RNA2DNAlign: nucleotide resolution allele asymmetries through quantitative assessment of RNA and DNA paired sequencing data.

We introduce RNA2DNAlign, a computational framework for quantitative assessment of allele counts across paired RNA and DNA sequencing datasets. RNA2DNAlign is based on quantitation of the relative abundance of variant and reference read counts, followed by binomial tests for genotype and allelic status at SNV positions between compatible sequences. RNA2DNAlign detects positions with differential allele distribution, suggesting asymmetries due to regulatory/structural events. Based on the type of asymmetry, RNA2DNAlign outlines positions likely to be implicated in RNA editing, allele-specific expression or loss, somatic mutagenesis or loss-of-heterozygosity (the first three also in a tumor-specific setting). We applied RNA2DNAlign on 360 matching normal and tumor exomes and transcriptomes from 90 breast cancer patients from TCGA. Under high-confidence settings, RNA2DNAlign identified 2038 distinct SNV sites associated with one of the aforementioned asymetries, the majority of which have not been linked to functionality before. The performance assessment shows very high specificity and sensitivity, due to the corroboration of signals across multiple matching datasets. RNA2DNAlign is freely available from http://github.com/HorvathLab/NGS as a self-contained binary package for 64-bit Linux systems.

Markov models for clinical decision-making in radiation oncology: A systematic review.

The intrinsic stochasticity of patients' response to treatment is a major consideration for clinical decision-making in radiation therapy. Markov models are powerful tools to capture this stochasticity and render effective treatment decisions. This paper provides an overview of the Markov models for clinical decision analysis in radiation oncology. A comprehensive literature search was conducted within MEDLINE using PubMed, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Only studies published from 2000 to 2023 were considered. Selected publications were summarized in two categories: (i) studies that compare two (or more) fixed treatment policies using Monte Carlo simulation and (ii) studies that seek an optimal treatment policy through Markov Decision Processes (MDPs). Relevant to the scope of this study, 61 publications were selected for detailed review. The majority of these publications (n = 56) focused on comparative analysis of two or more fixed treatment policies using Monte Carlo simulation. Classifications based on cancer site, utility measures and the type of sensitivity analysis are presented. Five publications considered MDPs with the aim of computing an optimal treatment policy; a detailed statement of the analysis and results is provided for each work. As an extension of Markov model-based simulation analysis, MDP offers a flexible framework to identify an optimal treatment policy among a possibly large set of treatment policies. However, the applications of MDPs to oncological decision-making have been understudied, and the full capacity of this framework to render complex optimal treatment decisions warrants further consideration.

Cluster-Based Toxicity Estimation of Osteoradionecrosis Via Unsupervised Machine Learning: Moving Beyond Single Dose-Parameter Normal Tissue Complication Probability by Using Whole Dose-Volume Histograms for Cohort Risk Stratification.

PURPOSE: Given the limitations of extant models for normal tissue complication probability estimation for osteoradionecrosis (ORN) of the mandible, the purpose of this study was to enrich statistical inference by exploiting structural properties of data and provide a clinically reliable model for ORN risk evaluation through an unsupervised-learning analysis that incorporates the whole radiation dose distribution on the mandible. METHODS AND MATERIALS: The analysis was conducted on retrospective data of 1259 patients with head and neck cancer treated at The University of Texas MD Anderson Cancer Center between 2005 and 2015. During a minimum 12-month posttherapy follow-up period, 173 patients in this cohort (13.7%) developed ORN (grades I to IV). The (structural) clusters of mandibular dose-volume histograms (DVHs) for these patients were identified using the K-means clustering method. A soft-margin support vector machine was used to determine the cluster borders and partition the dose-volume space. The risk of ORN for each dose-volume region was calculated based on incidence rates and other clinical risk factors. RESULTS: The K-means clustering method identified 6 clusters among the DVHs. Based on the first 5 clusters, the dose-volume space was partitioned by the soft-margin support vector machine into distinct regions with different risk indices. The sixth cluster entirely overlapped with the others; the region of this cluster was determined by its envelopes. For each region, the ORN incidence rate per preradiation dental extraction status (a statistically significant, nondose related risk factor for ORN) was reported as the corresponding risk index. CONCLUSIONS: This study presents an unsupervised-learning analysis of a large-scale data set to evaluate the risk of mandibular ORN among patients with head and neck cancer. The results provide a visual risk-assessment tool for ORN (based on the whole DVH and preradiation dental extraction status) as well as a range of constraints for dose optimization under different risk levels.

