Predicting amyloid positivity from FDG-PET images using radiomics: A parsimonious model.

BACKGROUND AND OBJECTIVE: Amyloid plaques are one of the physical hallmarks of Alzheimer's disease. The objective of this study is to predict amyloid positivity non-invasively from FDG-PET images using a radiomics approach. METHODS: We obtained FDG-PET images of 301 individuals from various groups, including control normal (CN), mild cognitive impairment (MCI), and Alzheimer's Disease (AD), from the ADNI database. Following the utilization of the CSF Aß1-42 (192) and Standardized Uptake Value Ratio (SUVR) (1.11) thresholds derived from Florbetapir scans, the subjects were categorized into two categories: those with a positive amyloid status (n = 185) and those with a negative amyloid status (n = 116). The process of segmenting the entire brain into 95 classes using the DKT-atlas was utilized. Following that, we obtained 120 characteristics for each of the 95 regions of interest (ROIs). We employed eight feature selection methods to analyze the features. Additionally, we utilized eight different classifiers on the 20 most significant features extracted from each feature selection method. Finally, in order to improve interpretability, we selected the most important features and ROIs. RESULT: We found that the GNB classifier and the LASSO feature selection method had the best performance with an average accuracy of (AUC=0.924) while using 18 features on 15 ROIs. We were then able to reduce the model to three regions (Hippocampus, inferior parietal, and isthmus cingulate) and three gray-level based features (AUC=0.853). CONCLUSION: The FDG-PET images which serve to study metabolic activity can be used to predict amyloid positivity without the use of invasive methods or another PET tracer and study. The proposed method has superior prediction accuracy with respect to similar studies reported in the literature using other imaging modalities. Only three brain regions had a high impact on amyloid positivity results.

Interpretable radiomics method for predicting human papillomavirus status in oropharyngeal cancer using Bayesian networks.

OBJECTIVES: To develop a simple interpretable Bayesian Network (BN) to classify HPV status in patients with oropharyngeal cancer. METHODS: Two hundred forty-six patients, 216 of whom were HPV positive, were used in this study. We extracted 851 radiomics markers from patients' contrast-enhanced Computed Tomography (CT) images. Mens eX Machina (MXM) approach selected two most relevant predictors: sphericity and max2DDiameterRow. The area under the curve (AUC) demonstrated BN model performance in 30% of the data reserved for testing. A Support Vector Machine (SVM) based method was also implemented for comparison purposes. RESULTS: The Mens eX Machina (MXM) approach selected two most relevant predictors: sphericity and max2DDiameterRow. Areas under the Curves (AUC) were found 0.78 and 0.72 on the training and test data, respectively. When using support vector machine (SVM) and 25 features, the AUC was found 0.83 on the test data. CONCLUSIONS: The straightforward structure and power of interpretability of our BN model will help clinicians make treatment decisions and enable the non-invasive detection of HPV status from contrast-enhanced CT images. Higher accuracy can be obtained using more complex structures at the expense of lower interpretability. ADVANCES IN KNOWLEDGE: Radiomics is being studied lately as a simple imaging data based HPV status detection technique which can be an alternative to laboratory approaches. However, it generally lacks interpretability. This work demonstrated the feasibility of using Bayesian networks based radiomics for predicting HPV positivity in an interpretable way.

An improved platform for cultured neuronal network electrophysiology: multichannel optogenetics integrated with MEAs.

Cultured neuronal networks (CNNs) are powerful tools for studying how neuronal representation and adaptation emerge in networks of controlled populations of neurons. To ensure the interaction of a CNN and an artificial setting, reliable operation in both open and closed loops should be provided. In this study, we integrated optogenetic stimulation with microelectrode array (MEA) recordings using a digital micromirror device and developed an improved research tool with a 64-channel interface for neuronal network control and data acquisition. We determined the ideal stimulation parameters including light intensity, frequency, and duty cycle for our configuration. This resulted in robust and reproducible neuronal responses. We also demonstrated both open and closed loop configurations in the new platform involving multiple bidirectional channels. Unlike previous approaches that combined optogenetic stimulation and MEA recordings, we did not use binary grid patterns, but assigned an adjustable-size, non-binary optical spot to each electrode. This approach allowed simultaneous use of multiple input-output channels and facilitated adaptation of the stimulation parameters. Hence, we advanced a 64-channel interface in that each channel can be controlled individually in both directions simultaneously without any interference or interrupts. The presented setup meets the requirements of research in neuronal plasticity, network encoding and representation, closed-loop control of firing rate and synchronization. Researchers who develop closed-loop control techniques and adaptive stimulation strategies for network activity will benefit much from this novel setup.

