Publications

2015
González G, Jimenez-Carretero D, Rodríguez-López S, Kumamaru KK, George E, San Jose Estépar R, Rybicki FJ, Ledesma-Carbayo MJ. Automated axial right ventricle to left ventricle diameter ratio computation in computed tomography pulmonary angiography. PloS onePloS one 2015;10:e0127797.Abstract

BACKGROUND AND PURPOSE:Right Ventricular to Left Ventricular (RV/LV) diameter ratio has been shown to be a prognostic biomarker for patients suffering from acute Pulmonary Embolism (PE). While Computed Tomography Pulmonary Angiography (CTPA) images used to confirm a clinical suspicion of PE do include information of the heart, a numerical RV/LV diameter ratio is not universally reported, likely because of lack in training, inter-reader variability in the measurements, and additional effort by the radiologist. This study designs and validates a completely automated Computer Aided Detection (CAD) system to compute the axial RV/LV diameter ratio from CTPA images so that the RV/LV diameter ratio can be a more objective metric that is consistently reported in patients for whom CTPA diagnoses PE.MATERIALS AND METHODS:The CAD system was designed specifically for RV/LV measurements. The system was tested in 198 consecutive CTPA patients with acute PE. Its accuracy was evaluated using reference standard RV/LV radiologist measurements and its prognostic value was established for 30-day PE-specific mortality and a composite outcome of 30-day PE-specific mortality or the need for intensive therapies. The study was Institutional Review Board (IRB) approved and HIPAA compliant.RESULTS:The CAD system analyzed correctly 92.4% (183/198) of CTPA studies. The mean difference between automated and manually computed axial RV/LV ratios was 0.03±0.22. The correlation between the RV/LV diameter ratio obtained by the CAD system and that obtained by the radiologist was high (r=0.81). Compared to the radiologist, the CAD system equally achieved high accuracy for the composite outcome, with areas under the receiver operating characteristic curves of 0.75 vs. 0.78. Similar results were found for 30-days PE-specific mortality, with areas under the curve of 0.72 vs. 0.75.CONCLUSIONS:An automated CAD system for determining the CT derived RV/LV diameter ratio in patients with acute PE has high accuracy when compared to manual measurements and similar prognostic significance for two clinical outcomes.

Paper
Toews M, Wachinger C, San Jose Estépar R, Wells WM. A Feature-Based Approach to Big Data Analysis of Medical Imaging. Information processing in medical imaging : proceedings of the .. conferenceInformation processing in medical imaging : proceedings of the .. conference 2015;24:339-350.Abstract

This paper proposes an inference method well-suited to large sets of medical images. The method is based upon a framework where distinctive 3D scale-invariant features are indexed efficiently to identify approximate nearest-neighbor (NN) feature matches in O(log N) computational complexity in the number of images N. It thus scales well to large data sets, in contrast to methods based on pair-wise image registration or feature matching requiring O(N) complexity. Our theoretical contribution is a density estimator based on a generative model that generalizes kernel density estimation and K-nearest neighbor (KNN) methods. The estimator can be used for on-the-fly queries, without requiring explicit parametric models or an off-line training phase. The method is validated on a large multi-site data set of 95,000,000 features extracted from 19,000 lung CT scans. Subject-level classification identifies all images of the same subjects across the entire data set despite deformation due to breathing state, including unintentional duplicate scans. State-of-the-art performance is achieved in predicting chronic pulmonary obstructive disorder (COPD) severity across the 5-category GOLD clinical rating, with an accuracy of 89% if both exact and one-off predictions are considered correct.

Paper
Batmanghelich NK, Saeedi A, Cho MH, San Jose Estépar R, Golland P. Generative Method to Discover Genetically Driven Image Biomarkers. Information processing in medical imaging : proceedings of the .. conferenceInformation processing in medical imaging : proceedings of the .. conference 2015;24:30-42.Abstract

Abstract. We present a generative probabilistic approach to discovery of disease subtypes determined by the genetic variants. In many diseases, multiple types of pathology may present simultaneously in a patient, making quantification of the disease challenging. Our method seeks com- mon co-occurring image and genetic patterns in a population as a way to model these two different data types jointly. We assume that each patient is a mixture of multiple disease subtypes and use the joint gen- erative model of image and genetic markers to identify disease subtypes guided by known genetic influences. Our model is based on a variant of the so-called topic models that uncover the latent structure in a collection of data. We derive an efficient variational inference algorithm to extract patterns of co-occurrence and to quantify the presence of heterogeneous disease processes in each patient. We evaluate the method on simulated data and illustrate its use in the context of Chronic Obstructive Pul- monary Disease (COPD) to characterize the relationship between image and genetic signatures of COPD subtypes in a large patient cohort. 

