whole-slide image (WSI)-level multiple instance learning (MIL) paradigms, while patient-level modeling remains underexplored. In routine pathological practice, however, pathologists derive diagnostic and prognostic conclusions by integrating evidence across multiple WSIs rather than relying on any single slide. This discrepancy creates a fundamental misalignment when patient-level supervision is directly imposed on conventional MIL frameworks, often leading to unstable optimization and degraded predictive reliability. To address this issue, we propose Anchor-Guided Evidence MIL (AGE-MIL), a weakly supervised framework for patient-level prediction. AGE-MIL constructs a patient-level anchor from slide representations to capture global pathological context and guide the retrieval and integration of diagnostically relevant local patches, enabling robust patient-level modeling. Patient-level risk is further modeled as an evidence accumulation process, promoting stable optimization under weak supervision. AGE-MIL is evaluated on six clinically relevant patient-level prediction tasks from two independent cohorts. Experimental results show that the proposed framework consistently outperforms eight state-of-the-art MIL methods. Code is available at https://github.com/wodeniua/AGE-MIL.
Multiple instance learning (MIL) is the standard approach for whole-slide image (WSI) classification and survival prediction, where attention-based models ag gregate patch features into slide-level predictions. These models treat attention weights as evidence for their predictions, but attention is optimized for classi fication, not for identifying which patches actually support the diagnosis. This conflation leads to three failures: selected patches are insufficient (keeping them alone drops Macro-F1 by 0.078), unnecessary (removing them barely changes the prediction), and unrecoverable (continuous attention scores disagree with discrete patch subsets used at inference). The central premise is that evidence quality should be optimized directly through explicit criteria- Sufficiency, Necessity, and Recov erability (S/N/R)- rather than inherited as a byproduct of classification. GCE-MIL is a backbone-agnostic wrapper implemented through three injection modes and three evidence components: a grounding mechanism that aligns selection with domain-specific concepts, noisy-OR coverage that acts as a differentiable proxy for interventional evidence search, and threshold-plus-repair recovery that converts continuous selectors into discrete subsets through marginal-guided repair. Across 9 backbones and 9 datasets (81 configurations), GCE-MIL improves average Macro-F1 by 0.024 and C-index by 0.014, reduces the continuous-discrete gap by 4-7, and increases complement degradation by 2-4. With optional tile prefiltering after discrete recovery, inference runs up to 5 faster while retaining 0.989 full-bag utility.
Attention-based Multiple Instance Learning aggregators in medical imaging are prone to attention concentration, producing overconfident and unstable predictions. We introduce QG-MIL, a gated transformer aggregator that addresses this through four synergistic architectural components: RMSNorm-based pre-normalization, per-head QK normalization, fine-grained attention output gating, and SwiGLU-style feed-forward modules. Together, these design choices stabilize training and distribute attention more uniformly across instances without auxiliary losses, masking, or multi-stage regularization. We evaluate QG-MIL across six benchmarks spanning whole-slide pathology and cell-level hematology, covering two fundamentally different MIL scales. The best-performing QG-MIL variants outperform leading baselines on all six benchmarks, with an average improvement of +6.1 mean macro F1 points. Attention overlays and attention mass analysis confirm more distributed instance weighting. Ablation studies show that while individual components can match the full model on specific datasets, the QG-MIL design provides the most consistent cross-domain performance and tightest variance when compared to selected baselines. We release a configurable implementation to support reproducibility at: https://github.com/unica-visual-intelligence-lab/QG-MIL
Luca Zedda, Davide Antonio Mura, Cecilia Di Ruberto +4