David J. Harrison

Georg Wölflein, Dyke Ferber, Asier R. Meneghetti et al.

Weakly supervised whole slide image classification is a key task in computational pathology, which involves predicting a slide-level label from a set of image patches constituting the slide. Constructing models to solve this task involves multiple design choices, often made without robust empirical or conclusive theoretical justification. To address this, we conduct a comprehensive benchmarking of feature extractors to answer three critical questions: 1) Is stain normalisation still a necessary preprocessing step? 2) Which feature extractors are best for downstream slide-level classification? 3) How does magnification affect downstream performance? Our study constitutes the most comprehensive evaluation of publicly available pathology feature extractors to date, involving more than 10,000 training runs across 14 feature extractors, 9 tasks, 5 datasets, 3 downstream architectures, 2 levels of magnification, and various preprocessing setups. Our findings challenge existing assumptions: 1) We observe empirically, and by analysing the latent space, that skipping stain normalisation and image augmentations does not degrade performance, while significantly reducing memory and computational demands. 2) We develop a novel evaluation metric to compare relative downstream performance, and show that the choice of feature extractor is the most consequential factor for downstream performance. 3) We find that lower-magnification slides are sufficient for accurate slide-level classification. Contrary to previous patch-level benchmarking studies, our approach emphasises clinical relevance by focusing on slide-level biomarker prediction tasks in a weakly supervised setting with external validation cohorts. Our findings stand to streamline digital pathology workflows by minimising preprocessing needs and informing the selection of feature extractors.

Georg Wölflein, Lucie Charlotte Magister, Pietro Liò et al.

Traditional supervised learning tasks require a label for every instance in the training set, but in many real-world applications, labels are only available for collections (bags) of instances. This problem setting, known as multiple instance learning (MIL), is particularly relevant in the medical domain, where high-resolution images are split into smaller patches, but labels apply to the image as a whole. Recent MIL models are able to capture correspondences between patches by employing self-attention, allowing them to weigh each patch differently based on all other patches in the bag. However, these approaches still do not consider the relative spatial relationships between patches within the larger image, which is especially important in computational pathology. To this end, we introduce a novel MIL model with distance-aware self-attention (DAS-MIL), which explicitly takes into account relative spatial information when modelling the interactions between patches. Unlike existing relative position representations for self-attention which are discrete, our approach introduces continuous distance-dependent terms into the computation of the attention weights, and is the first to apply relative position representations in the context of MIL. We evaluate our model on a custom MNIST-based MIL dataset that requires the consideration of relative spatial information, as well as on CAMELYON16, a publicly available cancer metastasis detection dataset, where we achieve a test AUROC score of 0.91. On both datasets, our model outperforms existing MIL approaches that employ absolute positional encodings, as well as existing relative position representation schemes applied to MIL. Our code is available at https://anonymous.4open.science/r/das-mil.

Craig Myles, In Hwa Um, Craig Marshall et al.

Cancer remains one of the leading causes of morbidity and mortality worldwide. Comprehensive datasets that combine histopathological images with genetic and survival data across various tumour sites are essential for advancing computational pathology and personalised medicine. We present SurGen, a dataset comprising 1,020 H&E-stained whole-slide images (WSIs) from 843 colorectal cancer cases. The dataset includes detailed annotations for key genetic mutations (KRAS, NRAS, BRAF) and mismatch repair status, as well as survival data for 426 cases. We illustrate SurGen's utility with a proof-of-concept model that predicts mismatch repair status directly from WSIs, achieving a test area under the receiver operating characteristic curve of 0.8273. These preliminary results underscore the dataset's potential to facilitate research in biomarker discovery, prognostic modelling, and advanced machine learning applications in colorectal cancer and beyond. SurGen offers a valuable resource for the scientific community, enabling studies that require high-quality WSIs linked with comprehensive clinical and genetic information on colorectal cancer. Our initial findings affirm the dataset's capacity to advance diagnostic precision and foster the development of personalised treatment strategies in colorectal oncology. Data available online: https://doi.org/10.6019/S-BIAD1285.

Shuyang Wu, Yifu Qiu, Ines P. Nearchou et al.

Multiple Instance Learning (MIL) for whole slide image (WSI) analysis in computational pathology often neglects instance-level learning as supervision is typically provided only at the bag level, hindering the integrated consideration of instance and bag-level information during the analysis. In this work, we present LadderMIL, a framework designed to improve MIL through two perspectives: (1) employing instance-level supervision and (2) learning inter-instance contextual information at bag level. Firstly, we propose a novel Coarse-to-Fine Self-Distillation (CFSD) paradigm that probes and distils a network trained with bag-level information to adaptively obtain instance-level labels which could effectively provide the instance-level supervision for the same network in a self-improving way. Secondly, to capture inter-instance contextual information in WSI, we propose a Contextual Encoding Generator (CEG), which encodes the contextual appearance of instances within a bag. We also theoretically and empirically prove the instance-level learnability of CFSD. Our LadderMIL is evaluated on multiple clinically relevant benchmarking tasks including breast cancer receptor status classification, multi-class subtype classification, tumour classification, and prognosis prediction. Average improvements of 8.1%, 11% and 2.4% in AUC, F1-score, and C-index, respectively, are demonstrated across the five benchmarks, compared to the best baseline.