Paper
Cho MH, Castaldi PJ, Hersh CP, Hobbs BD, Barr GR, Tal-Singer R, Bakke P, Gulsvik A, San Jose Estépar R, van Beek EJR, Coxson HO, Lynch DA, Washko GR, Laird NM, Crapo JD, Beaty TH, Silverman EK. A Genome-wide Association Study of Emphysema and Airway Quantitative Imaging Phenotypes. American journal of respiratory and critical care medicineAmerican journal of respiratory and critical care medicine 2015;Abstract

RATIONALE:Chronic obstructive pulmonary disease (COPD) is defined by the presence of airflow limitation on spirometry, yet COPD subjects can have marked differences in CT imaging. These differences may be driven by genetic factors. We hypothesized that a genome-wide association study of quantitative imaging would identify loci not previously identified in analyses of COPD or spirometry. In addition, we sought to determine whether previously described genome-wide significant COPD and spirometric loci were associated with emphysema or airway phenotypes.OBJECTIVE:To identify genetic determinants of quantitative imaging phenotypes.METHODS:We performed a genome-wide association study on two quantitative emphysema and two quantitative airway imaging phenotypes in the COPDGene (non-Hispanic white and African-American), ECLIPSE, NETT, and GenKOLS studies; and on % gas trapping in COPDGene. We also examined specific loci reported as genome-wide significant for spirometric phenotypes related to airflow limitation or COPD.RESULTS:The total sample size across all cohorts was 12,031, of which 9,338 were from COPDGene. We identified five loci associated with emphysema-related phenotypes, one with airway-related phenotypes, and two with gas trapping. These loci included previously reported associations, including the HHIP, 15q25, and AGER loci, as well as novel associations near SERPINA10 and DLC1. All previously reported COPD and a significant number of spirometric GWAS loci were at least nominally (P < 0.05) associated with either emphysema or airway phenotypes.CONCLUSIONS:Genome-wide analysis may identify novel risk factors for quantitative imaging characteristics in COPD, and also identify imaging features associated with previously identified lung function loci. .

Paper
Torrado-Carvajal A, Herraiz JL, Hernandez-Tamames JA, San Jose Estépar R, Eryaman Y, Rozenholc Y, Adalsteinsson E, Wald LL, Malpica N. Multi-atlas and label fusion approach for patient-specific MRI based skull estimation. Magnetic Resonance in MedicineMagnetic Resonance in Medicine 2015;:n/a-n/a.Abstract

PURPOSE:MRI-based skull segmentation is a useful procedure for many imaging applications. This study describes a methodology for automatic segmentation of the complete skull from a single T1-weighted volume.METHODS:The skull is estimated using a multi-atlas segmentation approach. Using a whole head computed tomography (CT) scan database, the skull in a new MRI volume is detected by nonrigid image registration of the volume to every CT, and combination of the individual segmentations by label-fusion. We have compared Majority Voting, Simultaneous Truth and Performance Level Estimation (STAPLE), Shape Based Averaging (SBA), and the Selective and Iterative Method for Performance Level Estimation (SIMPLE) algorithms.RESULTS:The pipeline has been evaluated quantitatively using images from the Retrospective Image Registration Evaluation database (reaching an overlap of 72.46 ± 6.99%), a clinical CT-MR dataset (maximum overlap of 78.31 ± 6.97%), and a whole head CT-MRI pair (maximum overlap 78.68%). A qualitative evaluation has also been performed on MRI acquisition of volunteers.CONCLUSION:It is possible to automatically segment the complete skull from MRI data using a multi-atlas and label fusion approach. This will allow the creation of complete MRI-based tissue models that can be used in electromagnetic dosimetry applications and attenuation correction in PET/MR. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

