Uncertainty-informed deep learning models enable high-confidence predictions for digital histopathology

A model's ability to express its own predictive uncertainty is an essential attribute for maintaining clinical user confidence as computational biomarkers are deployed into real-world medical settings. In the domain of cancer digital histopathology, we describe a clinically-oriented approach to uncertainty quantification for whole-slide images, estimating uncertainty using dropout and calculating thresholds on training data to establish cutoffs for low- and high-confidence predictions. We train models to identify lung adenocarcinoma vs. squamous cell carcinoma and show that high-confidence predictions outperform predictions without uncertainty, in both cross-validation and testing on two large external datasets spanning multiple institutions. Our testing strategy closely approximates real-world application, with predictions generated on unsupervised, unannotated slides using predetermined thresholds. Furthermore, we show that uncertainty thresholding remains reliable in the setting of domain shift, with accurate high-confidence predictions of adenocarcinoma vs. squamous cell carcinoma for out-of-distribution, non-lung cancer cohorts. Safe clinical deployment of deep learning models for digital pathology requires reliable estimates of predictive uncertainty. Here the authors describe an algorithm for quantifying whole-slide image uncertainty, demonstrating their approach with models trained to distinguish lung cancer subtypes.

Automated summary

A model's ability to express its own predictive uncertainty is crucial in maintaining clinical user confidence in real-world medical settings. This study presents a clinically-oriented approach to quantify uncertainty in cancer digital histopathology, using dropout to estimate uncertainty and establishing cutoffs for low- and high-confidence predictions based on threshold calculation on training data.