@article {1433688, title = {Abdominal Visceral Adipose Tissue is Associated with Myocardial Infarction in Patients with COPD}, journal = {Chronic Obstr Pulm Dis}, volume = {2}, number = {1}, year = {2015}, month = {2015}, pages = {8-16}, abstract = {BACKGROUND: Cardiovascular diseases are frequent and a major cause of death in patients with chronic obstructive pulmonary disease (COPD). In the general population, various fat depots including abdominal visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and liver fat have been linked to increased risk of cardiovascular diseases. We hypothesize that these adipose tissue compartments are associated with myocardial infarction (MI) in patients with COPD. METHODS: We collected measures of VAT and SAT areas and liver attenuation on the computed tomography scan of the chest from 1267 patients with COPD. MI was a self-reported physician-diagnosed outcome. The association between fat depots and self-reported history of MI was assessed by logistic regression analysis in which the patients within the 2 lowest tertiles of VAT and SAT areas were the reference group. RESULTS: Eighty three patients (6.6\%) reported a history of MI at the time of enrollment. Compared to patients who did not have an MI episode, those who had a prior MI had a higher VAT area (mean {\textpm} SD, 303.4 {\textpm} 208.5 vs. 226.8 {\textpm} 172.6 cm; P=0.002) with no differences in SAT area and liver fat. After adjustment for age, gender, obesity, pack years of smoking, hypertension, high cholesterol, and diabetes, patients within the upper tertile (vs. those in the lower tertiles) of VAT area had increased odds of MI (odds ratio [OR] 1.86, 95\% confidence interval [CI] 1.02 - 3.41). CONCLUSION: Increased abdominal visceral fat is independently associated with a history of MI in individuals with COPD.}, issn = {2372-952X}, doi = {10.15326/jcopdf.2.1.2014.0127}, author = {Diaz, Alejandro A and Young, Tom P and Kurugol, Sila and Eckbo, Erick and Muralidhar, Nina and Chapman, Joshua K and Kinney, Gregory L and Ross, James C and Estepar, Raul San Jose and Harmouche, Rola and Black-Shinn, Jennifer L and Budoff, Matthew and Bowler, Russell P and Hokanson, John and Washko, George R} } @article {1433689, title = {Anterior Mediastinal Masses in the Framingham Heart Study: Prevalence and CT Image Characteristics}, journal = {Eur J Radiol Open}, volume = {2}, year = {2015}, month = {2015}, pages = {26-31}, abstract = {PURPOSE: To investigate the prevalence and CT image characteristics of anterior mediastinal masses in a population-based cohort and their association with the demographics of the participants. MATERIALS AND METHODS: Chest CT scans of 2571 Framingham Heart Study participants (mean age 58.9 years, 51\% female) were evaluated by two board-certified radiologists with expertise in thoracic imaging for the presence of anterior mediastinal masses, their shape, contour, location, invasion of adjacent structures, fat content, and calcification. For participants with anterior mediastinal masses, a previous cardiac CT scan was reviewed for interval size change of the masses, when available. The demographics of the participants were studied for any association with the presence of anterior mediastinal masses. RESULTS: Of 2571, 23 participants (0.9\%, 95\% CI: 0.6 to 1.3) had anterior mediastinal masses on CT. The most common CT characteristics were oval shape, lobular contour, and midline location, showing soft tissue density (median 32.1 HU). Fat content was detected in a few cases (9\%, 2/23). Six out of eight masses with available prior cardiac CT scans demonstrated an interval growth over a median period of 6.5 years. No risk factors for anterior mediastinal masses were detected among participants{\textquoteright} demographics, including age, sex, BMI, and cigarette smoking. CONCLUSIONS: The prevalence of anterior mediastinal masses is 0.9\% in the Framingham Heart Study. Those masses may increase in size when observed over 5-7 years. Investigation of clinical significance in incidentally found anterior mediastinal masses with a longer period of follow-up would be necessary.}, issn = {2352-0477}, doi = {10.1016/j.ejro.2014.12.003}, author = {Araki, Tetsuro and Nishino, Mizuki and Gao, Wei and Dupuis, Jos{\'e}e and Washko, George R and Hunninghake, Gary M and Murakami, Takamichi and O{\textquoteright}Connor, George T and Hatabu, Hiroto} } @article {1433679, title = {Automated axial right ventricle to left ventricle diameter ratio computation in computed tomography pulmonary angiography}, journal = {PLoS One}, volume = {10}, number = {5}, year = {2015}, month = {2015}, pages = {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{\textpm}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.}, keywords = {Adult, Aged, Aged, 80 and over, Angiography, Female, Heart Ventricles, Humans, Lung, Male, Middle Aged, Predictive Value of Tests, Prognosis, Pulmonary Embolism, Reproducibility of Results, Sensitivity and Specificity, Tomography, X-Ray Computed, Young Adult}, issn = {1932-6203}, doi = {10.1371/journal.pone.0127797}, author = {Gonz{\'a}lez, Germ{\'a}n and Jim{\'e}nez-Carretero, Daniel and Rodr{\'\i}guez-L{\'o}pez, Sara and Kumamaru, Kanako K and George, Elizabeth and San Jos{\'e} Est{\'e}par, Ra{\'u}l and Rybicki, Frank J. and Ledesma-Carbayo, Maria J} } @article {1433666, title = {Automated quantitative 3D analysis of aorta size, morphology, and mural calcification distributions}, journal = {Med Phys}, volume = {42}, number = {9}, year = {2015}, month = {2015 Sep}, pages = {5467-78}, abstract = {PURPOSE: The purpose of this work is to develop a fully automated pipeline to compute aorta morphology and calcification measures in large cohorts of CT scans that can be used to investigate the potential of these measures as imaging biomarkers of cardiovascular disease. METHODS: The first step of the automated pipeline is aorta segmentation. The algorithm the authors propose first detects an initial aorta boundary by exploiting cross-sectional circularity of aorta in axial slices and aortic arch in reformatted oblique slices. This boundary is then refined by a 3D level-set segmentation that evolves the boundary to the location of nearby edges. The authors then detect the aortic calcifications with thresholding and filter out the false positive regions due to nearby high intensity structures based on their anatomical location. The authors extract the centerline and oblique cross sections of the segmented aortas and compute the aorta morphology and calcification measures of the first 2500 subjects from COPDGene study. These measures include volume and number of calcified plaques and measures of vessel morphology such as average cross-sectional area, tortuosity, and arch width. RESULTS: The authors computed the agreement between the algorithm and expert segmentations on 45 CT scans and obtained a closest point mean error of 0.62 {\textpm} 0.09 mm and a Dice coefficient of 0.92 {\textpm} 0.01. The calcification detection algorithm resulted in an improved true positive detection rate of 0.96 compared to previous work. The measurements of aorta size agreed with the measurements reported in previous work. The initial results showed associations of aorta morphology with calcification and with aging. These results may indicate aorta stiffening and unwrapping with calcification and aging. CONCLUSIONS: The authors have developed an objective tool to assess aorta morphology and aortic calcium plaques on CT scans that may be used to provide information about the presence of cardiovascular disease and its clinical impact in smokers.