Jered Sieren

Statistical Interior Tomography

This paper presents a statistical interior tomography (SIT) approach making use of compressed sensing (CS) theory. With the projection data modeled by the Poisson distribution, an objective function with a total variation (TV) regularization term is formulated in the maximization of a posteriori (MAP) framework to solve the interior problem. An alternating minimization method is used to optimize the objective function with an initial image from the direct inversion of the truncated Hilbert transform. The proposed SIT approach is extensively evaluated with both numerical and real datasets. The results demonstrate that SIT is robust with respect to data noise and down-sampling, and has better resolution and less bias than its deterministic counterpart in the case of low count data.

Very low-dose (0.15 mGy) chest CT protocols using the COPDGene 2 test object and a third-generation dual-source CT scanner with corresponding third-generation iterative reconstruction software.

ObjectivesThe purpose of this study was to evaluate the impact of ultralow radiation dose single-energy computed tomographic (CT) acquisitions with Sn prefiltration and third-generation iterative reconstruction on density-based quantitative measures of growing interest in phenotyping pulmonary disease. Materials and MethodsThe effects of both decreasing dose and different body habitus on the accuracy of the mean CT attenuation measurements and the level of image noise (SD) were evaluated using the COPDGene 2 test object, containing 8 different materials of interest ranging from air to acrylic and including various density foams. A third-generation dual-source multidetector CT scanner (Siemens SOMATOM FORCE; Siemens Healthcare AG, Erlangen, Germany) running advanced modeled iterative reconstruction (ADMIRE) software (Siemens Healthcare AG) was used.We used normal and very large body habitus rings at dose levels varying from 1.5 to 0.15 mGy using a spectral-shaped (0.6-mm Sn) tube output of 100 kV(p). Three CT scans were obtained at each dose level using both rings. Regions of interest for each material in the test object scans were automatically extracted. The Hounsfield unit values of each material using weighted filtered back projection (WFBP) at 1.5 mGy was used as the reference value to evaluate shifts in CT attenuation at lower dose levels using either WFBP or ADMIRE. Statistical analysis included basic statistics, Welch t tests, multivariable covariant model using the F test to assess the significance of the explanatory (independent) variables on the response (dependent) variable, and CT mean attenuation, in the multivariable covariant model including reconstruction method. ResultsMultivariable regression analysis of the mean CT attenuation values showed a significant difference with decreasing dose between ADMIRE and WFBP. The ADMIRE has reduced noise and more stable CT attenuation compared with WFBP. There was a strong effect on the mean CT attenuation values of the scanned materials for ring size (P < 0.0001) and dose level (P < 0.0001). The number of voxels in the region of interest for the particular material studied did not demonstrate a significant effect (P > 0.05). The SD was lower with ADMIRE compared with WFBP at all dose levels and ring sizes (P < 0.05). ConclusionsThe third-generation dual-source CT scanners using third-generation iterative reconstruction methods can acquire accurate quantitative CT images with acceptable image noise at very low-dose levels (0.15 mGy). This opens up new diagnostic and research opportunities in CT phenotyping of the lung for developing new treatments and increased understanding of pulmonary disease.

Development of quantitative computed tomography lung protocols.

The purpose of this review article is to review the process of developing optimal computed tomography (CT) protocols for quantitative lung CT (QCT). In this review, we discuss the following important topics: QCT-derived metrics of lung disease; QCT scanning protocols; quality control; and QCT image processing software. We will briefly discuss several QCT-derived metrics of lung disease that have been developed for the assessment of emphysema, small airway disease, and large airway disease. The CT scanning protocol is one of the most important elements in a successful QCT. We will provide a detailed description of the current move toward optimizing the QCT protocol for the assessment of chronic obstructive pulmonary disorder and asthma. Quality control of CT images is also a very important part of the QCT process. We will discuss why it is necessary to use CT scanner test objects (phantoms) to provide frequent periodic checks on the CT scanner calibration to ensure precise and accurate CT numbers. We will discuss the use of QCT image processing software to segment the lung and extract the desired QCT metrics of lung disease. We will discuss the practical issues of using this software. The data obtained from the image processing software are then combined with those from other clinical examinations, health status questionnaires, pulmonary physiology, and genomics to increase our understanding of obstructive lung disease and improve our ability to design new therapies for these diseases.

