Application of simultaneous uncertainty quantification for image segmentation with probabilistic deep learning: Performance benchmarking of oropharyngeal cancer target delineation as a use-case

Background Oropharyngeal cancer (OPC) is a widespread disease, with radiotherapy being a core treatment modality. Manual segmentation of the primary gross tumor volume (GTVp) is currently employed for OPC radiotherapy planning, but is subject to significant interobserver variability. Deep learning (DL) approaches have shown promise in automating GTVp segmentation, but comparative (auto)confidence metrics of these models predictions has not been well-explored. Quantifying instance-specific DL model uncertainty is crucial to improving clinician trust and facilitating broad clinical implementation. Therefore, in this study, probabilistic DL models for GTVp auto-segmentation were developed using large-scale PET/CT datasets, and various uncertainty auto-estimation methods were systematically investigated and benchmarked. Methods We utilized the publicly available 2021 HECKTOR Challenge training dataset with 224 co-registered PET/CT scans of OPC patients with corresponding GTVp segmentations as a development set. A separate set of 67 co-registered PET/CT scans of OPC patients with corresponding GTVp segmentations was used for external validation. Two approximate Bayesian deep learning methods, the MC Dropout Ensemble and Deep Ensemble, both with five submodels, were evaluated for GTVp segmentation and uncertainty performance. The segmentation performance was evaluated using the volumetric Dice similarity coefficient (DSC), mean surface distance (MSD), and Hausdorff distance at 95% (95HD). The uncertainty was evaluated using four measures from literature: coefficient of variation (CV), structure expected entropy, structure predictive entropy, and structure mutual information, and additionally with our novel Dice-risk measure. The utility of uncertainty information was evaluated with the accuracy of uncertainty-based segmentation performance prediction using the Accuracy vs Uncertainty (AvU) metric, and by examining the linear correlation between uncertainty estimates and DSC. In addition, batch-based and instance-based referral processes were examined, where the patients with high uncertainty were rejected from the set. In the batch referral process, the area under the referral curve with DSC (R-DSC AUC) was used for evaluation, whereas in the instance referral process, the DSC at various uncertainty thresholds were examined. Results Both models behaved similarly in terms of the segmentation performance and uncertainty estimation. Specifically, the MC Dropout Ensemble had 0.776 DSC, 1.703 mm MSD, and 5.385 mm 95HD. The Deep Ensemble had 0.767 DSC, 1.717 mm MSD, and 5.477 mm 95HD. The uncertainty measure with the highest DSC correlation was structure predictive entropy with correlation coefficients of 0.699 and 0.692 for the MC Dropout Ensemble and the Deep Ensemble, respectively. The highest AvU value was 0.866 for both models. The best performing uncertainty measure for both models was the CV which had R-DSC AUC of 0.783 and 0.782 for the MC Dropout Ensemble and Deep Ensemble, respectively. With referring patients based on uncertainty thresholds from 0.85 validation DSC for all uncertainty measures, on average the DSC improved from the full dataset by 4.7% and 5.0% while referring 21.8% and 22% patients for MC Dropout Ensemble and Deep Ensemble, respectively. Conclusion We found that many of the investigated methods provide overall similar but distinct utility in terms of predicting segmentation quality and referral performance. These findings are a critical first-step towards more widespread implementation of uncertainty quantification in OPC GTVp segmentation. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The work of Joel Jaskari, Jaakko Sahlsten, and Kimmo K. Kaski was supported in part by the Academy of Finland under Project 345449. Kareem A. Wahid is supported by the Dr. John J. Kopchick Fellowship through The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, the American Legion Auxiliary Fellowship in Cancer Research, and an NIH/National Institute for Dental and Craniofacial Research (NIDCR) F31 fellowship (1 F31DE031502-01). Benjamin H. Kann is supported by an NIH/National Institute for Dental and Craniofacial Research (NIDCR) K08 Grant (K08DE030216). Clifton D. Fuller receives related grant support from the NCI NRSA Image Guided Cancer Therapy Training Program (T32CA261856), as well as additional unrelated salary/effort support from NIH institutes. Dr. Fuller receives grant and infrastructure support from MD Anderson Cancer Center via: the Charles and Daneen Stiefel Center for Head and Neck Cancer Oropharyngeal Cancer Research Program; the Program in Image-guided Cancer Therapy; and the NIH/NCI Cancer Center Support Grant (CCSG) Radiation Oncology and Cancer Imaging Program (P30CA016672). Dr. Fuller has received unrelated direct industry grant/in-kind support, honoraria, and travel funding from Elekta AB. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The MDA external validation dataset was retrospectively collected under a HIPAA-compliant protocol approved by the MDA institutional review board (RCR03-0800) which gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.