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Many molecular alterations serve as clinically prognostic or therapy-predictive biomarkers, typically detected using single or multi-gene molecular assays. However, these assays are expensive, tissue destructive and often take weeks to complete. Using AI on routine H&E WSIs offers a fast and economical approach to screen for multiple molecular biomarkers. We present a high-throughput AI-based system leveraging Virchow2, a foundation model pre-trained on 3 million slides, to interrogate genomic features previously determined by an next-generation sequencing (NGS) assay, using 47,960 scanned hematoxylin and eosin (H&E) whole slide images (WSIs) from 38,984 cancer patients. Unlike traditional methods that train individual models for each biomarker or cancer type, our system employs a unified model to simultaneously predict a wide range of clinically relevant molecular biomarkers across cancer types. By training the network to replicate the MSK-IMPACT targeted biomarker panel of 505 genes, it identified 80 high performing biomarkers with a mean AU-ROC of 0.89 in 15 most common cancer types. In addition, 40 biomarkers demonstrated strong associations with specific cancer histologic subtypes. Furthermore, 58 biomarkers were associated with targets frequently assayed clinically for therapy selection and response prediction. The model can also predict the activity of five canonical signaling pathways, identify defects in DNA repair mechanisms, and predict genomic instability measured by tumor mutation burden, microsatellite instability (MSI), and chromosomal instability (CIN). The proposed model can offer potential to guide therapy selection, improve treatment efficacy, accelerate patient screening for clinical trials and provoke the interrogation of new therapeutic targets.

Foundation models are rapidly being developed for computational pathology applications. However, it remains an open question which factors are most important for downstream performance with data scale and diversity, model size, and training algorithm all playing a role. In this work, we propose algorithmic modifications, tailored for pathology, and we present the result of scaling both data and model size, surpassing previous studies in both dimensions. We introduce two new models: Virchow2, a 632 million parameter vision transformer, and Virchow2G, a 1.9 billion parameter vision transformer, each trained with 3.1 million histopathology whole slide images, with diverse tissues, originating institutions, and stains. We achieve state of the art performance on 12 tile-level tasks, as compared to the top performing competing models. Our results suggest that data diversity and domain-specific methods can outperform models that only scale in the number of parameters, but, on average, performance benefits from the combination of domain-specific methods, data scale, and model scale.

Recent advances in artificial intelligence (AI), in particular self-supervised learning of foundation models (FMs), are revolutionizing medical imaging and computational pathology (CPath). A constant challenge in the analysis of digital Whole Slide Images (WSIs) is the problem of aggregating tens of thousands of tile-level image embeddings to a slide-level representation. Due to the prevalent use of datasets created for genomic research, such as TCGA, for method development, the performance of these techniques on diagnostic slides from clinical practice has been inadequately explored. This study conducts a thorough benchmarking analysis of ten slide-level aggregation techniques across nine clinically relevant tasks, including diagnostic assessment, biomarker classification, and outcome prediction. The results yield following key insights: (1) Embeddings derived from domain-specific (histological images) FMs outperform those from generic ImageNet-based models across aggregation methods. (2) Spatial-aware aggregators enhance the performance significantly when using ImageNet pre-trained models but not when using FMs. (3) No single model excels in all tasks and spatially-aware models do not show general superiority as it would be expected. These findings underscore the need for more adaptable and universally applicable aggregation techniques, guiding future research towards tools that better meet the evolving needs of clinical-AI in pathology. The code used in this work is available at \url{https://github.com/fuchs-lab-public/CPath_SABenchmark}., Comment: 10 pages, 2 figures

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.

Artificial Intelligence (AI) has great potential to improve health outcomes by training systems on vast digitized clinical datasets. Computational Pathology, with its massive amounts of microscopy image data and impact on diagnostics and biomarkers, is at the forefront of this development. Gigapixel pathology slides pose a unique challenge due to their enormous size and are usually divided into tens of thousands of smaller tiles for analysis. This results in a discontinuity in the machine learning process by separating the training of tile-level encoders from slide-level aggregators and the need to adopt weakly supervised learning strategies. Training models from entire pathology slides end-to-end has been largely unexplored due to its computational challenges. To overcome this problem, we propose a novel approach to jointly train both a tile encoder and a slide-aggregator fully in memory and end-to-end at high-resolution, bridging the gap between input and slide-level supervision. While more computationally expensive, detailed quantitative validation shows promise for large-scale pre-training and fine-tuning of pathology foundation models.

