Development of a pulmonary imaging biomarker pipeline for phenotyping of chronic lung disease

We designed and generated pulmonary imaging biomarker pipelines to facilitate high-throughput research and point-of-care use in patients with chronic lung disease. Image processing modules and algorithm pipelines were embedded within a graphical user interface (based on the .NET framework) for pulmonary magnetic resonance imaging (MRI) and x-ray computed-tomography (CT) datasets. The software pipelines were generated using C++ and included: (1) inhale

Pulmonary Image Segmentation and Registration Algorithms: Towards Regional Evaluation of Obstructive Lung Disease

Pulmonary imaging, including pulmonary magnetic resonance imaging (MRI) and computed tomography (CT), provides a way to sensitively and regionally measure spatially heterogeneous lung structural-functional abnormalities. These unique imaging biomarkers offer the potential for better understanding pulmonary disease mechanisms, monitoring disease progression and response to therapy, and developing novel treatments for improved patient care. To generate these regional lung structure-function measurements and enable broad clinical applications of quantitative pulmonary MRI and CT biomarkers, as a first step, accurate, reproducible and rapid lung segmentation and registration methods are required. In this regard, we first developed a 1H MRI lung segmentation algorithm that employs complementary hyperpolarized 3He MRI functional information for improved lung segmentation. The 1H-3He MRI joint segmentation algorithm was formulated as a coupled continuous min-cut model and solved through convex relaxation, for which a dual coupled continuous max-flow model was proposed and a max-flow-based efficient numerical solver was developed. Experimental results on a clinical dataset of 25 chronic obstructive pulmonary disease (COPD) patients ranging in disease severity demonstrated that the algorithm provided rapid lung segmentation with high accuracy, reproducibility and diminished user interaction. We then developed a general 1H MRI left-right lung segmentation approach by exploring the left-to-right lung volume proportion prior. The challenging volume proportion-constrained multi-region segmentation problem was approximated through convex relaxation and equivalently represented by a max-flow model with bounded flow conservation conditions. This gave rise to a multiplier-based high performance numerical implementation based on convex optimization theories. In 20 patients with mild- to-moderate and severe asthma, the approach demonstrated high agreement with manual segmentation, excellent reproducibility and computational efficiency. Finally, we developed a CT-3He MRI deformable registration approach that coupled the complementary CT-1H MRI registration. The joint registration problem was solved by exploring optical-flow techniques, primal-dual analyses and convex optimization theories. In a diverse group of patients with asthma and COPD, the registration approach demonstrated lower target registration error than single registration and provided fast regional lung structure-function measurements that were strongly correlated with a reference method. Collectively, these lung segmentation and registration algorithms demonstrated accuracy, reproducibility and workflow efficiency that all may be clinically-acceptable. All of this is consistent with the need for broad and large-scale clinical applications of pulmonary MRI and CT

Imaging Biomarkers of Pulmonary Structure and Function

Asthma and chronic obstructive pulmonary disease (COPD) are characterized by airflow limitations resulting from airway obstruction and/or tissue destruction. The diagnosis and monitoring of these pulmonary diseases is primarily performed using spirometry, specifically the forced expiratory volume in one second (FEV1), which measures global airflow obstruction and provides no regional information of the different underlying disease pathologies. The limitations of spirometry and current therapies for lung disease patients have motivated the development of pulmonary imaging approaches, such as computed tomography (CT) and magnetic resonance imaging (MRI). Inhaled hyperpolarized noble gas MRI, specifically using helium-3 (3He) and xenon-129 (129Xe) gases, provides a way to quantify pulmonary ventilation by visualizing lung regions accessed by gas during a breath-hold, and alternatively, regions that are not accessed - coined “ventilation defects.” Despite the strong foundation and many advantages hyperpolarized 3He MRI has to offer research and patient care, clinical translation has been inhibited in part due to the cost and need for specialized equipment, including multinuclear-MR hardware and polarizers, and personnel. Accordingly, our objective was to develop and evaluate imaging biomarkers of pulmonary structure and function using MRI and CT without the use of exogenous contrast agents or specialized equipment. First, we developed and compared CT parametric response maps (PRM) with 3He MR ventilation images in measuring gas-trapping and emphysema in ex-smokers with and without COPD. We observed that in mild-moderate COPD, 3He MR ventilation abnormalities were related to PRM gas-trapping whereas in severe COPD, ventilation abnormalities correlated with both PRM gas-trapping and PRM emphysema. We then developed and compared pulmonary ventilation abnormalities derived from Fourier decomposition of free-breathing proton (1H) MRI (FDMRI) with 3He MRI in subjects with COPD and bronchiectasis. This work demonstrated that FDMRI and 3He MRI ventilation defects were strongly related in COPD, but not in bronchiectasis subjects. In COPD only, FDMRI ventilation defects were spatially related with 3He MRI ventilation defects and emphysema. Based on the FDMRI biomarkers developed in patients with COPD and bronchiectasis, we then evaluated ventilation heterogeneity in patients with severe asthma, both pre- and post-salbutamol as well as post-methacholine challenge, using FDMRI and 3He MRI. FDMRI free-breathing ventilation abnormalities were correlated with but under-estimated 3He MRI static ventilation defects. Finally, based on the previously developed free-breathing MRI approach, we developed a whole-lung free-breathing pulmonary 1H MRI technique to measure regional specific-ventilation and evaluated both asthmatics and healthy volunteers. These measurements not only provided similar information as specific-ventilation measured using plethysmography, but also information about regional ventilation defects that were correlated with 3He MRI ventilation abnormalities. These results demonstrated that whole-lung free-breathing 1H MRI biomarker of specific-ventilation may reflect ventilation heterogeneity and/or gas-trapping in asthma. These important findings indicate that imaging biomarkers of pulmonary structure and function using MRI and CT have the potential to regionally reveal the different pathologies in COPD and asthma without the use of exogenous contrast agents. The development and validation of these clinically meaningful imaging biomarkers are critically required to accelerate pulmonary imaging translation from the research workbench to being a part of the clinical workflow, with the overall goal to improve patient outcomes

