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Rationale: It is unknown whether air pollution is associated with radiographic features of interstitial lung disease in individuals with chronic obstructive pulmonary disease (COPD). Objectives: To determine whether air pollution increases the prevalence of interstitial lung abnormalities (ILA) or percent high-attenuation areas (HAA) on computed tomography (CT) in individuals with a heavy smoking history and COPD. Methods: We performed a cross-sectional study of SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study), focused on current or former smokers with COPD. Ten-year exposure to particulate matter ⩽2.5 μm in aerodynamic diameter (PM 2.5 ), nitrogen oxides (NO x ), nitrogen dioxide (NO 2 ), and ozone before enrollment CT (completed between 2010 and 2015) were estimated with validated spatiotemporal models at residential addresses. We applied adjusted multivariable modified Poisson regression and linear regression to investigate associations between pollution exposure and relative risk (RR) of ILA or increased percent HAA (between -600 and -250 Hounsfield units), respectively. We assessed for effect modification by MUC5B -promoter polymorphism (variant allele carriers GT or TT vs. GG at rs3705950), smoking status, sex, and percent emphysema. Results: Among 1,272 participants with COPD assessed for HAA, 424 were current smokers, and 249 were carriers of the variant MUC5B allele. A total of 519 participants were assessed for ILA. We found no association between pollution exposure and ILA or HAA. Associations between pollutant exposures and risk of ILA were modified by the presence of MUC5B polymorphism ( P value interaction term for NO x  = 0.04 and PM 2.5  = 0.05) and smoking status ( P value interaction term for NO x  = 0.05; NO 2  = 0.01; and ozone = 0.05). With higher exposure to NO x and PM 2.5 , MUC5B variant carriers had an increased risk of ILA (RR per 26 ppb NO x , 2.41; 95% confidence interval [CI], 0.97-6.0; and RR per 4 μg ⋅ m -3 PM 2.5 , 1.43; 95% CI, 0.93-2.2, respectively). With higher exposure to NO 2 , former smokers had an increased risk of ILA (RR per 10 ppb, 1.64; 95% CI, 1.0-2.7). Conclusions: Exposure to ambient air pollution was not associated with interstitial features on CT in this population of heavy smokers with COPD. MUC5B modified the association between pollution and ILA, suggesting that gene-environment interactions may influence prevalence of interstitial lung features in COPD.

Rationale: Rates of emphysema progression vary in chronic obstructive pulmonary disease (COPD), and the relationships with vascular and airway pathophysiology remain unclear. Objectives: We sought to determine if indices of peripheral (segmental and beyond) pulmonary arterial dilation measured on computed tomography (CT) are associated with a 1-year index of emphysema (EI; percentage of voxels <-950 Hounsfield units) progression. Methods: Five hundred ninety-nine former and never-smokers (Global Initiative for Chronic Obstructive Lung Disease stages 0-3) were evaluated from the SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) cohort: rapid emphysema progressors (RPs; n  = 188, 1-year ΔEI > 1%), nonprogressors ( n  = 301, 1-year ΔEI ± 0.5%), and never-smokers ( n  = 110). Segmental pulmonary arterial cross-sectional areas were standardized to associated airway luminal areas (segmental pulmonary artery-to-airway ratio [PAAR seg ]). Full-inspiratory CT scan-derived total (arteries and veins) pulmonary vascular volume (TPVV) was compared with small vessel volume (radius smaller than 0.75 mm). Ratios of airway to lung volume (an index of dysanapsis and COPD risk) were compared with ratios of TPVV to lung volume. Results: Compared with nonprogressors, RPs exhibited significantly larger PAAR seg (0.73 ± 0.29 vs. 0.67 ± 0.23; P  = 0.001), lower ratios of TPVV to lung volume (3.21 ± 0.42% vs. 3.48 ± 0.38%; P  = 5.0 × 10 -12 ), lower ratios of airway to lung volume (0.031 ± 0.003 vs. 0.034 ± 0.004; P  = 6.1 × 10 -13 ), and larger ratios of small vessel volume to TPVV (37.91 ± 4.26% vs. 35.53 ± 4.89%; P  = 1.9 × 10 -7 ). In adjusted analyses, an increment of 1 standard deviation in PAAR seg was associated with a 98.4% higher rate of severe exacerbations (95% confidence interval, 29-206%; P  = 0.002) and 79.3% higher odds of being in the RP group (95% confidence interval, 24-157%; P  = 0.001). At 2-year follow-up, the CT-defined RP group demonstrated a significant decline in postbronchodilator percentage predicted forced expiratory volume in 1 second. Conclusions: Rapid one-year progression of emphysema was associated with indices indicative of higher peripheral pulmonary vascular resistance and a possible role played by pulmonary vascular-airway dysanapsis.

Rational: Ground glass opacities (GGO) in the absence of interstitial lung disease are understudied., Objective: To assess the association of GGO with white blood cells (WBCs) and progression of quantified chest CT emphysema., Methods: We analyzed data of participants in the Subpopulations and Intermediate Outcome Measures In COPD Study (SPIROMICS). Chest radiologists and pulmonologists labeled regions of the lung as GGO and adaptive multiple feature method (AMFM) trained the computer to assign those labels to image voxels and quantify the volume of the lung with GGO (%GGO AMFM ). We used multivariable linear regression, zero-inflated negative binomial, and proportional hazards regression models to assess the association of %GGO AMFM with WBC, changes in %emphysema, and clinical outcomes., Measurements and Main Results: Among 2,714 participants, 1,680 had COPD and 1,034 had normal spirometry. Among COPD participants, based on the multivariable analysis, current smoking and chronic productive cough was associated with higher %GGO AMFM . Higher %GGO AMFM was cross-sectionally associated with higher WBCs and neutrophils levels. Higher %GGO AMFM per interquartile range at visit 1 (baseline) was associated with an increase in emphysema at one-year follow visit by 11.7% (Relative increase; 95%CI 7.5-16.1%;P<0.001). We found no association between %GGO AMFM and one-year FEV 1 decline but %GGO AMFM was associated with exacerbations and all-cause mortality during a median follow-up time of 1,544 days (Interquartile Interval=1,118-2,059). Among normal spirometry participants, we found similar results except that %GGO AMFM was associated with progression to COPD at one-year follow-up., Conclusions: Our findings suggest that GGO AMFM is associated with increased systemic inflammation and emphysema progression.