High attenuation areas on chest computed tomography in community-dwelling adults: the MESA study

Evidence suggests that lung injury, inflammation and extracellular matrix remodelling precede lung fibrosis in interstitial lung disease (ILD). We examined whether a quantitative measure of increased lung attenuation on computed tomography (CT) detects lung injury, inflammation and extracellular matrix remodelling in community-dwelling adults sampled without regard to respiratory symptoms or smoking. We measured high attenuation areas (HAA; percentage of lung voxels between −600 and −250 Hounsfield Units) on cardiac CT scans of adults enrolled in the Multi-Ethnic Study of Atherosclerosis. HAA was associated with higher serum matrix metalloproteinase-7 (mean adjusted difference 6.3% per HAA doubling, 95% CI 1.3–11.5), higher interleukin-6 (mean adjusted difference 8.8%, 95% CI 4.8–13.0), lower forced vital capacity (FVC) (mean adjusted difference −82 mL, 95% CI −119–−44), lower 6-min walk distance (mean adjusted difference −40 m, 95% CI −1–−80), higher odds of interstitial lung abnormalities at 9.5 years (adjusted OR 1.95, 95% CI 1.43–2.65), and higher all cause-mortality rate over 12.2 years (HR 1.58, 95% CI 1.39–1.79). High attenuation areas are associated with biomarkers of inflammation and extracellular matrix remodelling, reduced lung function, interstitial lung abnormalities, and a higher risk of death among community-dwelling adults. Increased lung attenuation on CT may identify subclinical lung injury and inflammation in community-dwelling adults http://ow.ly/97k3300tvKX

Sinogram Affirmed Iterative Reconstruction (SAFIRE) versus weighted filtered back projection (WFBP) effects on quantitative measure in the COPDGene 2 test object

PURPOSE Assessing pulmonary emphysema using Quantitative CT of the lung depends on accurate measures of CT density. Sinogram-Affirmed-Iterative-Reconstruction (SAFIRE) is a new approach for reconstructing CT data acquired at significantly lower doses. However, quantitative effects of this method remain unexplored. The authors investigated the effects on the median values of materials in the COPDGene2 test-object as a function of the reconstruction method [weighted filtered back projection (WFBP) versus SAFIRE], test-object size, dose, and material composition using a Siemens SOMATOM Definition FLASH CT scanner. METHODS The COPDGene2 test-object contains eight materials; acrylic, water, four foams (20 lb, 12 lb, lung-equivalent, and 4 lb emphysema-equivalent), internal and external-air. The test-object was scanned with three different outer ring sizes, simulating three different body habitus. There is an average size (36 cm) Ring A, large size (40 cm) Ring B, and small size Ring C (30 cm). The CT protocol used 120 kVp, 0.5 s rotation, 1.0 pitch, and a 0.6 slice collimation with progressively decreasing x-ray exposure values, 11.94-0.74 mGy. With a thorax length of 30 cm, the corresponding effective doses would be 5.01-0.31 mSv. The effects of using SAFIRE versus WFBP were assessed using a two tailed t-test for each ring size, material, and dose. Multivariable linear regression was used to evaluate the relative effects of ring size, material composition, dose, and reconstruction method on the measured median value in HU. RESULTS SAFIRE versus WFBP, at the largest ring size and two lowest doses there was a significant difference in median values of 4 lb-foam, p<0.01. Using the smallest ring size at the lowest dose level there was a significant difference in the median value of 4 lb-foam, but the effect size was small, 1 HU. There is a significant difference in median values of both internal and external air using both the small and medium size rings at the three lowest dose levels, p<0.05. There are significant differences noted at both high and low dose levels when using the large ring size in the median values of internal and external air when, p<0.05. These effects on 4 lb-foam, inside and outside air are shown to be in part due to truncation effects on the median value since the lowest HU value in the CT scale used is -1024 HU. Multivariable linear regression results demonstrated significant effects on the measured material median value and standard deviation due to ring size, material composition, dose level, and reconstruction method, p<0.05. CONCLUSIONS The authors have shown that there is no significant effect on the median values obtained when using WFBP versus SAFIRE in materials with CT density between 120 and -856 HU using three different test-object sizes and CT doses that vary from 11.94 to 0.74 mGy. The authors have demonstrated there are significant effects on median values obtained when using WFBP versus SAFIRE in materials with CT density values between -937 and -1000 HU depending on the ring size and dose used. As expected, there is considerable reduction in image noise (lower standard deviation) using SAFIRE versus WFBP with all ring sizes, doses, and materials in the COPDGene2 test-object.