}, keywords = {Aged, Aged, 80 and over, Algorithms, Aorta, Aortography, Automation, Calcinosis, Cohort Studies, Female, Humans, Imaging, Three-Dimensional, Male, Middle Aged, Tomography, X-Ray Computed}, issn = {2473-4209}, doi = {10.1118/1.4924500}, author = {Kurugol, Sila and Come, Carolyn E and Diaz, Alejandro A and Ross, James C and Kinney, Greg L and Black-Shinn, Jennifer L and Hokanson, John E and Budoff, Matthew J and Washko, George R and Estepar, Raul San Jose} } @article {1433670, title = {Chest computed tomography for phenotying chronic obstructive pulmonary disease. A pathway and a challenge for personalized medicine}, journal = {Ann Am Thorac Soc}, volume = {12}, number = {7}, year = {2015}, month = {2015 Jul}, pages = {966-7}, keywords = {Airway Remodeling, Dyspnea, Emphysema, Hospitalization, Humans, Male, Pulmonary Disease, Chronic Obstructive}, issn = {2325-6621}, doi = {10.1513/AnnalsATS.201504-239ED}, author = {Washko, George R} } @article {1433668, title = {Chronic Bronchitis Is Associated With Worse Symptoms and Quality of Life Than Chronic Airflow Obstruction}, journal = {Chest}, volume = {148}, number = {2}, year = {2015}, month = {2015 Aug}, pages = {408-416}, abstract = {BACKGROUND: COPD includes the chronic bronchitis (CB) and emphysema phenotypes. Although it is generally assumed that emphysema or chronic airflow obstruction (CAO) is associated with worse quality of life (QOL) than is CB, this assumption has not been tested. METHODS: The current study{\textquoteright}s analyses from the Lovelace Smokers{\textquoteright} Cohort (LSC) were validated in the COPD Gene Cohort (COPDGene). CB without CAO (CB only) was defined as self-reported cough productive of phlegm for >= 3 mo/y for 2 consecutive years and postbronchodilator FEV1/FVC >= 70\%. CAO without CB (CAO only) was defined as a postbronchodilator FEV1/FVC < 70\% with no evidence of CB. QOL outcomes were obtained from the St. George{\textquoteright}s Respiratory Questionnaire (SGRQ) and the 36-Item Short Form Health Survey (SF-36) questionnaires. A priori covariates included age, sex, pack-years of smoking, current smoking, and FEV1. RESULTS: Smokers with CB without CAO (LSC = 341; COPDGene = 523) were younger and had a greater BMI and less smoking exposure than did those with CAO only (LSC = 302; COPDGene = 2,208). Compared with the latter group, QOL scores were worse for those with CB only. Despite similar SGRQ Activity and SF-36 Role Physical and Physical Functioning, SGRQ Symptoms and Impact scores and SF-36 emotional and social measures were worse in the CB-only group, in both cohorts. After adjustment for covariates, the CB-only group remained a significant predictor for "worse" symptoms and emotional and social measures. CONCLUSIONS: To our knowledge, this analysis is the first to suggest that among subjects with COPD, those with CB only present worse QOL symptoms and mental well-being than do those with CAO only.}, keywords = {Activities of Daily Living, Adult, Aged, Bronchitis, Chronic, Cohort Studies, Female, Forced Expiratory Volume, Humans, Male, Middle Aged, Pulmonary Disease, Chronic Obstructive, Quality of Life, Severity of Illness Index}, issn = {1931-3543}, doi = {10.1378/chest.14-2240}, author = {Meek, Paula M and Petersen, Hans and Washko, George R and Diaz, Alejandro A and Klm, Victor and Sood, Akshay and Tesfaigzi, Yohannes} } @article {1433665, title = {Clinical and Radiologic Disease in Smokers With Normal Spirometry}, journal = {JAMA Intern Med}, volume = {175}, number = {9}, year = {2015}, month = {2015 Sep}, pages = {1539-49}, abstract = {IMPORTANCE: Airflow obstruction on spirometry is universally used to define chronic obstructive pulmonary disease (COPD), and current or former smokers without airflow obstruction may assume that they are disease free. OBJECTIVE: To identify clinical and radiologic evidence of smoking-related disease in a cohort of current and former smokers who did not meet spirometric criteria for COPD, for whom we adopted the discarded label of Global Initiative for Obstructive Lung Disease (GOLD) 0. DESIGN, SETTING, AND PARTICIPANTS: Individuals from the Genetic Epidemiology of COPD (COPDGene) cross-sectional observational study completed spirometry, chest computed tomography (CT) scans, a 6-minute walk, and questionnaires. Participants were recruited from local communities at 21 sites across the United States. The GOLD 0 group (n = 4388) (ratio of forced expiratory volume in the first second of expiration [FEV1] to forced vital capacity >0.7 and FEV1 >=80\% predicted) from the COPDGene study was compared with a GOLD 1 group (n = 794), COPD groups (n = 3690), and a group of never smokers (n = 108). Recruitment began in January 2008 and ended in July 2011. MAIN OUTCOMES AND MEASURES: Physical function impairments, respiratory symptoms, CT abnormalities, use of respiratory medications, and reduced respiratory-specific quality of life. RESULTS: One or more respiratory-related impairments were found in 54.1\% (2375 of 4388) of the GOLD 0 group. The GOLD 0 group had worse quality of life (mean [SD] St George{\textquoteright}s Respiratory Questionnaire total score, 17.0 [18.0] vs 3.8 [6.8] for the never smokers; P , keywords = {Aged, Case-Control Studies, Cross-Sectional Studies, Exercise Tolerance, Female, Humans, Male, Middle Aged, Nutrition Surveys, Pulmonary Disease, Chronic Obstructive, Quality of Life, Radiography, Thoracic, Smoking, Spirometry, Tomography, X-Ray Computed, United States}, issn = {2168-6114}, doi = {10.1001/jamainternmed.2015.2735}, author = {Regan, Elizabeth A and Lynch, David A and Curran-Everett, Douglas and Curtis, Jeffrey L and Austin, John H M and Grenier, Philippe A and Kauczor, Hans-Ulrich and Bailey, William C and DeMeo, Dawn L and Casaburi, Richard H and Friedman, Paul and van Beek, Edwin J R and Hokanson, John E and Bowler, Russell P and Beaty, Terri H and Washko, George R and Han, MeiLan K and Kim, Victor and Kim, Song Soo and Yagihashi, Kunihiro and Washington, Lacey and McEvoy, Charlene E and Tanner, Clint and Mannino, David M and Make, Barry J and Silverman, Edwin K and Crapo, James D} } @article {1433662, title = {A comparison of visual and quantitative methods to identify interstitial lung abnormalities}, journal = {BMC Pulm Med}, volume = {15}, year = {2015}, month = {2015 Oct 29}, pages = {134}, abstract = {BACKGROUND: Evidence suggests that individuals with interstitial lung abnormalities (ILA) on a chest computed tomogram (CT) may have an increased risk to develop a clinically significant interstitial lung disease (ILD). Although methods used to identify individuals with ILA on chest CT have included both automated quantitative and qualitative visual inspection methods, there has been not direct comparison between these two methods. To investigate this relationship, we created lung density metrics and compared these to visual assessments of ILA. METHODS: To provide a comparison between ILA detection methods based on visual assessment we generated measures of high attenuation areas (HAAs, defined by attenuation values between -600 and -250 Hounsfield Units) in >4500 participants from both the COPDGene and Framingham Heart studies (FHS). Linear and logistic regressions were used for analyses. RESULTS: Increased measures of HAAs (in >= 10 \% of the lung) were significantly associated with ILA defined by visual inspection in both cohorts (P < 0.0001); however, the positive predictive values were not very high (19 \% in COPDGene and 13 \% in the FHS). In COPDGene, the association between HAAs and ILA defined by visual assessment were modified by the percentage of emphysema and body mass index. Although increased HAAs were associated with reductions in total lung capacity in both cohorts, there was no evidence for an association between measurement of HAAs and MUC5B promoter genotype in the FHS. CONCLUSION: Our findings demonstrate that increased measures of lung density may be helpful in determining the severity of lung volume reduction, but alone, are not strongly predictive of ILA defined by visual assessment. Moreover, HAAs were not associated with MUC5B promoter genotype.}, keywords = {Aged, Aged, 80 and over, Body Mass Index, Cohort Studies, Female, Forced Expiratory Volume, Humans, Image Processing, Computer-Assisted, Linear Models, Logistic Models, Lung, Lung Diseases, Interstitial, Male, Middle Aged, Mucin-5B, Promoter Regions, Genetic, Pulmonary Disease, Chronic Obstructive, Pulmonary Emphysema, Spirometry, Tomography, X-Ray Computed, Total Lung Capacity, Vital Capacity}, issn = {1471-2466}, doi = {10.1186/s12890-015-0124-x}, author = {Kliment, Corrine R and Araki, Tetsuro and Doyle, Tracy J and Gao, Wei and Dupuis, Jos{\'e}e and Latourelle, Jeanne C and Zazueta, Oscar E and Fernandez, Isis E and Nishino, Mizuki and Okajima, Yuka and Ross, James C and San Jos{\'e} Est{\'e}par, Ra{\'u}l and Diaz, Alejandro A and Lederer, David J and Schwartz, David A and Silverman, Edwin K and Rosas, Ivan O and Washko, George R and O{\textquoteright}Connor, George T and Hatabu, Hiroto and Hunninghake, Gary M} } @article {1433669, title = {CT Scanning in COPD - Is it Time to Move On?