Explainable machine learning via intra-tumoral radiomics feature mapping for patient stratification in adjuvant chemotherapy for locoregionally advanced nasopharyngeal carcinoma.

PURPOSE: This study aimed to discover intra-tumor heterogeneity signature and validate its predictive value for adjuvant chemotherapy (ACT) following concurrent chemoradiotherapy (CCRT) in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). MATERIALS AND METHODS: 397 LA-NPC patients were retrospectively enrolled. Pre-treatment contrast-enhanced T1-weighted (CET1-w) MR images, clinical variables, and follow-up were retrospectively collected. We identified single predictive radiomic feature from primary gross tumor volume (GTVnp) and defined predicted subvolume by calculating voxel-wised feature mapping and within GTVnp. We independently validate predictive value of identified feature and associated predicted subvolume. RESULTS: Only one radiomic feature, gldm_DependenceVariance in 3 mm-sigma LoG-filtered image, was discovered as a signature. In the high-risk group determined by the signature, patients received CCRT + ACT achieved 3-year disease free survival (DFS) rate of 90% versus 57% (HR, 0.20; 95%CI, 0.05-0.94; P = 0.007) for CCRT alone. The multivariate analysis showed patients receiving CCRT + ACT had a HR of 0.21 (95%CI: 0.06-0.68, P = 0.009) for DFS compared to those receiving CCRT alone. The predictive value can also be generalized to the subvolume with multivariate HR of 0.27 (P = 0.017) for DFS. CONCLUSION: The signature with its heterogeneity mapping could be a reliable and explainable ACT decision-making tool in clinical practice.

Respiratory Invariant Textures From Static Computed Tomography Scans for Explainable Lung Function Characterization.

PURPOSE: The inherent characteristics of lung tissue independent of breathing maneuvers may provide fundamental information for function assessment. This paper attempted to correlate textural signatures from computed tomography (CT) with pulmonary function measurements. MATERIALS AND METHODS: Twenty-one lung cancer patients with thoracic 4-dimensional CT, DTPA-single-photon emission CT ventilation ( VNM ) scans, and available spirometry measurements (forced expiratory volume in 1 s, FEV 1 ; forced vital capacity, FVC; and FEV 1 /FVC) were collected. In subregional feature discovery, function-correlated candidates were identified from 79 radiomic features based on the statistical strength to differentiate defected/nondefected lung regions. Feature maps (FMs) of selected candidates were generated on 4-dimensional CT phases for a voxel-wise feature distribution study. Quantitative metrics were applied for validations, including the Spearman correlation coefficient (SCC) and the Dice similarity coefficient for FM- VNM spatial agreement assessments, intraclass correlation coefficient for FM interphase robustness evaluations, and FM-spirometry comparisons. RESULTS: At the subregion level, 8 function-correlated features were identified (effect size>0.330). The FMs of candidates yielded moderate-to-strong voxel-wise correlations with the reference VNM . The FMs of gray level dependence matrix dependence nonuniformity showed the highest robust (intraclass correlation coefficient=0.96 and P <0.0001) spatial correlation, with median SCCs ranging from 0.54 to 0.59 throughout the 10 breathing phases. Its phase-averaged FM achieved a median SCC of 0.60, a median Dice similarity coefficient of 0.60 (0.65) for high (low) functional lung volumes, and a correlation of 0.565 (0.646) between the spatially averaged feature values and FEV 1 (FEV 1 /FVC). CONCLUSIONS: The results provide further insight into the underlying association of specific pulmonary textures with both local ( VNM ) and global (FEV 1 /FVC, FEV 1 ) functions. Further validations of the FM generalizability and the standardization of implementation protocols are warranted before clinically relevant investigations.

Artificial intelligence-driven radiomics study in cancer: the role of feature engineering and modeling.