Paper
Samet J, Crowell R, San Jose Estépar R, McKee AB, Mulshine JL, Powe N, Rand C, Yung R. Providing Guidance on Lung Cancer Screening to Patients and Physicians. American Lung Association; 2015. Paper
Wells MJ, Iyer AS, Rahaghi FN, Bhatt SP, Gupta H, Denney TS, Lloyd SG, Dell'Italia LJ, Nath H, San Jose Estépar R, Washko GR, Dransfield MT. Pulmonary artery enlargement is associated with right ventricular dysfunction and loss of blood volume in small pulmonary vessels in chronic obstructive pulmonary disease. Circulation. Cardiovascular imagingCirculation. Cardiovascular imaging 2015;8Abstract

BACKGROUND:Chronic obstructive pulmonary disease causes significant morbidity and concomitant pulmonary vascular disease and cardiac dysfunction are associated with poor prognosis. Computed tomography-detected relative pulmonary artery (PA) enlargement defined as a PA to ascending aorta diameter ratio >1 (PA:A>1) is a marker for pulmonary hypertension and predicts chronic obstructive pulmonary disease exacerbations. However, little is known about the relationship between the PA:A ratio, pulmonary blood volume, and cardiac function.METHODS AND RESULTS:A single-center prospective cohort study of patients with chronic obstructive pulmonary disease was conducted. Clinical characteristics and computed tomography metrics, including the PA:A and pulmonary blood vessel volume, were measured. Ventricular functions, volumes, and dimensions were measured by cine cardiac MRI with 3-dimensional analysis. Linear regression examined the relationships between clinical characteristics, computed tomography and cardiac MRI metrics, and 6-minute walk distance. Twenty-four patients were evaluated and those with PA:A>1 had higher right ventricular (RV) end-diastolic and end-systolic volume indices accompanied by lower RV ejection fraction (52±7% versus 60±9%; P=0.04). The PA:A correlated inversely with total intraparenchymal pulmonary blood vessel volume and the volume of distal vessels with a cross-sectional area of <5 mm(2). Lower forced expiratory volume, PA:A>1, and hyperinflation correlated with reduced RV ejection fraction. Both PA diameter and reduced RV ejection fraction were independently associated with reduced 6-minute walk distance.CONCLUSIONS:The loss of blood volume in distal pulmonary vessels is associated with PA enlargement on computed tomography. Cardiac MRI detects early RV dysfunction and remodeling in nonsevere chronic obstructive pulmonary disease patients with a PA:A>1. Both RV dysfunction and PA enlargement are independently associated with reduced walk distance.CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT00608764.

Diaz AA, Rahaghi FN, Ross JC, Harmouche R, Tschirren J, San Jose Estépar R, Washko GR. Understanding the contribution of native tracheobronchial structure to lung function: CT assessment of airway morphology in never smokers. Respiratory researchRespiratory research 2015;16:23.Abstract

BACKGROUND:Computed tomographic (CT) airway lumen narrowing is associated with lower lung function. Although volumetric CT measures of airways (wall volume [WV] and lumen volume [LV]) compared to cross sectional measures can more accurately reflect bronchial morphology, data of their use in never smokers is scarce. We hypothesize that native tracheobronchial tree morphology as assessed by volumetric CT metrics play a significant role in determining lung function in normal subjects. We aimed to assess the relationships between airway size, the projected branching generation number (BGN) to reach airways of <2mm lumen diameter -the site for airflow obstruction in smokers- and measures of lung function including forced expiratory volume in 1 second (FEV1) and forced expiratory flow between 25% and 75% of vital capacity (FEF 25-75).METHODS:We assessed WV and LV of segmental and subsegmental airways from six bronchial paths as well as lung volume on CT scans from 106 never smokers. We calculated the lumen area ratio of the subsegmental to segmental airways and estimated the projected BGN to reach a <2mm-lumen-diameter airway assuming a dichotomized tracheobronchial tree model. Regression analysis was used to assess the relationships between airway size, BGN, FEF 25-75, and FEV1.RESULTS:We found that in models adjusted for demographics, LV and WV of segmental and subsegmental airways were directly related to FEV1 (P <0.05 for all the models). In adjusted models for age, sex, race, LV and lung volume or height, the projected BGN was directly associated with FEF 25-75 and FEV1 (P=0.001) where subjects with lower FEV1 had fewer calculated branch generations between the subsegmental bronchus and small airways. There was no association between airway lumen area ratio and lung volume.CONCLUSION:We conclude that in never smokers, those with smaller central airways had lower airflow and those with lower airflow had less parallel airway pathways independent of lung size. These findings suggest that variability in the structure of the tracheobronchial tree may influence the risk of developing clinically relevant smoking related airway obstruction.