Background: Quantitative CT is becoming increasingly common for the characterisation of lung disease; however, its added potential as a clinical tool for predicting severe exacerbations remains understudied. We aimed to develop and validate quantitative CT-based models for predicting severe chronic obstructive pulmonary disease (COPD) exacerbations., Methods: We analysed the Subpopulations and Intermediate Outcome Measures In COPD Study (SPIROMICS) cohort, a multicentre study done at 12 clinical sites across the USA, of individuals aged 40-80 years from four strata: individuals who never smoked, individuals who smoked but had normal spirometry, individuals who smoked and had mild to moderate COPD, and individuals who smoked and had severe COPD. We used 3-year follow-up data to develop logistic regression classifiers for predicting severe exacerbations. Predictors included age, sex, race, BMI, pulmonary function, exacerbation history, smoking status, respiratory quality of life, and CT-based measures of density gradient texture and airway structure. We externally validated our models in a subset from the Genetic Epidemiology of COPD (COPDGene) cohort. Discriminative model performance was assessed using the area under the receiver operating characteristic curve (AUC), which was also compared with other predictors, including exacerbation history and the BMI, airflow obstruction, dyspnoea, and exercise capacity (BODE) index. We evaluated model calibration using calibration plots and Brier scores., Findings: Participants in SPIROMICS were enrolled between Nov 12, 2010, and July 31, 2015. Participants in COPDGene were enrolled between Jan 10, 2008, and April 15, 2011. We included 1956 participants from the SPIROMICS cohort who had complete 3-year follow-up data: the mean age of the cohort was 63·1 years (SD 9·2) and 1017 (52%) were men and 939 (48%) were women. Among the 1956 participants, 434 (22%) had a history of at least one severe exacerbation. For the CT-based models, the AUC was 0·854 (95% CI 0·852-0·855) for at least one severe exacerbation within 3 years and 0·931 (0·930-0·933) for consistent exacerbations (defined as ≥1 acute episode in each of the 3 years). Models were well calibrated with low Brier scores (0·121 for at least one severe exacerbation; 0·039 for consistent exacerbations). For the prediction of at least one severe event during 3-year follow-up, AUCs were significantly higher with CT biomarkers (0·854 [0·852-0·855]) than exacerbation history (0·823 [0·822-0·825]) and BODE index 0·812 [0·811-0·814]). 6965 participants were included in the external validation cohort, with a mean age of 60·5 years (SD 8·9). In this cohort, AUC for at least one severe exacerbation was 0·768 (0·767-0·769; Brier score 0·088)., Interpretation: CT-based prediction models can be used for identification of patients with COPD who are at high risk of severe exacerbations. The newly identified CT biomarkers could potentially enable investigation into underlying disease mechanisms responsible for exacerbations., Funding: National Institutes of Health and the National Heart, Lung, and Blood Institute., Competing Interests: Declaration of interests EAH has received grants from the National Institutes of Health (NIH) and American Lung Association (ALA); has received royalties from VIDA Diagnostics; is a participant on Siemens photon counting CT advisory board; and is founder and shareholder of VIDA Diagnostics. JG has received grants from NIH and is a shareholder of VIDA Diagnostics. APC has received grants from NIH and is a paid consultant for GlaxoSmithKline and AstraZeneca. JDN has received grants from NIH and VIDA Diagnostics; has received royalties from Elsevier; and has received consulting fees, honoraria for lectures, travel expenses, fees for leadership roles, is also shareholder for, shares multiple patents with, and has received computer equipment from VIDA Diagnostics. PN has received grants from the NIH and honoraria from the GE Medical–University of Washington Imaging Symposium. SF has received grants from the American Thoracic Society, Fisher, and Paykel; and has served as a consultant for Genentech. GEC has received grants from the NIH; royalties from VIDA Diagnostics; fees for consultancy work from PowerPollen; and holds stocks or stock options in PowerPollen. FA has received grants from the NIH. IZB has received grants from Theravance & Viatris; fees for consultancy work from Theravance & Viatris, GlaxoSmithKline, AstraZeneca, and GE Healthcare; payment or honoraria for lectures, presentations, speaking, bureaus, manuscript writing, or educational events from Theravance & Viatris, AstraZeneca, and Grifols; is a participant on a data safety monitoring board for Theravance & Viatris, GlaxoSmithKline, and AstraZeneca; and is a member of the American Thoracic Society pulmonary function test committee. RGB has received grants from the NIH, the National Heart, Lung, and Blood Institute (NHLBI), The COPD Foundation, ALA, and the Foundation for the NIH; has received travel expenses from The COPD Foundation for an NIH-funded study; and has served The COPD Foundation in an unpaid leadership or fiduciary role. SPB has received grants from NIH; royalties from Springer Humana; fees for consultancy work from Boehringer Ingelheim, Sanofi/Regeneron, Sunovion, and GlaxoSmithKline; and holds stock options for Vigor Medical Systems. CBC has received grants from the NIH, The COPD Foundation, and the Foundation for the NIH; royalties from the Cambridge University Press; fees for consultancy work from Nuvaira and MGC Diagnostics; and personal fees from GlaxoSmithKline, and medicolegal personal fees from various law firms. MKH has received grants from the NHLBI, Sanofi, Novartis, Nuvaira, Sunovion; royalties from UpToDate and Norton Publishing; fees for consultancy work from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pulmonx, Teva, Verona, Merck, Sanofi, DevPro, Aerogen, and United Therapeutics; payments or honoraria from Cipla, Chiesi, Astra Zeneca, Boehringer Ingelheim, and GlaxoSmithKline; has participated on a data safety monitoring board or advisory board for Novartis and MedTronic; and is a member of The COPD Foundation Board, The COPD Foundation Scientific Advisory Committee, and ALA advisory committee. FJM has received grants from NHLBI, AstraZeneca, Chiesi, GlaxoSmithKline, and Sanofi/Regeneron; fees for consultancy work from Astra Zeneca, Boehringer Ingelheim, Chiesi, CsL Behring, Gala, GlaxoSmithKline, Novartis, Polarean, PulmonX, Sanofi/Regeneron, Sunovion, Teva, Theravance & Viatris, and Virona; payment or honoraria for lectures, presentations, speaking, bureaus, manuscript writing, or educational events from UpToDate; and is a member of the data safety monitoring board of MedTronic. MGM has received grants from the NIH and NHLBI. VEO is member of an independent data safety monitoring board for Sanofi and Regeneron. RP has received grants from NHLBI, The COPD Foundation, and Department of Veteran Affairs; and has received fees for consultancy work from Partner Therapeutics. PGW has received grants from The COPD Foundation, and Genentech; fees for consultancy work from Glenmark Pharmaceuticals, the University of Wisconsin, NGM Pharma, GlaxoSmithKline, Theravance, Sanofi, and AstraZeneca; and honoraria from the Western Society of Allergy, Asthma and Immunology. JMR has received grants from the NHLBI, and The Roy J Carver Charitable Trust; royalties from VIDA Diagnostics; personal fees from Boehringer Ingelheim; payment for expert testimony from Desmarais LLP; and is a shareholder of VIDA Diagnostics. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background Clustering key clinical characteristics of participants in the Severe Asthma Research Program (SARP), a large, multicenter prospective observational study of patients with asthma and healthy controls, has led to the identification of novel asthma phenotypes. Purpose To determine whether quantitative CT (qCT) could help distinguish between clinical asthma phenotypes. Materials and Methods A retrospective cross-sectional analysis was conducted with the use of qCT images (maximal bronchodilation at total lung capacity [TLC], or inspiration, and functional residual capacity [FRC], or expiration) from the cluster phenotypes of SARP participants (cluster 1: minimal disease; cluster 2: mild, reversible; cluster 3: obese asthma; cluster 4: severe, reversible; cluster 5: severe, irreversible) enrolled between September 2001 and December 2015. Airway morphometry was performed along standard paths (RB1, RB4, RB10, LB1, and LB10). Corresponding voxels from TLC and FRC images were mapped with use of deformable image registration to characterize disease probability maps (DPMs) of functional small airway disease (fSAD), voxel-level volume changes (Jacobian), and isotropy (anisotropic deformation index [ADI]). The association between cluster assignment and qCT measures was evaluated using linear mixed models. Results A total of 455 participants were evaluated with cluster assignments and CT (mean age ± SD, 42.1 years ± 14.7; 270 women). Airway morphometry had limited ability to help discern between clusters. DPM fSAD was highest in cluster 5 (cluster 1 in SARP III: 19.0% ± 20.6; cluster 2: 18.9% ± 13.3; cluster 3: 24.9% ± 13.1; cluster 4: 24.1% ± 8.4; cluster 5: 38.8% ± 14.4; P < .001). Lower whole-lung Jacobian and ADI values were associated with greater cluster severity. Compared to cluster 1, cluster 5 lung expansion was 31% smaller (Jacobian in SARP III cohort: 2.31 ± 0.6 vs 1.61 ± 0.3, respectively, P < .001) and 34% more isotropic (ADI in SARP III cohort: 0.40 ± 0.1 vs 0.61 ± 0.2, P < .001). Within-lung Jacobian and ADI SDs decreased as severity worsened (Jacobian SD in SARP III cohort: 0.90 ± 0.4 for cluster 1; 0.79 ± 0.3 for cluster 2; 0.62 ± 0.2 for cluster 3; 0.63 ± 0.2 for cluster 4; and 0.41 ± 0.2 for cluster 5; P < .001). Conclusion Quantitative CT assessments of the degree and intraindividual regional variability of lung expansion distinguished between well-established clinical phenotypes among participants with asthma from the Severe Asthma Research Program study. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Verschakelen in this issue.

Background Airway mucus plugs in asthma are associated with exacerbation frequency, increased eosinophilia, and reduced lung function. The relationship between mucus plugs and spatially overlapping ventilation abnormalities observed at hyperpolarized gas MRI has not been assessed quantitatively. Purpose To assess regional associations between CT mucus plugs scored by individual bronchopulmonary segment and corresponding measurements of segmental ventilation defect percentage (VDP) at hyperpolarized helium 3 ( 3 He) MRI. Materials and Methods In this secondary analysis of a Health Insurance Portability and Accountability Act-compliant prospective observational cohort, participants in the Severe Asthma Research Program (SARP) III (NCT01760915) between December 2012 and August 2015 underwent hyperpolarized 3 He MRI to determine segmental VDP. Segmental mucus plugs at CT were scored by two readers, with segments scored as plugged only if both readers agreed independently. A linear mixed-effects model controlling for interpatient variability was then used to assess differences in VDP in plugged versus plug-free segments. Results Forty-four participants with asthma were assessed (mean age ± standard deviation, 47 years ± 15; 29 women): 19 with mild-to-moderate asthma and 25 with severe asthma. Mucus plugs were observed in 49 total bronchopulmonary segments across eight of 44 patients. Segments containing mucus plugs had a median segmental VDP of 25.9% (25th-75th percentile, 7.3%-38.3%) versus 1.4% (25th-75th percentile, 0.1%-5.2%; P < .001) in plug-free segments. Similarly, the model estimated a segmental VDP of 18.9% (95% CI: 15.7, 22.2) for mucus-plugged segments versus 5.1% (95% CI: 3.3, 7.0) for plug-free segments ( P < .001). Participants with one or more mucus plugs had a median whole-lung VDP of 11.1% (25th-75th percentile, 7.1%-18.9%) versus 3.1% (25th-75th percentile, 1.1%-4.4%) in those without plugs ( P < .001). Conclusion Airway mucus plugging at CT was associated with reduced ventilation in the same bronchopulmonary segment at hyperpolarized helium 3 MRI, suggesting that mucus plugging may be an important cause of ventilation defects in asthma. © RSNA, 2021 Online supplemental material is available for this article.

