study inspired by the National Lung Screening Trial (NLST), illustrates the potential of VITs to expedite clinical trials, minimize risks to participants, and promote optimal use of imaging technologies in healthcare. This study aimed to show that a virtual imaging trial platform could investigate some key elements of a major clinical trial, specifically the NLST, which compared Computed tomography (CT) and chest radiography (CXR) for lung cancer screening. With simulated cancerous lung nodules, a virtual patient cohort of 294 subjects was created using XCAT human models. Each virtual patient underwent both CT and CXR imaging, with deep learning models, the AI CT-Reader and AI CXR-Reader, acting as virtual readers to perform recall patients with suspicion of lung cancer. The primary outcome was the difference in diagnostic performance between CT and CXR, measured by the Area Under the Curve (AUC). The AI CT-Reader showed superior diagnostic accuracy, achieving an AUC of 0.92 (95% CI: 0.90-0.95) compared to the AI CXR-Reader's AUC of 0.72 (95% CI: 0.67-0.77). Furthermore, at the same 94% CT sensitivity reported by the NLST, the VLST specificity of 73% was similar to the NLST specificity of 73.4%. This CT performance highlights the potential of VITs to replicate certain aspects of clinical trials effectively, paving the way toward a safe and efficient method for advancing imaging-based diagnostics.

OBJECTIVE: This study aims to develop and validate a novel framework, iPhantom, for automated creation of patient-specific phantoms or "digital-twins (DT)" using patient medical images. The framework is applied to assess radiation dose to radiosensitive organs in CT imaging of individual patients. METHOD: Given a volume of patient CT images, iPhantom segments selected anchor organs and structures (e.g., liver, bones, pancreas) using a learning-based model developed for multi-organ CT segmentation. Organs which are challenging to segment (e.g., intestines) are incorporated from a matched phantom template, using a diffeomorphic registration model developed for multi-organ phantom-voxels. The resulting digital-twin phantoms are used to assess organ doses during routine CT exams. RESULT: iPhantom was validated on both with a set of XCAT digital phantoms (n = 50) and an independent clinical dataset (n = 10) with similar accuracy. iPhantom precisely predicted all organ locations yielding Dice Similarity Coefficients (DSC) 0.6 - 1 for anchor organs and DSC of 0.3-0.9 for all other organs. iPhantom showed <10% errors in estimated radiation dose for the majority of organs, which was notably superior to the state-of-the-art baseline method (20-35% dose errors). CONCLUSION: iPhantom enables automated and accurate creation of patient-specific phantoms and, for the first time, provides sufficient and automated patient-specific dose estimates for CT dosimetry. SIGNIFICANCE: The new framework brings the creation and application of CHPs (computational human phantoms) to the level of individual CHPs through automation, achieving wide and precise organ localization, paving the way for clinical monitoring, personalized optimization, and large-scale research.

Our approach differs from the usual global measure of cardiac efficiency by using PET/MRI to measure efficiency of small pieces of cardiac tissue whose limiting size is equal to the spatial resolution of the PET scanner. We initiated a dynamic cardiac PET study immediately prior to the injection of 15.1 mCi of11C-acetate acquiring data for 25 minutes while simultaneously acquiring MRI cine data. 1) A 3D finite element (FE) biomechanical model of the imaged heart was constructed by utilizing nonrigid deformable image registration to alter the Dassault Systèmes FE Living Heart Model (LHM) to fit the geometry in the cardiac MRI cine data. The patient specific FE cardiac model with estimates of stress, strain, and work was transformed into PET/MRI format. 2) A 1-tissue compartment model was used to calculate wash-in (K1) and the linear portion of the decay in the PET11C-acetate time activity curve (TAC) was used to calculate the wash-out k2(mono) rate constant. K1was used to calculate blood flow and k2(mono) was used to calculate myocardial volume oxygen consumption (MVO2). 3) Estimates of stress and strain were used to calculate Myocardial Equivalent Minute Work (MEMW) and Cardiac Efficiency =MEMW/MVO2was then calculated for 17 tissue segments of the left ventricle. The global MBF was 0.96 ± 0.15 ml/min/gm andMVO2ranged from 8 to 17 ml/100gm/min. Six central slices of the MRI cine data provided a range ofMEMWof 0.1 to 0.4 joules/gm/min and a range of Cardiac Efficiency of 6 to 18%.