}, journal = {Chronic Obstr Pulm Dis}, volume = {2}, number = {3}, year = {2015}, month = {2015 Jul 14}, pages = {201-203}, issn = {2372-952X}, doi = {10.15326/jcopdf.2.3.2015.0150}, author = {Come, Carolyn E and Washko, George R} } @article {1433675, title = {Detection of Rheumatoid Arthritis-Interstitial Lung Disease Is Enhanced by Serum Biomarkers}, journal = {Am J Respir Crit Care Med}, volume = {191}, number = {12}, year = {2015}, month = {2015 Jun 15}, pages = {1403-12}, abstract = {RATIONALE: Interstitial lung disease (ILD), a leading cause of morbidity and mortality in rheumatoid arthritis (RA), is highly prevalent, yet RA-ILD is underrecognized. OBJECTIVES: To identify clinical risk factors, autoantibodies, and biomarkers associated with the presence of RA-ILD. METHODS: Subjects enrolled in Brigham and Women{\textquoteright}s Hospital Rheumatoid Arthritis Sequential Study (BRASS) and American College of Rheumatology (ACR) cohorts were evaluated for ILD. Regression models were used to assess the association between variables of interest and RA-ILD. Receiver operating characteristic curves were generated in BRASS to determine if a combination of clinical risk factors and autoantibodies can identify RA-ILD and if the addition of investigational biomarkers is informative. This combinatorial signature was subsequently tested in ACR. MEASUREMENTS AND MAIN RESULTS: A total of 113 BRASS subjects with clinically indicated chest computed tomography scans (41\% with a spectrum of clinically evident and subclinical RA-ILD) and 76 ACR subjects with research or clinical scans (51\% with a spectrum of RA-ILD) were selected. A combination of age, sex, smoking, rheumatoid factor, and anticyclic citrullinated peptide antibodies was strongly associated with RA-ILD (areas under the curve, 0.88 for BRASS and 0.89 for ACR). Importantly, a combinatorial signature including matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly increased the areas under the curve to 0.97 (P = 0.002, BRASS) and 1.00 (P = 0.016, ACR). Similar trends were seen for both clinically evident and subclinical RA-ILD. CONCLUSIONS: Clinical risk factors and autoantibodies are strongly associated with the presence of clinically evident and subclinical RA-ILD on computed tomography scan in two independent RA cohorts. A biomarker signature composed of matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly strengthens this association. These findings may facilitate identification of RA-ILD at an earlier stage, potentially leading to decreased morbidity and mortality.}, keywords = {Age Factors, Aged, Area Under Curve, Arthritis, Rheumatoid, Autoantibodies, Biomarkers, Chemokines, Cohort Studies, Enzyme-Linked Immunosorbent Assay, Female, Humans, Lung Diseases, Interstitial, Male, Matrix Metalloproteinase 7, Middle Aged, Prospective Studies, Pulmonary Surfactant-Associated Protein D, Risk Factors, ROC Curve, Sex Factors}, issn = {1535-4970}, doi = {10.1164/rccm.201411-1950OC}, author = {Doyle, Tracy J and Patel, Avignat S and Hatabu, Hiroto and Nishino, Mizuki and Wu, Guodong and Osorio, Juan C and Golzarri, Maria F and Traslosheros, Andres and Chu, Sarah G and Frits, Michelle L and Iannaccone, Christine K and Koontz, Diane and Fuhrman, Carl and Weinblatt, Michael E and El-Chemaly, Souheil Y and Washko, George R and Hunninghake, Gary M and Choi, Augustine M K and Dellaripa, Paul F and Oddis, Chester V and Shadick, Nancy A and Ascherman, Dana P and Rosas, Ivan O} } @article {1433661, title = {Effects of Mild Chronic Obstructive Pulmonary Disease on Gas Exchange during Cycling and Walking}, journal = {Am J Respir Crit Care Med}, volume = {192}, number = {9}, year = {2015}, month = {2015 Nov 01}, pages = {1137-8}, keywords = {Dyspnea, Exercise, Exercise Test, Female, Humans, Male, Pulmonary Disease, Chronic Obstructive, Pulmonary Gas Exchange}, issn = {1535-4970}, doi = {10.1164/rccm.201507-1361LE}, author = {Diaz, Alejandro A and Diaz, Orlando} } @article {1433673, title = {Emphysema and DLCO predict a clinically important difference for 6MWD decline in COPD}, journal = {Respir Med}, volume = {109}, number = {7}, year = {2015}, month = {2015 Jul}, pages = {882-9}, abstract = {BACKGROUND: Exercise impairment is a central feature of chronic obstructive pulmonary disease (COPD), and a minimal clinically important difference (MCID) for 6-min walk distance (6MWD) decline (>30~m) has been associated with increased mortality. The predictors of the MCID are not fully known. We hypothesize that physiological factors and radiographic measures predict the MCID. METHODS: We assessed 121 COPD subjects during 2 years using clinical variables, computed tomographic (CT) measures of emphysema, and functional measures including diffusion lung capacity for carbon monoxide (DLCO). The association between an MCID for 6MWD and clinical, CT, and physiologic predictors was assessed using logistic analysis. The C-statistic was used to assess the predictive ability of the models. RESULTS: Forty seven (39\%) subjects had an MCID. In an imaging-based model, log emphysema and age were the best predictors of MCID (emphysema Odds Ratio [OR] 2.47 95\%CI [1.28-4.76]). In a physiologic model, DLCO, age, and male gender were selected the best predictors (DLCO OR 1.19 [1.08-1.31]). The C-statistic for the ability of these models to predict an MCID was 0.71 and 0.75, respectively. CONCLUSION: In COPD patients the burden of emphysema on CT scan and DLCO predict a clinically meaningful decline in exercise capacity.}, keywords = {Aged, Carbon Monoxide, Exercise Tolerance, Female, Follow-Up Studies, Forced Expiratory Volume, Humans, Male, Middle Aged, Prognosis, Pulmonary Diffusing Capacity, Pulmonary Disease, Chronic Obstructive, Pulmonary Emphysema, Tomography, X-Ray Computed, Walking}, issn = {1532-3064}, doi = {10.1016/j.rmed.2015.04.009}, author = {D{\'\i}az, Alejandro A and Pinto-Plata, Victor and Hern{\'a}ndez, Camila and Pe{\~n}a, Javier and Ramos, Crist{\'o}bal and D{\'\i}az, Juan C and Klaassen, Julieta and Patino, Cecilia M and Sald{\'\i}as, Fernando and D{\'\i}az, Orlando} } @article {1433690, title = {A Feature-Based Approach to Big Data Analysis of Medical Images}, journal = {Inf Process Med Imaging}, volume = {24}, year = {2015}, month = {2015}, pages = {339-50}, 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.}, keywords = {Algorithms, Data Interpretation, Statistical, Databases, Factual, Humans, Imaging, Three-Dimensional, Information Storage and Retrieval, Lung, Pattern Recognition, Automated, Pulmonary Disease, Chronic Obstructive, Radiographic Image Enhancement, Radiographic Image Interpretation, Computer-Assisted, Reproducibility of Results, Sensitivity and Specificity, Tomography, X-Ray Computed}, issn = {1011-2499}, author = {Toews, Matthew and Wachinger, Christian and Estepar, Raul San Jose and Wells, William M} } @article {1433691, title = {Generative Method to Discover Genetically Driven Image Biomarkers}, journal = {Inf Process Med Imaging}, volume = {24}, year = {2015}, month = {2015}, pages = {30-42}, 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 common 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 generative 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 Pulmonary Disease (COPD) to characterize the relationship between image and genetic signatures of COPD subtypes in a large patient cohort.