Effect of Lung Inflation Level on Hyperpolarized 3He Apparent Diffusion Coefficient Measurements in Never-Smokers

PURPOSE To evaluate the effects of lung volume differences on apparent diffusion coefficient (ADC) measurements on a regional basis, with breath holds at volumes adjusted for differences in lung size across individuals according to the subjects vital capacity (VC). MATERIALS AND METHODS This study was approved by the local institutional review board and was compliant with HIPAA. Informed consent was obtained from all subjects. Imaging was performed under a physicians Investigational New Drug application from the Food and Drug Administration. ADC changes as a function of inflation levels were evaluated in 24 healthy never-smokers across three lung volumes (20%, 60%, and 100% VC) on the basis of the spirometric data collected from each subject. Response variables based on lung volume and anatomic position were assessed with multifactorial analysis of variance followed by posthoc pair-wise testing. Imaging was performed with a 1.5-T magnetic resonance (MR) unit with use of a two-dimensional gradient-echo fast low-angle shot sequence. RESULTS Significant differences in ADCs between lung volumes were observed for all inflation levels (20%, 60%, and 100% VC; P < .001), along with significant dependent-nondependent vertical gradients at 20% VC (P < .0001) and 60% VC (P < .0001, left lung only). In addition, significant differences between mean values in the left and right lungs with respect to those in the whole lung were observed at the lower lung inflation levels (20% and 60% VC, P < .01), reaching more uniform expansion at 100% VC. CONCLUSION The results confirm known anatomic differences in patterns of regional inflation and ventilation with corresponding lung volume changes, emphasizing the need for tight control over lung volume when performing hyperpolarized helium 3 ((3)He) lung studies if (3)He MR imaging is to be used to follow up small longitudinal changes in lung abnormalities.

Acute administration of ivacaftor to people with cystic fibrosis and a G551D-CFTR mutation reveals smooth muscle abnormalities

BACKGROUND Airflow obstruction is common in cystic fibrosis (CF), yet the underlying pathogenesis remains incompletely understood. People with CF often exhibit airway hyperresponsiveness, CF transmembrane conductance regulator (CFTR) is present in airway smooth muscle (ASM), and ASM from newborn CF pigs has increased contractile tone, suggesting that loss of CFTR causes a primary defect in ASM function. We hypothesized that restoring CFTR activity would decrease smooth muscle tone in people with CF. METHODS To increase or potentiate CFTR function, we administered ivacaftor to 12 adults with CF with the G551D-CFTR mutation; ivacaftor stimulates G551D-CFTR function. We studied people before and immediately after initiation of ivacaftor (48 hours) to minimize secondary consequences of CFTR restoration. We tested smooth muscle function by investigating spirometry, airway distensibility, and vascular tone. RESULTS Ivacaftor rapidly restored CFTR function, indicated by reduced sweat chloride concentration. Airflow obstruction and air trapping also improved. Airway distensibility increased in airways less than 4.5 mm but not in larger-sized airways. To assess smooth muscle function in a tissue outside the lung, we measured vascular pulse wave velocity (PWV) and augmentation index, which both decreased following CFTR potentiation. Finally, change in distensibility of <4.5-mm airways correlated with changes in PWV. CONCLUSIONS Acute CFTR potentiation provided a unique opportunity to investigate CFTR-dependent mechanisms of CF pathogenesis. The rapid effects of ivacaftor on airway distensibility and vascular tone suggest that CFTR dysfunction may directly cause increased smooth muscle tone in people with CF and that ivacaftor may relax smooth muscle. FUNDING This work was funded in part from an unrestricted grant from the Vertex Investigator-Initiated Studies Program.