Paper
Castaldi PJ, Cho MH, Zhou X, Qiu W, McGeachie M, Celli B, Bakke P, Gulsvik A, Lomas DA, Crapo JD, Beaty TH, Rennard S, Harshfield B, Lange C, Singh D, Tal-Singer R, Riley JH, Quackenbush J, Raby BA, Carey VJ, Silverman EK, Hersh CP. Genetic control of gene expression at novel and established chronic obstructive pulmonary disease loci. Hum Mol Genet 2015;24(4):1200-10.Abstract

Genetic risk loci have been identified for a wide range of diseases through genome-wide association studies (GWAS), but the relevant functional mechanisms have been identified for only a small proportion of these GWAS-identified loci. By integrating results from the largest current GWAS of chronic obstructive disease (COPD) with expression quantitative trait locus (eQTL) analysis in whole blood and sputum from 121 subjects with COPD from the ECLIPSE Study, this analysis identifies loci that are simultaneously associated with COPD and the expression of nearby genes (COPD eQTLs). After integrative analysis, 19 COPD eQTLs were identified, including all four previously identified genome-wide significant loci near HHIP, FAM13A, and the 15q25 and 19q13 loci. For each COPD eQTL, fine mapping and colocalization analysis to identify causal shared eQTL and GWAS variants identified a subset of sites with moderate-to-strong evidence of harboring at least one shared variant responsible for both the eQTL and GWAS signals. Transcription factor binding site (TFBS) analysis confirms that multiple COPD eQTL lead SNPs disrupt TFBS, and enhancer enrichment analysis for loci with the strongest colocalization signals showed enrichment for blood-related cell types (CD3 and CD4+ T cells, lymphoblastoid cell lines). In summary, integrative eQTL and GWAS analysis confirms that genetic control of gene expression plays a key role in the genetic architecture of COPD and identifies specific blood-related cell types as likely participants in the functional pathway from GWAS-associated variant to disease phenotype.

Kalhan R, Cuttica MJ, Colangelo LA, Shah SJ, Lima J, Kishi S, Arynchyn A, Jacobs DR, Thyagarajan B, Liu K, Lloyd-Jones D. Loss of Lung Health from Young Adulthood and Cardiac Phenotypes in Middle Age. Am J Respir Crit Care Med 2015;192(1):76-85.Abstract

RATIONALE: Chronic lung diseases are associated with cardiovascular disease. How these associations evolve from young adulthood forward is unknown. Understanding the preclinical history of these associations could inform prevention strategies for common heart-lung conditions. OBJECTIVES: To use the Coronary Artery Risk Development in Young Adults (CARDIA) study to explore the development of heart-lung interactions. METHODS: We analyzed cardiac structural and functional measurements determined by echocardiography at Year 25 of CARDIA and measures of pulmonary function over 20 years in 3,000 participants. MEASUREMENTS AND MAIN RESULTS: Decline in FVC from peak was associated with larger left ventricular mass (β = 6.05 g per SD of FVC decline; P < 0.0001) and greater cardiac output (β = 0.109 L/min per SD of FVC decline; P = 0.001). Decline in FEV1/FVC ratio was associated with smaller left atrial internal dimension (β = -0.038 cm per SD FEV1/FVC decline; P < 0.0001) and lower cardiac output (β = -0.070 L/min per SD of FEV1/FVC decline; P = 0.03). Decline in FVC was associated with diastolic dysfunction (odds ratio, 3.39; 95% confidence interval, 1.37-8.36; P = 0.006). CONCLUSIONS: Patterns of loss of lung health are associated with specific cardiovascular phenotypes in middle age. Decline in FEV1/FVC ratio is associated with underfilling of the left heart and low cardiac output. Decline in FVC with preserved FEV1/FVC ratio is associated with left ventricular hypertrophy and diastolic dysfunction. Cardiopulmonary interactions apparent with common complex heart and lung diseases evolve concurrently from early adulthood forward.