}, keywords = {Algorithms, Biomarkers, Computer Simulation, Genetic Markers, Genetic Predisposition to Disease, Genetic Testing, Humans, Models, Statistical, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive, Radiographic Image Interpretation, Computer-Assisted, Reproducibility of Results, Sensitivity and Specificity, Tomography, X-Ray Computed}, issn = {1011-2499}, author = {Batmanghelich, Nematollah K and Saeedi, Ardavan and Cho, Michael and Estepar, Raul San Jose and Golland, Polina} } @article {1433663, title = {A Genome-Wide Association Study of Emphysema and Airway Quantitative Imaging Phenotypes}, journal = {Am J Respir Crit Care Med}, volume = {192}, number = {5}, year = {2015}, month = {2015 Sep 01}, pages = {559-69}, abstract = {RATIONALE: Chronic obstructive pulmonary disease (COPD) is defined by the presence of airflow limitation on spirometry, yet subjects with COPD can have marked differences in computed tomography imaging. These differences may be driven by genetic factors. We hypothesized that a genome-wide association study (GWAS) 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. OBJECTIVES: To identify genetic determinants of quantitative imaging phenotypes. METHODS: We performed a GWAS on two quantitative emphysema and two quantitative airway imaging phenotypes in the COPDGene (non-Hispanic white and African American), ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints), NETT (National Emphysema Treatment Trial), and GenKOLS (Genetics of COPD, Norway) studies and on percentage gas trapping in COPDGene. We also examined specific loci reported as genome-wide significant for spirometric phenotypes related to airflow limitation or COPD. MEASUREMENTS AND MAIN RESULTS: The total sample size across all cohorts was 12,031, of whom 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 , keywords = {Aged, Carrier Proteins, Cohort Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, GTPase-Activating Proteins, Humans, Image Processing, Computer-Assisted, Iron Regulatory Protein 2, Longitudinal Studies, Lung, Male, Membrane Glycoproteins, Middle Aged, Nerve Tissue Proteins, Phenotype, Pulmonary Disease, Chronic Obstructive, Pulmonary Emphysema, Receptor for Advanced Glycation End Products, Receptors, Nicotinic, Serpins, Tomography, X-Ray Computed, Tumor Suppressor Proteins}, issn = {1535-4970}, doi = {10.1164/rccm.201501-0148OC}, author = {Cho, Michael H and Castaldi, Peter J and Hersh, Craig P and Hobbs, Brian D and Barr, R Graham and Tal-Singer, Ruth and Bakke, Per and Gulsvik, Amund and San Jos{\'e} Est{\'e}par, Ra{\'u}l and van Beek, Edwin J R and Coxson, Harvey O and Lynch, David A and Washko, George R and Laird, Nan M and Crapo, James D and Beaty, Terri H and Silverman, Edwin K} } @article {1433683, title = {Imaging to predict therapeutic outcomes}, journal = {Am J Respir Crit Care Med}, volume = {191}, number = {7}, year = {2015}, month = {2015 Apr 01}, pages = {724-5}, keywords = {Female, Humans, Male, Pneumonectomy, Pulmonary Emphysema, Pulmonary Valve, Tomography, X-Ray Computed}, issn = {1535-4970}, doi = {10.1164/rccm.201502-0285ED}, author = {Washko, George R} } @article {1433685, title = {Long-term exposure to traffic emissions and fine particulate matter and lung function decline in the Framingham heart study}, journal = {Am J Respir Crit Care Med}, volume = {191}, number = {6}, year = {2015}, month = {2015 Mar 15}, pages = {656-64}, abstract = {RATIONALE: Few studies have examined associations between long-term exposure to fine particulate matter (PM2.5) and lung function decline in adults. OBJECTIVES: To determine if exposure to traffic and PM2.5 is associated with longitudinal changes in lung function in a population-based cohort in the Northeastern United States, where pollution levels are relatively low. METHODS: FEV1 and FVC were measured up to two times between 1995 and 2011 among 6,339 participants of the Framingham Offspring or Third Generation studies. We tested associations between residential proximity to a major roadway and PM2.5 exposure in 2001 (estimated by a land-use model using satellite measurements of aerosol optical thickness) and lung function. We examined differences in average lung function using mixed-effects models and differences in lung function decline using linear regression models. Current smokers were excluded. Models were adjusted for age, sex, height, weight, pack-years, socioeconomic status indicators, cohort, time, season, and weather. MEASUREMENTS AND MAIN RESULTS: Living less than 100 m from a major roadway was associated with a 23.2 ml (95\% confidence interval [CI], -44.4 to -1.9) lower FEV1 and a 5.0 ml/yr (95\% CI, -9.0 to -0.9) faster decline in FEV1 compared with more than 400 m. Each 2 μg/m(3) increase in average of PM2.5 was associated with a 13.5 ml (95\% CI, -26.6 to -0.3) lower FEV1 and a 2.1 ml/yr (95\% CI, -4.1 to -0.2) faster decline in FEV1. There were similar associations with FVC. Associations with FEV1/FVC ratio were weak or absent. CONCLUSIONS: Long-term exposure to traffic and PM2.5, at relatively low levels, was associated with lower FEV1 and FVC and an accelerated rate of lung function decline.}, keywords = {Environmental Exposure, Female, Forced Expiratory Volume, Humans, Longitudinal Studies, Lung, Male, Middle Aged, Models, Statistical, particulate matter, Residence Characteristics, Vehicle Emissions, Vital Capacity}, issn = {1535-4970}, doi = {10.1164/rccm.201410-1875OC}, author = {Rice, Mary B and Ljungman, Petter L and Wilker, Elissa H and Dorans, Kirsten S and Gold, Diane R and Schwartz, Joel and Koutrakis, Petros and Washko, George R and O{\textquoteright}Connor, George T and Mittleman, Murray A} } @article {1433681, title = {Lung Cancer Workshop XI: Tobacco-Induced Disease: Advances in Policy, Early Detection and Management}, journal = {J Thorac Oncol}, volume = {10}, number = {5}, year = {2015}, month = {2015 May}, pages = {762-7}, abstract = {The Prevent Cancer Foundation Lung Cancer Workshop XI: Tobacco-Induced Disease: Advances in Policy, Early Detection and Management was held in New York, NY on May 16 and 17, 2014. The two goals of the Workshop were to define strategies to drive innovation in precompetitive quantitative research on the use of imaging to assess new therapies for management of early lung cancer and to discuss a process to implement a national program to provide high quality computed tomography imaging for lung cancer and other tobacco-induced disease. With the central importance of computed tomography imaging for both early detection and volumetric lung cancer assessment, strategic issues around the development of imaging and ensuring its quality are critical to ensure continued progress against this most lethal cancer. }, keywords = {Breast Neoplasms, Coronary Vessels, Early Detection of Cancer, Female, Health Policy, Humans, Lung Neoplasms, Male, Radiation Dosage, Smoking, Tomography, X-Ray Computed, Vascular Calcification}, issn = {1556-1380}, doi = {10.1097/JTO.0000000000000489}, author = {Mulshine, James L and Avila, Rick and Yankelevitz, David and Baer, Thomas M and Est{\'e}par, Raul San Jose and Ambrose, Laurie Fenton and Aldig{\'e}, Carolyn R} } @article {1433687, title = {Morphologic Response of the Pulmonary Vasculature to Endoscopic Lung Volume Reduction}, journal = {Chronic Obstr Pulm Dis}, volume = {2}, number = {3}, year = {2015}, month = {2015}, pages = {214-222}, abstract = {INTRODUCTION: Endoscopic Lung Volume Reduction has been used to reduce lung hyperinflation in selected patients with severe emphysema. Little is known about the effect of this procedure on the intraparenchymal pulmonary vasculature. In this study we used CT based vascular reconstruction to quantify the effect of the procedure on the pulmonary vasculature. METHODS: Intraparenchymal vasculature was reconstructed and quantified in 12 patients with CT scans at baseline and 12 weeks following bilateral introduction of sealants in the upper lobes. The volume of each lung and each lobe was measured, and the vascular volume profile was calculated for both lower lobes. The detected vasculature was further labeled manually as arterial or venous in the right lower lobe. RESULTS: There was an increase in the volume of the lower lobes (3.14L to 3.25L, p=0.0005). There was an increase in BV5, defined as the volume of blood vessels with cross sectional area of less than 5mm2, (53.2ml to 57.9ml, p=0.03). This was found to be correlated with the increase in lower lobe volumes (R=0.65, p=0.02). The changes appear to be symmetric for veins and arteries with a correlation coefficient of 0.87 and a slope of near identity. CONCLUSION: In the subjects studied, there was an increase, from baseline, in BV5 in the lower lobes that correlated with the change in the volume of the lower lobes. The change appeared to be symmetric for both arteries and veins. The study illustrates the use of intraparenchymal pulmonary vascular reconstruction to study morphologic changes in response to interventions.