Background: Soluble receptor for advanced glycation end products (sRAGE) is a proposed emphysema and airflow obstruction biomarker; however, previous publications have shown inconsistent associations and only one study has investigate the association between sRAGE and emphysema. No cohorts have examined the association between sRAGE and progressive decline of lung function. There have also been no evaluation of assay compatibility, receiver operating characteristics, and little examination of the effect of genetic variability in non-white population. This manuscript addresses these deficiencies and introduces novel data from Pittsburgh COPD SCCOR and as well as novel work on airflow obstruction. A meta-analysis is used to quantify sRAGE associations with clinical phenotypes., Methods: sRAGE was measured in four independent longitudinal cohorts on different analytic assays: COPDGene (n = 1443); SPIROMICS (n = 1623); ECLIPSE (n = 2349); Pittsburgh COPD SCCOR (n = 399). We constructed adjusted linear mixed models to determine associations of sRAGE with baseline and follow up forced expiratory volume at one second (FEV 1 ) and emphysema by quantitative high-resolution CT lung density at the 15th percentile (adjusted for total lung capacity)., Results: Lower plasma or serum sRAGE values were associated with a COPD diagnosis (P < 0.001), reduced FEV 1 (P < 0.001), and emphysema severity (P < 0.001). In an inverse-variance weighted meta-analysis, one SD lower log 10 -transformed sRAGE was associated with 105 ± 22 mL lower FEV 1 and 4.14 ± 0.55 g/L lower adjusted lung density. After adjusting for covariates, lower sRAGE at baseline was associated with greater FEV 1 decline and emphysema progression only in the ECLIPSE cohort. Non-Hispanic white subjects carrying the rs2070600 minor allele (A) and non-Hispanic African Americans carrying the rs2071288 minor allele (A) had lower sRAGE measurements compare to those with the major allele, but their emphysema-sRAGE regression slopes were similar., Conclusions: Lower blood sRAGE is associated with more severe airflow obstruction and emphysema, but associations with progression are inconsistent in the cohorts analyzed. In these cohorts, genotype influenced sRAGE measurements and strengthened variance modelling. Thus, genotype should be included in sRAGE evaluations.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease and the traditional variables extracted from computed tomography (CT) images may not be sufficient to describe all the topological features of lung tissues in COPD patients. We employed an unsupervised three-dimensional (3D) convolutional autoencoder (CAE)-feature constructor (FC) deep learning network to learn from CT data and derive tissue pattern-clusters jointly. We then applied exploratory factor analysis (EFA) to discover the unobserved latent traits (factors) among pattern-clusters. CT images at total lung capacity (TLC) and residual volume (RV) of 541 former smokers and 59 healthy non-smokers from the cohort of the SubPopulations and Intermediate Outcome Measures in the COPD Study (SPIROMICS) were analyzed. TLC and RV images were registered to calculate the Jacobian (determinant) values for all the voxels in TLC images. 3D Regions of interest (ROIs) with two data channels of CT intensity and Jacobian value were randomly extracted from training images and were fed to the 3D CAE-FC model. 80 pattern-clusters and 7 factors were identified. Factor scores computed for individual subjects were able to predict spirometry-measured pulmonary functions. Two factors which correlated with various emphysema subtypes, parametric response mapping (PRM) metrics, airway variants, and airway tree to lung volume ratio were discriminants of patients across all severity stages. Our findings suggest the potential of developing factor-based surrogate markers for new COPD phenotypes.

Hip fractures are associated with significant morbidity and mortality in smokers with lung disease, but whether lung-specific factors are associated with fracture risk is unknown. Our goal was to determine whether lung-specific factors associate with incident hip fracture and improve risk discrimination of traditional fracture risk models in smokers. The analysis consisted of a convenience sample of 9187 current and former smokers (58,477 participant follow-up years) participating in the Genetic Epidemiology of chronic obstructive pulmonary disease (COPD) longitudinal observational cohort study. Participants were enrolled between 2008 and 2011 with follow-up data collection through July 2018. Traditional risk factors associated with incident hip fracture (n = 361) included age, female sex, osteoporosis, prevalent spine and hip fracture, rheumatoid arthritis, and diabetes. Lung-specific risk factors included post-bronchodilator percent forced expiratory volume in 1 s (FEV 1 %) predicted (OR, 0.95; 95% CI, 0.92-0.99 for each 10% increase), Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification (OR, 1.09; 95% CI, 1.002-1.19 for each higher stage), presence of CT-determined emphysema (OR, 1.34; 95% CI, 1.06-1.69), symptom scores (OR, 1.10; 95% CI, 1.03-1.19 for each higher unit score), 6-min walk distance (OR, 0.92; 95% CI, 0.90-0.95 for each 30-m increase), body mass index, airflow obstruction, dyspnea, and exercise (BODE) index (OR, 1.07; 95% CI, 1.01-1.13 for each higher unit score), total exacerbations (OR, 1.13; 95% CI, 1.10-1.16 per exacerbation), and annual exacerbations (OR, 1.37; 95% CI, 1.21-1.55 per exacerbation). In multivariable modeling, age, black race, osteoporosis, prevalent hip and spine fracture, rheumatoid arthritis, and diabetes were associated with incident hip fracture. The presence of emphysema, 6-min walk distance, and total number of exacerbations added to traditional models improved risk discrimination (integrated discrimination improvement [IDI] values 0.001 [95% CI, 0.0003-0.002], 0.001 [95% CI, 0.0001-0.002], and 0.008 [95% CI, 0.003-0.013], corresponding to relative IDIs of 12.8%, 6.3%, and 34.6%, respectively). These findings suggest that the incorporation of lung-specific risk factors into fracture risk assessment tools may more accurately predict fracture risk in smokers. © 2020 American Society for Bone and Mineral Research., (© 2020 American Society for Bone and Mineral Research.)

Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterized by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide association studies have reported signals of association implicating multiple pathways including host defense, telomere maintenance, signaling, and cell-cell adhesion. Objectives: To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations. Methods: We conducted genome-wide analyses across three independent studies and meta-analyzed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression, and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF. Measurements and Main Results: We identified and replicated three new genome-wide significant ( P  < 5 × 10 -8 ) signals of association with IPF susceptibility (associated with altered gene expression of KIF15 , MAD1L1 , and DEPTOR ) and confirmed associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as yet unreported IPF susceptibility variants contribute to IPF susceptibility. Conclusions: The observation that decreased DEPTOR expression associates with increased susceptibility to IPF supports recent studies demonstrating the importance of mTOR signaling in lung fibrosis. New signals of association implicating KIF15 and MAD1L1 suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.

Rationale: Interstitial lung abnormalities (ILAs) are associated with the highest genetic risk locus for idiopathic pulmonary fibrosis (IPF); however, the extent to which there are unique associations among individuals with ILAs or additional overlap with IPF is not known. Objectives: To perform a genome-wide association study (GWAS) of ILAs. Methods: ILAs and a subpleural-predominant subtype were assessed on chest computed tomography (CT) scans in the AGES (Age Gene/Environment Susceptibility), COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]), Framingham Heart, ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points), MESA (Multi-Ethnic Study of Atherosclerosis), and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) studies. We performed a GWAS of ILAs in each cohort and combined the results using a meta-analysis. We assessed for overlapping associations in independent GWASs of IPF. Measurements and Main Results: Genome-wide genotyping data were available for 1,699 individuals with ILAs and 10,274 control subjects. The MUC5B (mucin 5B) promoter variant rs35705950 was significantly associated with both ILAs ( P  = 2.6 × 10 -27 ) and subpleural ILAs ( P  = 1.6 × 10 -29 ). We discovered novel genome-wide associations near IPO11 (rs6886640, P  = 3.8 × 10 -8 ) and FCF1P3 (rs73199442, P  = 4.8 × 10 -8 ) with ILAs, and near HTRE1 (rs7744971, P  = 4.2 × 10 -8 ) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPF GWAS loci, five ( DPP9 , DSP , FAM13A , IVD , and MUC5B ) were significantly associated ( P  < 0.05/12) with ILAs. Conclusions: In a GWAS of ILAs in six studies, we confirmed the association with a MUC5B promoter variant and found strong evidence for an effect of previously described IPF loci; however, novel ILA associations were not associated with IPF. These findings highlight common genetically driven biologic pathways between ILAs and IPF, and also suggest distinct ones.

