Daily Papers

Representation learning of pathology whole-slide images (WSIs) has primarily relied on weak supervision with Multiple Instance Learning (MIL). This approach leads to slide representations highly tailored to a specific clinical task. Self-supervised learning (SSL) has been successfully applied to train histopathology foundation models (FMs) for patch embedding generation. However, generating patient or slide level embeddings remains challenging. Existing approaches for slide representation learning extend the principles of SSL from patch level learning to entire slides by aligning different augmentations of the slide or by utilizing multimodal data. By integrating tile embeddings from multiple FMs, we propose a new single modality SSL method in feature space that generates useful slide representations. Our contrastive pretraining strategy, called COBRA, employs multiple FMs and an architecture based on Mamba-2. COBRA exceeds performance of state-of-the-art slide encoders on four different public CPTAC cohorts on average by at least +3.8% AUC, despite only being pretrained on 3048 WSIs from TCGA. Additionally, COBRA is readily compatible at inference time with previously unseen feature extractors.

Foundation models in computational pathology promise to unlock the development of new clinical decision support systems and models for precision medicine. However, there is a mismatch between most clinical analysis, which is defined at the level of one or more whole slide images, and foundation models to date, which process the thousands of image tiles contained in a whole slide image separately. The requirement to train a network to aggregate information across a large number of tiles in multiple whole slide images limits these models' impact. In this work, we present a slide-level foundation model for H&E-stained histopathology, PRISM, that builds on Virchow tile embeddings and leverages clinical report text for pre-training. Using the tile embeddings, PRISM produces slide-level embeddings with the ability to generate clinical reports, resulting in several modes of use. Using text prompts, PRISM achieves zero-shot cancer detection and sub-typing performance approaching and surpassing that of a supervised aggregator model. Using the slide embeddings with linear classifiers, PRISM surpasses supervised aggregator models. Furthermore, we demonstrate that fine-tuning of the PRISM slide encoder yields label-efficient training for biomarker prediction, a task that typically suffers from low availability of training data; an aggregator initialized with PRISM and trained on as little as 10% of the training data can outperform a supervised baseline that uses all of the data.

The field of computational pathology has been transformed with recent advances in foundation models that encode histopathology region-of-interests (ROIs) into versatile and transferable feature representations via self-supervised learning (SSL). However, translating these advancements to address complex clinical challenges at the patient and slide level remains constrained by limited clinical data in disease-specific cohorts, especially for rare clinical conditions. We propose TITAN, a multimodal whole slide foundation model pretrained using 335,645 WSIs via visual self-supervised learning and vision-language alignment with corresponding pathology reports and 423,122 synthetic captions generated from a multimodal generative AI copilot for pathology. Without any finetuning or requiring clinical labels, TITAN can extract general-purpose slide representations and generate pathology reports that generalize to resource-limited clinical scenarios such as rare disease retrieval and cancer prognosis. We evaluate TITAN on diverse clinical tasks and find that TITAN outperforms both ROI and slide foundation models across machine learning settings such as linear probing, few-shot and zero-shot classification, rare cancer retrieval and cross-modal retrieval, and pathology report generation.

The use of artificial intelligence to enable precision medicine and decision support systems through the analysis of pathology images has the potential to revolutionize the diagnosis and treatment of cancer. Such applications will depend on models' abilities to capture the diverse patterns observed in pathology images. To address this challenge, we present Virchow, a foundation model for computational pathology. Using self-supervised learning empowered by the DINOv2 algorithm, Virchow is a vision transformer model with 632 million parameters trained on 1.5 million hematoxylin and eosin stained whole slide images from diverse tissue and specimen types, which is orders of magnitude more data than previous works. The Virchow model enables the development of a pan-cancer detection system with 0.949 overall specimen-level AUC across 17 different cancer types, while also achieving 0.937 AUC on 7 rare cancer types. The Virchow model sets the state-of-the-art on the internal and external image tile level benchmarks and slide level biomarker prediction tasks. The gains in performance highlight the importance of training on massive pathology image datasets, suggesting scaling up the data and network architecture can improve the accuracy for many high-impact computational pathology applications where limited amounts of training data are available.

