VLST: Virtual Lung Screening Trial for Lung Cancer Detection Using Virtual Imaging Trial.

Importance: The efficacy of lung cancer screening can be significantly impacted by the imaging modality used. This Virtual Lung Screening Trial (VLST) addresses the critical need for precision in lung cancer diagnostics and the potential for reducing unnecessary radiation exposure in clinical settings. Objectives: To establish a virtual imaging trial (VIT) platform that accurately simulates real-world lung screening trials (LSTs) to assess the diagnostic accuracy of CT and CXR modalities. Design Setting and Participants: Utilizing computational models and machine learning algorithms, we created a diverse virtual patient population. The cohort, designed to mirror real-world demographics, was assessed using virtual imaging techniques that reflect historical imaging technologies. Main Outcomes and Measures: The primary outcome was the difference in the Area Under the Curve (AUC) for CT and CXR modalities across lesion types and sizes. Results: The study analyzed 298 CT and 313 CXR simulated images from 313 virtual patients, with a lesion-level AUC of 0.81 (95% CI: 0.78-0.84) for CT and 0.55 (95% CI: 0.53-0.56) for CXR. At the patient level, CT demonstrated an AUC of 0.85 (95% CI: 0.80-0.89), compared to 0.53 (95% CI: 0.47-0.60) for CXR. Subgroup analyses indicated CT's superior performance in detecting homogeneous lesions (AUC of 0.97 for lesion-level) and heterogeneous lesions (AUC of 0.71 for lesion-level) as well as in identifying larger nodules (AUC of 0.98 for nodules > 8 mm). Conclusion and Relevance: The VIT platform validated the superior diagnostic accuracy of CT over CXR, especially for smaller nodules, underscoring its potential to replicate real clinical imaging trials. These findings advocate for the integration of virtual trials in the evaluation and improvement of imaging-based diagnostic tools.

Development and Application of a Virtual Imaging Trial Framework for Longitudinal Quantification of Emphysema in CT.

Pulmonary emphysema is a progressive lung disease that requires accurate evaluation for optimal management. This task, possible using quantitative CT, is particularly challenging as scanner and patient attributes change over time, negatively impacting the CT-derived quantitative measures. Efforts to minimize such variations have been limited by the absence of ground truth in clinical data, thus necessitating reliance on clinical surrogates, which may not have one-to-one correspondence to CT-based findings. This study aimed to develop the first suite of human models with emphysema at multiple time points, enabling longitudinal assessment of disease progression with access to ground truth. A total of 14 virtual subjects were modeled across three time points. Each human model was virtually imaged using a validated imaging simulator (DukeSim), modeling an energy-integrating CT scanner. The models were scanned at two dose levels and reconstructed with two reconstruction kernels, slice thicknesses, and pixel sizes. The developed longitudinal models were further utilized to demonstrate utility in algorithm testing and development. Two previously developed image processing algorithms (CT-HARMONICA, EmphysemaSeg) were evaluated. The results demonstrated the efficacy of both algorithms in improving the accuracy and precision of longitudinal quantifications, from 6.1±6.3% to 1.1±1.1% and 1.6±2.2% across years 0-5. Further investigation in EmphysemaSeg identified that baseline emphysema severity, defined as >5% emphysema at year 0, contributed to its reduced performance. This finding highlights the value of virtual imaging trials in enhancing the explainability of algorithms. Overall, the developed longitudinal human models enabled ground-truth based assessment of image processing algorithms for lung quantifications.

Quantitative accuracy of lung function measurement using parametric response mapping: A virtual imaging study.