}, issn = {2372-952X}, doi = {10.15326/jcopdf.2.3.2014.0164}, author = {Rahaghi, Farbod N and Come, Carolyn E and Ross, James and Harmouche, Rola and Diaz, Alejandro A and Estepar, Raul San Jose and Washko, George} } @article {1433684, title = {An official American Thoracic Society/European Respiratory Society statement: research questions in COPD}, journal = {Eur Respir J}, volume = {45}, number = {4}, year = {2015}, month = {2015 Apr}, pages = {879-905}, abstract = {Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and resource use worldwide. The goal of this official American Thoracic Society (ATS)/European Respiratory Society (ERS) research statement is to describe evidence related to diagnosis, assessment and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. Clinicians, researchers, and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarised, and then salient knowledge gaps were identified. Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. Great strides have been made in the diagnosis, assessment and management of COPD, as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS research statement highlights the types of research that leading clinicians, researchers, and patient advocates believe will have the greatest impact on patient-centred outcomes. }, keywords = {Biomedical Research, Disease Management, Europe, Evidence-Based Medicine, Female, Humans, Male, Practice Guidelines as Topic, Prognosis, Pulmonary Disease, Chronic Obstructive, Societies, Medical, Surveys and Questionnaires, Survival Analysis, United States}, issn = {1399-3003}, doi = {10.1183/09031936.00009015}, author = {Celli, Bartolome R and Decramer, Marc and Wedzicha, Jadwiga A and Wilson, Kevin C and Agust{\'\i}, Alvar and Criner, Gerard J and MacNee, William and Make, Barry J and Rennard, Stephen I and Stockley, Robert A and Vogelmeier, Claus and Anzueto, Antonio and Au, David H and Barnes, Peter J and Burgel, Pierre-Regis and Calverley, Peter M and Casanova, Ciro and Clini, Enrico M and Cooper, Christopher B and Coxson, Harvey O and Dusser, Daniel J and Fabbri, Leonardo M and Fahy, Bonnie and Ferguson, Gary T and Fisher, Andrew and Fletcher, Monica J and Hayot, Maurice and Hurst, John R and Jones, Paul W and Mahler, Donald A and Maltais, Fran{\c c}ois and Mannino, David M and Martinez, Fernando J and Miravitlles, Marc and Meek, Paula M and Papi, Alberto and Rabe, Klaus F and Roche, Nicolas and Sciurba, Frank C and Sethi, Sanjay and Siafakas, Nikos and Sin, Don D and Soriano, Joan B and Stoller, James K and Tashkin, Donald P and Troosters, Thierry and Verleden, Geert M and Verschakelen, Johny and Vestbo, Jorgen and Walsh, John W and Washko, George R and Wise, Robert A and Wouters, Emiel F M and ZuWallack, Richard L} } @article {1433678, title = {An official American Thoracic Society/European Respiratory Society statement: research questions in COPD}, journal = {Eur Respir Rev}, volume = {24}, number = {136}, year = {2015}, month = {2015 Jun}, pages = {159-72}, abstract = {Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality and resource use worldwide. The goal of this official American Thoracic Society (ATS)/European Respiratory Society (ERS) Research Statement is to describe evidence related to diagnosis, assessment, and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. Clinicians, researchers and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarised, and then salient knowledge gaps were identified. Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. Great strides have been made in the diagnosis, assessment and management of COPD, as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS research statement highlights the types of research that leading clinicians, researchers and patient advocates believe will have the greatest impact on patient-centred outcomes. }, keywords = {Biomedical Research, Comorbidity, Consensus, Humans, Lung, Predictive Value of Tests, Pulmonary Disease, Chronic Obstructive, Respiratory Function Tests, Risk Factors, Risk Reduction Behavior, Severity of Illness Index, Treatment Outcome}, issn = {1600-0617}, doi = {10.1183/16000617.00000315}, author = {Celli, Bartolome R and Decramer, Marc and Wedzicha, Jadwiga A and Wilson, Kevin C and Agust{\'\i}, Alvar A and Criner, Gerard J and MacNee, William and Make, Barry J and Rennard, Stephen I and Stockley, Robert A and Vogelmeier, Claus and Anzueto, Antonio and Au, David H and Barnes, Peter J and Burgel, Pierre-Regis and Calverley, Peter M and Casanova, Ciro and Clini, Enrico M and Cooper, Christopher B and Coxson, Harvey O and Dusser, Daniel J and Fabbri, Leonardo M and Fahy, Bonnie and Ferguson, Gary T and Fisher, Andrew and Fletcher, Monica J and Hayot, Maurice and Hurst, John R and Jones, Paul W and Mahler, Donald A and Maltais, Fran{\c c}ois and Mannino, David M and Martinez, Fernando J and Miravitlles, Marc and Meek, Paula M and Papi, Alberto and Rabe, Klaus F and Roche, Nicolas and Sciurba, Frank C and Sethi, Sanjay and Siafakas, Nikos and Sin, Don D and Soriano, Joan B and Stoller, James K and Tashkin, Donald P and Troosters, Thierry and Verleden, Geert M and Verschakelen, Johny and Vestbo, Jorgen and Walsh, John W and Washko, George R and Wise, Robert A and Wouters, Emiel F M and ZuWallack, Richard L} } @article {1433682, title = {An Official American Thoracic Society/European Respiratory Society Statement: Research questions in chronic obstructive pulmonary disease}, journal = {Am J Respir Crit Care Med}, volume = {191}, number = {7}, year = {2015}, month = {2015 Apr 01}, pages = {e4-e27}, abstract = {BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and resource use worldwide. The goal of this Official American Thoracic Society (ATS)/European Respiratory Society (ERS) Research Statement is to describe evidence related to diagnosis, assessment, and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. METHODS: Clinicians, researchers, and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarized, and then salient knowledge gaps were identified. RESULTS: Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. CONCLUSIONS: Great strides have been made in the diagnosis, assessment, and management of COPD as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS Research Statement highlights the types of research that leading clinicians, researchers, and patient advocates believe will have the greatest impact on patient-centered outcomes.}, keywords = {Biomedical Research, Europe, Evidence-Based Medicine, Humans, Organizational Objectives, Policy Making, Pulmonary Disease, Chronic Obstructive, Societies, Medical, United States}, issn = {1535-4970}, doi = {10.1164/rccm.201501-0044ST}, author = {Celli, Bartolome R and Decramer, Marc and Wedzicha, Jadwiga A and Wilson, Kevin C and Agust{\'\i}, Alvar and Criner, Gerard J and MacNee, William and Make, Barry J and Rennard, Stephen I and Stockley, Robert A and Vogelmeier, Claus and Anzueto, Antonio and Au, David H and Barnes, Peter J and Burgel, Pierre-Regis and Calverley, Peter M and Casanova, Ciro and Clini, Enrico M and Cooper, Christopher B and Coxson, Harvey O and Dusser, Daniel J and Fabbri, Leonardo M and Fahy, Bonnie and Ferguson, Gary T and Fisher, Andrew and Fletcher, Monica J and Hayot, Maurice and Hurst, John R and Jones, Paul W and Mahler, Donald A and Maltais, Fran{\c c}ois and Mannino, David M and Martinez, Fernando J and Miravitlles, Marc and Meek, Paula M and Papi, Alberto and Rabe, Klaus F and Roche, Nicolas and Sciurba, Frank C and Sethi, Sanjay and Siafakas, Nikos and Sin, Don D and Soriano, Joan B and Stoller, James K and Tashkin, Donald P and Troosters, Thierry and Verleden, Geert M and Verschakelen, Johny and Vestbo, Jorgen and Walsh, John W and Washko, George R and Wise, Robert A and Wouters, Emiel F M and ZuWallack, Richard L} } @article {1433674, title = {Optimizing parameters of an open-source airway segmentation algorithm using different CT images}, journal = {Biomed Eng Online}, volume = {14}, year = {2015}, month = {2015 Jun 26}, pages = {62}, abstract = {BACKGROUND: Computed tomography (CT) helps physicians locate and diagnose pathological conditions. In some conditions, having an airway segmentation method which facilitates reconstruction of the airway from chest CT images can help hugely in the assessment of lung diseases. Many efforts have been made to develop airway segmentation algorithms, but methods are usually not optimized to be reliable across different CT scan