Modern medicine is reliant on various medical imaging technologies for non-invasively observing patients' anatomy. However, the interpretation of medical images can be highly subjective and dependent on the expertise of clinicians. Moreover, some potentially useful quantitative information in medical images, especially that which is not visible to the naked eye, is often ignored during clinical practice. In contrast, radiomics performs high-throughput feature extraction from medical images, which enables quantitative analysis of medical images and prediction of various clinical endpoints. Studies have reported that radiomics exhibits promising performance in diagnosis and predicting treatment responses and prognosis, demonstrating its potential to be a non-invasive auxiliary tool for personalized medicine. However, radiomics remains in a developmental phase as numerous technical challenges have yet to be solved, especially in feature engineering and statistical modeling. In this review, we introduce the current utility of radiomics by summarizing research on its application in the diagnosis, prognosis, and prediction of treatment responses in patients with cancer. We focus on machine learning approaches, for feature extraction and selection during feature engineering and for imbalanced datasets and multi-modality fusion during statistical modeling. Furthermore, we introduce the stability, reproducibility, and interpretability of features, and the generalizability and interpretability of models. Finally, we offer possible solutions to current challenges in radiomics research.

Multi-omics to predict acute radiation esophagitis in patients with lung cancer treated with intensity-modulated radiation therapy.

PURPOSE: The study aimed to predict acute radiation esophagitis (ARE) with grade ≥ 2 for patients with locally advanced lung cancer (LALC) treated with intensity-modulated radiation therapy (IMRT) using multi-omics features, including radiomics and dosiomics. METHODS: 161 patients with stage IIIA-IIIB LALC who received chemoradiotherapy (CRT) or radiotherapy by IMRT with a prescribed dose from 45 to 70 Gy from 2015 to 2019 were enrolled retrospectively. All the toxicity gradings were given following the Common Terminology Criteria for Adverse Events V4.0. Multi-omics features, including radiomics, dosiomics (including dose-volume histogram dosimetric parameters), were extracted based on the planning CT image and three-dimensional dose distribution. All data were randomly divided into training cohorts (N = 107) and testing cohorts (N = 54). In the training cohorts, features with reliably high outcome relevance and low redundancy were selected under random patient subsampling. Four classification models (using clinical factors (CF) only, using radiomics features (RFs) only, dosiomics features (DFs) only, and the hybrid features (HFs) containing clinical factors, radiomics and dosiomics) were constructed employing the Ridge classifier using two-thirds of randomly selected patients as the training cohort. The remaining patient was treated as the testing cohort. A series of models were built with 30 times training-testing splits. Their performances were assessed using the area under the ROC curve (AUC) and accuracy. RESULTS: Among all patients, 51 developed ARE grade ≥ 2, with an incidence of 31.7%. Next, 8990 radiomics and 213 dosiomics features were extracted, and 3, 6, 12, and 13 features remained after feature selection in the CF, DF, RF and DF models, respectively. The RF and HF models achieved similar classification performance, with the training and testing AUCs of 0.796 ± 0.023 (95% confidence interval (CI [0.79, 0.80])/0.744 ± 0.044 (95% CI [0.73, 0.76]) and 0.801 ± 0.022 (95% CI [0.79, 0.81]) (p = 0.74), respectively. The model performances using CF and DF features were poorer, with training and testing AUCs of 0.573 ± 0.026 (95% CI [0.56, 0.58])/ 0.509 ± 0.072 (95% CI [0.48, 0.53]) and 0.679 ± 0.027 (95% CI [0.67, 0.69])/0.604 ± 0.041 (95% CI [0.53, 0.63]) compared with the above two models (p < 0.001), respectively. CONCLUSIONS: In LALC patients treated with CRT IMRT, the ARE grade ≥ 2 can be predicted using the pretreatment radiotherapy image features. To predict ARE, the multi-omics features had similar predictability with radiomics features; however, the dosiomics features and clinical factors had a limited classification performance.

Radiomic feature repeatability and its impact on prognostic model generalizability: A multi-institutional study on nasopharyngeal carcinoma patients.

