Benefits of spatial uncertainty aggregation for segmentation in digital pathology.

Purpose: Uncertainty estimation has gained significant attention in recent years for its potential to enhance the performance of deep learning (DL) algorithms in medical applications and even potentially address domain shift challenges. However, it is not straightforward to incorporate uncertainty estimation with a DL system to achieve a tangible positive effect. The objective of our work is to evaluate if the proposed spatial uncertainty aggregation (SUA) framework may improve the effectiveness of uncertainty estimation in segmentation tasks. We evaluate if SUA boosts the observed correlation between the uncertainty estimates and false negative (FN) predictions. We also investigate if the observed benefits can translate to tangible improvements in segmentation performance. Approach: Our SUA framework processes negative prediction regions from a segmentation algorithm and detects FNs based on an aggregated uncertainty score. It can be utilized with many existing uncertainty estimation methods to boost their performance. We compare the SUA framework with a baseline of processing individual pixel's uncertainty independently. Results: The results demonstrate that SUA is able to detect FN regions. It achieved Fß=0.5 of 0.92 on the in-domain and 0.85 on the domain-shift test data compared with 0.81 and 0.48 achieved by the baseline uncertainty, respectively. We also demonstrate that SUA yields improved general segmentation performance compared with utilizing the baseline uncertainty. Conclusions: We propose the SUA framework for incorporating and utilizing uncertainty estimates for FN detection in DL segmentation algorithms for histopathology. The evaluation confirms the benefits of our approach compared with assessing pixel uncertainty independently.

Generalization of Deep Learning in Digital Pathology: Experience in Breast Cancer Metastasis Detection.

Poor generalizability is a major barrier to clinical implementation of artificial intelligence in digital pathology. The aim of this study was to test the generalizability of a pretrained deep learning model to a new diagnostic setting and to a small change in surgical indication. A deep learning model for breast cancer metastases detection in sentinel lymph nodes, trained on CAMELYON multicenter data, was used as a base model, and achieved an AUC of 0.969 (95% CI 0.926-0.998) and FROC of 0.838 (95% CI 0.757-0.913) on CAMELYON16 test data. On local sentinel node data, the base model performance dropped to AUC 0.929 (95% CI 0.800-0.998) and FROC 0.744 (95% CI 0.566-0.912). On data with a change in surgical indication (axillary dissections) the base model performance indicated an even larger drop with a FROC of 0.503 (95%CI 0.201-0.911). The model was retrained with addition of local data, resulting in about a 4% increase for both AUC and FROC for sentinel nodes, and an increase of 11% in AUC and 49% in FROC for axillary nodes. Pathologist qualitative evaluation of the retrained model´s output showed no missed positive slides. False positives, false negatives and one previously undetected micro-metastasis were observed. The study highlights the generalization challenge even when using a multicenter trained model, and that a small change in indication can considerably impact the model´s performance.

Generalisation effects of predictive uncertainty estimation in deep learning for digital pathology.

Deep learning (DL) has shown great potential in digital pathology applications. The robustness of a diagnostic DL-based solution is essential for safe clinical deployment. In this work we evaluate if adding uncertainty estimates for DL predictions in digital pathology could result in increased value for the clinical applications, by boosting the general predictive performance or by detecting mispredictions. We compare the effectiveness of model-integrated methods (MC dropout and Deep ensembles) with a model-agnostic approach (Test time augmentation, TTA). Moreover, four uncertainty metrics are compared. Our experiments focus on two domain shift scenarios: a shift to a different medical center and to an underrepresented subtype of cancer. Our results show that uncertainty estimates increase reliability by reducing a model's sensitivity to classification threshold selection as well as by detecting between 70 and 90% of the mispredictions done by the model. Overall, the deep ensembles method achieved the best performance closely followed by TTA.