parameters. METHODS: In this paper, we present a simple and reliable semi-automatic algorithm which can segment tracheal and bronchial anatomy using the open-source 3D Slicer platform. The method is based on a region growing approach where trachea, right and left bronchi are cropped and segmented independently using three different thresholds. The algorithm and its parameters have been optimized to be efficient across different CT scan acquisition parameters. The performance of the proposed method has been evaluated on EXACT{\textquoteright}09 cases and local clinical cases as well as on a breathing pig lung phantom using multiple scans and changing parameters. In particular, to investigate multiple scan parameters reconstruction kernel, radiation dose and slice thickness have been considered. Volume, branch count, branch length and leakage presence have been evaluated. A new method for leakage evaluation has been developed and correlation between segmentation metrics and CT acquisition parameters has been considered. RESULTS: All the considered cases have been segmented successfully with good results in terms of leakage presence. Results on clinical data are comparable to other teams{\textquoteright} methods, as obtained by evaluation against the EXACT09 challenge, whereas results obtained from the phantom prove the reliability of the method across multiple CT platforms and acquisition parameters. As expected, slice thickness is the parameter affecting the results the most, whereas reconstruction kernel and radiation dose seem not to particularly affect airway segmentation. CONCLUSION: The system represents the first open-source airway segmentation platform. The quantitative evaluation approach presented represents the first repeatable system evaluation tool for like-for-like comparison between different airway segmentation platforms. Results suggest that the algorithm can be considered stable across multiple CT platforms and acquisition parameters and can be considered as a starting point for the development of a complete airway segmentation algorithm.}, keywords = {Algorithms, Animals, Bronchi, Bronchography, Humans, Image Processing, Computer-Assisted, Respiration, Software, Swine, Tomography, X-Ray Computed, Trachea}, issn = {1475-925X}, doi = {10.1186/s12938-015-0060-2}, author = {Nardelli, Pietro and Khan, Kashif A and Corv{\`o}, Alberto and Moore, Niamh and Murphy, Mary J and Twomey, Maria and O{\textquoteright}Connor, Owen J and Kennedy, Marcus P and San Jos{\'e} Est{\'e}par, Ra{\'u}l and Maher, Michael M and Cantillon-Murphy, P{\'a}draig} } @article {1433672, title = {Paraseptal emphysema: Prevalence and distribution on CT and association with interstitial lung abnormalities}, journal = {Eur J Radiol}, volume = {84}, number = {7}, year = {2015}, month = {2015 Jul}, pages = {1413-8}, abstract = {OBJECTIVE: To investigate the prevalence and distribution of paraseptal emphysema on chest CT images in the Framingham Heart Study (FHS) population, and assess its impact on pulmonary function. Also pursued was the association with interstitial lung abnormalities. MATERIALS AND METHODS: We assessed 2633 participants in the FHS for paraseptal emphysema on chest CT. Characteristics of the participants, including age, sex, smoking status, clinical symptoms, and results of pulmonary function tests, were compared between those with and without paraseptal emphysema. The association between paraseptal emphysema and interstitial lung abnormalities was investigated. RESULTS: Of the 2633 participants, 86 (3\%) had pure paraseptal emphysema (defined as paraseptal emphysema with no other subtypes of emphysema other than paraseptal emphysema or a very few centrilobular emphysema involved) in at least one lung zone. The upper zone of the lungs was almost always involved. Compared to the participants without paraseptal emphysema, those with pure paraseptal emphysema were significantly older, and were more frequently male and smokers (mean 64 years, 71\% male, mean 36 pack-years, P, keywords = {Age Factors, Aged, Carbon Monoxide, Female, Humans, Lung, Male, Middle Aged, Prevalence, Pulmonary Emphysema, Respiratory Function Tests, Sex Factors, Smoking, Tomography, X-Ray Computed}, issn = {1872-7727}, doi = {10.1016/j.ejrad.2015.03.010}, author = {Araki, Tetsuro and Nishino, Mizuki and Zazueta, Oscar E and Gao, Wei and Dupuis, Jos{\'e}e and Okajima, Yuka and Latourelle, Jeanne C and Rosas, Ivan O and Murakami, Takamichi and O{\textquoteright}Connor, George T and Washko, George R and Hunninghake, Gary M and Hatabu, Hiroto} } @article {1433660, title = {Pulmonary cysts identified on chest CT: are they part of aging change or of clinical significance?}, journal = {Thorax}, volume = {70}, number = {12}, year = {2015}, month = {2015 Dec}, pages = {1156-62}, abstract = {OBJECTIVE: To investigate the prevalence and natural course of pulmonary cysts in a population-based cohort and to describe the CT image characteristics in association with participant demographics and pulmonary functions. MATERIALS AND METHODS: Chest CT scans of 2633 participants (mean age 59.2 years; 50\% female) of the Framingham Heart Study (FHS) were visually evaluated for the presence of pulmonary cysts and their image characteristics. These findings were correlated with participant demographics and results of pulmonary function tests as well as the presence of emphysema independently detected on CT. The interval change was investigated by comparison with previous CT scans (median interval 6.1 years). RESULTS: Pulmonary cysts were seen in 7.6\% (95\% CI 6.6\% to 8.7\%; 200/2633). They were not observed in participants younger than 40 years old, and the prevalence increased with age. Multiple cysts (at least five) were seen in 0.9\% of all participants. Participants with pulmonary cysts showed significantly lower body mass index (BMI) (p, keywords = {Adult, Age Factors, Aged, Aged, 80 and over, Aging, Asymptomatic Diseases, Cysts, Female, Humans, Lung Diseases, Male, Middle Aged, Respiratory Function Tests, Tomography, X-Ray Computed}, issn = {1468-3296}, doi = {10.1136/thoraxjnl-2015-207653}, author = {Araki, Tetsuro and Nishino, Mizuki and Gao, Wei and Dupuis, Jos{\'e}e and Putman, Rachel K and Washko, George R and Hunninghake, Gary M and O{\textquoteright}Connor, George T and Hatabu, Hiroto} } @article {1433676, title = {Pulmonary Vessel Cross-sectional Area before and after Liver Transplantation: Quantification with Computed Tomography}, journal = {Acad Radiol}, volume = {22}, number = {6}, year = {2015}, month = {2015 Jun}, pages = {752-9}, abstract = {RATIONALE AND OBJECTIVES: Pulmonary vascular complications of liver disease have a substantial impact on morbidity and mortality in patients who undergo liver transplant. The effect of liver transplantation on the pulmonary vasculature in patients without pulmonary vascular disease, however, has not been described. This study was undertaken to characterize the regional effect of liver transplant on the cross-sectional area (CSA) of pulmonary vessels. MATERIALS AND METHODS: We performed a single-center, retrospective, cohort study of patients who had a liver transplant between 2002 and 2012 and who had chest computed tomography scans within 1 year before and after transplant. Using ImageJ software, we measured the CSA of small pulmonary vessels (0-5 mm(2)) and the total lung CSA to calculate the percent CSA of pulmonary vessels , keywords = {Cohort Studies, Female, Humans, Liver Transplantation, Male, Middle Aged, Pulmonary Artery, Pulmonary Veins, Retrospective Studies, Tomography, X-Ray Computed}, issn = {1878-4046}, doi = {10.1016/j.acra.2015.01.018}, author = {DuBrock, Hilary M and Bankier, Alexander A and Silva, Mario and Litmanovich, Diana E and Curry, Michael P and Washko, George R} } @article {1433664, title = {A randomised trial of lung sealant versus medical therapy for advanced emphysema}, journal = {Eur Respir J}, volume = {46}, number = {3}, year = {2015}, month = {2015 Sep}, pages = {651-62}, abstract = {Uncontrolled pilot studies demonstrated promising results of endoscopic lung volume reduction using emphysematous lung sealant (ELS) in patients with advanced, upper lobe predominant emphysema. We aimed to evaluate the safety and efficacy of ELS in a randomised controlled setting.Patients were randomised to ELS plus medical treatment or medical treatment alone. Despite early termination for business reasons and inability to assess the primary 12-month end-point, 95 out of 300 patients were successfully randomised, providing sufficient data for 3- and 6-month analysis.57 patients (34 treatment and 23 control) had efficacy results at 3 months; 34 (21 treatment and 13 control) at 6 months. In the treatment group, 3-month lung function, dyspnoea, and quality of life improved significantly from baseline when compared to control. Improvements persisted at 6 months with >50\% of treated patients experiencing clinically important improvements, including some whose lung function improved by >100\%. 