Texture Analysis and Machine Learning to Predict Pulmonary Ventilation from Thoracic Computed Tomography

Chronic obstructive pulmonary disease (COPD) leads to persistent airflow limitation, causing a large burden to patients and the health care system. Thoracic CT provides an opportunity to observe the structural pathophysiology of COPD, whereas hyperpolarized gas MRI provides images of the consequential ventilation heterogeneity. However, hyperpolarized gas MRI is currently limited to research centres, due to the high cost of gas and polarization equipment. Therefore, I developed a pipeline using texture analysis and machine learning methods to create predicted ventilation maps based on non-contrast enhanced, single-volume thoracic CT. In a COPD cohort, predicted ventilation maps were qualitatively and quantitatively related to ground-truth MRI ventilation, and both maps were related to important patient lung function and quality-of-life measures. This study is the first to demonstrate the feasibility of predicting hyperpolarized MRI-based ventilation from single-volume, breath-hold thoracic CT, which has potential to translate pulmonary ventilation information to widely available thoracic CT imaging

Pulmonary Imaging to Better Understand Asthma

Asthma is characterized using the spirometry measurement of the forced expiratory volume in one second (FEV1). Simple and inexpensive, FEV1 provides a global estimate of lung function but this metric cannot regionally identify airways responsible for airflow limitation, asthma symptoms or control. Work that brought about an understanding that airway abnormalities are heterogeneously distributed within the lung in asthma patients has motivated the development of pulmonary imaging approaches, such as hyperpolarized helium-3 (3He) and xenon-129 (129Xe) magnetic resonance imaging (MRI). These methods provide a way to visualize and quantify lung regions accessed by gas during a breath-hold, as well as those not accessed, referred to as “ventilation defects.” Despite the strong foundation for the use of MRI in asthma clinical care, clinical translation has been inhibited in part due to the current limited clinical and physiological understanding of ventilation defects. Accordingly, our objective was to better understand the structural determinants and clinical consequences of MRI ventilation defects observed in asthma and to provide a foundation for imaging to guide clinical decisions and asthma therapy. We evaluated the effect of gas properties on ventilation defects. In asthmatics, we compared hyperpolarized 3He and 129Xe MRI before and after bronchodilator administration and showed greater gas distribution abnormalities using 129Xe compared to 3He before bronchodilation. The temporal behavior of asthma ventilation defects was then investigated by generating personalized temporal-spatial pulmonary function maps from 3He MR images acquired on three occasions. Persistent and intermittent defects were visualized and quantified using this tool and were recognized as potential intermediate endpoints or targets for treatment. We then evaluated clinical and emerging computed tomography-derived airway morphology measurements in asthmatics with and without defects. Ventilation defects were observed in two-thirds of well-controlled asthmatics who had worse lung function, increased airway inflammation, airway hyperresponsiveness and greater airway wall thickness than asthmatics without ventilation defects. Acknowledging that asthma control is the primary goal of asthma treatment, we investigated the relationship, and established a link between worse ventilation and poor control. These findings provide a better understanding of asthma ventilation defects and strongly support their potential as a novel treatment target

Comparison of CT ventilation imaging and hyperpolarised gas MRI: effects of breathing manoeuvre.

