Stephen B. Gruber

Sophia J. Wagner, Daniel Reisenbüchler, Nicholas P. West et al.

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.

Theodore Huang, Gregory Idos, Christine Hong et al.

Improving existing widely-adopted prediction models is often a more efficient and robust way towards progress than training new models from scratch. Existing models may (a) incorporate complex mechanistic knowledge, (b) leverage proprietary information and, (c) have surmounted barriers to adoption. Compared to model training, model improvement and modification receive little attention. In this paper we propose a general approach to model improvement: we combine gradient boosting with any previously developed model to improve model performance while retaining important existing characteristics. To exemplify, we consider the context of Mendelian models, which estimate the probability of carrying genetic mutations that confer susceptibility to disease by using family pedigrees and health histories of family members. Via simulations we show that integration of gradient boosting with an existing Mendelian model can produce an improved model that outperforms both that model and the model built using gradient boosting alone. We illustrate the approach on genetic testing data from the USC-Stanford Cancer Genetics Hereditary Cancer Panel (HCP) study.