Despite the progress made by multimodal large language models (MLLMs) in computational pathology, they remain limited by a predominant focus on patch-level analysis, missing essential contextual information at the whole-slide level. The lack of large-scale instruction datasets and the gigapixel scale of whole slide images (WSIs) pose significant developmental challenges. In this paper, we present SlideChat, the first vision-language assistant capable of understanding gigapixel whole-slide images, exhibiting excellent multimodal conversational capability and response complex instruction across diverse pathology scenarios. To support its development, we created SlideInstruction, the largest instruction-following dataset for WSIs consisting of 4.2K WSI captions and 176K VQA pairs with multiple categories. Furthermore, we propose SlideBench, a multimodal benchmark that incorporates captioning and VQA tasks to assess SlideChat's capabilities in varied clinical settings such as microscopy, diagnosis. Compared to both general and specialized MLLMs, SlideChat exhibits exceptional capabilities achieving state-of-the-art performance on 18 of 22 tasks. For example, it achieved an overall accuracy of 81.17% on SlideBench-VQA (TCGA), and 54.15% on SlideBench-VQA (BCNB). We will fully release SlideChat, SlideInstruction and SlideBench as open-source resources to facilitate research and development in computational pathology.

Gathering histopathology slides from over 100 publicly available cohorts, we compile a diverse dataset of 460 million pathology tiles covering more than 30 cancer sites. Using this dataset, we train a large self-supervised vision transformer using DINOv2 and publicly release one iteration of this model for further experimentation, coined Phikon-v2. While trained on publicly available histology slides, Phikon-v2 surpasses our previously released model (Phikon) and performs on par with other histopathology foundation models (FM) trained on proprietary data. Our benchmarks include eight slide-level tasks with results reported on external validation cohorts avoiding any data contamination between pre-training and evaluation datasets. Our downstream training procedure follows a simple yet robust ensembling strategy yielding a +1.75 AUC increase across tasks and models compared to one-shot retraining (p<0.001). We compare Phikon (ViT-B) and Phikon-v2 (ViT-L) against 14 different histology feature extractors, making our evaluation the most comprehensive to date. Our result support evidences that DINOv2 handles joint model and data scaling better than iBOT. Also, we show that recent scaling efforts are overall beneficial to downstream performance in the context of biomarker prediction with GigaPath and H-Optimus-0 (two ViT-g with 1.1B parameters each) standing out. However, the statistical margins between the latest top-performing FMs remain mostly non-significant; some even underperform on specific indications or tasks such as MSI prediction - deposed by a 13x smaller model developed internally. While latest foundation models may exhibit limitations for clinical deployment, they nonetheless offer excellent grounds for the development of more specialized and cost-efficient histology encoders fueling AI-guided diagnostic tools.

Pathology, the microscopic examination of diseased tissue, is critical for diagnosing various medical conditions, particularly cancers. Traditional methods are labor-intensive and prone to human error. Digital pathology, which converts glass slides into high-resolution digital images for analysis by computer algorithms, revolutionizes the field by enhancing diagnostic accuracy, consistency, and efficiency through automated image analysis and large-scale data processing. Foundational transformer pretraining is crucial for developing robust, generalizable models as it enables learning from vast amounts of unannotated data. This paper introduces the Hibou family of foundational vision transformers for pathology, leveraging the DINOv2 framework to pretrain two model variants, Hibou-B and Hibou-L, on a proprietary dataset of over 1 million whole slide images (WSIs) representing diverse tissue types and staining techniques. Our pretrained models demonstrate superior performance on both patch-level and slide-level benchmarks, surpassing existing state-of-the-art methods. Notably, Hibou-L achieves the highest average accuracy across multiple benchmark datasets. To support further research and application in the field, we have open-sourced the Hibou-B model, which can be accessed at https://github.com/HistAI/hibou

Foundation models are reshaping computational pathology by enabling transfer learning, where models pre-trained on vast datasets can be adapted for downstream diagnostic, prognostic, and therapeutic response tasks. Despite these advances, foundation models are still limited in their ability to encode the entire gigapixel whole-slide images without additional training and often lack complementary multimodal data. Here, we introduce Threads, a slide-level foundation model capable of generating universal representations of whole-slide images of any size. Threads was pre-trained using a multimodal learning approach on a diverse cohort of 47,171 hematoxylin and eosin (H&E)-stained tissue sections, paired with corresponding genomic and transcriptomic profiles - the largest such paired dataset to be used for foundation model development to date. This unique training paradigm enables Threads to capture the tissue's underlying molecular composition, yielding powerful representations applicable to a wide array of downstream tasks. In extensive benchmarking across 54 oncology tasks, including clinical subtyping, grading, mutation prediction, immunohistochemistry status determination, treatment response prediction, and survival prediction, Threads outperformed all baselines while demonstrating remarkable generalizability and label efficiency. It is particularly well suited for predicting rare events, further emphasizing its clinical utility. We intend to make the model publicly available for the broader community.