Background: Chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality. Present-day diagnostic criteria are largely based solely on spirometric criteria. Accumulating evidence has identified a substantial number of individuals without spirometric evidence of COPD who suffer from respiratory symptoms and/or increased morbidity and mortality. There is a clear need for an expanded definition of COPD that is linked to physiologic, structural (computed tomography [CT]) and clinical evidence of disease. Using data from the COPD Genetic Epidemiology study (COPDGene ® ), we hypothesized that an integrated approach that includes environmental exposure, clinical symptoms, chest CT imaging and spirometry better defines disease and captures the likelihood of progression of respiratory obstruction and mortality., Methods: Four key disease characteristics - environmental exposure (cigarette smoking), clinical symptoms (dyspnea and/or chronic bronchitis), chest CT imaging abnormalities (emphysema, gas trapping and/or airway wall thickening), and abnormal spirometry - were evaluated in a group of 8784 current and former smokers who were participants in COPDGene ® Phase 1. Using these 4 disease characteristics, 8 categories of participants were identified and evaluated for odds of spirometric disease progression (FEV 1 > 350 ml loss over 5 years), and the hazard ratio for all-cause mortality was examined., Results: Using smokers without symptoms, CT imaging abnormalities or airflow obstruction as the reference population, individuals were classified as Possible COPD, Probable COPD and Definite COPD. Current Global initiative for obstructive Lung Disease (GOLD) criteria would diagnose 4062 (46%) of the 8784 study participants with COPD. The proposed COPDGene ® 2019 diagnostic criteria would add an additional 3144 participants. Under the new criteria, 82% of the 8784 study participants would be diagnosed with Possible, Probable or Definite COPD. These COPD groups showed increased risk of disease progression and mortality. Mortality increased in patients as the number of their COPD characteristics increased, with a maximum hazard ratio for all cause-mortality of 5.18 (95% confidence interval [CI]: 4.15-6.48) in those with all 4 disease characteristics., Conclusions: A substantial portion of smokers with respiratory symptoms and imaging abnormalities do not manifest spirometric obstruction as defined by population normals. These individuals are at significant risk of death and spirometric disease progression. We propose to redefine the diagnosis of COPD through an integrated approach using environmental exposure, clinical symptoms, CT imaging and spirometric criteria. These expanded criteria offer the potential to stimulate both current and future interventions that could slow or halt disease progression in patients before disability or irreversible lung structural changes develop., Competing Interests: The COPDGene® study is funded by National Heart, Lung, and Blood Institute grants U01 HL089897 and U01 HL089856. The COPDGene® study (NCT00608764) is also supported by the COPD Foundation through contributions made to an Industry Advisory Committee comprised of AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion. While some individual authors of this manuscript were employed by one of the listed funders at the time the work of this study was conducted, these employment relationships did not constitute undue influence by funders. These funders have had no official role in the collection, management, analysis and interpretation of the data or design and conduct of the study. All authors have completed a Conflict of Interest form, disclosing any real or apparent financial relationships including receiving royalties, honoraria or fees for consulting, lectures, speakers’ bureaus, continuing education, medical advisory boards or expert testimony; receipt of grants; travel reimbursement; direct employment compensation. These disclosure forms have been filed with the Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation Editorial Office and are available for review, upon request, at COPDC@njhealth.org., (JCOPDF © 2019.)

Background: Quantitative computed tomographic (QCT) imaging-based metrics enable to quantify smoking induced disease alterations and to identify imaging-based clusters for current smokers. We aimed to derive clinically meaningful sub-groups of former smokers using dimensional reduction and clustering methods to develop a new way of COPD phenotyping., Methods: An imaging-based cluster analysis was performed for 406 former smokers with a comprehensive set of imaging metrics including 75 imaging-based metrics. They consisted of structural and functional variables at 10 segmental and 5 lobar locations. The structural variables included lung shape, branching angle, airway-circularity, airway-wall-thickness, airway diameter; the functional variables included regional ventilation, emphysema percentage, functional small airway disease percentage, Jacobian (volume change), anisotropic deformation index (directional preference in volume change), and tissue fractions at inspiration and expiration., Results: We derived four distinct imaging-based clusters as possible phenotypes with the sizes of 100, 80, 141, and 85, respectively. Cluster 1 subjects were asymptomatic and showed relatively normal airway structure and lung function except airway wall thickening and moderate emphysema. Cluster 2 subjects populated with obese females showed an increase of tissue fraction at inspiration, minimal emphysema, and the lowest progression rate of emphysema. Cluster 3 subjects populated with older males showed small airway narrowing and a decreased tissue fraction at expiration, both indicating air-trapping. Cluster 4 subjects populated with lean males were likely to be severe COPD subjects showing the highest progression rate of emphysema., Conclusions: QCT imaging-based metrics for former smokers allow for the derivation of statistically stable clusters associated with unique clinical characteristics. This approach helps better categorization of COPD sub-populations; suggesting possible quantitative structural and functional phenotypes.

Purpose: Computed tomography (CT) is an effective method for detecting and characterizing lung nodules in vivo. With the growing use of chest CT, the detection frequency of lung nodules is increasing. Noninvasive methods to distinguish malignant from benign nodules have the potential to decrease the clinical burden, risk, and cost involved in follow-up procedures on the large number of false-positive lesions detected. This study examined the benefit of including perinodular parenchymal features in machine learning (ML) tools for pulmonary nodule assessment., Methods: Lung nodule cases with pathology confirmed diagnosis (74 malignant, 289 benign) were used to extract quantitative imaging characteristics from computed tomography scans of the nodule and perinodular parenchyma tissue. A ML tool development pipeline was employed using k-medoids clustering and information theory to determine efficient predictor sets for different amounts of parenchyma inclusion and build an artificial neural network classifier. The resulting ML tool was validated using an independent cohort (50 malignant, 50 benign)., Results: The inclusion of parenchymal imaging features improved the performance of the ML tool over exclusively nodular features (P < 0.01). The best performing ML tool included features derived from nodule diameter-based surrounding parenchyma tissue quartile bands. We demonstrate similar high-performance values on the independent validation cohort (AUC-ROC = 0.965). A comparison using the independent validation cohort with the Fleischner pulmonary nodule follow-up guidelines demonstrated a theoretical reduction in recommended follow-up imaging and procedures., Conclusions: Radiomic features extracted from the parenchyma surrounding lung nodules contain valid signals with spatial relevance for the task of lung cancer risk classification. Through standardization of feature extraction regions from the parenchyma, ML tool validation performance of 100% sensitivity and 96% specificity was achieved., (© 2019 American Association of Physicists in Medicine.)

The Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) study, which began in 2007, is an ongoing multicenter observational cohort study of more than 10,000 current and former smokers. The study is aimed at understanding the etiology, progression, and heterogeneity of chronic obstructive pulmonary disease (COPD). In addition to genetic analysis, the participants have been extensively characterized by clinical questionnaires, spirometry, volumetric inspiratory and expiratory computed tomography, and longitudinal follow-up, including follow-up computed tomography at 5 years after enrollment. The purpose of this state-of-the-art review is to summarize the major advances in our understanding of COPD resulting from the imaging findings in the COPDGene study. Imaging features that are associated with adverse clinical outcomes include early interstitial lung abnormalities, visual presence and pattern of emphysema, the ratio of pulmonary artery to ascending aortic diameter, quantitative evaluation of emphysema, airway wall thickness, and expiratory gas trapping. COPD is characterized by the early involvement of the small conducting airways, and the addition of expiratory scans has enabled measurement of small airway disease. Computational advances have enabled indirect measurement of nonemphysematous gas trapping. These metrics have provided insights into the pathogenesis and prognosis of COPD and have aided early identification of disease. Important quantifiable extrapulmonary findings include coronary artery calcification, cardiac morphology, intrathoracic and extrathoracic fat, and osteoporosis. Current active research includes identification of novel quantitative measures for emphysema and airway disease, evaluation of dose reduction techniques, and use of deep learning for phenotyping COPD.

Background: Chronic obstructive pulmonary disease (COPD) is characterized by airway remodeling. Characterization of airway changes on computed tomography has been challenging due to the complexity of the recurring branching patterns, and this can be better measured using fractal dimensions., Methods: We analyzed segmented airway trees of 8,135 participants enrolled in the COPDGene cohort. The fractal complexity of the segmented airway tree was measured by the Airway Fractal Dimension (AFD) using the Minkowski-Bougliand box-counting dimension. We examined associations between AFD and lung function and respiratory morbidity using multivariable regression analyses. We further estimated the extent of peribronchial emphysema (%) within 5 mm of the airway tree, as this is likely to affect AFD. We classified participants into 4 groups based on median AFD, percentage of peribronchial emphysema, and estimated survival., Results: AFD was significantly associated with forced expiratory volume in one second (FEV1; P < 0.001) and FEV1/forced vital capacity (FEV1/FVC; P < 0.001) after adjusting for age, race, sex, smoking status, pack-years of smoking, BMI, CT emphysema, air trapping, airway thickness, and CT scanner type. On multivariable analysis, AFD was also associated with respiratory quality of life and 6-minute walk distance, as well as exacerbations, lung function decline, and mortality on longitudinal follow-up. We identified a subset of participants with AFD below the median and peribronchial emphysema above the median who had worse survival compared with participants with high AFD and low peribronchial emphysema (adjusted hazards ratio [HR]: 2.72; 95% CI: 2.20-3.35; P < 0.001), a substantial number of whom were not identified by traditional spirometry severity grades., Conclusion: Airway fractal dimension as a measure of airway branching complexity and remodeling in smokers is associated with respiratory morbidity and lung function change, offers prognostic information additional to traditional CT measures of airway wall thickness, and can be used to estimate mortality risk., Trial Registration: ClinicalTrials.gov identifier: NCT00608764., Funding: This study was supported by NIH K23 HL133438 (SPB) and the COPDGene study (NIH Grant Numbers R01 HL089897 and R01 HL089856). The COPDGene project is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, Siemens, Sunovion and GlaxoSmithKline.