Wells MJ, Iyer AS, Rahaghi FN, Bhatt SP, Gupta H, Denney TS, Lloyd SG, Dell'Italia LJ, Nath H, Estepar RSJ, Washko GR, Dransfield MT. Pulmonary artery enlargement is associated with right ventricular dysfunction and loss of blood volume in small pulmonary vessels in chronic obstructive pulmonary disease. Circ Cardiovasc Imaging 2015;8(4)Abstract
BACKGROUND: Chronic obstructive pulmonary disease causes significant morbidity and concomitant pulmonary vascular disease and cardiac dysfunction are associated with poor prognosis. Computed tomography-detected relative pulmonary artery (PA) enlargement defined as a PA to ascending aorta diameter ratio >1 (PA:A>1) is a marker for pulmonary hypertension and predicts chronic obstructive pulmonary disease exacerbations. However, little is known about the relationship between the PA:A ratio, pulmonary blood volume, and cardiac function. METHODS AND RESULTS: A single-center prospective cohort study of patients with chronic obstructive pulmonary disease was conducted. Clinical characteristics and computed tomography metrics, including the PA:A and pulmonary blood vessel volume, were measured. Ventricular functions, volumes, and dimensions were measured by cine cardiac MRI with 3-dimensional analysis. Linear regression examined the relationships between clinical characteristics, computed tomography and cardiac MRI metrics, and 6-minute walk distance. Twenty-four patients were evaluated and those with PA:A>1 had higher right ventricular (RV) end-diastolic and end-systolic volume indices accompanied by lower RV ejection fraction (52±7% versus 60±9%; P=0.04). The PA:A correlated inversely with total intraparenchymal pulmonary blood vessel volume and the volume of distal vessels with a cross-sectional area of <5 mm(2). Lower forced expiratory volume, PA:A>1, and hyperinflation correlated with reduced RV ejection fraction. Both PA diameter and reduced RV ejection fraction were independently associated with reduced 6-minute walk distance. CONCLUSIONS: The loss of blood volume in distal pulmonary vessels is associated with PA enlargement on computed tomography. Cardiac MRI detects early RV dysfunction and remodeling in nonsevere chronic obstructive pulmonary disease patients with a PA:A>1. Both RV dysfunction and PA enlargement are independently associated with reduced walk distance. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00608764.
2014
Kim V, Desai P, Newell JD, Make BJ, Washko GR, Silverman EK, Crapo JD, Bhatt SP, Criner GJ. Airway wall thickness is increased in COPD patients with bronchodilator responsiveness. Respir Res 2014;15:84.Abstract
RATIONALE: Bronchodilator responsiveness (BDR) is a common but variable phenomenon in COPD. The CT characteristics of airway dimensions that differentiate COPD subjects with BDR from those without BDR have not been well described. We aimed to assess airway dimensions in COPD subjects with and without BDR. METHODS: We analyzed subjects with GOLD 1-4 disease in the COPDGene® study who had CT airway analysis. We divided patients into two groups: BDR + (post bronchodilator ΔFEV1 ≥ 10%) and BDR-(post bronchodilator ΔFEV1 < 10%). The mean wall area percent (WA%) of six segmental bronchi in each subject was quantified using VIDA. Using 3D SLICER, airway wall thickness was also expressed as the square root wall area of an airway of 10 mm (Pi10) and 15 mm (Pi15) diameter. %Emphysema and %gas trapping were also calculated. RESULTS: 2355 subjects in the BDR-group and 1306 in the BDR + group formed our analysis. The BDR + group had a greater Pi10, Pi15, and mean segmental WA% compared to the BDR-group. In multivariate logistic regression using gender, race, current smoking, history of asthma, %emphysema, %gas trapping, %predicted FEV1, and %predicted FVC, airway wall measures remained independent predictors of BDR. Using a threshold change in FEV1 ≥ 15% and FEV1 ≥ 12% and 200 mL to divide patients into groups, the results were similar. CONCLUSION: BDR in COPD is independently associated with CT evidence of airway pathology. This study provides us with greater evidence of changes in lung structure that correlate with physiologic manifestations of airflow obstruction in COPD.
Freeman CM, McCubbrey AL, Crudgington S, Nelson J, Martinez FJ, Han MLK, Washko GR, Chensue SW, Arenberg DA, Meldrum CA, McCloskey L, Curtis JL. Basal gene expression by lung CD4+ T cells in chronic obstructive pulmonary disease identifies independent molecular correlates of airflow obstruction and emphysema extent. PLoS One 2014;9(5):e96421.Abstract