BACKGROUND AND PURPOSE: To investigate the radiomic feature (RF) repeatability via perturbation and its impact on cross-institutional prognostic model generalizability in Nasopharyngeal Carcinoma (NPC) patients. MATERIALS AND METHODS: 286 and 183 NPC patients from two institutions were included for model training and validation. Perturbations with random translations and rotations were applied to contrast-enhanced T1-weighted (CET1-w) MR images. RFs were extracted from primary tumor volume under a wide range of image filtering and discretization settings. RF repeatability was assessed by intraclass correlation coefficient (ICC), which was used to equally separate the RFs into low- and high-repeatable groups by the median value. After feature selection, multivariate Cox regression and Kaplan-Meier analysis were independently employed to develop and analyze prognostic models. Concordance index (C-index) and P-value from log-rank test were used to assess model performance. RESULTS: Most textural RFs from high-pass wavelet-filtered images were susceptible to image perturbations. It was more prominent when a smaller discretization bin number was used (e.g., 8, mean ICC = 0.69). Using high-repeatable RFs for model development yielded a significantly higher C-index (0.63) in the validation cohort than when only low-repeatable RFs were used (0.57, P = 0.024), suggesting higher model generalizability. Besides, significant risk stratification in the validation cohort was observed only when high-repeatable RFs were used (P < 0.001). CONCLUSION: Repeatability of RFs from high-pass wavelet-filtered CET1-w MR images of primary NPC tumor was poor, particularly when a smaller bin number was used. Exclusive use of high-repeatable RFs is suggested to safeguard model generalizability for wide-spreading clinical utilization.

Dynamic DNA Nanostructures for Cell Manipulation.

Dynamic DNA nanostructures are DNA nanostructures with reconfigurable elements that can undergo structural transformations in response to specific stimuli. Thus, anchoring dynamic DNA nanostructures on cell membranes is an attractive and promising strategy for well-controlled cell manipulation. Here, we review the latest progress in dynamic DNA nanostructures for cell manipulation. Commonly used mechanisms for dynamic DNA nanostructures are first introduced. Subsequently, we summarize the anchoring strategies for dynamic DNA nanostructures on cell membranes and list possible applications (including programming cell membrane receptors, controlling ligand activity and drug delivery, capturing and releasing cells, and assembling cells into clusters). Finally, insights into the remaining challenges are presented.

Radiomics-Based Detection of COVID-19 from Chest X-ray Using Interpretable Soft Label-Driven TSK Fuzzy Classifier.

The COVID-19 pandemic has posed a significant global public health threat with an escalating number of new cases and death toll daily. The early detection of COVID-related CXR abnormality potentially allows the early isolation of suspected cases. Chest X-Ray (CXR) is a fast and highly accessible imaging modality. Recently, a number of CXR-based AI models have been developed for the automated detection of COVID-19. However, most existing models are difficult to interpret due to the use of incomprehensible deep features in their models. Confronted with this, we developed an interpretable TSK fuzzy system in this study for COVID-19 detection using radiomics features extracted from CXR images. There are two main contributions. (1) When TSK fuzzy systems are applied to classification tasks, the commonly used binary label matrix of training samples is transformed into a soft one in order to learn a more discriminant transformation matrix and hence improve classification accuracy. (2) Based on the assumption that the samples in the same class should be kept as close as possible when they are transformed into the label space, the compactness class graph is introduced to avoid overfitting caused by label matrix relaxation. Our proposed model for a multi-categorical classification task (COVID-19 vs. No-Findings vs. Pneumonia) was evaluated using 600 CXR images from publicly available datasets and compared against five state-of-the-art AI models in aspects of classification accuracy. Experimental findings showed that our model achieved classification accuracy of over 83%, which is better than the state-of-the-art models, while maintaining high interpretability.

Lung Subregion Partitioning by Incremental Dose Intervals Improves Omics-Based Prediction for Acute Radiation Pneumonitis in Non-Small-Cell Lung Cancer Patients.