Optimal Timing of Organs-at-risk-sparing Adaptive Radiation Therapy for Head-and-neck Cancer under Re-planning Resource Constraints.

Background and Purpose: Prior work on adaptive organ-at-risk (OAR)-sparing radiation therapy has typically reported outcomes based on fixed-number or fixed-interval re-plannings, which represent a one-size-fits-all approach and do not account for the variable progression of individual patients' toxicities. The purpose of this study was to determine the personalized optimal timing for re-planning in adaptive OAR-sparing radiation therapy, considering limited re-planning resources, specifically for patients with head and neck cancer (HNC). Methods and Materials: A novel Markov decision process (MDP) model was developed to determine optimal timing of re-plannings based on the patient's expected toxicity, characterized by normal tissue complication probability (NTCP), for four toxicities. The MDP parameters were derived from a dataset comprising 52 HNC patients treated at the University of Texas MD Anderson Cancer Center between 2007 and 2013. Optimal replanning strategies were obtained when the permissible number of re-plannings throughout the treatment was limited to 1, 2, and 3. Results: The MDP (optimal) solution recommended re-planning when the difference between planned and actual NTCPs (ΔNTCP) was greater than or equal to 1%, 2%, 2%, and 4% at treatment fractions 10, 15, 20, and 25, respectively, exhibiting a temporally increasing pattern. The ΔNTCP thresholds remained constant across the number of re-planning allowances (1, 2, and 3). Conclusion: The MDP model determines the optimal timing for implementing patient-specific adaptive re-planning. This approach incorporates ΔNTCP thresholds and considers varying total re-plannings. The methods are versatile and applicable across cancer types, institutional settings, and different OARs and NTCP models.

Computed tomography radiomics-based cross-sectional detection of mandibular osteoradionecrosis in head and neck cancer survivors.

Purpose: This study aims to identify radiomic features extracted from contrast-enhanced CT scans that differentiate osteoradionecrosis (ORN) from normal mandibular bone in patients with head and neck cancer (HNC) treated with radiotherapy (RT). Materials and Methods: Contrast-enhanced CT (CECT) images were collected for 150 patients (80% train, 20% test) with confirmed ORN diagnosis at The University of Texas MD Anderson Cancer Center between 2008 and 2018. Using PyRadiomics, radiomic features were extracted from manually segmented ORN regions and the corresponding automated control regions, the later defined as the contralateral healthy mandible region. A subset of pre-selected features was obtained based on correlation analysis (r > 0.95) and used to train a Random Forest (RF) classifier with Recursive Feature Elimination. Model explainability SHapley Additive exPlanations (SHAP) analysis was performed on the 20 most important features identified by the trained RF classifier. Results: From a total of 1316 radiomic features extracted, 810 features were excluded due to high collinearity. From a set of 506 pre-selected radiomic features, the optimal subset resulting on the best discriminative accuracy of the RF classifier consisted of 67 features. The RF classifier was well calibrated (Log Loss 0.296, ECE 0.125) and achieved an accuracy of 88% and a ROC AUC of 0.96. The SHAP analysis revealed that higher values of Wavelet-LLH First-order Mean and Median were associated with ORN of the jaw (ORNJ). Conversely, higher Exponential GLDM Dependence Entropy and lower Square First-order Kurtosis were more characteristic of normal mandibular tissue. Conclusion: This study successfully developed a CECT-based radiomics model for differentiating ORNJ from healthy mandibular tissue in HNC patients after RT. Future work will focus on the detection of subclinical ORNJ regions to guide earlier interventions.

Dysphagia and shortness-of-breath as markers for treatment failure and survival in oropharyngeal cancer after radiation.