UNLABELLED: Lung CD4+ T cells accumulate as chronic obstructive pulmonary disease (COPD) progresses, but their role in pathogenesis remains controversial. To address this controversy, we studied lung tissue from 53 subjects undergoing clinically-indicated resections, lung volume reduction, or transplant. Viable single-cell suspensions were analyzed by flow cytometry or underwent CD4+ T cell isolation, followed either by stimulation with anti-CD3 and cytokine/chemokine measurement, or by real-time PCR analysis. In lung CD4+ T cells of most COPD subjects, relative to lung CD4+ T cells in smokers with normal spirometry: (a) stimulation induced minimal IFN-γ or other inflammatory mediators, but many subjects produced more CCL2; (b) the T effector memory subset was less uniformly predominant, without correlation with decreased IFN-γ production. Analysis of unstimulated lung CD4+ T cells of all subjects identified a molecular phenotype, mainly in COPD, characterized by markedly reduced mRNA transcripts for the transcription factors controlling TH1, TH2, TH17 and FOXP3+ T regulatory subsets and their signature cytokines. This mRNA-defined CD4+ T cell phenotype did not result from global inability to elaborate mRNA; increased transcripts for inhibitory CD28 family members or markers of anergy; or reduced telomerase length. As a group, these subjects had significantly worse spirometry, but not DLCO, relative to subjects whose lung CD4+ T cells expressed a variety of transcripts. Analysis of mRNA transcripts of unstimulated lung CD4+ T cell among all subjects identified two distinct molecular correlates of classical COPD clinical phenotypes: basal IL-10 transcripts correlated independently and inversely with emphysema extent (but not spirometry); by contrast, unstimulated IFN-γ transcripts correlated independently and inversely with reduced spirometry (but not reduced DLCO or emphysema extent). Aberrant lung CD4+ T cells polarization appears to be common in advanced COPD, but also exists in some smokers with normal spirometry, and may contribute to development and progression of specific COPD phenotypes. TRIAL REGISTRATION: ClinicalTrials.gov as NCT00281229.
Rahaghi FN, van Beek EJR, Washko GR. Cardiopulmonary coupling in chronic obstructive pulmonary disease: the role of imaging. J Thorac Imaging 2014;29(2):80-91.Abstract
Chronic obstructive pulmonary disorder (COPD) is a systemic disease that affects the cardiovascular system through multiple pathways. Pulmonary hypertension, ventricular dysfunction, and atherosclerosis are associated with smoking and COPD, causing significant morbidity and poor prognosis. Coupling between the pulmonary and cardiovascular system involves mechanical interdependence and inflammatory pathways that potentially affect the entire circulation. Although treatments specific for COPD-related cardiovascular and pulmonary vascular disease are limited, early diagnosis, study of pathophysiology, and monitoring the effects of treatment are enhanced with improved imaging techniques. In this article, we review recent advancements in the imaging of the vasculature and the heart in patients with COPD. We also explore the potential mechanism of coupling between the progression of COPD and vascular disease. Imaging methods reviewed include specific implementations of computed tomography, magnetic resonance imaging, dual-energy computed tomography, positron emission tomography, and echocardiography. Specific applications to the proximal and distal pulmonary vasculature, as well as to the heart and systemic circulation, are also discussed.
Diaz AA, Hardin ME, Come CE, San José Estépar R, Ross JC, Kurugol S, Okajima Y, Han MLK, Kim V, Ramsdell J, Silverman EK, Crapo JD, Lynch DA, Make B, Barr GR, Hersh CP, Washko GR. Childhood-onset asthma in smokers. association between CT measures of airway size, lung function, and chronic airflow obstruction. Ann Am Thorac Soc 2014;11(9):1371-8.Abstract
RATIONALE AND OBJECTIVES: Asthma is associated with chronic airflow obstruction. Our goal was to assess the association of computed tomographic measures of airway wall volume and lumen volume with the FEV1 and chronic airflow obstruction in smokers with childhood-onset asthma. METHODS: We analyzed clinical, lung function, and volumetric computed tomographic airway volume data from 7,266 smokers, including 590 with childhood-onset asthma. Small wall volume and small lumen volume of segmental airways were defined as measures 1 SD below the mean. We assessed the association between small wall volume, small lumen volume, FEV1, and chronic airflow obstruction (post-bronchodilator FEV1/FVC ratio < 0.7) using linear and logistic models. MEASUREMENTS AND MAIN RESULTS: Compared