Metadata are general characteristics of the data in a well-curated and condensed format, and have been proven to be useful for decision making, knowledge discovery, and also heterogeneous data organization of biobank. Among all data types in the biobank, pathology is the key component of the biobank and also serves as the gold standard of diagnosis. To maximize the utility of biobank and allow the rapid progress of biomedical science, it is essential to organize the data with well-populated pathology metadata. However, manual annotation of such information is tedious and time-consuming. In the study, we develop a multimodal multitask learning framework to predict four major slide-level metadata of pathology images. The framework learns generalizable representations across tissue slides, pathology reports, and case-level structured data. We demonstrate improved performance across all four tasks with the proposed method compared to a single modal single task baseline on two test sets, one external test set from a distinct data source (TCGA) and one internal held-out test set (TTH). In the test sets, the performance improvements on the averaged area under receiver operating characteristic curve across the four tasks are 16.48% and 9.05% on TCGA and TTH, respectively. Such pathology metadata prediction system may be adopted to mitigate the effort of expert annotation and ultimately accelerate the data-driven research by better utilization of the pathology biobank.

Pathology is the study of microscopic inspection of tissue, and a pathology diagnosis is often the medical gold standard to diagnose disease. Pathology images provide a unique challenge for computer-vision-based analysis: a single pathology Whole Slide Image (WSI) is gigapixel-sized and often contains hundreds of thousands to millions of objects of interest across multiple resolutions. In this work, we propose PathoLogy Universal TransfOrmer (PLUTO): a light-weight pathology FM that is pre-trained on a diverse dataset of 195 million image tiles collected from multiple sites and extracts meaningful representations across multiple WSI scales that enable a large variety of downstream pathology tasks. In particular, we design task-specific adaptation heads that utilize PLUTO's output embeddings for tasks which span pathology scales ranging from subcellular to slide-scale, including instance segmentation, tile classification, and slide-level prediction. We compare PLUTO's performance to other state-of-the-art methods on a diverse set of external and internal benchmarks covering multiple biologically relevant tasks, tissue types, resolutions, stains, and scanners. We find that PLUTO matches or outperforms existing task-specific baselines and pathology-specific foundation models, some of which use orders-of-magnitude larger datasets and model sizes when compared to PLUTO. Our findings present a path towards a universal embedding to power pathology image analysis, and motivate further exploration around pathology foundation models in terms of data diversity, architectural improvements, sample efficiency, and practical deployability in real-world applications.

We present WeakSTIL, an interpretable two-stage weak label deep learning pipeline for scoring the percentage of stromal tumor infiltrating lymphocytes (sTIL%) in H&E-stained whole-slide images (WSIs) of breast cancer tissue. The sTIL% score is a prognostic and predictive biomarker for many solid tumor types. However, due to the high labeling efforts and high intra- and interobserver variability within and between expert annotators, this biomarker is currently not used in routine clinical decision making. WeakSTIL compresses tiles of a WSI using a feature extractor pre-trained with self-supervised learning on unlabeled histopathology data and learns to predict precise sTIL% scores for each tile in the tumor bed by using a multiple instance learning regressor that only requires a weak WSI-level label. By requiring only a weak label, we overcome the large annotation efforts required to train currently existing TIL detection methods. We show that WeakSTIL is at least as good as other TIL detection methods when predicting the WSI-level sTIL% score, reaching a coefficient of determination of 0.45pm0.15 when compared to scores generated by an expert pathologist, and an AUC of 0.89pm0.05 when treating it as the clinically interesting sTIL-high vs sTIL-low classification task. Additionally, we show that the intermediate tile-level predictions of WeakSTIL are highly interpretable, which suggests that WeakSTIL pays attention to latent features related to the number of TILs and the tissue type. In the future, WeakSTIL may be used to provide consistent and interpretable sTIL% predictions to stratify breast cancer patients into targeted therapy arms.

