DinoBloom: A Foundation Model for Generalizable Cell Embeddings in Hematology

In hematology, computational models offer significant potential to improve diagnostic accuracy, streamline workflows, and reduce the tedious work of analyzing single cells in peripheral blood or bone marrow smears. However, clinical adoption of computational models has been hampered by the lack of generalization due to large batch effects, small dataset sizes, and poor performance in transfer learning from natural images. To address these challenges, we introduce DinoBloom, the first foundation model for single cell images in hematology, utilizing a tailored DINOv2 pipeline. Our model is built upon an extensive collection of 13 diverse, publicly available datasets of peripheral blood and bone marrow smears, the most substantial open-source cohort in hematology so far, comprising over 380,000 white blood cell images. To assess its generalization capability, we evaluate it on an external dataset with a challenging domain shift. We show that our model outperforms existing medical and non-medical vision models in (i) linear probing and k-nearest neighbor evaluations for cell-type classification on blood and bone marrow smears and (ii) weakly supervised multiple instance learning for acute myeloid leukemia subtyping by a large margin. A family of four DinoBloom models (small, base, large, and giant) can be adapted for a wide range of downstream applications, be a strong baseline for classification problems, and facilitate the assessment of batch effects in new datasets. All models are available at github.com/marrlab/DinoBloom.

B-Cos Aligned Transformers Learn Human-Interpretable Features

Vision Transformers (ViTs) and Swin Transformers (Swin) are currently state-of-the-art in computational pathology. However, domain experts are still reluctant to use these models due to their lack of interpretability. This is not surprising, as critical decisions need to be transparent and understandable. The most common approach to understanding transformers is to visualize their attention. However, attention maps of ViTs are often fragmented, leading to unsatisfactory explanations. Here, we introduce a novel architecture called the B-cos Vision Transformer (BvT) that is designed to be more interpretable. It replaces all linear transformations with the B-cos transform to promote weight-input alignment. In a blinded study, medical experts clearly ranked BvTs above ViTs, suggesting that our network is better at capturing biomedically relevant structures. This is also true for the B-cos Swin Transformer (Bwin). Compared to the Swin Transformer, it even improves the F1-score by up to 4.7% on two public datasets.

Low-resource finetuning of foundation models beats state-of-the-art in histopathology

To handle the large scale of whole slide images in computational pathology, most approaches first tessellate the images into smaller patches, extract features from these patches, and finally aggregate the feature vectors with weakly-supervised learning. The performance of this workflow strongly depends on the quality of the extracted features. Recently, foundation models in computer vision showed that leveraging huge amounts of data through supervised or self-supervised learning improves feature quality and generalizability for a variety of tasks. In this study, we benchmark the most popular vision foundation models as feature extractors for histopathology data. We evaluate the models in two settings: slide-level classification and patch-level classification. We show that foundation models are a strong baseline. Our experiments demonstrate that by finetuning a foundation model on a single GPU for only two hours or three days depending on the dataset, we can match or outperform state-of-the-art feature extractors for computational pathology. These findings imply that even with little resources one can finetune a feature extractor tailored towards a specific downstream task and dataset. This is a considerable shift from the current state, where only few institutions with large amounts of resources and datasets are able to train a feature extractor. We publish all code used for training and evaluation as well as the finetuned models.

From Whole-slide Image to Biomarker Prediction: A Protocol for End-to-End Deep Learning in Computational Pathology

Hematoxylin- and eosin (H&E) stained whole-slide images (WSIs) are the foundation of diagnosis of cancer. In recent years, development of deep learning-based methods in computational pathology enabled the prediction of biomarkers directly from WSIs. However, accurately linking tissue phenotype to biomarkers at scale remains a crucial challenge for democratizing complex biomarkers in precision oncology. This protocol describes a practical workflow for solid tumor associative modeling in pathology (STAMP), enabling prediction of biomarkers directly from WSIs using deep learning. The STAMP workflow is biomarker agnostic and allows for genetic- and clinicopathologic tabular data to be included as an additional input, together with histopathology images. The protocol consists of five main stages which have been successfully applied to various research problems: formal problem definition, data preprocessing, modeling, evaluation and clinical translation. The STAMP workflow differentiates itself through its focus on serving as a collaborative framework that can be used by clinicians and engineers alike for setting up research projects in the field of computational pathology. As an example task, we applied STAMP to the prediction of microsatellite instability (MSI) status in colorectal cancer, showing accurate performance for the identification of MSI-high tumors. Moreover, we provide an open-source codebase which has been deployed at several hospitals across the globe to set up computational pathology workflows. The STAMP workflow requires one workday of hands-on computational execution and basic command line knowledge.