with subjects without childhood-onset asthma, those with childhood-onset asthma had smaller wall volume and lumen volume (P < 0.0001) of segmental airways. Among subjects with childhood-onset asthma, those with the smallest wall volume and lumen volume had the lowest FEV1 and greatest odds of chronic airflow obstruction. A similar tendency was seen in those without childhood-onset asthma. When comparing these two groups, both small wall volume and small lumen volume were more strongly associated with FEV1 and chronic airflow obstruction among subjects with childhood-asthma in multivariate models. CONCLUSION: In smokers with childhood-onset asthma, smaller airways are associated with reduced lung function and chronic airflow obstruction. Clinical trial registered with www.clinicaltrials.gov (NCT00608764).
Castaldi PJ, Dy J, Ross J, Chang Y, Washko GR, Curran-Everett D, Williams A, Lynch DA, Make BJ, Crapo JD, Bowler RP, Regan EA, Hokanson JE, Kinney GL, Han MLK, Soler X, Ramsdell JW, Barr GR, Foreman M, van Beek E, Casaburi R, Criner GJ, Lutz SM, Rennard SI, Santorico S, Sciurba FC, DeMeo DL, Hersh CP, Silverman EK, Cho MH. Cluster analysis in the COPDGene study identifies subtypes of smokers with distinct patterns of airway disease and emphysema. Thorax 2014;69(5):415-22.Abstract
BACKGROUND: There is notable heterogeneity in the clinical presentation of patients with COPD. To characterise this heterogeneity, we sought to identify subgroups of smokers by applying cluster analysis to data from the COPDGene study. METHODS: We applied a clustering method, k-means, to data from 10 192 smokers in the COPDGene study. After splitting the sample into a training and validation set, we evaluated three sets of input features across a range of k (user-specified number of clusters). Stable solutions were tested for association with four COPD-related measures and five genetic variants previously associated with COPD at genome-wide significance. The results were confirmed in the validation set. FINDINGS: We identified four clusters that can be characterised as (1) relatively resistant smokers (ie, no/mild obstruction and minimal emphysema despite heavy smoking), (2) mild upper zone emphysema-predominant, (3) airway disease-predominant and (4) severe emphysema. All clusters are strongly associated with COPD-related clinical characteristics, including exacerbations and dyspnoea (p<0.001). We found strong genetic associations between the mild upper zone emphysema group and rs1980057 near HHIP, and between the severe emphysema group and rs8034191 in the chromosome 15q region (p<0.001). All significant associations were replicated at p<0.05 in the validation sample (12/12 associations with clinical measures and 2/2 genetic associations). INTERPRETATION: Cluster analysis identifies four subgroups of smokers that show robust associations with clinical characteristics of COPD and known COPD-associated genetic variants.
Rudyanto RD, Kerkstra S, van Rikxoort EM, Fetita C, Brillet P-Y, Lefevre C, Xue W, Zhu X, Liang J, Öksüz I, Ünay D, Kadipaşaoğlu K, San José Estépar R, Ross JC, Washko GR, Prieto J-C, Hoyos MH, Orkisz M, Meine H, Hüllebrand M, Stöcker C, Mir FL, Naranjo V, Villanueva E, Staring M, Xiao C, Stoel BC, Fabijanska A, Smistad E, Elster AC, Lindseth F, Foruzan AH, Kiros R, Popuri K, Cobzas D, Jimenez-Carretero D, Santos A, Ledesma-Carbayo MJ, Helmberger M, Urschler M, Pienn M, Bosboom DGH, Campo A, Prokop M, de Jong PA, Ortiz-de-Solorzano C, Muñoz-Barrutia A, van Ginneken B. Comparing algorithms for automated vessel segmentation in computed tomography scans of the lung: the VESSEL12 study. Med Image Anal 2014;18(7):1217-32.Abstract
The VESSEL12 (VESsel SEgmentation in the Lung) challenge objectively compares the performance of different algorithms to identify vessels in thoracic computed tomography (CT) scans. Vessel segmentation is fundamental in computer aided processing of data generated by 3D imaging modalities. As manual vessel segmentation is prohibitively time consuming, any real world application requires some form of automation. Several approaches exist for automated vessel segmentation, but judging their relative merits is difficult due to a lack of standardized evaluation. We present an annotated reference dataset containing 20 CT scans and propose nine categories to perform a comprehensive evaluation of vessel segmentation algorithms from both academia and industry. Twenty algorithms participated in the VESSEL12 challenge, held at International Symposium on Biomedical Imaging (ISBI) 2012. All results have been published at the VESSEL12 website http://vessel12.grand-challenge.org. The challenge remains ongoing and open to new participants. Our three contributions are: (1) an annotated reference dataset available online for evaluation of new algorithms; (2) a quantitative scoring system for objective comparison of algorithms; and (3) performance analysis of the strengths and weaknesses of the various vessel segmentation methods in the presence of various lung diseases.