The purpose of this study was to develop a CT simulation platform that is: 1) compatible with voxel-based computational phantoms; 2) capable of modeling the geometry and physics of commercial CT scanners; and 3) computationally efficient. Such a simulation platform is designed to enable the virtual evaluation and optimization of CT protocols and parameters for achieving a targeted image quality while reducing radiation dose. Given a voxelized computational phantom and a parameter file describing the desired scanner and protocol, the developed platform DukeSim calculates projection images using a combination of ray-tracing and Monte Carlo techniques. DukeSim includes detailed models for the detector quantum efficiency, quantum and electronic noise, detector crosstalk, subsampling of the detector and focal spot areas, focal spot wobbling, and the bowtie filter. DukeSim was accelerated using GPU computing. The platform was validated using physical and computational versions of a phantom (Mercury phantom). Clinical and simulated CT scans of the phantom were acquired at multiple dose levels using a commercial CT scanner (Somatom Definition Flash; Siemens Healthcare). The real and simulated images were compared in terms of image contrast, noise magnitude, noise texture, and spatial resolution. The relative error between the clinical and simulated images was less than 1.4%, 0.5%, 2.6%, and 3%, for image contrast, noise magnitude, noise texture, and spatial resolution, respectively, demonstrating the high realism of DukeSim. The runtime, dependent on the imaging task and the hardware, was approximately 2-3 minutes per rotation in our study using a computer with 4 GPUs. DukeSim, when combined with realistic human phantoms, provides the necessary toolset with which to perform large-scale and realistic virtual clinical trials in a patient and scanner-specific manner.

The purpose of this paper was to extend the extended cardiac-torso (XCAT) series of computational phantoms to include a detailed lung architecture including airways and pulmonary vasculature. Eleven XCAT phantoms of varying anatomy were used in this paper. The lung lobes and initial branches of the airways, pulmonary arteries, and veins were previously defined in each XCAT model. These models were extended from the initial branches of the airways and vessels to the level of terminal branches using an anatomically-based volume-filling branching algorithm. This algorithm grew the airway and vasculature branches separately and iteratively without intersecting each other using cylindrical models with diameters estimated by order-based anatomical measurements. Geometrical features of the extended branches were compared with the literature anatomy values to quantitatively evaluate the models. These features include branching angle, length to diameter ratio, daughter to parent diameter ratio, asymmetrical branching pattern, diameter, and length ratios. The XCAT phantoms were then used to simulate CT images to qualitatively compare them with the original phantom images. The proposed growth model produced 46369 ± 12521 airways, 44737 ± 11773 arteries, and 39819 ± 9988 veins to the XCAT phantoms. Furthermore, the growth model was shown to produce asymmetrical airway, artery, and vein networks with geometrical attributes close to morphometry and model based studies. The simulated CT images of the phantoms were judged to be more realistic, including more airways and pulmonary vessels compared with the original phantoms. Future work will seek to add a heterogeneous parenchymal background into the XCAT lungs to make the phantoms even more representative of human anatomy, paving the way towards the use of XCAT models as a tool to virtually evaluate the current and emerging medical imaging technologies.

The four-dimensional (4-D) eXtended CArdiac-Torso (XCAT) series of phantoms was developed to provide accurate computerized models of the human anatomy and physiology. The XCAT series encompasses a vast population of phantoms of varying ages from newborn to adult, each including parameterized models for the cardiac and respiratory motions. With great flexibility in the XCAT's design, any number of body sizes, different anatomies, cardiac or respiratory motions or patterns, patient positions and orientations, and spatial resolutions can be simulated. As such, the XCAT phantoms are gaining a wide use in biomedical imaging research. There they can provide a virtual patient base from which to quantitatively evaluate and improve imaging instrumentation, data acquisition, techniques, and image reconstruction and processing methods which can lead to improved image quality and more accurate clinical diagnoses. The phantoms have also found great use in radiation dosimetry, radiation therapy, medical device design, and even the security and defense industry. This review paper highlights some specific areas in which the XCAT phantoms have found use within biomedical imaging and other fields. From these examples, we illustrate the increasingly important role that computerized phantoms and computer simulation are playing in the research community.

Mammography is currently the most widely utilized tool for detection and diagnosis of breast cancer. However, in women with dense breast tissue, tissue overlap may obscure lesions. Digital breast tomosynthesis can reduce tissue overlap. Furthermore, imaging with contrast enhancement can provide additional functional information about lesions, such as morphology and kinetics, which in turn may improve lesion identification and characterization. The performance of these imaging techniques is strongly dependent on the structural composition of the breast, which varies significantly among patients. Therefore, imaging system and imaging technique optimization should take patient variability into consideration. Furthermore, optimization of imaging techniques that employ contrast agents should include the temporally varying breast composition with respect to the contrast agent uptake kinetics. To these ends, we have developed a suite of 4-D virtual breast phantoms, which are incorporated with the kinetics of contrast agent propagation in different tissues and can realistically model normal breast parenchyma as well as benign and malignant lesions. This development presents a new approach in performing simulation studies using truly anthropomorphic models. To demonstrate the utility of the proposed 4-D phantoms, we present a simplified example study to compare the performance of 14 imaging paradigms qualitatively and quantitatively.