Parametric response mapping (PRM) is a voxel-based quantitative CT imaging biomarker that measures the severity of chronic obstructive pulmonary disease (COPD) by analyzing both inspiratory and expiratory CT scans. Although PRM-derived measurements have been shown to predict disease severity and phenotyping, their quantitative accuracy is impacted by the variability of scanner settings and patient conditions. The aim of this study was to evaluate the variability of PRM-based measurements due to the changes in the scanner types and configurations. We developed 10 human chest models with emphysema and air-trapping at end-inspiration and end-expiration states. These models were virtually imaged using a scanner-specific CT simulator (DukeSim) to create CT images at different acquisition settings for energy-integrating and photon-counting CT systems. The CT images were used to estimate PRM maps. The quantified measurements were compared with ground truth values to evaluate the deviations in the measurements. Results showed that PRM measurements varied with scanner type and configurations. The emphysema volume was overestimated by 3 ± 9.5 % (mean ± standard deviation) of the lung volume, and the functional small airway disease (fSAD) volume was underestimated by 7.5±19 % of the lung volume. PRM measurements were more accurate and precise when the acquired settings were photon-counting CT, higher dose, smoother kernel, and larger pixel size. This study demonstrates the development and utility of virtual imaging tools for systematic assessment of a quantitative biomarker accuracy.

A systematic assessment and optimization of photon-counting CT for lung density quantifications.

BACKGROUND: Photon-counting computed tomography (PCCT) has recently emerged into clinical use; however, its optimum imaging protocols and added benefits remains unknown in terms of providing more accurate lung density quantification compared to energy-integrating computed tomography (EICT) scanners. PURPOSE: To systematically assess the performance of a clinical PCCT scanner for lung density quantifications and compare it against EICT. METHODS: This cross-sectional study involved a retrospective analysis of subjects scanned (August-December 2021) using a clinical PCCT system. The influence of altering reconstruction parameters was studied (reconstruction kernel, pixel size, slice thickness). A virtual CT dataset of anthropomorphic virtual subjects was acquired to demonstrate the correspondence of findings to clinical dataset, and to perform systematic imaging experiments, not possible using human subjects. The virtual subjects were imaged using a validated, scanner-specific CT simulator of a PCCT and two EICT (defined as EICT A and B) scanners. The images were evaluated using mean absolute error (MAE) of lung and emphysema density against their corresponding ground truth. RESULTS: Clinical and virtual PCCT datasets showed similar trends, with sharper kernels and smaller voxel sizes increasing percentage of low-attenuation areas below -950 HU (LAA-950) by up to 15.7 ± 6.9% and 11.8 ± 5.5%, respectively. Under the conditions studied, higher doses, thinner slices, smaller pixel sizes, iterative reconstructions, and quantitative kernels with medium sharpness resulted in lower lung MAE values. While using these settings for PCCT, changes in the dose level (13 to 1.3 mGy), slice thickness (0.4 to 1.5 mm), pixel size (0.49 to 0.98 mm), reconstruction technique (70 keV-VMI to wFBP), and kernel (Qr48 to Qr60) increased lung MAE by 15.3 ± 2.0, 1.4 ± 0.6, 2.2 ± 0.3, 4.2 ± 0.8, and 9.1 ± 1.6 HU, respectively. At the optimum settings identified per scanner, PCCT images exhibited lower lung and emphysema MAE than those of EICT scanners (by 2.6 ± 1.0 and 9.6 ± 3.4 HU, compared to EICT A, and by 4.8 ± 0.8 and 7.4 ± 2.3 HU, compared to EICT B). The accuracy of lung density measurements was correlated with subjects' mean lung density (p < 0.05), measured by PCCT at optimum setting under the conditions studied. CONCLUSION: Photon-counting CT demonstrated superior performance in density quantifications, with its influences of imaging parameters in line with energy-integrating CT scanners. The technology offers improvement in lung quantifications, thus demonstrating potential toward more objective assessment of respiratory conditions.

Accuracy of artificial intelligence CT quantification in predicting COVID-19 subjects' prognosis.

