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.

Multiple instance learning (MIL) is an effective and widely used approach for weakly supervised machine learning. In histopathology, MIL models have achieved remarkable success in tasks like tumor detection, biomarker prediction, and outcome prognostication. However, MIL explanation methods are still lagging behind, as they are limited to small bag sizes or disregard instance interactions. We revisit MIL through the lens of explainable AI (XAI) and introduce xMIL, a refined framework with more general assumptions. We demonstrate how to obtain improved MIL explanations using layer-wise relevance propagation (LRP) and conduct extensive evaluation experiments on three toy settings and four real-world histopathology datasets. Our approach consistently outperforms previous explanation attempts with particularly improved faithfulness scores on challenging biomarker prediction tasks. Finally, we showcase how xMIL explanations enable pathologists to extract insights from MIL models, representing a significant advance for knowledge discovery and model debugging in digital histopathology.

Periodic signals called Steady-State Visual Evoked Potentials (SSVEP) are elicited in the brain by flickering stimuli. They are usually detected by means of regression techniques that need relatively long trial lengths to provide feedback and/or sufficient number of calibration trials to be reliably estimated in the context of brain-computer interface (BCI). Thus, for BCI systems designed to operate with SSVEP signals, reliability is achieved at the expense of speed or extra recording time. Furthermore, regardless of the trial length, calibration free regression-based methods have been shown to suffer from significant performance drops when cognitive perturbations are present affecting the attention to the flickering stimuli. In this study we present a novel technique called Oscillatory Source Tensor Discriminant Analysis (OSTDA) that extracts oscillatory sources and classifies them using the newly developed tensor-based discriminant analysis with shrinkage. The proposed approach is robust for small sample size settings where only a few calibration trials are available. Besides, it works well with both low- and high-number-of-channel settings, using trials as short as one second. OSTDA performs similarly or significantly better than other three benchmarked state-of-the-art techniques under different experimental settings, including those with cognitive disturbances (i.e. four datasets with control, listening, speaking and thinking conditions). Overall, in this paper we show that OSTDA is the only pipeline among all the studied ones that can achieve optimal results in all analyzed conditions.