Purpose: To evaluate the effectiveness of features obtained from our proposed incremental-dose-interval-based lung subregion segmentation (IDLSS) for predicting grade ≥ 2 acute radiation pneumonitis (ARP) in lung cancer patients upon intensity-modulated radiotherapy (IMRT). (1) Materials and Methods: A total of 126 non-small-cell lung cancer patients treated with IMRT were retrospectively analyzed. Five lung subregions (SRs) were generated by the intersection of the whole lung (WL) and five sub-regions receiving incremental dose intervals. A total of 4610 radiomics features (RF) from pre-treatment planning computed tomographic (CT) and 213 dosiomics features (DF) were extracted. Six feature groups, including WL-RF, WL-DF, SR-RF, SR-DF, and the combined feature sets of WL-RDF and SR-RDF, were generated. Features were selected by using a variance threshold, followed by a Student t-test. Pearson's correlation test was applied to remove redundant features. Subsequently, Ridge regression was adopted to develop six models for ARP using the six feature groups. Thirty iterations of resampling were implemented to assess overall model performance by using the area under the Receiver-Operating-Characteristic curve (AUC), accuracy, precision, recall, and F1-score. (2) Results: The SR-RDF model achieved the best classification performance and provided significantly better predictability than the WL-RDF model in training cohort (Average AUC: 0.98 ± 0.01 vs. 0.90 ± 0.02, p < 0.001) and testing cohort (Average AUC: 0.88 ± 0.05 vs. 0.80 ± 0.04, p < 0.001). Similarly, predictability of the SR-DF model was significantly stronger than that of the WL-DF model in training cohort (Average AUC: 0.88 ± 0.03 vs. 0.70 ± 0.030, p < 0.001) and in testing cohort (Average AUC: 0.74 ± 0.08 vs. 0.65 ± 0.06, p < 0.001). By contrast, the SR-RF model significantly outperformed the WL-RF model only in the training set (Average AUC: 0.93 ± 0.02 vs. 0.85 ± 0.03, p < 0.001), but not in the testing set (Average AUC: 0.79 ± 0.05 vs. 0.77 ± 0.07, p = 0.13). (3) Conclusions: Our results demonstrated that the IDLSS method improved model performance for classifying ARP with grade ≥ 2 when using dosiomics or combined radiomics-dosiomics features.

Function-Wise Dual-Omics analysis for radiation pneumonitis prediction in lung cancer patients.

Purpose: This study investigates the impact of lung function on radiation pneumonitis prediction using a dual-omics analysis method. Methods: We retrospectively collected data of 126 stage III lung cancer patients treated with chemo-radiotherapy using intensity-modulated radiotherapy, including pre-treatment planning CT images, radiotherapy dose distribution, and contours of organs and structures. Lung perfusion functional images were generated using a previously developed deep learning method. The whole lung (WL) volume was divided into function-wise lung (FWL) regions based on the lung perfusion functional images. A total of 5,474 radiomics features and 213 dose features (including dosiomics features and dose-volume histogram factors) were extracted from the FWL and WL regions, respectively. The radiomics features (R), dose features (D), and combined dual-omics features (RD) were used for the analysis in each lung region of WL and FWL, labeled as WL-R, WL-D, WL-RD, FWL-R, FWL-D, and FWL-RD. The feature selection was carried out using ANOVA, followed by a statistical F-test and Pearson correlation test. Thirty times train-test splits were used to evaluate the predictability of each group. The overall average area under the receiver operating characteristic curve (AUC), accuracy, precision, recall, and f1-score were calculated to assess the performance of each group. Results: The FWL-RD achieved a significantly higher average AUC than the WL-RD group in the training (FWL-RD: 0.927 ± 0.031, WL-RD: 0.849 ± 0.064) and testing cohorts (FWL-RD: 0.885 ± 0.028, WL-RD: 0.762 ± 0.053, p < 0.001). When using radiomics features only, the FWL-R group yielded a better classification result than the model trained with WL-R features in the training (FWL-R: 0.919 ± 0.036, WL-R: 0.820 ± 0.052) and testing cohorts (FWL-R: 0.862 ± 0.028, WL-R: 0.750 ± 0.057, p < 0.001). The FWL-D group obtained an average AUC of 0.782 ± 0.032, obtaining a better classification performance than the WL-D feature-based model of 0.740 ± 0.028 in the training cohort, while no significant difference was observed in the testing cohort (FWL-D: 0.725 ± 0.064, WL-D: 0.710 ± 0.068, p = 0.54). Conclusion: The dual-omics features from different lung functional regions can improve the prediction of radiation pneumonitis for lung cancer patients under IMRT treatment. This function-wise dual-omics analysis method holds great promise to improve the prediction of radiation pneumonitis for lung cancer patients.