Hypoxia-Related Radiomics and Immunotherapy Response: A Multicohort Study of Non-Small Cell Lung Cancer.

Background: Immunotherapy yields survival benefit for some advanced stage non-small cell lung cancer (NSCLC) patients. Because highly predictive biomarkers of immunotherapy response are an unmet clinical need, we used pretreatment radiomics and clinical data to train and validate a parsimonious model associated with survival outcomes among NSCLC patients treated with immunotherapy. Methods: Three cohorts of NSCLC patients treated with immunotherapy were analyzed: training (n = 180), validation 1 (n = 90), and validation 2 (n = 62). The most informative clinical and radiomic features were subjected to decision tree analysis, which stratified patients into risk groups of low, moderate, high, and very high risk of death after initiation of immunotherapy. All statistical tests were 2-sided. Results: The very high-risk group was associated with extremely poor overall survival (OS) in validation cohorts 1 (hazard ratio [HR] = 5.35, 95% confidence interval [CI] = 2.14 to 13.36; 1-year OS = 11.1%, 95% CI = 1.9% to 29.8%; 3-year OS = 0%) and 2 (HR = 13.81, 95% CI = 2.58 to 73.93; 1-year OS = 47.6%, 95% CI = 18.2% to 72.4%; 3-year OS = 0%) when compared with the low-risk group (HR = 1.00) in validation cohorts 1 (1-year OS = 85.0%, 95% CI = 60.4% to 94.9%; 3-year OS = 38.9%, 95% CI = 17.1% to 60.3%) and 2 (1-year OS = 80.2%, 95% CI = 40.3% to 94.8%; 3-year OS = 40.1%, 95% CI = 1.3% to 83.5%). The most informative radiomic feature, gray-level co-occurrence matrix (GLCM) inverse difference, was positively associated with hypoxia-related carbonic anhydrase 9 using gene-expression profiling and immunohistochemistry. Conclusion: Utilizing standard-of-care imaging and clinical data, we identified and validated a novel parsimonious model associated with survival outcomes among NSCLC patients treated with immunotherapy. Based on this model, clinicians can identify patients who are unlikely to respond to immunotherapy.

Improving the detectability of overactive glands in dual-phase parathyroid SPECT/CT: a Monte Carlo simulation study.

Objective. SPECT-CT is a standard procedure conducted before minimally invasive surgery for the treatment of primary hyperthyroidism. In order to improve image quality, it is important to know how defect detectability is influenced by acquisition and processing parameters. The objective of this study is to continue prior physical phantom optimization studies by performing Monte Carlo simulations for the dual phase parathyroid SPECT-CT protocol using a digital anthropomorphic phantom.Methods. The dual phase parathyroid SPECT-CT imaging procedure with 99mTc-Sestamibi was simulated using the previously extensively validated SIMIND software for the first time. An anthropomorphic ZUBAL based phantom was built to represent an adenoma. Its diameter was set to 0.76 cm which corresponded to more than three times the pixel size and the target-to-background ratio was set to 16:1 based on previous studies. Four different collimators were tested. Contrast-to-noise (CNR) values were determined for different scatter correction options and processing parameter values. The OSEM algorithm was used for image reconstruction.Results. CNR values were improved from about zero (LEGP collimator, 16 iterations, attenuation correction: on, scatter correction: off) up to 3.7 (LEUHR collimator, 16 iterations, attenuation correction: on, scatter correction: off). The subjective visual assessment of detectability on simulated images agreed with the quantitative CNR values.Conclusion. Higher resolution collimators gave better CNR as confirmed by similar studies. The effect of scatter correction was found beneficial only if both the resolution and sensitivity of the collimator were relatively high. This is a significant finding since there is a shortage of definitive guideline on the use of scatter correction for parathyroid SPECT imaging.

Adult mouse dorsal root ganglia neurons form aberrant glutamatergic connections in dissociated cultures.