Image registration of lung CT images acquired at different inflation levels has been proposed as a surrogate method to map lung 'ventilation'. Prior to clinical use, it is important to understand how this technique compares with direct ventilation imaging modalities such as hyperpolarised gas MRI. However, variations in lung inflation level have been shown to affect regional ventilation distributions. Therefore, the aim of this study was to evaluate the impact of lung inflation levels when comparing CT ventilation imaging to ventilation from 3He-MRI.
 
 7 asthma patients underwent breath-hold CT at total lung capacity (TLC) and functional residual capacity (FRC). 3He-MRI and a same-breath 1H-MRI were acquired at FRC+1L and TLC. Percentage ventilated volumes (%VVs) were calculated for FRC+1L and TLC 3He-MRI. TLC-CT and registered FRC-CT were used to compute a surrogate ventilation map from voxel-wise intensity differences in Hounsfield unit values, which was thresholded at the 10th and 20th percentiles. For direct comparison of CT and 3He-MRI ventilation, FRC+1L and TLC 3He-MRI were registered to TLC-CT indirectly via the corresponding same-breath 1H-MRI data. For 3He-MRI and CT ventilation comparison, Dice similarity coefficients (DSCs) between the binary segmentations were computed.
 
 The median (range) of %VVs for FRC+1L and TLC 3He-MRI were 90.5 (54.9-93.6) and 91.8 (67.8-96.2), respectively (p=0.018). For MRI versus CT ventilation comparison, statistically significant improvements in DSCs were observed for TLC 3He MRI when compared with FRC+1L, with median (range) values of 0.93 (0.86-0.93) and 0.86 (0.68-0.92), respectively (p=0.017), for the 10-100th percentile and 0.87 (0.83-0.88) and 0.81 (0.66-0.87), respectively (p=0.027), for the 20-100th percentile.
 
 Correlation of CT ventilation imaging and hyperpolarised gas MRI is sensitive to lung inflation level. For ventilation maps derived from CT acquired at FRC and TLC, a higher correlation with gas ventilation MRI can be achieved if the MRI is acquired at TLC. &#13

Free-breathing Pulmonary MR Imaging to Quantify Regional Ventilation

Purpose: To measure regional specific ventilation with free-breathing hydrogen 1 (1H) magnetic resonance (MR) imaging without exogenous contrast material and to investigate correlations with hyperpolarized helium 3 (3He) MR imaging and pulmonary function test measurements in healthy volunteers and patients with asthma. Materials and Methods: Subjects underwent free-breathing 1H and static breath-hold hyperpolarized 3He MR imaging as well as spirometry and plethysmography; participants were consecutively recruited between January and June 2017. Free-breathing 1H MR imaging was performed with an optimized balanced steady-state free-precession sequence; images were retrospectively grouped into tidal inspiration or tidal expiration volumes with exponentially weighted phase interpolation. MR imaging volumes were coregistered by using optical flow deformable registration to generate 1H MR imaging-derived specific ventilation maps. Hyperpolarized 3He MR imaging- and 1H MR imaging-derived specific ventilation maps were coregistered to quantify regional specific ventilation within hyperpolarized 3He MR imaging ventilation masks. Differences between groups were determined with the Mann-Whitney test and relationships were determined with Spearman (ρ) correlation coefficients. Statistical analyses were performed with software. Results: Thirty subjects (median age: 50 years; interquartile range [IQR]: 30 years), including 23 with asthma and seven healthy volunteers, were evaluated. Both 1H MR imaging-derived specific ventilation and hyperpolarized 3He MR imaging-derived ventilation percentage were significantly greater in healthy volunteers than in patients with asthma (specific ventilation: 0.14 [IQR: 0.05] vs 0.08 [IQR: 0.06], respectively, P \u3c .0001; ventilation percentage: 99% [IQR: 1%] vs 94% [IQR: 5%], P \u3c .0001). For all subjects, 1H MR imaging-derived specific ventilation correlated with plethysmography-derived specific ventilation (ρ = 0.54, P = .002) and hyperpolarized 3He MR imaging-derived ventilation percentage (ρ = 0.67, P \u3c .0001) as well as with forced expiratory volume in 1 second (FEV1) (ρ = 0.65, P = .0001), ratio of FEV1 to forced vital capacity (ρ = 0.75, P \u3c .0001), ratio of residual volume to total lung capacity (ρ = -0.68, P \u3c .0001), and airway resistance (ρ = -0.51, P = .004). 1H MR imaging-derived specific ventilation was significantly greater in the gravitational-dependent versus nondependent lung in healthy subjects (P = .02) but not in patients with asthma (P = .1). In patients with asthma, coregistered 1H MR imaging specific ventilation and hyperpolarized 3He MR imaging maps showed that specific ventilation was diminished in corresponding 3He MR imaging ventilation defects (0.05 ± 0.04) compared with well-ventilated regions (0.09 ± 0.05) (P \u3c .0001). Conclusion: 1H MR imaging-derived specific ventilation correlated with plethysmography-derived specific ventilation and ventilation defects seen by using hyperpolarized 3He MR imaging. © RSNA, 2018 Online supplemental material is available for this article