Early stages of chronic obstructive pulmonary disease (COPD) are characterized by the loss and narrowing of terminal bronchioles in the lung, resulting in "air-trapping," often occurring before overt emphysema manifests. Individuals with an airway-predominant phenotype of COPD display extensive lung air-trapping and are at greater cardiovascular disease (CVD) risk than COPD patients with an emphysema-predominant phenotype. We hypothesized that the degree of computed tomography (CT)-quantified lung air-trapping would be associated with greater aortic and carotid artery stiffness and lower endothelial function, known biomarkers of CVD risk. Lung air-trapping was associated with greater aortic stiffness (carotid femoral pulse wave velocity, CFPWV) ( r  = 0.60, P = 0.007) and carotid β-stiffness ( r  = 0.75, P = 0.0001) among adults with ( n = 10) and without ( n = 9) a clinical diagnosis of COPD and remained significant after adjusting for blood pressure (BP) and smoking history (pack-years) (carotid β-stiffness: r  = 0.68, P < 0.01; CFPWV r  = 0.53, P  = 0.03). The association between lung air-trapping and carotid β-stiffness remained significant after additionally adjusting for age and forced expiratory volume 1(FEV 1 ) ( r  = 0.64, P = 0.01). In the COPD group only ( n = 10), lung air-trapping remained associated with carotid β-stiffness ( r  = 0.82, P = 0.05) after adjustment for age, pack-years, and FEV 1 . In contrast, no association was observed between CFPWV and lung air-trapping after adjustment for BP, pack-years, age, and FEV 1 ( r  = 0.12, P = 0.83). Lung air-trapping was not associated with endothelial function (brachial artery flow-mediated dilation) in the entire cohort ( P = 0.80) or in patients with COPD only ( P = 0.71). These data suggest that carotid artery stiffness may be a mechanism explaining the link between airway-predominant phenotypes of COPD and high CVD risk. NEW & NOTEWORTHY Previous cross-sectional studies have demonstrated greater large elastic artery stiffness and lower endothelium-dependent dilation in chronic obstructive pulmonary disease (COPD) patients compared with controls. Furthermore, COPD patients with emphysema have greater aortic stiffness than non-COPD controls, and the degree of stiffness is associated with emphysema severity. The present study is the first to demonstrate that even before overt emphysema manifests, lung air-trapping is associated with carotid artery stiffness in COPD patients independent of blood pressure, age, or smoking history.

Background: Classification of COPD is usually based on the severity of airflow, which may not sensitively differentiate subpopulations. Using a multiscale imaging-based cluster analysis (MICA), we aim to identify subpopulations for current smokers with COPD., Methods: Among the SPIROMICS subjects, we analyzed computed tomography images at total lung capacity (TLC) and residual volume (RV) of 284 current smokers. Functional variables were derived from registration of TLC and RV images, e.g. functional small airways disease (fSAD%). Structural variables were assessed at TLC images, e.g. emphysema and airway wall thickness and diameter. We employed an unsupervised method for clustering., Results: Four clusters were identified. Cluster 1 had relatively normal airway structures; Cluster 2 had an increase of fSAD% and wall thickness; Cluster 3 exhibited a further increase of fSAD% but a decrease of wall thickness and airway diameter; Cluster 4 had a significant increase of fSAD% and emphysema. Clinically, Cluster 1 showed normal FEV1/FVC and low exacerbations. Cluster 4 showed relatively low FEV1/FVC and high exacerbations. While Cluster 2 and Cluster 3 showed similar exacerbations, Cluster 2 had the highest BMI among all clusters., Conclusions: Association of imaging-based clusters with existing clinical metrics suggests the sensitivity of MICA in differentiating subpopulations.

Background: COPD is associated with cardiovascular disease (CVD), and coronary artery calcification (CAC) provides additional prognostic information. With increasing use of nongated CT scans in clinical practice, this study hypothesized that the visual Weston CAC score would perform as well as the Agatston score in predicting prevalent and incident coronary artery disease (CAD) and CVD in COPD., Methods: CAC was measured by using Agatston and Weston scores on baseline CT scans in 1,875 current and former smokers enrolled in the Genetic Epidemiology of COPD (COPDGene) study. Baseline cardiovascular disease and incident cardiac events on longitudinal follow-up were recorded. Accuracy of the CAC scores was measured by using receiver-operating characteristic analysis, and Cox proportional hazards analyses were used to estimate the risk of incident cardiac events., Results: CAD was reported by 133 (7.1%) subjects at baseline. A total of 413 (22.0%) and 241 (12.9%) patients had significant CAC according to the Weston (≥ 7) and Agatston (≥ 400) scores, respectively; the two methods were significantly correlated (r = 0.84; P < .001). Over 5 years of follow-up, 127 patients (6.8%) developed incident CVD. For predicting prevalent CAD, c-indices for the Weston and Agatston scores were 0.78 and 0.74 and for predicting incident CVD, they were 0.62 and 0.61. After adjustment for age, race, sex, smoking pack-years, FEV 1 , percent emphysema, and CT scanner type, a Weston score ≥ 7 was associated with time to first acute coronary event (hazard ratio, 2.16 [95% CI, 1.32 to 3.53]; P = .002), but a Agatston score ≥ 400 was not (hazard ratio, 1.75 [95% CI, 0.99-3.09]; P = .053)., Conclusions: A simple visual score for CAC performed well in predicting incident CAD in smokers with and without COPD., Trial Registry: ClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Purpose: Quantitative computed tomography (QCT)-derived measures of lung density are valued methods for objectively characterizing lung parenchymal and peripheral airways disease and are being used in a growing number of lung disease focused trials. Detector and reconstruction improvements in CT technology have allowed for significant radiation dose reduction in image acquisition with comparable qualitative image quality. We report the impact of detector type and reconstruction type on QCT lung density measures in relation to decreasing dose indices., Methods: Two sets of studies were completed in an in vivo pig model with a SOMATOM Definition Flash CT system: (a) prior to system upgrade with conventional detectors (UFC) and filtered back projection (FBP), and (b) post system upgrade with integrated electronic detectors (STELLAR) and iterative reconstruction (SAFIRE). CT data were acquired across estimated CT volume dose indices (CTDI vol ) ranging from 0.75 to 15 mGy at both inspiratory and expiratory breath holds. Semiautomated lung segmentations allowed calculation of histogram median, kurtosis, and 15th percentile. Percentage of voxels below -910 HU and -950 HU (inspiratory), and -856 HU (expiratory) were also examined. The changes in these QCT metrics from dose reduction (15 mGy down to 0.75 mGy) were calculated relative to paired reference values (15 mGy). Results were compared based on detector and reconstruction type., Results: In this study, STELLAR detectors improved concordance with 15 mGy values down to 3 mGy for inspiratory scans and 6 mGy for expiratory scans. The addition of SAFIRE reconstruction in all acquired measurements resulted in minimal deviation from reference values at 0.75 mGy., Conclusion: The use of STELLAR integrated electronic detectors and SAFIRE iterative reconstruction may allow for comparable lung density measures with CT dose indices down to 0.75 mGy., (© 2018 American Association of Physicists in Medicine.)

Lung imaging is increasingly being used to diagnose, quantify, and phenotype chronic obstructive pulmonary disease (COPD). Although spirometry is the gold standard for the diagnosis of COPD and for severity staging, the role of computed tomography (CT) imaging has expanded in both clinical practice and research. COPD is a heterogeneous disease with considerable variability in clinical features, radiographic disease, progression, and outcomes. Recent studies have examined the utility of CT imaging in enhancing diagnostic certainty, improving phenotyping, predicting disease progression and prognostication, selecting patients for intervention, and also in furthering our understanding of the complex pathophysiology of this disease. Multiple CT metrics show promise for use as imaging biomarkers in COPD.

Rationale: A substantial proportion of subjects without overt airflow obstruction have significant respiratory morbidity and structural abnormalities as visualized by computed tomography. Whether regions of the lung that appear normal using traditional computed tomography criteria have mild disease is not known., Objectives: To identify subthreshold structural disease in normal-appearing lung regions in smokers., Methods: We analyzed 8,034 subjects with complete inspiratory and expiratory computed tomographic data participating in the COPDGene Study, including 103 lifetime nonsmokers. The ratio of the mean lung density at end expiration (E) to end inspiration (I) was calculated in lung regions with normal density (ND) by traditional thresholds for mild emphysema (-910 Hounsfield units) and gas trapping (-856 Hounsfield units) to derive the ND-E/I ratio. Multivariable regression analysis was used to measure the associations between ND-E/I, lung function, and respiratory morbidity., Measurements and Main Results: The ND-E/I ratio was greater in smokers than in nonsmokers, and it progressively increased from mild to severe chronic obstructive pulmonary disease severity. A proportion of 26.3% of smokers without airflow obstruction had ND-E/I greater than the 90th percentile of normal. ND-E/I was independently associated with FEV 1 (adjusted β = -0.020; 95% confidence interval [CI], -0.032 to -0.007; P = 0.001), St. George's Respiratory Questionnaire scores (adjusted β = 0.952; 95% CI, 0.529 to 1.374; P < 0.001), 6-minute-walk distance (adjusted β = -10.412; 95% CI, -12.267 to -8.556; P < 0.001), and body mass index, airflow obstruction, dyspnea, and exercise capacity index (adjusted β = 0.169; 95% CI, 0.148 to 0.190; P < 0.001), and also with FEV 1 change at follow-up (adjusted β = -3.013; 95% CI, -4.478 to -1.548; P = 0.001)., Conclusions: Subthreshold gas trapping representing mild small airway disease is prevalent in normal-appearing lung regions in smokers without airflow obstruction, and it is associated with respiratory morbidity. Clinical trial registered with www.clinicaltrials.gov (NCT00608764).