BACKGROUND: Artificial intelligence (AI)-aided analysis of chest CT expedites the quantification of abnormalities and may facilitate the diagnosis and assessment of the prognosis of subjects with COVID-19. OBJECTIVES: This study investigates the performance of an AI-aided quantification model in predicting the clinical outcomes of hospitalized subjects with COVID-19 and compares it with radiologists' performance. SUBJECTS AND METHODS: A total of 90 subjects with COVID-19 (men, n = 59 [65.6%]; age, 52.9±16.7 years) were recruited in this cross-sectional study. Quantification of the total and compromised lung parenchyma was performed by two expert radiologists using a volumetric image analysis software and compared against an AI-assisted package consisting of a modified U-Net model for segmenting COVID-19 lesions and an off-the-shelf U-Net model augmented with COVID-19 data for segmenting lung volume. The fraction of compromised lung parenchyma (%CL) was calculated. Based on clinical results, the subjects were divided into two categories: critical (n = 45) and noncritical (n = 45). All admission data were compared between the two groups. RESULTS: There was an excellent agreement between the radiologist-obtained and AI-assisted measurements (intraclass correlation coefficient = 0.88, P < 0.001). Both the AI-assisted and radiologist-obtained %CLs were significantly higher in the critical subjects (P = 0.009 and 0.02, respectively) than in the noncritical subjects. In the multivariate logistic regression analysis to distinguish the critical subjects, an AI-assisted %CL ≥35% (odds ratio [OR] = 17.0), oxygen saturation level of <88% (OR = 33.6), immunocompromised condition (OR = 8.1), and other comorbidities (OR = 15.2) independently remained as significant variables in the models. Our proposed model obtained an accuracy of 83.9%, a sensitivity of 79.1%, and a specificity of 88.6% in predicting critical outcomes. CONCLUSIONS: AI-assisted measurements are similar to quantitative radiologist-obtained measurements in determining lung involvement in COVID-19 subjects.

Development and Application of a Virtual Imaging Trial framework for Airway Quantifications via CT.

Chronic obstructive pulmonary disease (COPD) is one of the top three causes of death worldwide, characterized by emphysema and bronchitis. Airway measurements reflect the severity of bronchitis and other airway-related diseases. Airway structures can be objectively evaluated with quantitative computed tomography (CT). The accuracy of such quantifications is limited by the spatial resolution and image noise characteristics of the imaging system and can be potentially improved with the emerging photon-counting CT (PCCT) technology. This study evaluated the quantitative performance of PCCT against energy-integrating CT (EICT) systems for airway measurements, and further identified optimum CT imaging parameters for such quantifications. The study was performed using a novel virtual imaging framework by developing the first library of virtual patients with bronchitis. These virtual patients were developed based on CT images of confirmed COPD patients with varied bronchitis severity. The human models were virtually imaged at 6.3 and 12.6 mGy dose levels using a scanner-specific simulator (DukeSim), synthesizing clinical PCCT and EICT scanners (NAEOTOM Alpha, FLASH, Siemens). The projections were reconstructed with two algorithms and kernels at different matrix sizes and slice thicknesses. The CT images were used to quantify clinically relevant airway measurements ("Pi10" and "WA%") and compared against their ground truth values. Compared to EICT, PCCT provided more accurate Pi10 and WA% measurements by 63.1% and 68.2%, respectively. For both technologies, sharper kernels and larger matrix sizes led to more reliable bronchitis quantifications. This study highlights the potential advantages of PCCT against EICT in characterizing bronchitis utilizing a virtual imaging platform.

Harmonizing CT Images via Physics-based Deep Neural Networks.

The rendition of medical images influences the accuracy and precision of quantifications. Image variations or biases make measuring imaging biomarkers challenging. The objective of this paper is to reduce the variability of computed tomography (CT) quantifications for radiomics and biomarkers using physics-based deep neural networks (DNNs). With the proposed framework, it is possible to harmonize the different renditions of a single CT scan (with variations in reconstruction kernel and dose) into an image that is in close agreement with the ground truth. To this end, a generative adversarial network (GAN) model was developed where the generator is informed by the scanner's modulation transfer function (MTF). To train the network, a virtual imaging trial (VIT) platform was used to acquire CT images, from a set of forty computational models (XCAT) serving as the patient model. Phantoms with varying levels of pulmonary disease, such as lung nodules and emphysema, were used. We scanned the patient models with a validated CT simulator (DukeSim) modeling a commercial CT scanner at 20 and 100 mAs dose levels and then reconstructed the images by twelve kernels representing smooth to sharp kernels. An evaluation of the harmonized virtual images was conducted in four different ways: 1) visual quality of the images, 2) bias and variation in density-based biomarkers, 3) bias and variation in morphological-based biomarkers, and 4) Noise Power Spectrum (NPS) and lung histogram. The trained model harmonized the test set images with a structural similarity index of 0.95±0.1, a normalized mean squared error of 10.2±1.5%, and a peak signal-to-noise ratio of 31.8±1.5 dB. Moreover, emphysema-based imaging biomarkers of LAA-950 (-1.5±1.8), Perc15 (13.65±9.3), and Lung mass (0.1±0.3) had more precise quantifications.