BACKGROUND: Post-treatment symptoms are a focal point of follow-up visits for head and neck cancer patients. While symptoms such as dysphagia and shortness-of-breath early after treatment may motivate additional work up, their precise association with disease control and survival outcomes is not well established. METHODS: This prospective data cohort study of 470 oropharyngeal cancer patients analyzed patient-reported swallowing, choking and shortness-of-breath symptoms at 3-to-6 months following radiotherapy to evaluate their association with overall survival and disease control. Associations between the presence of moderate-to-severe swallowing, choking and mild-to-severe shortness-of-breath and treatment outcomes were analyzed via Cox regression and Kaplan-Meier. The main outcome was overall survival (OS), and the secondary outcomes were local, regional, and distant disease control. RESULTS: The majority of patients (91.3%) were HPV-positive. Median follow-up time was 31.7 months (IQR: 21.9-42.1). Univariable analysis showed significant associations between OS and all three symptoms of swallowing, choking, and shortness-of-breath. A composite variable integrating scores of all three symptoms was significantly associated with OS on multivariable Cox regression (p = 0.0018). Additionally, this composite symptom score showed the best predictive value for OS (c-index = 0.75). Multivariable analysis also revealed that the composite score was significantly associated with local (p = 0.044) and distant (p = 0.035) recurrence/progression. Notably, the same significant associations with OS were seen for HPV-positive only subset analysis (p < 0.01 for all symptoms). CONCLUSIONS: Quantitative patient-reported measures of dysphagia and shortness-of-breath 3-to-6 months post-treatment are significant predictors of OS and disease recurrence/progression in OPC patients and in HPV-positive OPC only.

Cluster-Based Toxicity Estimation of Osteoradionecrosis via Unsupervised Machine Learning: Moving Beyond Single Dose-Parameter Normal Tissue Complication Probability by Using Whole Dose-Volume Histograms for Cohort Risk Stratification.

Purpose: Given the limitations of extant models for normal tissue complication probability estimation for osteoradionecrosis (ORN) of the mandible, the purpose of this study was to enrich statistical inference by exploiting structural properties of data and provide a clinically reliable model for ORN risk evaluation through an unsupervised-learning analysis. Materials and Methods: The analysis was conducted on retrospective data of 1,259 head and neck cancer (HNC) patients treated at the University of Texas MD Anderson Cancer Center between 2005 and 2015. The (structural) clusters of mandibular dose-volume histograms (DVHs) were identified through the K-means clustering method. A soft-margin support vector machine (SVM) was used to determine the cluster borders and partition the dose-volume space. The risk of ORN for each dose-volume region was calculated based on the clinical risk factors and incidence rates. Results: The K-means clustering method identified six clusters among the DVHs. Based on the first five clusters, the dose-volume space was partitioned almost perfectly by the soft-margin SVM into distinct regions with different risk indices. The sixth cluster overlapped the others entirely; the region of this cluster was determined by its envelops. These regions and the associated risk indices provide a range of constraints for dose optimization under different risk levels. Conclusion: This study presents an unsupervised-learning analysis of a large-scale data set to evaluate the risk of mandibular ORN among HNC patients. The results provide a visual risk-assessment tool (based on the whole DVH) and a spectrum of dose constraints for radiation planning.

Quality assurance assessment of intra-acquisition diffusion-weighted and T2-weighted magnetic resonance imaging registration and contour propagation for head and neck cancer radiotherapy.