Bhatt SP, Sieren JC, Dransfield MT, Washko GR, Newell JD, Stinson DS, Zamba GKD, Hoffman EA. Comparison of spirometric thresholds in diagnosing smoking-related airflow obstruction. Thorax 2014;69(5):409-14.Abstract
BACKGROUND: Diagnosis of chronic obstructive pulmonary disease is based on detection of airflow obstruction on spirometry. There is no consensus regarding using a fixed threshold to define airflow obstruction versus using the lower limit of normal (LLN) adjusted for age. We compared the accuracy and discrimination of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommended fixed ratio of forced expiratory volume in the first second/forced vital capacity<0.70 with LLN in diagnosing smoking-related airflow obstruction using CT-defined emphysema and gas trapping as the disease gold standard. METHODS: Data from a large multicentre study (COPDGene), which included current and former smokers (age range 45-80 years) with and without airflow obstruction, were analysed. Concordance between spirometric thresholds was measured. The accuracy of the thresholds in diagnosing emphysema and gas trapping was assessed using quantitative CT as gold standard. RESULTS: 7743 subjects were included. There was very good agreement between the two spirometric cutoffs (κ=0.85; 95% CI 0.83 to 0.86, p<0.001). 7.3% were discordant. Subjects with airflow obstruction by fixed ratio only had a greater degree of emphysema (4.1% versus 1.2%, p<0.001) and gas trapping (19.8% vs 7.5%, p<0.001) than those positive by LLN only, and also smoking controls without airflow obstruction (4.1% vs 1.9% and 19.8% vs 10.9%, respectively, p<0.001). On follow-up, the fixed ratio only group had more exacerbations than smoking controls. CONCLUSIONS: Compared with the fixed ratio, the use of LLN fails to identify a number of patients with significant pulmonary pathology and respiratory morbidity.
Bhatt SP, Washko GR, Dransfield MT, Sieren JC, Newell JD, Hoffman EA. Comparison of spirometric thresholds in diagnosing smoking-related airflow obstruction: authors' response. Thorax 2014;69(12):1147-8.
Doyle TJ, Dellaripa PF, Batra K, Frits ML, Iannaccone CK, Hatabu H, Nishino M, Weinblatt ME, Ascherman DP, Washko GR, Hunninghake GM, Choi AMK, Shadick NA, Rosas IO. Functional impact of a spectrum of interstitial lung abnormalities in rheumatoid arthritis. Chest 2014;146(1):41-50.Abstract
BACKGROUND: Approximately 10% of patients with rheumatoid arthritis (RA) have interstitial lung disease (ILD), and one-third have subclinical ILD on chest CT scan. In this study, we aimed to further characterize functional decrements in a spectrum of RA-associated ILD. METHODS: All subjects were enrolled in the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS). The presence of interstitial lung abnormalities (ILAs) on clinically indicated chest CT scans was determined using a previously validated sequential reading method. Univariate and multivariate analyses were used to assess the association between degree of ILAs and physiologic, functional, and demographic variables of interest. RESULTS: Of 1,145 BRASS subjects, 91 subjects (8%) were included in this study. Twelve had radiologically severe ILAs, 34 had ILAs, and 38 had no ILAs on CT scan. Subjects with radiologically severe ILAs were older (P = .0037), had increased respiratory symptoms (cough, P = .027; dyspnea, P = .010), and more severe RA disease (rheumatoid factor, P = .018; total swollen joints, P = .046) compared with subjects with no ILAs. Participants also had a trend toward having an increased smoking history (P = .16) and having lower FVC % predicted (77% vs 94%, P = .097) and diffusion capacity of carbon monoxide % predicted (52% vs 77%, P = .068). Similar but attenuated increases in respiratory symptoms, functional decrements, and RA disease severity were observed in subjects with ILAs compared with those with no ILAs. CONCLUSIONS: We have shown that patients with RA have varying degrees of ILAs that are associated with a spectrum of functional and physiologic decrements. Our findings suggest that improved risk stratification and detection of ILAs will provide a therapeutic window that could improve RA-ILD outcomes.

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