Fully transformer-based biomarker prediction from colorectal cancer histology: a large-scale multicentric study

Background: Deep learning (DL) can extract predictive and prognostic biomarkers from routine pathology slides in colorectal cancer. For example, a DL test for the diagnosis of microsatellite instability (MSI) in CRC has been approved in 2022. Current approaches rely on convolutional neural networks (CNNs). Transformer networks are outperforming CNNs and are replacing them in many applications, but have not been used for biomarker prediction in cancer at a large scale. In addition, most DL approaches have been trained on small patient cohorts, which limits their clinical utility. Methods: In this study, we developed a new fully transformer-based pipeline for end-to-end biomarker prediction from pathology slides. We combine a pre-trained transformer encoder and a transformer network for patch aggregation, capable of yielding single and multi-target prediction at patient level. We train our pipeline on over 9,000 patients from 10 colorectal cancer cohorts. Results: A fully transformer-based approach massively improves the performance, generalizability, data efficiency, and interpretability as compared with current state-of-the-art algorithms. After training on a large multicenter cohort, we achieve a sensitivity of 0.97 with a negative predictive value of 0.99 for MSI prediction on surgical resection specimens. We demonstrate for the first time that resection specimen-only training reaches clinical-grade performance on endoscopic biopsy tissue, solving a long-standing diagnostic problem. Interpretation: A fully transformer-based end-to-end pipeline trained on thousands of pathology slides yields clinical-grade performance for biomarker prediction on surgical resections and biopsies. Our new methods are freely available under an open source license.

Local Attention Graph-based Transformer for Multi-target Genetic Alteration Prediction

Classical multiple instance learning (MIL) methods are often based on the identical and independent distributed assumption between instances, hence neglecting the potentially rich contextual information beyond individual entities. On the other hand, Transformers with global self-attention modules have been proposed to model the interdependencies among all instances. However, in this paper we question: Is global relation modeling using self-attention necessary, or can we appropriately restrict self-attention calculations to local regimes in large-scale whole slide images (WSIs)? We propose a general-purpose local attention graph-based Transformer for MIL (LA-MIL), introducing an inductive bias by explicitly contextualizing instances in adaptive local regimes of arbitrary size. Additionally, an efficiently adapted loss function enables our approach to learn expressive WSI embeddings for the joint analysis of multiple biomarkers. We demonstrate that LA-MIL achieves state-of-the-art results in mutation prediction for gastrointestinal cancer, outperforming existing models on important biomarkers such as microsatellite instability for colorectal cancer. This suggests that local self-attention sufficiently models dependencies on par with global modules. Our implementation will be published.

S5CL: Unifying Fully-Supervised, Self-Supervised, and Semi-Supervised Learning Through Hierarchical Contrastive Learning

In computational pathology, we often face a scarcity of annotations and a large amount of unlabeled data. One method for dealing with this is semi-supervised learning which is commonly split into a self-supervised pretext task and a subsequent model fine-tuning. Here, we compress this two-stage training into one by introducing S5CL, a unified framework for fully-supervised, self-supervised, and semi-supervised learning. With three contrastive losses defined for labeled, unlabeled, and pseudo-labeled images, S5CL can learn feature representations that reflect the hierarchy of distance relationships: similar images and augmentations are embedded the closest, followed by different looking images of the same class, while images from separate classes have the largest distance. Moreover, S5CL allows us to flexibly combine these losses to adapt to different scenarios. Evaluations of our framework on two public histopathological datasets show strong improvements in the case of sparse labels: for a H&E-stained colorectal cancer dataset, the accuracy increases by up to 9% compared to supervised cross-entropy loss; for a highly imbalanced dataset of single white blood cells from leukemia patient blood smears, the F1-score increases by up to 6%.

Multi-Modality Microscopy Image Style Transfer for Nuclei Segmentation

Annotating microscopy images for nuclei segmentation is laborious and time-consuming. To leverage the few existing annotations, also across multiple modalities, we propose a novel microscopy-style augmentation technique based on a generative adversarial network (GAN). Unlike other style transfer methods, it can not only deal with different cell assay types and lighting conditions, but also with different imaging modalities, such as bright-field and fluorescence microscopy. Using disentangled representations for content and style, we can preserve the structure of the original image while altering its style during augmentation. We evaluate our data augmentation on the 2018 Data Science Bowl dataset consisting of various cell assays, lighting conditions, and imaging modalities. With our style augmentation, the segmentation accuracy of the two top-ranked Mask R-CNN-based nuclei segmentation algorithms in the competition increases significantly. Thus, our augmentation technique renders the downstream task more robust to the test data heterogeneity and helps counteract class imbalance without resampling of minority classes.

Structure-Preserving Multi-Domain Stain Color Augmentation using Style-Transfer with Disentangled Representations

In digital pathology, different staining procedures and scanners cause substantial color variations in whole-slide images (WSIs), especially across different laboratories. These color shifts result in a poor generalization of deep learning-based methods from the training domain to external pathology data. To increase test performance, stain normalization techniques are used to reduce the variance between training and test domain. Alternatively, color augmentation can be applied during training leading to a more robust model without the extra step of color normalization at test time. We propose a novel color augmentation technique, HistAuGAN, that can simulate a wide variety of realistic histology stain colors, thus making neural networks stain-invariant when applied during training. Based on a generative adversarial network (GAN) for image-to-image translation, our model disentangles the content of the image, i.e., the morphological tissue structure, from the stain color attributes. It can be trained on multiple domains and, therefore, learns to cover different stain colors as well as other domain-specific variations introduced in the slide preparation and imaging process. We demonstrate that HistAuGAN outperforms conventional color augmentation techniques on a classification task on the publicly available dataset Camelyon17 and show that it is able to mitigate present batch effects.