Development and Clinical Applications of a Virtual Imaging Framework for Optimizing Photon-counting CT.

The purpose of this study was to develop a virtual imaging framework that simulates a new photon-counting CT (PCCT) system (NAEOTOM Alpha, Siemens). The PCCT simulator was built upon the DukeSim platform, which generates projection images of computational phantoms given the geometry and physics of the scanner and imaging parameters. DukeSim was adapted to account for the geometry of the PCCT prototype. To model the photon-counting detection process, we utilized a Monte Carlo-based detector model with the known properties of the detectors. We validated the simulation platform against experimental measurements. The images were acquired at four dose levels (CTDIvol of 1.5, 3.0, 6.0, and 12.0 mGy) and reconstructed with three kernels (Br36, Br40, Br48). The experimental acquisitions were replicated using our developed simulation platform. The real and simulated images were quantitatively compared in terms of image quality metrics (HU values, noise magnitude, noise power spectrum, and modulation transfer function). The clinical utility of our framework was demonstrated by conducting two clinical applications (COPD quantifications and lung nodule radiomics). The phantoms with relevant pathologies were imaged with DukeSim modeling the PCCT systems. Different imaging parameters (e.g., dose, reconstruction techniques, pixel size, and slice thickness) were altered to investigate their effects on task-based quantifications. We successfully implemented the acquisition and physics attributes of the PCCT prototype into the DukeSim platform. The discrepancy between the real and simulated data was on average about 2 HU in terms of noise magnitude, 0.002 mm-1 in terms of noise power spectrum peak frequency and 0.005 mm-1 in terms of the frequency at 50% MTF. Analysis suggested that lung lesion radiomics to be more accurate with reduced pixel size and slice thickness. For COPD quantifications, higher doses, thinner slices, and softer kernels yielded more accurate quantification of density-based biomarkers. Our developed virtual imaging platform enables systematic comparison of new PCCT technologies as well as optimization of the imaging parameters for specific clinical tasks.

A truth-based primal-dual learning approach to reconstruct CT images utilizing the virtual imaging trial platform.

Inherent to Computed tomography (CT) is image reconstruction, constructing 3D voxel values from noisy projection data. Modeling this inverse operation is not straightforward. Given the ill-posed nature of inverse problem in CT reconstruction, data-driven methods need regularization to enhance the accuracy of the reconstructed images. Besides, generalization of the results hinges upon the availability of large training datasets with access to ground truth. This paper offers a new strategy to reconstruct CT images with the advantage of ground truth accessible through a virtual imaging trial (VIT) platform. A learned primal-dual deep neural network (LPD-DNN) employed the forward model and its adjoint as a surrogate of the imaging's geometry and physics. VIT offered simulated CT projections paired with ground truth labels from anthropomorphic human models without image noise and resolution degradation. The models included a library of anthropomorphic, computational patient models (XCAT). The DukeSim simulator was utilized to form realistic projection data emulating the impact of the physics and geometry of a commercial-equivalent CT scanner. The resultant noisy sinogram data associated with each slice was thus generated for training. Corresponding linear attenuation coefficients of phantoms' materials at the effective energy of the x-ray spectrum were used as the ground truth labels. The LPD-DNN was deployed to learn the complex operators and hyper-parameters in the proximal primal-dual optimization. The obtained validation results showed a 12% normalized root mean square error with respect to the ground truth labels, a peak signal-to-noise ratio of 32 dB, a signal-to-noise ratio of 1.5, and a structural similarity index of 96%. These results were highly favorable compared to standard filtered-back projection reconstruction (65%, 17 dB, 1.0, 26%).