Cultured sensory neurons can exhibit complex activity patterns following stimulation in terms of increased excitability and interconnected responses of multiple neurons. Although these complex activity patterns suggest a network-like configuration, research so far had little interest in synaptic network formation ability of the sensory neurons. To identify interaction profiles of Dorsal Root Ganglia (DRG) neurons and explore their putative connectivity, we developed an in vitro experimental approach. A double transgenic mouse model, expressing genetically encoded calcium indicator (GECI) in their glutamatergic neurons, was produced. Dissociated DRG cultures from adult mice were prepared with a serum-free protocol and no additional growth factors or cytokines were utilized for neuronal sensitization. DRG neurons were grown on microelectrode arrays (MEA) to induce stimulus-evoked activity with a modality-free stimulation strategy. With an almost single-cell level electrical stimulation, spontaneous and evoked activity of GCaMP6s expressing neurons were detected under confocal microscope. Typical responses were analyzed, and correlated calcium events were detected across individual DRG neurons. Next, correlated responses were successfully blocked by glutamatergic receptor antagonists, which indicated functional synaptic coupling. Immunostaining confirmed the presence of synapses mainly in the axonal terminals, axon-soma junctions and axon-axon intersection sites. Concisely, the results presented here illustrate a new type of neuron-to-neuron interaction in cultured DRG neurons conducted through synapses. The developed assay can be a valuable tool to analyze individual and collective responses of the cultured sensory neurons.

Design and evaluation of an accurate CNR-guided small region iterative restoration-based tumor segmentation scheme for PET using both simulated and real heterogeneous tumors.

Tumor delineation accuracy directly affects the effectiveness of radiotherapy. This study presents a methodology that minimizes potential errors during the automated segmentation of tumors in PET images. Iterative blind deconvolution was implemented in a region of interest encompassing the tumor with the number of iterations determined from contrast-to-noise ratios. The active contour and random forest classification-based segmentation method was evaluated using three distinct image databases that included both synthetic and real heterogeneous tumors. Ground truths about tumor volumes were known precisely. The volumes of the tumors were in the range of 0.49-26.34 cm3, 0.64-1.52 cm3, and 40.38-203.84 cm3 respectively. Widely available software tools, namely, MATLAB, MIPAV, and ITK-SNAP were utilized. When using the active contour method, image restoration reduced mean errors in volumes estimation from 95.85 to 3.37%, from 815.63 to 17.45%, and from 32.61 to 6.80% for the three datasets. The accuracy gains were higher using datasets that include smaller tumors for which PVE is known to be more predominant. Computation time was reduced by a factor of about 10 in the smaller deconvolution region. Contrast-to-noise ratios were improved for all tumors in all data. The presented methodology has the potential to improve delineation accuracy in particular for smaller tumors at practically feasible computational times. Graphical abstract Evaluation of accurate lesion volumes using CNR-guided and ROI-based restoration method for PET images.

Stability and reproducibility of computed tomography radiomic features extracted from peritumoral regions of lung cancer lesions.

PURPOSE: Recent efforts have demonstrated that radiomic features extracted from the peritumoral region, the area surrounding the tumor parenchyma, have clinical utility in various cancer types. However, as like any radiomic features, peritumoral features could also be unstable and/or nonreproducible. Hence, the purpose of this study was to assess the stability and reproducibility of computed tomography (CT) radiomic features extracted from the peritumoral regions of lung lesions where stability was defined as the consistency of a feature by different segmentations, and reproducibility was defined as the consistency of a feature to different image acquisitions. METHODS: Stability was measured utilizing the "moist run" dataset and reproducibility was measured utilizing the Reference Image Database to Evaluate Therapy Response test-retest dataset. Peritumoral radiomic features were extracted from incremental distances of 3-12 mm outside the tumor segmentation. A total of 264 statistical, histogram, and texture radiomic features were assessed from the selected peritumoral region-of-interests (ROIs). All features (except wavelet texture features) were extracted using standardized algorithms defined by the Image Biomarker Standardisation Initiative. Stability and reproducibility of features were assessed using the concordance correlation coefficient. The clinical utility of stable and reproducible peritumoral features was tested in three previously published lung cancer datasets using overall survival as the endpoint. RESULTS: Features found to be stable and reproducible, regardless of the peritumoral distances, included statistical, histogram, and a subset of texture features suggesting that these features are less affected by changes (e.g., size or shape) of the peritumoral region due to different segmentations and image acquisitions. The stability and reproducibility of Laws and wavelet texture features were inconsistent across all peritumoral distances. The analyses also revealed that a subset of features were consistently stable irrespective of the initial parameters (e.g., seed point) for a given segmentation algorithm. No significant differences were found in stability for features that were extracted from ROIs bounded by a lung parenchyma mask versus ROIs that were not bounded by a lung parenchyma mask (i.e., peritumoral regions that extended outside of lung parenchyma). After testing the clinical utility of peritumoral features, stable and reproducible features were shown to be more likely to create repeatable models than unstable and nonreproducible features. CONCLUSIONS: This study identified a subset of stable and reproducible CT radiomic features extracted from the peritumoral region of lung lesions. The stable and reproducible features identified in this study could be applied to a feature selection pipeline for CT radiomic analyses. According to our findings, top performing features in survival models were more likely to be stable and reproducible hence, it may be best practice to utilize them to achieve repeatable studies and reduce the chance of overfitting.