The whole slide image (WSI) classification is often formulated as a multiple instance learning (MIL) problem. Since the positive tissue is only a small fraction of the gigapixel WSI, existing MIL methods intuitively focus on identifying salient instances via attention mechanisms. However, this leads to a bias towards easy-to-classify instances while neglecting hard-to-classify instances. Some literature has revealed that hard examples are beneficial for modeling a discriminative boundary accurately. By applying such an idea at the instance level, we elaborate a novel MIL framework with masked hard instance mining (MHIM-MIL), which uses a Siamese structure (Teacher-Student) with a consistency constraint to explore the potential hard instances. With several instance masking strategies based on attention scores, MHIM-MIL employs a momentum teacher to implicitly mine hard instances for training the student model, which can be any attention-based MIL model. This counter-intuitive strategy essentially enables the student to learn a better discriminating boundary. Moreover, the student is used to update the teacher with an exponential moving average (EMA), which in turn identifies new hard instances for subsequent training iterations and stabilizes the optimization. Experimental results on the CAMELYON-16 and TCGA Lung Cancer datasets demonstrate that MHIM-MIL outperforms other latest methods in terms of performance and training cost. The code is available at: https://github.com/DearCaat/MHIM-MIL.

Weakly supervised whole slide image classification is usually formulated as a multiple instance learning (MIL) problem, where each slide is treated as a bag, and the patches cut out of it are treated as instances. Existing methods either train an instance classifier through pseudo-labeling or aggregate instance features into a bag feature through attention mechanisms and then train a bag classifier, where the attention scores can be used for instance-level classification. However, the pseudo instance labels constructed by the former usually contain a lot of noise, and the attention scores constructed by the latter are not accurate enough, both of which affect their performance. In this paper, we propose an instance-level MIL framework based on contrastive learning and prototype learning to effectively accomplish both instance classification and bag classification tasks. To this end, we propose an instance-level weakly supervised contrastive learning algorithm for the first time under the MIL setting to effectively learn instance feature representation. We also propose an accurate pseudo label generation method through prototype learning. We then develop a joint training strategy for weakly supervised contrastive learning, prototype learning, and instance classifier training. Extensive experiments and visualizations on four datasets demonstrate the powerful performance of our method. Codes will be available.

Whole Slide Image (WSI) classification with multiple instance learning (MIL) in digital pathology faces significant computational challenges. Current methods mostly rely on extensive self-supervised learning (SSL) for satisfactory performance, requiring long training periods and considerable computational resources. At the same time, no pre-training affects performance due to domain shifts from natural images to WSIs. We introduce Snuffy architecture, a novel MIL-pooling method based on sparse transformers that mitigates performance loss with limited pre-training and enables continual few-shot pre-training as a competitive option. Our sparsity pattern is tailored for pathology and is theoretically proven to be a universal approximator with the tightest probabilistic sharp bound on the number of layers for sparse transformers, to date. We demonstrate Snuffy's effectiveness on CAMELYON16 and TCGA Lung cancer datasets, achieving superior WSI and patch-level accuracies. The code is available on https://github.com/jafarinia/snuffy.

Presenters commonly use slides as visual aids for informative talks. When presenters fail to verbally describe the content on their slides, blind and visually impaired audience members lose access to necessary content, making the presentation difficult to follow. Our analysis of 90 presentation videos revealed that 72% of 610 visual elements (e.g., images, text) were insufficiently described. To help presenters create accessible presentations, we introduce Presentation A11y, a system that provides real-time and post-presentation accessibility feedback. Our system analyzes visual elements on the slide and the transcript of the verbal presentation to provide element-level feedback on what visual content needs to be further described or even removed. Presenters using our system with their own slide-based presentations described more of the content on their slides, and identified 3.26 times more accessibility problems to fix after the talk than when using a traditional slide-based presentation interface. Integrating accessibility feedback into content creation tools will improve the accessibility of informational content for all.