44\% of treated patients experienced adverse events requiring hospitalisation (2.5-fold more than control, p=0.01), with two deaths in the treated cohort. Treatment responders tended to be those experiencing respiratory adverse events.Despite early termination, results show that minimally invasive ELS may be efficacious, yet significant risks (probably inflammatory) limit its current utility.}, keywords = {Aged, Female, Fibrin Tissue Adhesive, Follow-Up Studies, Humans, Male, Middle Aged, Pneumonectomy, Pulmonary Emphysema, Quality of Life, Respiratory Function Tests, Risk Assessment, Severity of Illness Index, Survival Rate, Time Factors, Tomography, X-Ray Computed, Treatment Outcome}, issn = {1399-3003}, doi = {10.1183/09031936.00205614}, author = {Come, Carolyn E and Kramer, Mordechai R and Dransfield, Mark T and Abu-Hijleh, Muhanned and Berkowitz, David and Bezzi, Michela and Bhatt, Surya P and Boyd, Michael B and Cases, Enrique and Chen, Alexander C and Cooper, Christopher B and Flandes, Javier and Gildea, Thomas and Gotfried, Mark and Hogarth, D Kyle and Kolandaivelu, Kumaran and Leeds, William and Liesching, Timothy and Marchetti, Nathaniel and Marquette, Charles and Mularski, Richard A and Pinto-Plata, Victor M and Pritchett, Michael A and Rafeq, Samaan and Rubio, Edmundo R and Slebos, Dirk-Jan and Stratakos, Grigoris and Sy, Alexander and Tsai, Larry W and Wahidi, Momen and Walsh, John and Wells, J Michael and Whitten, Patrick E and Yusen, Roger and Zulueta, Javier J and Criner, Gerard J and Washko, George R} } @article {1433680, title = {Reduced Bone Density and Vertebral Fractures in Smokers. Men and COPD Patients at Increased Risk}, journal = {Ann Am Thorac Soc}, volume = {12}, number = {5}, year = {2015}, month = {2015 May}, pages = {648-56}, abstract = {RATIONALE: Former smoking history and chronic obstructive pulmonary disease (COPD) are potential risk factors for osteoporosis and fractures. Under existing guidelines for osteoporosis screening, women are included but men are not, and only current smoking is considered. OBJECTIVES: To demonstrate the impact of COPD and smoking history on the risk of osteoporosis and vertebral fracture in men and women. METHODS: Characteristics of participants with low volumetric bone mineral density (vBMD) were identified and related to COPD and other risk factors. We tested associations of sex and COPD with both vBMD and fractures adjusting for age, race, body mass index (BMI), smoking, and glucocorticoid use. MEASUREMENTS AND MAIN RESULTS: vBMD by calibrated quantitative computed tomography (QCT), visually scored vertebral fractures, and severity of lung disease were determined from chest CT scans of 3,321 current and ex-smokers in the COPDGene study. Low vBMD as a surrogate for osteoporosis was calculated from young adult normal values. Male smokers had a small but significantly greater risk of low vBMD (2.5 SD below young adult mean by calibrated QCT) and more fractures than female smokers. Low vBMD was present in 58\% of all subjects, was more frequent in those with worse COPD, and rose to 84\% among subjects with very severe COPD. Vertebral fractures were present in 37\% of all subjects and were associated with lower vBMD at each Global Initiative for Chronic Obstructive Lung Disease stage of severity. Vertebral fractures were most common in the midthoracic region. COPD and especially emphysema were associated with both low vBMD and vertebral fractures after adjustment for steroid use, age, pack-years of smoking, current smoking, and exacerbations. Airway disease was associated with higher bone density after adjustment for other variables. Calibrated QCT identified more subjects with abnormal values than the standard dual-energy X-ray absorptiometry in a subset of subjects and correlated well with prevalent fractures. CONCLUSIONS: Male smokers, with or without COPD, have a significant risk of low vBMD and vertebral fractures. COPD was associated with low vBMD after adjusting for race, sex, BMI, smoking, steroid use, exacerbations, and age. Screening for low vBMD by using QCT in men and women who are smokers will increase opportunities to identify and treat osteoporosis in this at-risk population.}, keywords = {Adult, Bone Density, Female, Humans, Incidence, Male, Middle Aged, Osteoporosis, Pulmonary Disease, Chronic Obstructive, Risk Factors, Smoking, Spinal Fractures, Tomography, X-Ray Computed, United States}, issn = {2325-6621}, doi = {10.1513/AnnalsATS.201412-591OC}, author = {Jaramillo, Joshua D and Wilson, Carla and Stinson, Douglas S and Stinson, Douglas J and Lynch, David A and Bowler, Russell P and Lutz, Sharon and Bon, Jessica M and Arnold, Ben and McDonald, Merry-Lynn N and Washko, George R and Wan, Emily S and DeMeo, Dawn L and Foreman, Marilyn G and Soler, Xavier and Lindsay, Sarah E and Lane, Nancy E and Genant, Harry K and Silverman, Edwin K and Hokanson, John E and Make, Barry J and Crapo, James D and Regan, Elizabeth A} } @article {1433667, title = {Regional Emphysema of a Non-Small Cell Tumor Is Associated with Larger Tumors and Decreased Survival Rates}, journal = {Ann Am Thorac Soc}, volume = {12}, number = {8}, year = {2015}, month = {2015 Aug}, pages = {1197-205}, abstract = {RATIONALE: Chronic obstructive pulmonary disease is associated with a worse overall survival in non-small cell lung cancer. Lung emphysema is one component of chronic obstructive pulmonary disease. We hypothesized that emphysema of the tumor region may result in larger tumors and a poorer overall survival. METHODS: We evaluated 304 cases of non-small cell lung cancer from a prospectively enrolled cohort. The lung was divided into equal volumetric thirds (upper, middle, or lower region). Emphysema was defined as percentage of low-attenuation areas less than -950 Hounsfield units (\%LAA-950) and measured for each region. Whole-lung \%LAA-950 was defined as the emphysema score of the entire lung parenchyma, whereas regional \%LAA-950 was the score within that particular region (upper, middle, or lower). The emphysema score of the region in which the tumor occurred was defined as the tumor \%LAA-950. Tumor diameter was measured while blinded to characteristics of the lung parenchyma. A proportional hazards model was used to control for multiple factors associated with survival. MEASUREMENTS AND MAIN RESULTS: Increasing tumor \%LAA-950 was associated with larger tumors (P = 0.024). Survival, stratified by stage, was significantly worse in those with tumor \%LAA-950 greater than or equal to the 50th percentile versus less than the 50th percentile (P = 0.046). Whole-lung \%LAA-950 and regional \%LAA-950 (e.g., regional emphysema without tumor occurring in the region) were not significantly associated with survival. There were no differences in presenting symptoms or locations of mediastinal or distant metastasis by emphysema score. Increasing tumor \%LAA-950 was associated with an increased risk of death (adjusted hazard ratio, 1.36; confidence interval, 1.09-1.68; P = 0.006) after adjustment for age, sex, smoking status, histology, stage, performance status, chemotherapy, radiation, and surgery. Sensitivity analyses revealed no significant difference in the effect size or test of significance for each of the following conditions: (1) exclusion of cases with central tumor location, (2) exclusion of cases where surgery was performed, (3) exclusion of cases where radiation therapy was performed, (4) exclusion of cases where epidermal growth factor receptor tyrosine kinase inhibitors were administered, and (5) inclusion of only stage IV disease. CONCLUSIONS: Increasing emphysema of the region in which a non-small cell lung cancer tumor occurs is associated with increasing tumor size and worse overall survival.