Purpose: Quantitative computed tomography (CT) measures are increasingly being developed and used to characterize lung disease. With recent advances in CT technologies, we sought to evaluate the quantitative accuracy of lung imaging at low- and ultralow-radiation doses with the use of iterative reconstruction (IR), tube current modulation (TCM), and spectral shaping., Methods: We investigated the effect of five independent CT protocols reconstructed with IR on quantitative airway measures and global lung measures using an in vivo large animal model as a human subject surrogate. A control protocol was chosen (NIH-SPIROMICS + TCM) and five independent protocols investigating TCM, low- and ultralow-radiation dose, and spectral shaping. For all scans, quantitative global parenchymal measurements (mean, median and standard deviation of the parenchymal HU, along with measures of emphysema) and global airway measurements (number of segmented airways and pi10) were generated. In addition, selected individual airway measurements (minor and major inner diameter, wall thickness, inner and outer area, inner and outer perimeter, wall area fraction, and inner equivalent circle diameter) were evaluated. Comparisons were made between control and target protocols using difference and repeatability measures., Results: Estimated CT volume dose index (CTDIvol) across all protocols ranged from 7.32 mGy to 0.32 mGy. Low- and ultralow-dose protocols required more manual editing and resolved fewer airway branches; yet, comparable pi10 whole lung measures were observed across all protocols. Similar trends in acquired parenchymal and airway measurements were observed across all protocols, with increased measurement differences using the ultralow-dose protocols. However, for small airways (1.9 ± 0.2 mm) and medium airways (5.7 ± 0.4 mm), the measurement differences across all protocols were comparable to the control protocol repeatability across breath holds. Diameters, wall thickness, wall area fraction, and equivalent diameter had smaller measurement differences than area and perimeter measurements., Conclusions: In conclusion, the use of IR with low- and ultralow-dose CT protocols with CT volume dose indices down to 0.32 mGy maintains selected quantitative parenchymal and airway measurements relevant to pulmonary disease characterization., (© 2017 American Association of Physicists in Medicine.)

Rationale: The rate of decline of lung function is greater than age-related change in a substantial proportion of patients with chronic obstructive pulmonary disease, even after smoking cessation. Regions of the lung adjacent to emphysematous areas are subject to abnormal stretch during respiration, and this biomechanical stress likely influences emphysema initiation and progression., Objectives: To assess whether quantifying this penumbra of lung at risk would predict FEV 1 decline., Methods: We analyzed paired inspiratory-expiratory computed tomography images at baseline of 680 subjects participating in a large multicenter study (COPDGene) over approximately 5 years. By matching inspiratory and expiratory images voxel by voxel using image registration, we calculated the Jacobian determinant, a measure of local lung expansion and contraction with respiration. We measured the distance between each normal voxel to the nearest emphysematous voxel, and quantified the percentage of normal voxels within each millimeter distance from emphysematous voxels as mechanically affected lung (MAL). Multivariable regression analyses were performed to assess the relationship between the Jacobian determinant, MAL, and FEV 1 decline., Measurements and Main Results: The mean (SD) rate of decline in FEV 1 was 39.0 (58.6) ml/yr. There was a progressive decrease in the mean Jacobian determinant of both emphysematous and normal voxels with increasing disease stage (P < 0.001). On multivariable analyses, the mean Jacobian determinant of normal voxels within 2 mm of emphysematous voxels (MAL 2 ) was significantly associated with FEV 1 decline. In mild-moderate disease, for participants at or above the median MAL 2 (threshold, 36.9%), the mean decline in FEV 1 was 56.4 (68.0) ml/yr versus 43.2 (59.9) ml/yr for those below the median (P = 0.044)., Conclusions: Areas of normal-appearing lung are mechanically influenced by emphysematous areas and this lung at risk is associated with lung function decline. Clinical trial registered with www.clinicaltrials.gov (NCT00608764).

Objectives: Extra-thoracic tumors send out pilot cells that attach to the pulmonary endothelium. We hypothesized that this could alter regional lung mechanics (tissue stiffening or accumulation of fluid and inflammatory cells) through interactions with host cells. We explored this with serial inspiratory computed tomography (CT) and image matching to assess regional changes in lung expansion., Materials and Methods: We retrospectively assessed 44 pairs of two serial CT scans on 21 sarcoma patients: 12 without lung metastases and 9 with lung metastases. For each subject, two or more serial inspiratory clinically-derived CT scans were retrospectively collected. Two research-derived control groups were included: 7 normal nonsmokers and 12 asymptomatic smokers with two inspiratory scans taken the same day or one year apart respectively. We performed image registration for local-to-local matching scans to baseline, and derived local expansion and density changes at an acinar scale. Welch two sample t test was used for comparison between groups. Statistical significance was determined with a p value < 0.05., Results: Lung regions of metastatic sarcoma patients (but not the normal control group) demonstrated an increased proportion of normalized lung expansion between the first and second CT. These hyper-expanded regions were associated with, but not limited to, visible metastatic lung lesions. Compared with the normal control group, the percent of increased normalized hyper-expanded lung in sarcoma subjects was significantly increased (p < 0.05). There was also evidence of increased lung "tissue" volume (non-air components) in the hyper-expanded regions of the cancer subjects relative to non-hyper-expanded regions. "Tissue" volume increase was present in the hyper-expanded regions of metastatic and non-metastatic sarcoma subjects. This putatively could represent regional inflammation related to the presence of tumor pilot cell-host related interactions., Conclusions: This new quantitative CT (QCT) method for linking serial acquired inspiratory CT images may provide a diagnostic and prognostic means to objectively characterize regional responses in the lung following oncological treatment and monitoring for lung metastases.

Background: Traditional metrics of lung disease such as those derived from spirometry and static single-volume CT images are used to explain respiratory morbidity in patients with COPD, but are insufficient. We hypothesised that the mean Jacobian determinant, a measure of local lung expansion and contraction with respiration, would contribute independently to clinically relevant functional outcomes., Methods: We applied image registration techniques to paired inspiratory-expiratory CT scans and derived the Jacobian determinant of the deformation field between the two lung volumes to map local volume change with respiration. We analysed 490 participants with COPD with multivariable regression models to assess strengths of association between traditional CT metrics of disease and the Jacobian determinant with respiratory morbidity including dyspnoea (modified Medical Research Council), St Georges Respiratory Questionnaire (SGRQ) score, 6-min walk distance (6MWD) and the Body Mass Index, Airflow Obstruction, Dyspnoea and Exercise Capacity (BODE) index, as well as all-cause mortality., Results: The Jacobian determinant was significantly associated with SGRQ (adjusted regression coefficient β=-11.75,95% CI -21.6 to -1.7; p=0.020), and with 6MWD (β=321.15, 95% CI 134.1 to 508.1; p<0.001), independent of age, sex, race, body mass index, FEV 1 , smoking pack-years, CT emphysema, CT gas trapping, airway wall thickness and CT scanner type. The mean Jacobian determinant was also independently associated with the BODE index (β=-0.41, 95% CI -0.80 to -0.02; p=0.039) and mortality on follow-up (adjusted HR=4.26, 95% CI 0.93 to 19.23; p=0.064)., Conclusions: Biomechanical metrics representing local lung expansion and contraction improve prediction of respiratory morbidity and mortality and offer additional prognostic information beyond traditional measures of lung function and static single-volume CT metrics., Trial Registration Number: NCT00608764; Post-results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Chronic Obstructive Pulmonary Disease is the third leading cause of death in the US, and is associated with periodic exacerbations, which account for the largest proportion of health care utilization, and lead to significant morbidity, mortality, and worsening lung function. A subset of patients with COPD have frequent exacerbations, occurring 2 or more times per year. Despite many interventions to reduce COPD exacerbations, there is a significant lack of knowledge in regards to their mechanisms and predisposing factors. We describe here an important observation that defines antibody deficiency as a potential risk factor for frequent COPD exacerbations. We report a case series of patients who have frequent COPD exacerbations, and who were found to have an underlying primary antibody deficiency syndrome. We also report on the outcome of COPD exacerbations following treatment in a subset with of these patients with antibody deficiency. We identified patients with COPD who had 2 or more moderate to severe exacerbations per year; immune evaluation including serum immunoglobulin levels and pneumococcal IgG titers was performed. Patients diagnosed with an antibody deficiency syndrome were treated with either immunoglobulin replacement therapy or prophylactic antibiotics, and their COPD exacerbations were monitored over time. A total of 42 patients were identified who had 2 or more moderate to severe COPD exacerbations per year. Twenty-nine patients had an underlying antibody deficiency syndrome: common variable immunodeficiency (8), specific antibody deficiency (20), and selective IgA deficiency (1). Twenty-two patients had a follow-up for at least 1 year after treatment of their antibody deficiency, which resulted in a significant reduction of COPD exacerbations, courses of oral corticosteroid use and cumulative annual dose of oral corticosteroid use, rescue antibiotic use, and hospitalizations for COPD exacerbations. This case series identifies antibody deficiency as a potentially treatable risk factor for frequent COPD exacerbations; testing for antibody deficiency should be considered in difficult to manage frequently exacerbating COPD patients. Further prospective studies are warranted to further test this hypothesis.