Tissue phenotyping is a fundamental task in learning objective characterizations of histopathologic biomarkers within the tumor-immune microenvironment in cancer pathology. However, whole-slide imaging (WSI) is a complex computer vision in which: 1) WSIs have enormous image resolutions with precludes large-scale pixel-level efforts in data curation, and 2) diversity of morphological phenotypes results in inter- and intra-observer variability in tissue labeling. To address these limitations, current efforts have proposed using pretrained image encoders (transfer learning from ImageNet, self-supervised pretraining) in extracting morphological features from pathology, but have not been extensively validated. In this work, we conduct a search for good representations in pathology by training a variety of self-supervised models with validation on a variety of weakly-supervised and patch-level tasks. Our key finding is in discovering that Vision Transformers using DINO-based knowledge distillation are able to learn data-efficient and interpretable features in histology images wherein the different attention heads learn distinct morphological phenotypes. We make evaluation code and pretrained weights publicly-available at: https://github.com/Richarizardd/Self-Supervised-ViT-Path.

Multiple Instance learning (MIL) models have been extensively used in pathology to predict biomarkers and risk-stratify patients from gigapixel-sized images. Machine learning problems in medical imaging often deal with rare diseases, making it important for these models to work in a label-imbalanced setting. In pathology images, there is another level of imbalance, where given a positively labeled Whole Slide Image (WSI), only a fraction of pixels within it contribute to the positive label. This compounds the severity of imbalance and makes imbalanced classification in pathology challenging. Furthermore, these imbalances can occur in out-of-distribution (OOD) datasets when the models are deployed in the real-world. We leverage the idea that decoupling feature and classifier learning can lead to improved decision boundaries for label imbalanced datasets. To this end, we investigate the integration of supervised contrastive learning with multiple instance learning (SC-MIL). Specifically, we propose a joint-training MIL framework in the presence of label imbalance that progressively transitions from learning bag-level representations to optimal classifier learning. We perform experiments with different imbalance settings for two well-studied problems in cancer pathology: subtyping of non-small cell lung cancer and subtyping of renal cell carcinoma. SC-MIL provides large and consistent improvements over other techniques on both in-distribution (ID) and OOD held-out sets across multiple imbalanced settings.

Automated slice classification is clinically relevant since it can be incorporated into medical image segmentation workflows as a preprocessing step that would flag slices with a higher probability of containing tumors, thereby directing physicians attention to the important slices. In this work, we train a ResNet-18 network to classify axial slices of lymphoma PET/CT images (collected from two institutions) depending on whether the slice intercepted a tumor (positive slice) in the 3D image or if the slice did not (negative slice). Various instances of the network were trained on 2D axial datasets created in different ways: (i) slice-level split and (ii) patient-level split; inputs of different types were used: (i) only PET slices and (ii) concatenated PET and CT slices; and different training strategies were employed: (i) center-aware (CAW) and (ii) center-agnostic (CAG). Model performances were compared using the area under the receiver operating characteristic curve (AUROC) and the area under the precision-recall curve (AUPRC), and various binary classification metrics. We observe and describe a performance overestimation in the case of slice-level split as compared to the patient-level split training. The model trained using patient-level split data with the network input containing only PET slices in the CAG training regime was the best performing/generalizing model on a majority of metrics. Our models were additionally more closely compared using the sensitivity metric on the positive slices from their respective test sets.

Procedural Content Generation (PCG) algorithms provide a technique to generate complex and diverse environments in an automated way. However, while generating content with PCG methods is often straightforward, generating meaningful content that reflects specific intentions and constraints remains challenging. Furthermore, many PCG algorithms lack the ability to generate content in an open-ended manner. Recently, Large Language Models (LLMs) have shown to be incredibly effective in many diverse domains. These trained LLMs can be fine-tuned, re-using information and accelerating training for new tasks. In this work, we introduce MarioGPT, a fine-tuned GPT2 model trained to generate tile-based game levels, in our case Super Mario Bros levels. We show that MarioGPT can not only generate diverse levels, but can be text-prompted for controllable level generation, addressing one of the key challenges of current PCG techniques. As far as we know, MarioGPT is the first text-to-level model. We also combine MarioGPT with novelty search, enabling it to generate diverse levels with varying play-style dynamics (i.e. player paths). This combination allows for the open-ended generation of an increasingly diverse range of content.