Interpretability analysis on a pathology foundation model reveals biologically relevant embeddings across modalities

Mechanistic interpretability has been explored in detail for large language models (LLMs). For the first time, we provide a preliminary investigation with similar interpretability methods for medical imaging. Specifically, we analyze the features from a ViT-Small encoder obtained from a pathology Foundation Model via application to two datasets: one dataset of pathology images, and one dataset of pathology images paired with spatial transcriptomics. We discover an interpretable representation of cell and tissue morphology, along with gene expression within the model embedding space. Our work paves the way for further exploration around interpretable feature dimensions and their utility for medical and clinical applications.

PLUTO: Pathology-Universal Transformer

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.

ContriMix: Unsupervised disentanglement of content and attribute for domain generalization in microscopy image analysis

Domain generalization is critical for real-world applications of machine learning models to microscopy images, including histopathology and fluorescence imaging. Artifacts in histopathology arise through a complex combination of factors relating to tissue collection and laboratory processing, as well as factors intrinsic to patient samples. In fluorescence imaging, these artifacts stem from variations across experimental batches. The complexity and subtlety of these artifacts make the enumeration of data domains intractable. Therefore, augmentation-based methods of domain generalization that require domain identifiers and manual fine-tuning are inadequate in this setting. To overcome this challenge, we introduce ContriMix, a domain generalization technique that learns to generate synthetic images by disentangling and permuting the biological content ("content") and technical variations ("attributes") in microscopy images. ContriMix does not rely on domain identifiers or handcrafted augmentations and makes no assumptions about the input characteristics of images. We assess the performance of ContriMix on two pathology datasets (Camelyon17-WILDS and a prostate cell classification dataset) and one fluorescence microscopy dataset (RxRx1-WILDS). ContriMix outperforms current state-of-the-art methods in all datasets, motivating its usage for microscopy image analysis in real-world settings where domain information is hard to come by.

Synthetic DOmain-Targeted Augmentation (S-DOTA) Improves Model Generalization in Digital Pathology

Machine learning algorithms have the potential to improve patient outcomes in digital pathology. However, generalization of these tools is currently limited by sensitivity to variations in tissue preparation, staining procedures and scanning equipment that lead to domain shift in digitized slides. To overcome this limitation and improve model generalization, we studied the effectiveness of two Synthetic DOmain-Targeted Augmentation (S-DOTA) methods, namely CycleGAN-enabled Scanner Transform (ST) and targeted Stain Vector Augmentation (SVA), and compared them against the International Color Consortium (ICC) profile-based color calibration (ICC Cal) method and a baseline method using traditional brightness, color and noise augmentations. We evaluated the ability of these techniques to improve model generalization to various tasks and settings: four models, two model types (tissue segmentation and cell classification), two loss functions, six labs, six scanners, and three indications (hepatocellular carcinoma (HCC), nonalcoholic steatohepatitis (NASH), prostate adenocarcinoma). We compared these methods based on the macro-averaged F1 scores on in-distribution (ID) and out-of-distribution (OOD) test sets across multiple domains, and found that S-DOTA methods (i.e., ST and SVA) led to significant improvements over ICC Cal and baseline on OOD data while maintaining comparable performance on ID data. Thus, we demonstrate that S-DOTA may help address generalization due to domain shift in real world applications.

SC-MIL: Supervised Contrastive Multiple Instance Learning for Imbalanced Classification in Pathology

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. 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.

Self-training of Machine Learning Models for Liver Histopathology: Generalization under Clinical Shifts

Histopathology images are gigapixel-sized and include features and information at different resolutions. Collecting annotations in histopathology requires highly specialized pathologists, making it expensive and time-consuming. Self-training can alleviate annotation constraints by learning from both labeled and unlabeled data, reducing the amount of annotations required from pathologists. We study the design of teacher-student self-training systems for Non-alcoholic Steatohepatitis (NASH) using clinical histopathology datasets with limited annotations. We evaluate the models on in-distribution and out-of-distribution test data under clinical data shifts. We demonstrate that through self-training, the best student model statistically outperforms the teacher with a $3\%$ absolute difference on the macro F1 score. The best student model also approaches the performance of a fully supervised model trained with twice as many annotations.

Additive MIL: Intrinsic Interpretability for Pathology

Multiple Instance Learning (MIL) has been widely applied in pathology towards solving critical problems such as automating cancer diagnosis and grading, predicting patient prognosis, and therapy response. Deploying these models in a clinical setting requires careful inspection of these black boxes during development and deployment to identify failures and maintain physician trust. In this work, we propose a simple formulation of MIL models, which enables interpretability while maintaining similar predictive performance. Our Additive MIL models enable spatial credit assignment such that the contribution of each region in the image can be exactly computed and visualized. We show that our spatial credit assignment coincides with regions used by pathologists during diagnosis and improves upon classical attention heatmaps from attention MIL models. We show that any existing MIL model can be made additive with a simple change in function composition. We also show how these models can debug model failures, identify spurious features, and highlight class-wise regions of interest, enabling their use in high-stakes environments such as clinical decision-making.

Rethinking Machine Learning Model Evaluation in Pathology

Machine Learning has been applied to pathology images in research and clinical practice with promising outcomes. However, standard ML models often lack the rigorous evaluation required for clinical decisions. Machine learning techniques for natural images are ill-equipped to deal with pathology images that are significantly large and noisy, require expensive labeling, are hard to interpret, and are susceptible to spurious correlations. We propose a set of practical guidelines for ML evaluation in pathology that address the above concerns. The paper includes measures for setting up the evaluation framework, effectively dealing with variability in labels, and a recommended suite of tests to address issues related to domain shift, robustness, and confounding variables. We hope that the proposed framework will bridge the gap between ML researchers and domain experts, leading to wider adoption of ML techniques in pathology and improving patient outcomes.