Background: Adults with interstitial lung disease (ILD) often have serologic evidence of autoimmunity of uncertain significance without overt autoimmune disease. We examined associations of rheumatoid arthritis (RA)-associated antibodies with subclinical ILD in community-dwelling adults., Methods: We measured serum rheumatoid factor (RF) and anticyclic citrullinated peptide antibody (anti-CCP) and high attenuation areas (HAAs; CT attenuation values between -600 and -250 Hounsfield units) on cardiac CT in 6736 community-dwelling US adults enrolled in the Multi-Ethnic Study of Atherosclerosis. We measured interstitial lung abnormalities (ILAs) in 2907 full-lung CTs at 9.5-year median follow-up. We used generalised linear and additive models to examine associations between autoantibodies and both HAA and ILA, and tested for effect modification by smoking., Results: In adjusted models, HAA increased by 0.49% (95% CI 0.11% to 0.86%) per doubling of RF IgM and by 0.95% (95% CI 0.50% to 1.40%) per RF IgA doubling. ILA prevalence increased by 11% (95% CI 3% to 20%) per RF IgA doubling. Smoking modified the associations of both RF IgM and anti-CCP with both HAA and ILA (interaction p values varied from 0.01 to 0.09). Among ever smokers, HAA increased by 0.81% (95% CI 0.33% to 1.30%) and ILA prevalence increased by 14% (95% CI 5% to 24%,) per RF IgM doubling; and HAA increased by 1.31% (95% CI 0.45% to 2.18%) and ILA prevalence increased by 13% (95% CI 2% to 24%) per anti-CCP doubling. Among never smokers, no meaningful associations were detected., Conclusions: RA-related autoimmunity is associated with both quantitative and qualitative subclinical ILD phenotypes on CT, particularly among ever smokers., Competing Interests: Competing interests: DJL has received consulting fees from Genentech/Roche, Boehringer-Ingelheim, Gilead, Pharmakea, Veracyte, Patara Pharmaceuticals, Degge Group and the France Foundation related to IPF; Columbia University has received funding for clinical trials in IPF from Boehringer-Ingelheim, Gilead, Bayer, Global Blood Therapeutics and Fibrogen; Columbia University has received funding from the Pulmonary Fibrosis Foundation for DJL's consulting services; DJL has received fees for serving as a Deputy Editor for the Annals of the American Thoracic Society and as a Statistical Editor for Thorax. EAH is a founder and shareholder in VIDA Diagnostics. JDN is a consultant for VIDA Diagnostics and GSK; he is also a patent holder with and has stock options in VIDA Diagnostics. JRW is a member of the IPF Rally Educational Advisory Board and has received honoraria and travel expenses from the IPF Rally Educational Advisory Board., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

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., (Copyright ©ERS 2016.)

Multidetector row computed tomography (MDCT) is increasingly taking a central role in identifying subphenotypes within chronic obstructive pulmonary disease (COPD), asthma, and other lung-related disease populations, allowing for the quantification of the amount and distribution of altered parenchyma along with the characterization of airway and vascular anatomy. The embedding of quantitative CT (QCT) into a multicenter trial with a variety of scanner makes and models along with the variety of pressures within a clinical radiology setting has proven challenging, especially in the context of a longitudinal study. SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study), sponsored by the National Institutes of Health, has established a QCT lung assessment system (QCT-LAS), which includes scanner-specific imaging protocols for lung assessment at total lung capacity and residual volume. Also included are monthly scanning of a standardized test object and web-based tools for subject registration, protocol assignment, and data transmission coupled with automated image interrogation to assure protocol adherence. The SPIROMICS QCT-LAS has been adopted and contributed to by a growing number of other multicenter studies in which imaging is embedded. The key components of the SPIROMICS QCT-LAS along with evidence of implementation success are described herein. While imaging technologies continue to evolve, the required components of a QCT-LAS provide the framework for future studies, and the QCT results emanating from SPIROMICS and the growing number of other studies using the SPIROMICS QCT-LAS will provide a shared resource of image-derived pulmonary metrics.

Through interior tomography, high-resolution microcomputed tomography (μCT) systems provide the ability to nondestructively assess the pulmonary acinus at micron and submicron resolutions. With the application of systematic uniform random sampling (SURS) principles applied to in situ fixed, intact, ex vivo lungs, we have sought to characterize morphometric differences in central vs. surface acini to better understand how well surface acini reflect global acinar geometry. Lungs from six mice (A/J strain, 15-20 wk of age) were perfusion fixed in situ and imaged using a multiresolution μCT system (Micro XCT 400, Zeiss). With the use of lower-resolution whole lung images, SURS methods were used for identification of central and surface foci for high-resolution imaging. Acinar morphometric metrics included diameters, lengths, and branching angles for each alveolar duct and total path lengths from entrance of the acinus to the terminal alveolar sacs. In addition, acinar volume, alveolar surface area, and surface area/volume ratios were assessed. A generation-based analysis demonstrated that central acini have significantly smaller branch diameters at each generation with no significant increase in branch lengths. In addition to larger-diameter alveolar ducts, surface acini had significantly increased numbers of branches and terminal alveolar sacs. The total path lengths from the acinar entrance to the terminal nodes were found to be higher in the case of surface acini. Volumes and surface areas of surface acini are greater than central acini, but there were no differences in surface/volume ratios. In conclusion, there are significant structural differences between surface and central acini in the A/J mouse., (Copyright © 2016 the American Physiological Society.)

Objectives: The objective of this study was to increase the spatial and temporal resolution of dynamic 3-dimensional (3D) magnetic resonance imaging (MRI) of lung volumes and diaphragm motion. To achieve this goal, we evaluate the utility of the proposed blind compressed sensing (BCS) algorithm to recover data from highly undersampled measurements., Materials and Methods: We evaluated the performance of the BCS scheme to recover dynamic data sets from retrospectively and prospectively undersampled measurements. We also compared its performance against that of view-sharing, the nuclear norm minimization scheme, and the l1 Fourier sparsity regularization scheme. Quantitative experiments were performed on a healthy subject using a fully sampled 2D data set with uniform radial sampling, which was retrospectively undersampled with 16 radial spokes per frame to correspond to an undersampling factor of 8. The images obtained from the 4 reconstruction schemes were compared with the fully sampled data using mean square error and normalized high-frequency error metrics. The schemes were also compared using prospective 3D data acquired on a Siemens 3 T TIM TRIO MRI scanner on 8 healthy subjects during free breathing. Two expert cardiothoracic radiologists (R1 and R2) qualitatively evaluated the reconstructed 3D data sets using a 5-point scale (0-4) on the basis of spatial resolution, temporal resolution, and presence of aliasing artifacts., Results: The BCS scheme gives better reconstructions (mean square error = 0.0232 and normalized high frequency = 0.133) than the other schemes in the 2D retrospective undersampling experiments, producing minimally distorted reconstructions up to an acceleration factor of 8 (16 radial spokes per frame). The prospective 3D experiments show that the BCS scheme provides visually improved reconstructions than the other schemes do. The BCS scheme provides improved qualitative scores over nuclear norm and l1 Fourier sparsity regularization schemes in the temporal blurring and spatial blurring categories. The qualitative scores for aliasing artifacts in the images reconstructed by nuclear norm scheme and BCS scheme are comparable.The comparisons of the tidal volume changes also show that the BCS scheme has less temporal blurring as compared with the nuclear norm minimization scheme and the l1 Fourier sparsity regularization scheme. The minute ventilation estimated by BCS for tidal breathing in supine position (4 L/min) and the measured supine inspiratory capacity (1.5 L) is in good correlation with the literature. The improved performance of BCS can be explained by its ability to efficiently adapt to the data, thus providing a richer representation of the signal., Conclusion: The feasibility of the BCS scheme was demonstrated for dynamic 3D free breathing MRI of lung volumes and diaphragm motion. A temporal resolution of ∼500 milliseconds, spatial resolution of 2.7 × 2.7 × 10 mm, with whole lung coverage (16 slices) was achieved using the BCS scheme.