Clinical note classification is a common clinical NLP task. However, annotated data-sets are scarse. Prompt-based learning has recently emerged as an effective method to adapt pre-trained models for text classification using only few training examples. A critical component of prompt design is the definition of the template (i.e. prompt text). The effect of template position, however, has been insufficiently investigated. This seems particularly important in the clinical setting, where task-relevant information is usually sparse in clinical notes. In this study we develop a keyword-optimized template insertion method (KOTI) and show how optimizing position can improve performance on several clinical tasks in a zero-shot and few-shot training setting.

Recent breakthroughs in self-supervised learning have enabled the use of large unlabeled datasets to train visual foundation models that can generalize to a variety of downstream tasks. While this training paradigm is well suited for the medical domain where annotations are scarce, large-scale pre-training in the medical domain, and in particular pathology, has not been extensively studied. Previous work in self-supervised learning in pathology has leveraged smaller datasets for both pre-training and evaluating downstream performance. The aim of this project is to train the largest academic foundation model and benchmark the most prominent self-supervised learning algorithms by pre-training and evaluating downstream performance on large clinical pathology datasets. We collected the largest pathology dataset to date, consisting of over 3 billion images from over 423 thousand microscopy slides. We compared pre-training of visual transformer models using the masked autoencoder (MAE) and DINO algorithms. We evaluated performance on six clinically relevant tasks from three anatomic sites and two institutions: breast cancer detection, inflammatory bowel disease detection, breast cancer estrogen receptor prediction, lung adenocarcinoma EGFR mutation prediction, and lung cancer immunotherapy response prediction. Our results demonstrate that pre-training on pathology data is beneficial for downstream performance compared to pre-training on natural images. Additionally, the DINO algorithm achieved better generalization performance across all tasks tested. The presented results signify a phase change in computational pathology research, paving the way into a new era of more performant models based on large-scale, parallel pre-training at the billion-image scale.

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.

An every increasing number of clinical trials features a time-to-event outcome and records non-tabular patient data, such as magnetic resonance imaging or text data in the form of electronic health records. Recently, several neural-network based solutions have been proposed, some of which are binary classifiers. Parametric, distribution-free approaches which make full use of survival time and censoring status have not received much attention. We present deep conditional transformation models (DCTMs) for survival outcomes as a unifying approach to parametric and semiparametric survival analysis. DCTMs allow the specification of non-linear and non-proportional hazards for both tabular and non-tabular data and extend to all types of censoring and truncation. On real and semi-synthetic data, we show that DCTMs compete with state-of-the-art DL approaches to survival analysis.

Osteosarcoma is the most common primary bone cancer whose standard treatment includes pre-operative chemotherapy followed by resection. Chemotherapy response is used for predicting prognosis and further management of patients. Necrosis is routinely assessed post-chemotherapy from histology slides on resection specimens where necrosis ratio is defined as the ratio of necrotic tumor to overall tumor. Patients with necrosis ratio >=90% are known to have better outcome. Manual microscopic review of necrosis ratio from multiple glass slides is semi-quantitative and can have intra- and inter-observer variability. We propose an objective and reproducible deep learning-based approach to estimate necrosis ratio with outcome prediction from scanned hematoxylin and eosin whole slide images. We collected 103 osteosarcoma cases with 3134 WSIs to train our deep learning model, to validate necrosis ratio assessment, and to evaluate outcome prediction. We trained Deep Multi-Magnification Network to segment multiple tissue subtypes including viable tumor and necrotic tumor in pixel-level and to calculate case-level necrosis ratio from multiple WSIs. We showed necrosis ratio estimated by our segmentation model highly correlates with necrosis ratio from pathology reports manually assessed by experts where mean absolute differences for Grades IV (100%), III (>=90%), and II (>=50% and <90%) necrosis response are 4.4%, 4.5%, and 17.8%, respectively. We successfully stratified patients to predict overall survival with p=10^-6 and progression-free survival with p=0.012. Our reproducible approach without variability enabled us to tune cutoff thresholds, specifically for our model and our data set, to 80% for OS and 60% for PFS. Our study indicates deep learning can support pathologists as an objective tool to analyze osteosarcoma from histology for assessing treatment response and predicting patient outcome.