BACKGROUND/PURPOSE: Adequate image registration of anatomical and functional magnetic resonance imaging (MRI) scans is necessary for MR-guided head and neck cancer (HNC) adaptive radiotherapy planning. Despite the quantitative capabilities of diffusion-weighted imaging (DWI) MRI for treatment plan adaptation, geometric distortion remains a considerable limitation. Therefore, we systematically investigated various deformable image registration (DIR) methods to co-register DWI and T2-weighted (T2W) images. MATERIALS/METHODS: We compared three commercial (ADMIRE, Velocity, Raystation) and three open-source (Elastix with default settings [Elastix Default], Elastix with parameter set 23 [Elastix 23], Demons) post-acquisition DIR methods applied to T2W and DWI MRI images acquired during the same imaging session in twenty immobilized HNC patients. In addition, we used the non-registered images (None) as a control comparator. Ground-truth segmentations of radiotherapy structures (tumour and organs at risk) were generated by a physician expert on both image sequences. For each registration approach, structures were propagated from T2W to DWI images. These propagated structures were then compared with ground-truth DWI structures using the Dice similarity coefficient and mean surface distance. RESULTS: 19 left submandibular glands, 18 right submandibular glands, 20 left parotid glands, 20 right parotid glands, 20 spinal cords, and 12 tumours were delineated. Most DIR methods took <30 s to execute per case, with the exception of Elastix 23 which took ∼458 s to execute per case. ADMIRE and Elastix 23 demonstrated improved performance over None for all metrics and structures (Bonferroni-corrected p < 0.05), while the other methods did not. Moreover, ADMIRE and Elastix 23 significantly improved performance in individual and pooled analysis compared to all other methods. CONCLUSIONS: The ADMIRE DIR method offers improved geometric performance with reasonable execution time so should be favoured for registering T2W and DWI images acquired during the same scan session in HNC patients. These results are important to ensure the appropriate selection of registration strategies for MR-guided radiotherapy.

Temporal characterization of acute pain and toxicity kinetics during radiation therapy for head and neck cancer. A retrospective study.

Objectives: Pain during Radiation Therapy (RT) for oral cavity/oropharyngeal cancer (OC/OPC) is a clinical challenge due to its multifactorial etiology and variable management. The objective of this study was to define complex pain profiles through temporal characterization of pain descriptors, physiologic state, and RT-induced toxicities for pain trajectories understanding. Materials and methods: Using an electronic health record registry, 351 OC/OPC patients treated with RT from 2013 to 2021 were included. Weekly numeric scale pain scores, pain descriptors, vital signs, physician-reported toxicities, and analgesics were analyzed using linear mixed effect models and Spearman's correlation. Area under the pain curve (AUCpain) was calculated to measure pain burden over time. Results: Median pain scores increased from 0 during the weekly visit (WSV)-1 to 5 during WSV-7. By WSV-7, 60% and 74% of patients reported mouth and throat pain, respectively, with a median pain score of 5. Soreness and burning pain peaked during WSV-6/7 (51%). Median AUCpain was 16% (IQR (9.3-23)), and AUCpain significantly varied based on gender, tumor site, surgery, drug use history, and pre-RT pain. A temporal increase in mucositis and dermatitis, declining mean bodyweight (-7.1%; P < 0.001) and mean arterial pressure (MAP) 6.8 mmHg; P < 0.001 were detected. Pulse rate was positively associated while weight and MAP were negatively associated with pain over time (P < 0.001). Conclusion: This study provides insight on in-depth characterization and associations between dynamic pain, physiologic, and toxicity kinetics. Our findings support further needs of optimized pain control through temporal data-driven clinical decision support systems for acute pain management.

Progression Free Survival Prediction for Head and Neck Cancer Using Deep Learning Based on Clinical and PET/CT Imaging Data.

Determining progression-free survival (PFS) for head and neck squamous cell carcinoma (HNSCC) patients is a challenging but pertinent task that could help stratify patients for improved overall outcomes. PET/CT images provide a rich source of anatomical and metabolic data for potential clinical biomarkers that would inform treatment decisions and could help improve PFS. In this study, we participate in the 2021 HECKTOR Challenge to predict PFS in a large dataset of HNSCC PET/CT images using deep learning approaches. We develop a series of deep learning models based on the DenseNet architecture using a negative log-likelihood loss function that utilizes PET/CT images and clinical data as separate input channels to predict PFS in days. Internal model validation based on 10-fold cross-validation using the training data (N = 224) yielded C-index values up to 0.622 (without) and 0.842 (with) censoring status considered in C-index computation, respectively. We then implemented model ensembling approaches based on the training data cross-validation folds to predict the PFS of the test set patients (N = 101). External validation on the test set for the best ensembling method yielded a C-index value of 0.694, placing 2nd in the competition. Our results are a promising example of how deep learning approaches can effectively utilize imaging and clinical data for medical outcome prediction in HNSCC, but further work in optimizing these processes is needed.