Standardizing CT lung density measure across scanner manufacturers

Purpose: Computed Tomography (CT) imaging of the lung, reported in Hounsfield Units (HU), can be parameterized as a quantitative image biomarker for the diagnosis and monitoring of lung density changes due to emphysema, a type of chronic obstructive pulmonary disease (COPD). CT lung density metrics are global measurements based on lung CT number histograms, and are typically a quantity specifying either the percentage of voxels with CT numbers below a threshold, or a single CT number below which a fixed relative lung volume, nth percentile, falls. To reduce variability in the density metrics specified by CT attenuation, the Quantitative Imaging Biomarkers Alliance (QIBA) Lung Density Committee has organized efforts to conduct phantom studies in a variety of scanner models to establish a baseline for assessing the variations in patient studies that can be attributed to scanner calibration and measurement uncertainty. Methods: Data were obtained from a phantom study on CT scanners from four manufacturers with several protocols at various tube potential voltage (kVp) and exposure settings. Free from biological variation, these phantom studies provide an assessment of the accuracy and precision of the density metrics across platforms solely due to machine calibration and uncertainty of the reference materials. The phantom used in this study has three foam density references in the lung density region, which, after calibration against a suite of Standard Reference Materials (SRM) foams with certified physical density, establishes a HU‐electron density relationship for each machine‐protocol. We devised a 5‐step calibration procedure combined with a simplified physical model that enabled the standardization of the CT numbers reported across a total of 22 scanner‐protocol settings to a single energy (chosen at 80 keV). A standard deviation was calculated for overall CT numbers for each density, as well as by scanner and other variables, as a measure of the variability, before and after the standardization. In addition, a linear mixed‐effects model was used to assess the heterogeneity across scanners, and the 95% confidence interval of the mean CT number was evaluated before and after the standardization. Results: We show that after applying the standardization procedures to the phantom data, the instrumental reproducibility of the CT density measurement of the reference foams improved by more than 65%, as measured by the standard deviation of the overall mean CT number. Using the lung foam that did not participate in the calibration as a test case, a mixed effects model analysis shows that the 95% confidence intervals are [−862.0 HU, −851.3 HU] before standardization, and [‐859.0 HU, −853.7 HU] after standardization to 80 keV. This is in general agreement with the expected CT number value at 80 keV of −855.9 HU with 95% CI of [−857.4 HU, −854.5 HU] based on the calibration and the uncertainty in the SRM certified density. Conclusions: This study provides a quantitative assessment of the variations expected in CT lung density measures attributed to non‐biological sources such as scanner calibration and scanner x‐ray spectrum and filtration. By removing scanner‐protocol dependence from the measured CT numbers, higher accuracy and reproducibility of quantitative CT measures were attainable. The standardization procedures developed in study may be explored for possible application in CT lung density clinical data.

Computed Tomography and Magnetic Resonance Imaging for Longitudinal Characterization of Lung Structure Changes in a Yucatan Miniature Pig Silicosis Model.

Medical imaging is a rapidly advancing field enabling the repeated, noninvasive assessment of physiological structure and function. These beneficial characteristics can supplement studies in swine by mirroring the clinical functions of detection, diagnosis, and monitoring in humans. In addition, swine may serve as a human surrogate, facilitating the development and comparison of new imaging protocols for translation to humans. This study presents methods for pulmonary imaging developed for monitoring pulmonary disease initiation and progression in a pig exposure model with computed tomography and magnetic resonance imaging. In particular, a focus was placed on systematic processes, including positioning, image acquisition, and structured reporting to monitor longitudinal change. The image-based monitoring procedure was applied to 6 Yucatan miniature pigs. A subset of animals (n = 3) were injected with crystalline silica into the apical bronchial tree to induce silicosis. The methodology provided longitudinal monitoring and evidence of progressive lung disease while simultaneously allowing for a cross-modality comparative study highlighting the practical application of medical image data collection in swine. The integration of multimodality imaging with structured reporting allows for cross comparison of modalities, refinement of CT and MRI protocols, and consistently monitors potential areas of interest for guided biopsy and/or necropsy.

Dependence of subject-specific parameters for a fast helical CT respiratory motion model on breathing rate: an animal study

To determine if the parameters relating lung tissue displacement to a breathing surrogate signal in a previously published respiratory motion model vary with the rate of breathing during image acquisition. An anesthetized pig was imaged using multiple fast helical scans to sample the breathing cycle with simultaneous surrogate monitoring. Three datasets were collected while the animal was mechanically ventilated with different respiratory rates: 12 bpm (breaths per minute), 17 bpm, and 24 bpm. Three sets of motion model parameters describing the correspondences between surrogate signals and tissue displacements were determined. The model error was calculated individually for each dataset, as well asfor pairs of parameters and surrogate signals from different experiments. The values of one model parameter, a vector field denoted [Formula: see text] which related tissue displacement to surrogate amplitude, determined for each experiment were compared. The mean model error of the three datasets was 1.00  ±  0.36 mm with a 95th percentile value of 1.69 mm. The mean error computed from all combinations of parameters and surrogate signals from different datasets was 1.14  ±  0.42 mm with a 95th percentile of 1.95 mm. The mean difference in [Formula: see text] over all pairs of experiments was 4.7%  ±  5.4%, and the 95th percentile was 16.8%. The mean angle between pairs of [Formula: see text] was 5.0  ±  4.0 degrees, with a 95th percentile of 13.2 mm. The motion model parameters were largely unaffected by changes in the breathing rate during image acquisition. The mean error associated with mismatched sets of parameters and surrogate signals was 0.14 mm greater than the error achieved when using parameters and surrogate signals acquired with the same breathing rate, while maximum respiratory motion was 23.23 mm on average.