Improving radiomic model reliability using robust features from perturbations for head-and-neck carcinoma.

Background: Using high robust radiomic features in modeling is recommended, yet its impact on radiomic model is unclear. This study evaluated the radiomic model's robustness and generalizability after screening out low-robust features before radiomic modeling. The results were validated with four datasets and two clinically relevant tasks. Materials and methods: A total of 1,419 head-and-neck cancer patients' computed tomography images, gross tumor volume segmentation, and clinically relevant outcomes (distant metastasis and local-regional recurrence) were collected from four publicly available datasets. The perturbation method was implemented to simulate images, and the radiomic feature robustness was quantified using intra-class correlation of coefficient (ICC). Three radiomic models were built using all features (ICC > 0), good-robust features (ICC > 0.75), and excellent-robust features (ICC > 0.95), respectively. A filter-based feature selection and Ridge classification method were used to construct the radiomic models. Model performance was assessed with both robustness and generalizability. The robustness of the model was evaluated by the ICC, and the generalizability of the model was quantified by the train-test difference of Area Under the Receiver Operating Characteristic Curve (AUC). Results: The average model robustness ICC improved significantly from 0.65 to 0.78 (P< 0.0001) using good-robust features and to 0.91 (P< 0.0001) using excellent-robust features. Model generalizability also showed a substantial increase, as a closer gap between training and testing AUC was observed where the mean train-test AUC difference was reduced from 0.21 to 0.18 (P< 0.001) in good-robust features and to 0.12 (P< 0.0001) in excellent-robust features. Furthermore, good-robust features yielded the best average AUC in the unseen datasets of 0.58 (P< 0.001) over four datasets and clinical outcomes. Conclusions: Including robust only features in radiomic modeling significantly improves model robustness and generalizability in unseen datasets. Yet, the robustness of radiomic model has to be verified despite building with robust radiomic features, and tightly restricted feature robustness may prevent the optimal model performance in the unseen dataset as it may lower the discrimination power of the model.

Building reliable radiomic models using image perturbation.

Radiomic model reliability is a central premise for its clinical translation. Presently, it is assessed using test-retest or external data, which, unfortunately, is often scarce in reality. Therefore, we aimed to develop a novel image perturbation-based method (IPBM) for the first of its kind toward building a reliable radiomic model. We first developed a radiomic prognostic model for head-and-neck cancer patients on a training (70%) and evaluated on a testing (30%) cohort using C-index. Subsequently, we applied the IPBM to CT images of both cohorts (Perturbed-Train and Perturbed-Test cohort) to generate 60 additional samples for both cohorts. Model reliability was assessed using intra-class correlation coefficient (ICC) to quantify consistency of the C-index among the 60 samples in the Perturbed-Train and Perturbed-Test cohorts. Besides, we re-trained the radiomic model using reliable RFs exclusively (ICC > 0.75) to validate the IPBM. Results showed moderate model reliability in Perturbed-Train (ICC: 0.565, 95%CI 0.518-0.615) and Perturbed-Test (ICC: 0.596, 95%CI 0.527-0.670) cohorts. An enhanced reliability of the re-trained model was observed in Perturbed-Train (ICC: 0.782, 95%CI 0.759-0.815) and Perturbed-Test (ICC: 0.825, 95%CI 0.782-0.867) cohorts, indicating validity of the IPBM. To conclude, we demonstrated capability of the IPBM toward building reliable radiomic models, providing community with a novel model reliability assessment strategy prior to prospective evaluation.