Head and Neck Cancer Primary Tumor Auto Segmentation Using Model Ensembling of Deep Learning in PET/CT Images.

Auto-segmentation of primary tumors in oropharyngeal cancer using PET/CT images is an unmet need that has the potential to improve radiation oncology workflows. In this study, we develop a series of deep learning models based on a 3D Residual Unet (ResUnet) architecture that can segment oropharyngeal tumors with high performance as demonstrated through internal and external validation of large-scale datasets (training size = 224 patients, testing size = 101 patients) as part of the 2021 HECKTOR Challenge. Specifically, we leverage ResUNet models with either 256 or 512 bottleneck layer channels that demonstrate internal validation (10-fold cross-validation) mean Dice similarity coefficient (DSC) up to 0.771 and median 95% Hausdorff distance (95% HD) as low as 2.919 mm. We employ label fusion ensemble approaches, including Simultaneous Truth and Performance Level Estimation (STAPLE) and a voxel-level threshold approach based on majority voting (AVERAGE), to generate consensus segmentations on the test data by combining the segmentations produced through different trained cross-validation models. We demonstrate that our best performing ensembling approach (256 channels AVERAGE) achieves a mean DSC of 0.770 and median 95% HD of 3.143 mm through independent external validation on the test set. Our DSC and 95% HD test results are within 0.01 and 0.06 mm of the top ranked model in the competition, respectively. Concordance of internal and external validation results suggests our models are robust and can generalize well to unseen PET/CT data. We advocate that ResUNet models coupled to label fusion ensembling approaches are promising candidates for PET/CT oropharyngeal primary tumors auto-segmentation. Future investigations should target the ideal combination of channel combinations and label fusion strategies to maximize segmentation performance.

Combining Tumor Segmentation Masks with PET/CT Images and Clinical Data in a Deep Learning Framework for Improved Prognostic Prediction in Head and Neck Squamous Cell Carcinoma.

PET/CT images provide a rich data source for clinical prediction models in head and neck squamous cell carcinoma (HNSCC). Deep learning models often use images in an end-to-end fashion with clinical data or no additional input for predictions. However, in the context of HNSCC, the tumor region of interest may be an informative prior in the generation of improved prediction performance. In this study, we utilize a deep learning framework based on a DenseNet architecture to combine PET images, CT images, primary tumor segmentation masks, and clinical data as separate channels to predict progression-free survival (PFS) in days for HNSCC patients. Through internal validation (10-fold cross-validation) based on a large set of training data provided by the 2021 HECKTOR Challenge, we achieve a mean C-index of 0.855 ± 0.060 and 0.650 ± 0.074 when observed events are and are not included in the C-index calculation, respectively. Ensemble approaches applied to cross-validation folds yield C-index values up to 0.698 in the independent test set (external validation), leading to a 1st place ranking on the competition leaderboard. Importantly, the value of the added segmentation mask is underscored in both internal and external validation by an improvement of the C-index when compared to models that do not utilize the segmentation mask. These promising results highlight the utility of including segmentation masks as additional input channels in deep learning pipelines for clinical outcome prediction in HNSCC.

Muscle and adipose tissue segmentations at the third cervical vertebral level in patients with head and neck cancer.

The accurate determination of sarcopenia is critical for disease management in patients with head and neck cancer (HNC). Quantitative determination of sarcopenia is currently dependent on manually-generated segmentations of skeletal muscle derived from computed tomography (CT) cross-sectional imaging. This has prompted the increasing utilization of machine learning models for automated sarcopenia determination. However, extant datasets currently do not provide the necessary manually-generated skeletal muscle segmentations at the C3 vertebral level needed for building these models. In this data descriptor, a set of 394 HNC patients were selected from The Cancer Imaging Archive, and their skeletal muscle and adipose tissue was manually segmented at the C3 vertebral level using sliceOmatic. Subsequently, using publicly disseminated Python scripts, we generated corresponding segmentations files in Neuroimaging Informatics Technology Initiative format. In addition to segmentation data, additional clinical demographic data germane to body composition analysis have been retrospectively collected for these patients. These data are a valuable resource for studying sarcopenia and body composition analysis in patients with HNC.