Novel clinical and radiomic predictors of rapid disease progression phenotypes among lung cancer patients treated with immunotherapy: An early report.

OBJECTIVES: Immune-checkpoint blockades have exhibited durable responses and improved long-term survival in a subset of advanced non-small cell lung cancer (NSCLC) patients. However, highly predictive markers of positive and negative responses to immunotherapy are a significant unmet clinical need. The objective of this study was to identify clinical and computational image-based predictors of rapid disease progression phenotypes in NSCLC patients treated with immune-checkpoint blockades. MATERIALS AND METHODS: Using time-to-progression (TTP) and/or tumor growth rates, rapid disease progression phenotypes were developed including hyperprogressive disease. The pre-treatment baseline predictors that were used to identify these phenotypes included patient demographics, clinical data, driver mutations, hematology data, and computational image-based features (radiomics) that were extracted from pre-treatment computed tomography scans. Synthetic Minority Oversampling Technique (SMOTE) was used to subsample minority groups to eliminate classification bias. Patient-level probabilities were calculated from the final clinical-radiomic models to subgroup patients by progression-free survival (PFS). RESULTS: Among 228 NSCLC patients treated with single agent or double agent immunotherapy, we identified parsimonious clinical-radiomic models with modest to high ability to predict rapid disease progression phenotypes with area under the receiver-operator characteristics ranging from 0.804 to 0.865. Patients who had TTP < 2 months or hyperprogressive disease were classified with 73.41% and 82.28% accuracy after SMOTE subsampling, respectively. When the patient subgroups based on patient-level probabilities were analyzed for survival outcomes, patients with higher probability scores had significantly worse PFS. CONCLUSIONS: The models found in this study have potential important translational implications to identify highly vulnerable NSCLC patients treated with immunotherapy that experience rapid disease progression and poor survival outcomes.

Hypoxia and acidosis: immune suppressors and therapeutic targets.

Due to imbalances between vascularity and cellular growth patterns, the tumour microenvironment harbours multiple metabolic stressors including hypoxia and acidosis, which have significant influences on remodelling both tumour and peritumoral tissues. These stressors are also immunosuppressive and can contribute to escape from immune surveillance. Understanding these effects and characterizing the pathways involved can identify new targets for therapy and may redefine our understanding of traditional anti-tumour therapies. In this review, the effects of hypoxia and acidosis on tumour immunity will be summarized, and how modulating these parameters and their sequelae can be a useful tool for future therapeutic interventions is discussed.

Radial gradient and radial deviation radiomic features from pre-surgical CT scans are associated with survival among lung adenocarcinoma patients.

The goal of this study was to extract features from radial deviation and radial gradient maps which were derived from thoracic CT scans of patients diagnosed with lung adenocarcinoma and assess whether these features are associated with overall survival. We used two independent cohorts from different institutions for training (n= 61) and test (n= 47) and focused our analyses on features that were non-redundant and highly reproducible. To reduce the number of features and covariates into a single parsimonious model, a backward elimination approach was applied. Out of 48 features that were extracted, 31 were eliminated because they were not reproducible or were redundant. We considered 17 features for statistical analysis and identified a final model containing the two most highly informative features that were associated with lung cancer survival. One of the two features, radial deviation outside-border separation standard deviation, was replicated in a test cohort exhibiting a statistically significant association with lung cancer survival (multivariable hazard ratio = 0.40; 95% confidence interval 0.17-0.97). Additionally, we explored the biological underpinnings of these features and found radial gradient and radial deviation image features were significantly associated with semantic radiological features.

Implementation and statistical evaluation of a web-based software for bone age assessment.

Bone age assessment is a tedious procedure carried out for assessing growth disorders of children using the left hand radiograph. The purpose of this work was to implement and evaluate a web-based software based on the Tanner and Whitehouse method in a pediatric endocrine department of a social security hospital processing 600-1,000 radiographs per year. The system was evaluated by using a statistical technique for comparing measurement methods in order to test the performance of the procedure and a time study to assess its feasibility under local conditions. It was found that the intra-observer variation for the web-based Tanner and Whitehouse method was smaller (95% confidence limits, -0.77 to 0.97 vs. -0.45 to 0.37) then the conventional Greulich and Pyle manual method and the average net time required for an age assessment was 2.4 min. We therefore concluded that the web-based system should be adopted for its higher precision and relatively low turnaround time for cases requiring serial readings on the same patient. The statistical method demonstrated in this study can also serve as an example for evaluating similar biomedical parameter assessing software.