The 4D extended cardiac-torso (XCAT) phantom was developed to provide a realistic and flexible model of the human anatomy and cardiac and respiratory motions for use in medical imaging research. A prior limitation to the phantom was that it did not accurately simulate altered functions of the heart that result from cardiac pathologies such as coronary artery disease (CAD). We overcame this limitation in a previous study by combining the phantom with a finite-element (FE) mechanical model of the left ventricle (LV) capable of more realistically simulating regional defects caused by ischemia. In the present work, we extend this model giving it the ability to accurately simulate motion abnormalities caused by myocardial infarction (MI), a far more complex situation in terms of altered mechanics compared with the modeling of acute ischemia. The FE model geometry is based on high resolution CT images of a normal male subject. An anterior region was defined as infarcted and the material properties and fiber distribution were altered, according to the bio-physiological properties of two types of infarction, i.e., fibrous and remodeled infarction (30% thinner wall than fibrous case). Compared with the original, surface-based 4D beating heart model of the XCAT, where regional abnormalities are modeled by simply scaling down the motion in those regions, the FE model was found to provide a more accurate representation of the abnormal motion of the LV due to the effects of fibrous infarction as well as depicting the motion of remodeled infarction. In particular, the FE models allow for the accurate depiction of dyskinetic motion. The average circumferential strain results were found to be consistent with measured dyskinetic experimental results. Combined with the 4D XCAT phantom, the FE model can be used to produce realistic multimodality sets of imaging data from a variety of patients in which the normal or abnormal cardiac function is accurately represented.

The purpose of the work described in this paper was the development of a framework for the creation of a realistic positron emission tomography (PET) simulated database incorporating patient-specific variability. The ground truth used was therefore based on clinical PET/computed tomography (CT) data of oncology patients. In the first step, the NURBS-based cardiac-torso phantom was adapted to the patient's CT acquisitions to reproduce their specific anatomy while the corresponding PET acquisitions were used to derive the activity distribution of each organ of interest. Secondly, realistic tumor shapes with homogeneous or heterogeneous activity distributions were modeled based on segmentation of the PET tumor volume and incorporated in the patient-specific models obtained at the first step. Lastly, patient-specific respiratory motion was also modeled. The derived patient-specific models were subsequently combined with the PET SORTEO Monte Carlo simulation tool for the simulation of the whole-body PET acquisition process. The accuracy of the simulated datasets was assessed in comparison to the original clinical patient images. In addition, a couple of applications for such simulated images were also demonstrated. Future work will focus on the creation of a comprehensive database of simulated raw data and reconstructed whole-body images, facilitating the rigorous evaluation of image-processing algorithms in PET for oncology applications.

Recent work in the development of computerized phantoms has focused on the creation of ideal "hybrid" models that seek to combine the realism of a patient-based voxelized phantom with the flexibility of a mathematical or stylized phantom. We have been leading the development of such computerized phantoms for use in medical imaging research. This paper will summarize our developments dating from the original four-dimensional (4-D) Mathematical Cardiac-Torso (MCAT) phantom, a stylized model based on geometric primitives, to the current 4-D extended Cardiac-Torso (XCAT) and Mouse Whole-Body (MOBY) phantoms, hybrid models of the human and laboratory mouse based on state-of-the-art computer graphics techniques. This paper illustrates the evolution of computerized phantoms toward more accurate models of anatomy and physiology. This evolution was catalyzed through the introduction of nonuniform rational b-spline (NURBS) and subdivision (SD) surfaces, tools widely used in computer graphics, as modeling primitives to define a more ideal hybrid phantom. With NURBS and SD surfaces as a basis, we progressed from a simple geometrically based model of the male torso (MCAT) containing only a handful of structures to detailed, whole-body models of the male and female (XCAT) anatomies (at different ages from newborn to adult), each containing more than 9000 structures. The techniques we applied for modeling the human body were similarly used in the creation of the 4-D MOBY phantom, a whole-body model for the mouse designed for small animal imaging research. From our work, we have found the NURBS and SD surface modeling techniques to be an efficient and flexible way to describe the anatomy and physiology for realistic phantoms. Based on imaging data, the surfaces can accurately model the complex organs and structures in the body, providing a level of realism comparable to that of a voxelized phantom. In addition, they are very flexible. Like stylized models, they can easily be manipulated to model anatomical variations and patient motion. With the vast improvement in realism, the phantoms developed in our lab can be combined with accurate models of the imaging process (SPECT, PET, CT, magnetic resonance imaging, and ultrasound) to generate simulated imaging data close to that from actual human or animal subjects. As such, they can provide vital tools to generate predictive imaging data from many different subjects under various scanning parameters from which to quantitatively evaluate and improve imaging devices and techniques. From the MCAT to XCAT, we will demonstrate how NURBS and SD surface modeling have resulted in a major evolutionary advance in the development of computerized phantoms for imaging research.