INSR novel mutations identified in a Chinese family with severe INSR-related insulin resistance syndromes: A case report.

RATIONALE: Severe insulin receptor gene (INSR)-related insulin resistance syndromes (SIR) include Donohue syndrome (DS), Rabson-Mendenhall syndrome (RMS), and type A insulin resistance. The incidence of DS is about 1 in 4 million births. We identified novel INSR mutations (c.2246delG and c.2646 + 5G > A) in a patient with SIR, which expanded the variant spectrum and helped to improve the understanding of the diagnosis and treatment of this condition. PATIENT CONCERNS: A 10-year-old Chinese boy was admitted to the hospital for deepening skin color. He presented with growth retardation, peculiar facial features, acanthosis nigricans, hypertrichosis, extremely high insulin levels, fasting hypoglycemia, and postprandial hyperglycemia, Whole-exome gene testing suggested compound heterozygous mutations in INSR (c.2246delG and c.2646 + 5G > A). DIAGNOSIS: The diagnosis was SIR. What's more, based on the phenotypic and biographical results, this child did not present typical RMS and DS but rather an intermediate phenotype between the 2 conditions. INTERVENTIONS: On the basis of a sensible diet and exercise, the patient was prescribed metformin (250 mg) at breakfast and lunch, which was increased to 500 mg after 1 month. OUTCOMES: After 2 months of treatment, the patient's glycated hemoglobin (HbA1c) levels decreased to 6% but his insulin resistance did not improve significantly. LESSONS: In children who are not obese but with severe insulin resistance, growth retardation, hirsutism, and hyperglycemia, genetic testing should be performed for early diagnosis, active treatment, and follow-up.

Multi-Organ Omics-Based Prediction for Adaptive Radiation Therapy Eligibility in Nasopharyngeal Carcinoma Patients Undergoing Concurrent Chemoradiotherapy.

PURPOSE: To investigate the role of different multi-organ omics-based prediction models for pre-treatment prediction of Adaptive Radiotherapy (ART) eligibility in patients with nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: Pre-treatment contrast-enhanced computed tomographic and magnetic resonance images, radiotherapy dose and contour data of 135 NPC patients treated at Hong Kong Queen Elizabeth Hospital were retrospectively analyzed for extraction of multi-omics features, namely Radiomics (R), Morphology (M), Dosiomics (D), and Contouromics (C), from a total of eight organ structures. During model development, patient cohort was divided into a training set and a hold-out test set in a ratio of 7 to 3 via 20 iterations. Four single-omics models (R, M, D, C) and four multi-omics models (RD, RC, RM, RMDC) were developed on the training data using Ridge and Multi-Kernel Learning (MKL) algorithm, respectively, under 10-fold cross validation, and evaluated on hold-out test data using average area under the receiver-operator-characteristics curve (AUC). The best-performing single-omics model was first determined by comparing the AUC distribution across the 20 iterations among the four single-omics models using two-sided student t-test, which was then retrained using MKL algorithm for a fair comparison with the four multi-omics models. RESULTS: The R model significantly outperformed all other three single-omics models (all p-value<0.0001), achieving an average AUC of 0.942 (95%CI: 0.938-0.946) and 0.918 (95%CI: 0.903-0.933) in training and hold-out test set, respectively. When trained with MKL, the R model (R_MKL) yielded an increased AUC of 0.984 (95%CI: 0.981-0.988) and 0.927 (95%CI: 0.905-0.948) in training and hold-out test set respectively, while demonstrating no significant difference as compared to all studied multi-omics models in the hold-out test sets. Intriguingly, Radiomic features accounted for the majority of the final selected features, ranging from 64% to 94%, in all the studied multi-omics models. CONCLUSIONS: Among all the studied models, the Radiomic model was found to play a dominant role for ART eligibility in NPC patients, and Radiomic features accounted for the largest proportion of features in all the multi-omics models.