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.

Test-time interventions for language models can enhance factual accuracy, mitigate harmful outputs, and improve model efficiency without costly retraining. But despite a flood of new methods, different types of interventions are largely developing independently. In practice, multiple interventions must be applied sequentially to the same model, yet we lack standardized ways to study how interventions interact. We fill this gap by introducing composable interventions, a framework to study the effects of using multiple interventions on the same language models, featuring new metrics and a unified codebase. Using our framework, we conduct extensive experiments and compose popular methods from three emerging intervention categories -- Knowledge Editing, Model Compression, and Machine Unlearning. Our results from 310 different compositions uncover meaningful interactions: compression hinders editing and unlearning, composing interventions hinges on their order of application, and popular general-purpose metrics are inadequate for assessing composability. Taken together, our findings showcase clear gaps in composability, suggesting a need for new multi-objective interventions. All of our code is public: https://github.com/hartvigsen-group/composable-interventions.

Self-supervised learning (SSL) has been successful in building patch embeddings of small histology images (e.g., 224x224 pixels), but scaling these models to learn slide embeddings from the entirety of giga-pixel whole-slide images (WSIs) remains challenging. Here, we leverage complementary information from gene expression profiles to guide slide representation learning using multimodal pre-training. Expression profiles constitute highly detailed molecular descriptions of a tissue that we hypothesize offer a strong task-agnostic training signal for learning slide embeddings. Our slide and expression (S+E) pre-training strategy, called Tangle, employs modality-specific encoders, the outputs of which are aligned via contrastive learning. Tangle was pre-trained on samples from three different organs: liver (n=6,597 S+E pairs), breast (n=1,020), and lung (n=1,012) from two different species (Homo sapiens and Rattus norvegicus). Across three independent test datasets consisting of 1,265 breast WSIs, 1,946 lung WSIs, and 4,584 liver WSIs, Tangle shows significantly better few-shot performance compared to supervised and SSL baselines. When assessed using prototype-based classification and slide retrieval, Tangle also shows a substantial performance improvement over all baselines. Code available at https://github.com/mahmoodlab/TANGLE.

Advances in digitizing tissue slides and the fast-paced progress in artificial intelligence, including deep learning, have boosted the field of computational pathology. This field holds tremendous potential to automate clinical diagnosis, predict patient prognosis and response to therapy, and discover new morphological biomarkers from tissue images. Some of these artificial intelligence-based systems are now getting approved to assist clinical diagnosis; however, technical barriers remain for their widespread clinical adoption and integration as a research tool. This Review consolidates recent methodological advances in computational pathology for predicting clinical end points in whole-slide images and highlights how these developments enable the automation of clinical practice and the discovery of new biomarkers. We then provide future perspectives as the field expands into a broader range of clinical and research tasks with increasingly diverse modalities of clinical data.

Integrating whole-slide images (WSIs) and bulk transcriptomics for predicting patient survival can improve our understanding of patient prognosis. However, this multimodal task is particularly challenging due to the different nature of these data: WSIs represent a very high-dimensional spatial description of a tumor, while bulk transcriptomics represent a global description of gene expression levels within that tumor. In this context, our work aims to address two key challenges: (1) how can we tokenize transcriptomics in a semantically meaningful and interpretable way?, and (2) how can we capture dense multimodal interactions between these two modalities? Specifically, we propose to learn biological pathway tokens from transcriptomics that can encode specific cellular functions. Together with histology patch tokens that encode the different morphological patterns in the WSI, we argue that they form appropriate reasoning units for downstream interpretability analyses. We propose fusing both modalities using a memory-efficient multimodal Transformer that can model interactions between pathway and histology patch tokens. Our proposed model, SURVPATH, achieves state-of-the-art performance when evaluated against both unimodal and multimodal baselines on five datasets from The Cancer Genome Atlas. Our interpretability framework identifies key multimodal prognostic factors, and, as such, can provide valuable insights into the interaction between genotype and phenotype, enabling a deeper understanding of the underlying biological mechanisms at play. We make our code public at: https://github.com/ajv012/SurvPath.