With continuing improvements in spatial resolution of positron emission tomography (PET) scanners, small patient movements during PET imaging become a significant source of resolution degradation. This work develops and investigates a comprehensive formalism for accurate motion-compensated reconstruction which at the same time is very feasible in the context of high-resolution PET. In particular, this paper proposes an effective method to incorporate presence of scattered and random coincidences in the context of motion (which is similarly applicable to various other motion correction schemes). The overall reconstruction framework takes into consideration missing projection data which are not detected due to motion, and additionally, incorporates information from all detected events, including those which fall outside the field-of-view following motion correction. The proposed approach has been extensively validated using phantom experiments as well as realistic simulations of a new mathematical brain phantom developed in this work, and the results for a dynamic patient study are also presented.

The four-dimensional (4-D) NURBS-based cardiac-torso (NCAT) phantom, which provides a realistic model of the normal human anatomy and cardiac and respiratory motions, is used in medical imaging research to evaluate and improve imaging devices and techniques, especially dynamic cardiac applications. One limitation of the phantom is that it lacks the ability to accurately simulate altered functions of the heart that result from cardiac pathologies such as coronary artery disease (CAD). The goal of this work was to enhance the 4-D NCAT phantom by incorporating a physiologically based, finite-element (FE) mechanical model of the left ventricle (LV) to simulate both normal and abnormal cardiac motions. The geometry of the FE mechanical model was based on gated high-resolution X-ray multislice computed tomography (MSCT) data of a healthy male subject. The myocardial wall was represented as a transversely isotropic hyperelastic material, with the fiber angle varying from -90 degrees at the epicardial surface, through 0 degrees at the midwall, to 90 degrees at the endocardial surface. A time-varying elastance model was used to simulate fiber contraction, and physiological intraventricular systolic pressure-time curves were applied to simulate the cardiac motion over the entire cardiac cycle. To demonstrate the ability of the FE mechanical model to accurately simulate the normal cardiac motion as well as the abnormal motions indicative of CAD, a normal case and two pathologic cases were simulated and analyzed. In the first pathologic model, a subendocardial anterior ischemic region was defined. A second model was created with a transmural ischemic region defined in the same location. The FE-based deformations were incorporated into the 4-D NCAT cardiac model through the control points that define the cardiac structures in the phantom which were set to move according to the predictions of the mechanical model. A simulation study was performed using the FE-NCAT combination to investigate how the differences in contractile function between the subendocardial and transmural infarcts manifest themselves in myocardial Single photon emission computed tomography (SPECT) images. The normal FE model produced strain distributions that were consistent with those reported in the literature and a motion consistent with that defined in the normal 4-D NCAT beating heart model based on tagged magnetic resonance imaging (MRI) data. The addition of a subendocardial ischemic region changed the average transmural circumferential strain from a contractile value of -0.09 to a tensile value of 0.02. The addition of a transmural ischemic region changed average circumferential strain to a value of 0.13, which is consistent with data reported in the literature. Model results demonstrated differences in contractile function between subendocardial and transmural infarcts and how these differences in function are documented in simulated myocardial SPECT images produced using the 4-D NCAT phantom. Compared with the original NCAT beating heart model, the FE mechanical model produced a more accurate simulation for the cardiac motion abnormalities. Such a model, when incorporated into the 4-D NCAT phantom, has great potential for use in cardiac imaging research. With its enhanced physiologically based cardiac model, the 4-D NCAT phantom can be used to simulate realistic, predictive imaging data of a patient population with varying whole-body anatomy and with varying healthy and diseased states of the heart that will provide a known truth from which to evaluate and improve existing and emerging 4-D imaging techniques used in the diagnosis of cardiac disease.