A method for quantitative analysis of regional lung ventilation using deformable image registration of CT and hybrid hyperpolarized gas/H-1 MRI

Hyperpolarized gas magnetic resonance imaging (MRI) generates highly detailed maps of lung ventilation and physiological function while CT provides corresponding anatomical and structural information. Fusion of such complementary images enables quantitative analysis of pulmonary structure-function. However, direct image registration of hyperpolarized gas MRI to CT is problematic, particularly in lungs whose boundaries are difficult to delineate due to ventilation heterogeneity. This study presents a novel indirect method of registering hyperpolarized gas MRI to CT utilizing 1H-structural MR images that are acquired in the same breath-hold as the gas MRI. The feasibility of using this technique for regional quantification of ventilation of specific pulmonary structures is demonstrated for the lobes. The direct and indirect methods of hyperpolarized gas MRI to CT image registration were compared using lung images from 15 asthma patients. Both affine and diffeomorphic image transformations were implemented. Registration accuracy was evaluated using the target registration error (TRE) of anatomical landmarks identified on 1H MRI and CT. The Wilcoxon signed-rank test was used to test statistical significance. For the affine transformation, the indirect method of image registration was significantly more accurate than the direct method (TRE = 14.7  ±  3.2 versus 19.6  ±  12.7 mm, p = 0.036). Using a deformable transformation, the indirect method was also more accurate than the direct method (TRE = 13.5  ±  3.3 versus 20.4  ±  12.8 mm, p = 0.006). Accurate image registration is critical for quantification of regional lung ventilation with hyperpolarized gas MRI within the anatomy delineated by CT. Automatic deformable image registration of hyperpolarized gas MRI to CT via same breath-hold 1H MRI is more accurate than direct registration. Potential applications include improved multi-modality image fusion, functionally weighted radiotherapy planning, and quantification of lobar ventilation in obstructive airways disease

Comparison of hyperpolarised gas MRI and CT-based surrogates of ventilation

Background: Non-contrast CT-based surrogates of regional ventilation derived from pulmonary images acquired at multiple inflation levels have been proposed as alternatives to established modalities. However, their physiological accuracy has yet to be validated prior to clinical translation. Purpose: To address the hypothesis that these surrogates can provide information comparable to a direct measure of ventilation from hyperpolarised gas MRI ventilation via: i. development of a methodology for registering CT and gas MRI. ii. comparison of these surrogates with gas MRI at the lobar level. iii. evaluation of the impact of inflation levels when comparing gas MRI and ventilation CT. iv. development of an image acquisition and analysis framework to facilitate spatial correlations of both techniques. v. assessment of the effect of using different gases on the correlation. Methods: i. A method to indirectly register gas MRI to CT via same-breath 1H-structural MR images was developed and its accuracy was assessed. ii. A ventilation model based on expansion of lobar CT segmentations was compared with gas MRI lobar ventilation measurements. iii. The spatial overlap of ventilation CT was compared to gas MRI acquired at two different inflation levels. iv. An image acquisition protocol was designed to minimise differences in acquisition settings between scans such as posture and breathing manoeuvre and analysis methods were developed to enable direct regional and voxel level correlations. v. The effect of using two different noble gases, namely, 3He and 129Xe, on correlation with ventilation CT was assessed. Results: i. The indirect method of registration was more accurate than direct registration. ii. Despite subtle differences, lobar ventilation measurements derived from CT and hyperpolarised gas MRI were comparable. iii. Comparison of ventilation CT and gas MRI varied with inflation state. iv. The spatial correlation between ventilation CT and gas MRI increased at coarser levels. v. A marked improvement in correlation was observed for 3He and 129Xe MRI in contrast to when ventilation CT was compared with either 3He and 129Xe MRI. Conclusion: Although CT-based surrogates of ventilation show promise for replacing established ventilation modalities such as hyperpolarised gas MRI, particularly at coarser levels, they cannot be assumed to be equivalent to the techniques they purport to replace