Purpose: A test object (phantom) is an important tool to evaluate comparability and stability of CT scanners used in multicenter and longitudinal studies. However, there are many sources of error that can interfere with the test object-derived quantitative measurements. Here the authors investigated three major possible sources of operator error in the use of a test object employed to assess pulmonary density-related as well as airway-related metrics., Methods: Two kinds of experiments were carried out to assess measurement variability caused by imperfect scanning status. The first one consisted of three experiments. A COPDGene test object was scanned using a dual source multidetector computed tomographic scanner (Siemens Somatom Flash) with the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) inspiration protocol (120 kV, 110 mAs, pitch = 1, slice thickness = 0.75 mm, slice spacing = 0.5 mm) to evaluate the effects of tilt angle, water bottle offset, and air bubble size. After analysis of these results, a guideline was reached in order to achieve more reliable results for this test object. Next the authors applied the above findings to 2272 test object scans collected over 4 years as part of the SPIROMICS study. The authors compared changes of the data consistency before and after excluding the scans that failed to pass the guideline., Results: This study established the following limits for the test object: tilt index ≤0.3, water bottle offset limits of [-6.6 mm, 7.4 mm], and no air bubble within the water bottle, where tilt index is a measure incorporating two tilt angles around x- and y-axis. With 95% confidence, the density measurement variation for all five interested materials in the test object (acrylic, water, lung, inside air, and outside air) resulting from all three error sources can be limited to ±0.9 HU (summed in quadrature), when all the requirements are satisfied. The authors applied these criteria to 2272 SPIROMICS scans and demonstrated a significant reduction in measurement variation associated with the test object., Conclusions: Three operator errors were identified which significantly affected the usability of the acquired scan images of the test object used for monitoring scanner stability in a multicenter study. The authors' results demonstrated that at the time of test object scan receipt at a radiology core laboratory, quality control procedures should include an assessment of tilt index, water bottle offset, and air bubble size within the water bottle. Application of this methodology to 2272 SPIROMICS scans indicated that their findings were not limited to the scanner make and model used for the initial test but was generalizable to both Siemens and GE scanners which comprise the scanner types used within the SPIROMICS study.

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., (© The Author(s) 2016.)

Background: Although the relation between radiographic abnormalities and spirometric impairment in people with asbestosis has been studied extensively, the extent of spirometric impairment associated with milder radiographic abnormalities is not established., Objective: To test associations between mild radiographic abnormalities and Lower Limit of Normal (LLN)-based spirometry interpretation., Methods: Spirometry and CXRs were collected for 1,026 at low risk of exposure to pneumoconiotic agents participants in a medical screening program., Results: Individuals with each type of isolated or combined International Labour Organization (ILO) abnormalities had up to over sixfold statistically significant increase in odds of LLN-based restrictive pattern physiology (OR = 1.96, 95%CI 1.03-3.73 for parenchymal to OR = 6.09, 95%CI 1.94-19.10 for parenchymal and pleural) compared to those with normal films., Conclusions: The findings from this study confirm the association of mild profusion abnormalities with clinically relevant, LLN-based lung function abnormalities.

Rationale: Endothelial dysfunction is of interest in relation to smoking-associated emphysema, a component of chronic obstructive pulmonary disease (COPD). We previously demonstrated that computed tomography (CT)-derived pulmonary blood flow (PBF) heterogeneity is greater in smokers with normal pulmonary function tests (PFTs) but who have visual evidence of centriacinar emphysema (CAE) on CT., Objectives: We introduced dual-energy CT (DECT) perfused blood volume (PBV) as a PBF surrogate to evaluate whether the CAE-associated increased PBF heterogeneity is reversible with sildenafil., Methods: Seventeen PFT-normal current smokers were divided into CAE-susceptible (SS; n = 10) and nonsusceptible (NS; n = 7) smokers, based on the presence or absence of CT-detected CAE. DECT-PBV images were acquired before and 1 hour after administration of 20 mg oral sildenafil. Regional PBV and PBV coefficients of variation (CV), a measure of spatial blood flow heterogeneity, were determined, followed by quantitative assessment of the central arterial tree., Measurements and Main Results: After sildenafil administration, regional PBV-CV decreased in SS subjects but did not decrease in NS subjects (P < 0.05), after adjusting for age and pack-years. Quantitative evaluation of the central pulmonary arteries revealed higher arterial volume and greater cross-sectional area (CSA) in the lower lobes of SS smokers, which suggested arterial enlargement in response to increased peripheral resistance. After sildenafil, arterial CSA decreased in SS smokers but did not decrease in NS smokers (P < 0.01)., Conclusions: These results demonstrate that sildenafil restores peripheral perfusion and reduces central arterial enlargement in normal SS subjects with little effect in NS subjects, highlighting DECT-PBV as a biomarker of reversible endothelial dysfunction in smokers with CAE.

Rationale and Objectives: We evaluated the role of automated quantitative computed tomography (CT) scan interpretation algorithm in detecting interstitial lung disease (ILD) and/or emphysema in a sample of elderly subjects with mild lung disease. We hypothesized that the quantification and distributions of CT attenuation values on lung CT, over a subset of Hounsfield units (HUs) range (-1000 HU, 0 HU), can differentiate early or mild disease from normal lung., Materials and Methods: We compared the results of quantitative spiral rapid end-exhalation (functional residual capacity, FRC) and end-inhalation (total lung capacity, TLC) CT scan analyses of 52 subjects with radiographic evidence of mild fibrotic lung disease to the results of 17 normal subjects. Several CT value distributions were explored, including (1) that from the peripheral lung taken at TLC (with peels at 15 or 65 mm), (2) the ratio of (1) to that from the core of lung, and (3) the ratio of (2) to its FRC counterpart. We developed a fused-lasso logistic regression model that can automatically identify sub-intervals of -1000 HU and 0 HU over which a CT value distribution provides optimal discrimination between abnormal and normal scans., Results: The fused-lasso logistic regression model based on (2) with 15-mm peel identified the relative frequency of CT values of over -1000 HU and -900 and those over -450 HU and -200 HU as a means of discriminating abnormal versus normal lung, resulting in a zero out-sample false-positive rate, and 15% false-negative rate of that was lowered to 12% by pooling information., Conclusions: We demonstrated the potential usefulness of this novel quantitative imaging analysis method in discriminating ILD and/or emphysema from normal lungs., (Copyright © 2015 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

The purpose of this statement is to describe and define the phenotypic abnormalities that can be identified on visual and quantitative evaluation of computed tomographic (CT) images in subjects with chronic obstructive pulmonary disease (COPD), with the goal of contributing to a personalized approach to the treatment of patients with COPD. Quantitative CT is useful for identifying and sequentially evaluating the extent of emphysematous lung destruction, changes in airway walls, and expiratory air trapping. However, visual assessment of CT scans remains important to describe patterns of altered lung structure in COPD. The classification system proposed and illustrated in this article provides a structured approach to visual and quantitative assessment of COPD. Emphysema is classified as centrilobular (subclassified as trace, mild, moderate, confluent, and advanced destructive emphysema), panlobular, and paraseptal (subclassified as mild or substantial). Additional important visual features include airway wall thickening, inflammatory small airways disease, tracheal abnormalities, interstitial lung abnormalities, pulmonary arterial enlargement, and bronchiectasis., ((©) RSNA, 2015.)

Current computer-aided diagnosis (CAD) models for determining pulmonary nodule malignancy characterize nodule shape, density, and border in computed tomography (CT) data. Analyzing the lung parenchyma surrounding the nodule has been minimally explored. We hypothesize that improved nodule classification is achievable by including features quantified from the surrounding lung tissue. To explore this hypothesis, we have developed expanded quantitative CT feature extraction techniques, including volumetric Laws texture energy measures for the parenchyma and nodule, border descriptors using ray-casting and rubber-band straightening, histogram features characterizing densities, and global lung measurements. Using stepwise forward selection and leave-one-case-out cross-validation, a neural network was used for classification. When applied to 50 nodules (22 malignant and 28 benign) from high-resolution CT scans, 52 features (8 nodule, 39 parenchymal, and 5 global) were statistically significant. Nodule-only features yielded an area under the ROC curve of 0.918 (including nodule size) and 0.872 (excluding nodule size). Performance was improved through inclusion of parenchymal (0.938) and global features (0.932). These results show a trend toward increased performance when the parenchyma is included, coupled with the large number of significant parenchymal features that support our hypothesis: the pulmonary parenchyma is influenced differentially by malignant versus benign nodules, assisting CAD-based nodule characterizations.

Objectives: The 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 Methods: The 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., Results: Multivariable 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)., Conclusions: The 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.

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.

Cancer is the second deadliest disease in the United States, necessitating improvements in tumor diagnosis and treatment. Current model systems of cancer are informative, but translating promising imaging approaches and therapies to clinical practice has been challenging. In particular, the lack of a large-animal model that accurately mimics human cancer has been a major barrier to the development of effective diagnostic tools along with surgical and therapeutic interventions. Here, we developed a genetically modified porcine model of cancer in which animals express a mutation in TP53 (which encodes p53) that is orthologous to one commonly found in humans (R175H in people, R167H in pigs). TP53(R167H/R167H) mutant pigs primarily developed lymphomas and osteogenic tumors, recapitulating the tumor types observed in mice and humans expressing orthologous TP53 mutant alleles. CT and MRI imaging data effectively detected developing tumors, which were validated by histopathological evaluation after necropsy. Molecular genetic analyses confirmed that these animals expressed the R167H mutant p53, and evaluation of tumors revealed characteristic chromosomal instability. Together, these results demonstrated that TP53(R167H/R167H) pigs represent a large-animal tumor model that replicates the human condition. Our data further suggest that this model will be uniquely suited for developing clinically relevant, noninvasive imaging approaches to facilitate earlier detection, diagnosis, and treatment of human cancers.