Deep learning auto-segmentation of cervical skeletal muscle for sarcopenia analysis in patients with head and neck cancer.

Background/Purpose: Sarcopenia is a prognostic factor in patients with head and neck cancer (HNC). Sarcopenia can be determined using the skeletal muscle index (SMI) calculated from cervical neck skeletal muscle (SM) segmentations. However, SM segmentation requires manual input, which is time-consuming and variable. Therefore, we developed a fully-automated approach to segment cervical vertebra SM. Materials/Methods: 390 HNC patients with contrast-enhanced CT scans were utilized (300-training, 90-testing). Ground-truth single-slice SM segmentations at the C3 vertebra were manually generated. A multi-stage deep learning pipeline was developed, where a 3D ResUNet auto-segmented the C3 section (33 mm window), the middle slice of the section was auto-selected, and a 2D ResUNet auto-segmented the auto-selected slice. Both the 3D and 2D approaches trained five sub-models (5-fold cross-validation) and combined sub-model predictions on the test set using majority vote ensembling. Model performance was primarily determined using the Dice similarity coefficient (DSC). Predicted SMI was calculated using the auto-segmented SM cross-sectional area. Finally, using established SMI cutoffs, we performed a Kaplan-Meier analysis to determine associations with overall survival. Results: Mean test set DSC of the 3D and 2D models were 0.96 and 0.95, respectively. Predicted SMI had high correlation to the ground-truth SMI in males and females (r>0.96). Predicted SMI stratified patients for overall survival in males (log-rank p = 0.01) but not females (log-rank p = 0.07), consistent with ground-truth SMI. Conclusion: We developed a high-performance, multi-stage, fully-automated approach to segment cervical vertebra SM. Our study is an essential step towards fully-automated sarcopenia-related decision-making in patients with HNC.

Evaluation of deep learning-based multiparametric MRI oropharyngeal primary tumor auto-segmentation and investigation of input channel effects: Results from a prospective imaging registry.

BACKGROUND/PURPOSE: Oropharyngeal cancer (OPC) primary gross tumor volume (GTVp) segmentation is crucial for radiotherapy. Multiparametric MRI (mpMRI) is increasingly used for OPC adaptive radiotherapy but relies on manual segmentation. Therefore, we constructed mpMRI deep learning (DL) OPC GTVp auto-segmentation models and determined the impact of input channels on segmentation performance. MATERIALS/METHODS: GTVp ground truth segmentations were manually generated for 30 OPC patients from a clinical trial. We evaluated five mpMRI input channels (T2, T1, ADC, Ktrans, Ve). 3D Residual U-net models were developed and assessed using leave-one-out cross-validation. A baseline T2 model was compared to mpMRI models (T2 + T1, T2 + ADC, T2 + Ktrans, T2 + Ve, all five channels [ALL]) primarily using the Dice similarity coefficient (DSC). False-negative DSC (FND), false-positive DSC, sensitivity, positive predictive value, surface DSC, Hausdorff distance (HD), 95% HD, and mean surface distance were also assessed. For the best model, ground truth and DL-generated segmentations were compared through a blinded Turing test using three physician observers. RESULTS: Models yielded mean DSCs from 0.71 ± 0.12 (ALL) to 0.73 ± 0.12 (T2 + T1). Compared to the T2 model, performance was significantly improved for FND, sensitivity, surface DSC, HD, and 95% HD for the T2 + T1 model (p < 0.05) and for FND for the T2 + Ve and ALL models (p < 0.05). No model demonstrated significant correlations between tumor size and DSC (p > 0.05). Most models demonstrated significant correlations between tumor size and HD or Surface DSC (p < 0.05), except those that included ADC or Ve as input channels (p > 0.05). On average, there were no significant differences between ground truth and DL-generated segmentations for all observers (p > 0.05). CONCLUSION: DL using mpMRI provides reasonably accurate segmentations of OPC GTVp that may be comparable to ground truth segmentations generated by clinical experts. Incorporating additional mpMRI channels may increase the performance of FND, sensitivity, surface DSC, HD, and 95% HD, and improve model robustness to tumor size.