Photon-counting CT versus conventional CT for COPD quantifications: intra-scanner optimization and inter-scanner assessments using virtual imaging trials.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease and a major cause of death and disability worldwide. Quantitative CT is a powerful tool to better understand the heterogeneity and severity of this disease. Quantitative CT is being increasingly used in COPD research, and the recent advancements in CT technology have made it even more encouraging. One recent advancement has been the development of photon-counting detectors, offering higher spatial resolution, higher image contrast, and lower noise levels in the images. However, the quantification performance of this new technology compared to conventional scanners remains unknown. Additionally, different protocol settings (e.g., different dose levels, slice thicknesses, reconstruction kernels and algorithms) affect quantifications in an unsimilar fashion. This study investigates the potential advantages of photon-counting CT (PCCT) against conventional energy-integrating detector (EID) CT and explores the effects of protocol settings on lung density quantifications in COPD patients. This study was made possible using a virtual imaging platform, taking advantage of anthropomorphic phantoms with COPD (COPD-XCAT) and a scanner-specific CT simulator (DukeSim). Having the physical and geometrical properties of three Siemens commercial scanners (Flash, Force for EID and NAEOTOM Alpha for PCCT) modeled, we simulated CT images of ten COPD-XCAT phantoms at 0.63 and 3.17 mGy dose levels and reconstructed at three levels of kernel sharpness. The simulated CT images were quantified in terms of "Lung mean absolute error (MAE)," "LAA -950," "Perc 15," "Lung mass" imaging biomarkers and compared against the ground truth values of the phantoms. The intra-scanner assessment demonstrated the superior qualitative and quantitative performance of the PCCT scanner over the conventional scanners (21.01% and 22.74% mean lung MAE improvement, and 53.97% and 68.13% mean LAA -950 error improvement compared to Flash and Force). The results also showed that higher mAs, thinner slices, smoother kernels, and iterative reconstruction could lead to more accurate and precise quantification scores. This study underscored the qualitative and quantitative benefits of PCCT against conventional EID scanners as well as the importance of optimal protocol choice within scanners for more accurate quantifications.

Multi-scale convolutional neural network for automated AMD classification using retinal OCT images.

BACKGROUND AND OBJECTIVE: Age-related macular degeneration (AMD) is the most common cause of blindness in developed countries, especially in people over 60 years of age. The workload of specialists and the healthcare system in this field has increased in recent years mainly due to three reasons: 1) increased use of retinal optical coherence tomography (OCT) imaging technique, 2) prevalence of population aging worldwide, and 3) chronic nature of AMD. Recent advancements in the field of deep learning have provided a unique opportunity for the development of fully automated diagnosis frameworks. Considering the presence of AMD-related retinal pathologies in varying sizes in OCT images, our objective was to propose a multi-scale convolutional neural network (CNN) that can capture inter-scale variations and improve performance using a feature fusion strategy across convolutional blocks. METHODS: Our proposed method introduces a multi-scale CNN based on the feature pyramid network (FPN) structure. This method is used for the reliable diagnosis of normal and two common clinical characteristics of dry and wet AMD, namely drusen and choroidal neovascularization (CNV). The proposed method is evaluated on the national dataset gathered at Hospital (NEH) for this study, consisting of 12649 retinal OCT images from 441 patients, and the UCSD public dataset, consisting of 108312 OCT images from 4686 patients. RESULTS: Experimental results show the superior performance of our proposed multi-scale structure over several well-known OCT classification frameworks. This feature combination strategy has proved to be effective on all tested backbone models, with improvements ranging from 0.4% to 3.3%. In addition, gradual learning has proved to be effective in improving performance in two consecutive stages. In the first stage, the performance was boosted from 87.2%±2.5% to 92.0%±1.6% using pre-trained ImageNet weights. In the second stage, another performance boost from 92.0%±1.6% to 93.4%±1.4% was observed as a result of fine-tuning the previous model on the UCSD dataset. Lastly, generating heatmaps provided additional proof for the effectiveness of our multi-scale structure, enabling the detection of retinal pathologies appearing in different sizes. CONCLUSION: The promising quantitative results of the proposed architecture, along with qualitative evaluations through generating heatmaps, prove the suitability of the proposed method to be used as a screening tool in healthcare centers assisting ophthalmologists in making better diagnostic decisions.