Lung cancer is the leading cause of cancer death worldwide, with lung adenocarcinoma being the most prevalent form of lung cancer. EGFR positive lung adenocarcinomas have been shown to have high response rates to TKI therapy, underlying the essential nature of molecular testing for lung cancers. Despite current guidelines consider testing necessary, a large portion of patients are not routinely profiled, resulting in millions of people not receiving the optimal treatment for their lung cancer. Sequencing is the gold standard for molecular testing of EGFR mutations, but it can take several weeks for results to come back, which is not ideal in a time constrained scenario. The development of alternative screening tools capable of detecting EGFR mutations quickly and cheaply while preserving tissue for sequencing could help reduce the amount of sub-optimally treated patients. We propose a multi-modal approach which integrates pathology images and clinical variables to predict EGFR mutational status achieving an AUC of 84% on the largest clinical cohort to date. Such a computational model could be deployed at large at little additional cost. Its clinical application could reduce the number of patients who receive sub-optimal treatments by 53.1% in China, and up to 96.6% in the US.

AIMS: Clinical radiographic imaging is seated upon the principle of differential keV photon transmission through an object. At clinical x-ray energies the scattering of photons causes signal noise and is utilized solely for transmission measurements. However, scatter - particularly Compton scatter, is characterizable. In this work we hypothesized that modern radiation sources and detectors paired with deep learning techniques can use scattered photon information constructively to resolve superimposed attenuators in planar x-ray imaging. METHODS: We simulated a monoenergetic x-ray imaging system consisting of a pencil beam x-ray source directed at an imaging target positioned in front of a high spatial- and energy-resolution detector array. The signal was analyzed by a convolutional neural network, and a description of scattering material along the axis of the beam was derived. The system was virtually designed/tested using Monte Carlo processing of simple phantoms consisting of 10 pseudo-randomly stacked air/bone/water materials, and the network was trained by solving a classification problem. RESULTS: The average accuracy of the material identification along the beam was 0.91 +- 0.01, with slightly higher accuracy towards the entrance/exit peripheral surfaces of the object. The average sensitivity and specificity was 0.91 and 0.95, respectively. CONCLUSIONS: Our work provides proof of principle that deep learning techniques can be used to analyze scattered photon patterns which can constructively contribute to the information content in radiography, here used to infer depth information in a traditional 2D planar setup. This principle, and our results, demonstrate that the information in Compton scattered photons may provide a basis for further development. The ability to scale performance to the clinic remains unexplored and requires further study., Comment: 10 pages, 6 figures. To be published in Journal of Instrumentation

Deep learning has been widely used to analyze digitized hematoxylin and eosin (H&E)-stained histopathology whole slide images. Automated cancer segmentation using deep learning can be used to diagnose malignancy and to find novel morphological patterns to predict molecular subtypes. To train pixel-wise cancer segmentation models, manual annotation from pathologists is generally a bottleneck due to its time-consuming nature. In this paper, we propose Deep Interactive Learning with a pretrained segmentation model from a different cancer type to reduce manual annotation time. Instead of annotating all pixels from cancer and non-cancer regions on giga-pixel whole slide images, an iterative process of annotating mislabeled regions from a segmentation model and training/finetuning the model with the additional annotation can reduce the time. Especially, employing a pretrained segmentation model can further reduce the time than starting annotation from scratch. We trained an accurate ovarian cancer segmentation model with a pretrained breast segmentation model by 3.5 hours of manual annotation which achieved intersection-over-union of 0.74, recall of 0.86, and precision of 0.84. With automatically extracted high-grade serous ovarian cancer patches, we attempted to train another deep learning model to predict BRCA mutation. The segmentation model and code have been released at https://github.com/MSKCC-Computational-Pathology/DMMN-ovary.