}, keywords = {Aged, Carcinoma, Non-Small-Cell Lung, Female, Humans, Linear Models, Lung, Male, Middle Aged, Proportional Hazards Models, Prospective Studies, Pulmonary Emphysema, Risk Factors, Survival Rate, Tomography, X-Ray Computed}, issn = {2325-6621}, doi = {10.1513/AnnalsATS.201411-539OC}, author = {Kinsey, C Matthew and San Jos{\'e} Est{\'e}par, Ra{\'u}l and Wei, Yongyue and Washko, George R and Christiani, David C} } @article {1433677, title = {The Relationship of Educational Attainment with Pulmonary Emphysema and Airway Wall Thickness}, journal = {Ann Am Thorac Soc}, volume = {12}, number = {6}, year = {2015}, month = {2015 Jun}, pages = {813-20}, abstract = {RATIONALE: Low educational attainment is a risk factor of chronic obstructive pulmonary disease (COPD). There is limited knowledge on the relationship between educational level and computed tomography measures of emphysema and airway wall thickness (AWT). OBJECTIVES: We hypothesized that low educational attainment is associated with increased emphysema and AWT in ever-smokers with and without COPD. METHODS: We included 462 and 485 ever-smokers with and without COPD in a cross-sectional study, aged 40-86 years. The sample was divided into groups reflecting educational attainment: primary, secondary, and university. We performed linear regression to examine associations between educational attainment and both emphysema and AWT separately for those with and without COPD. We adjusted for sex, age, smoking status, age of onset of smoking, pack-years, height, and body mass index. MEASUREMENTS AND MAIN RESULTS: Compared with university education, in subjects with COPD, primary education was associated with a 68.1\% (95\% confidence interval = 14.2-147.6\%; P = 0.01) relative increase in emphysema and secondary education was associated with a 50.6\% (95\% confidence interval = 5.7-114.6\%; P = 0.02) relative increase. There was a nonsignificant trend toward an association between lower educational attainment and increased emphysema among those without COPD (P = 0.18), yet greater age appeared to modify this association (P = 0.01). We did not detect significant linear relationships between educational attainment and AWT in subjects with or without COPD. CONCLUSIONS: Lower educational attainment was associated with increased emphysema among adults with COPD. Among those without COPD, this association was more pronounced with increasing age. No significant linear relationship between educational attainment and AWT was found. Clinicians treating adults with emphysema should keep in mind that factors related to low education beyond that of smoking and occupational dust exposure might be of importance to the disease.}, keywords = {Adult, Age of Onset, Aged, Cross-Sectional Studies, Educational Status, Female, Health Surveys, Humans, Lung, Male, Middle Aged, Norway, Pulmonary Disease, Chronic Obstructive, Pulmonary Emphysema, Risk Factors, Smoking, Spirometry, Statistics as Topic, Tomography, X-Ray Computed}, issn = {2325-6621}, doi = {10.1513/AnnalsATS.201410-485OC}, author = {Gjerdevik, Miriam and Grydeland, Thomas B and Washko, George R and Coxson, Harvey O and Silverman, Edwin K and Gulsvik, Amund and Bakke, Per S} } @article {1433692, title = {Smart stylet: the development and use of a bedside external ventricular drain image-guidance system}, journal = {Stereotact Funct Neurosurg}, volume = {93}, number = {1}, year = {2015}, month = {2015}, pages = {50-8}, abstract = {BACKGROUND: Placement accuracy of ventriculostomy catheters is reported in a wide and variable range. Development of an efficient image-guidance system may improve physician performance and patient safety. OBJECTIVE: We evaluate the prototype of Smart Stylet, a new electromagnetic image-guidance system for use during bedside ventriculostomy. METHODS: Accuracy of the Smart Stylet system was assessed. System operators were evaluated for their ability to successfully target the ipsilateral frontal horn in a phantom model. RESULTS: Target registration error across 15 intracranial targets ranged from 1.3 to 4.6 mm (mean 3.1 mm). Using Smart Stylet guidance, a test operator successfully passed a ventriculostomy catheter to a shifted ipsilateral frontal horn 20/20 (100\%) times from the frontal approach in a skull phantom. Without Smart Stylet guidance, the operator was successful 4/10 (40\%) times from the right frontal approach and 6/10 (60\%) times from the left frontal approach. In a separate experiment, resident operators were successful 2/4 (50\%) times when targeting the shifted ipsilateral frontal horn with Smart Stylet guidance and 0/4 (0\%) times without image guidance using a skull phantom. CONCLUSIONS: Smart Stylet may improve the ability to successfully target the ventricles during frontal ventriculostomy.}, keywords = {Calibration, Catheters, Electromagnetic Phenomena, Equipment Design, Fiducial Markers, Humans, Hydrocephalus, Imaging, Three-Dimensional, In Vitro Techniques, Internship and Residency, Lateral Ventricles, Neuronavigation, Neurosurgery, Phantoms, Imaging, Point-of-Care Systems, Surgery, Computer-Assisted, Tomography, X-Ray Computed, User-Computer Interface, Ventriculostomy}, issn = {1423-0372}, doi = {10.1159/000368906}, author = {Vaibhav Patil and Rajiv Gupta and San Jos{\'e} Est{\'e}par, Ra{\'u}l and Lacson, Ronilda and Cheung, Arnold and Wong, Judith M and Popp, A John and Golby, Alexandra and Ogilvy, Christopher and Kirby G. Vosburgh} } @article {1433671, title = {Socioeconomic Characteristics Are Major Contributors to Ethnic Differences in Health Status in Obstructive Lung Disease: An Analysis of the National Health and Nutrition Examination Survey 2007-2010}, journal = {Chest}, volume = {148}, number = {1}, year = {2015}, month = {2015 Jul}, pages = {151-158}, abstract = {BACKGROUND: Understanding ethnic differences in health status (HS) could help in designing culturally appropriate interventions. We hypothesized that racial and ethnic differences exist in HS between non-Hispanic whites and Mexican Americans with obstructive lung disease (OLD) and that these differences are mediated by socioeconomic factors. METHODS: We analyzed 826 US adults aged >= 30 years self-identified as Mexican American or non-Hispanic white with spirometry-confirmed OLD (FEV$_{1}$/FVC < 0.7) who participated in the National Health and Nutrition Examination Survey 2007-2010. We assessed associations between Mexican American ethnicity and self-reported HS using logistic regression models adjusted for demographics, smoking status, number of comorbidities, limitations for work, and lung function and tested the contribution of education and health-care access to ethnic differences in HS. RESULTS: Among Mexican Americans with OLD, worse (fair or poor) HS was more prevalent than among non-Hispanic whites (weighted percentage [SE], 46.6\% [5.0] vs 15.2\% [1.6]; P < .001). In bivariate analysis, socioeconomic characteristics were associated with lower odds of reporting poor HS (high school graduation: OR, 0.24 [95\% CI, 0.10-0.40]; access to health care: OR, 0.50 [95\% CI, 0.30-0.80]). In fully adjusted models, a strong association was found between Mexican American ethnicity (vs non-Hispanic white) and fair or poor HS (OR, 7.52; 95\% CI, 4.43-12.78; P < .001). Higher education and access to health care contributed to lowering the Mexican American ethnicity odds of fair or poor HS by 47\% and 16\%, respectively, and together, they contributed 55\% to reducing the differences in HS with non-Hispanic whites. CONCLUSIONS: Mexican Americans with OLD report poorer overall HS than non-Hispanic whites, and education and access to health care are large contributors to the difference.}, keywords = {Adult, Aged, Cross-Sectional Studies, European Continental Ancestry Group, Female, Forced Expiratory Volume, Health Status Disparities, Healthcare Disparities, Humans, Logistic Models, Lung Diseases, Obstructive, Male, Mexican Americans, Middle Aged, Nutrition Surveys, Socioeconomic Factors, Spirometry, United States}, issn = {1931-3543}, doi = {10.1378/chest.14-1814}, author = {Martinez, Carlos H and Mannino, David M and Curtis, Jeffrey L and Han, MeiLan K and Diaz, Alejandro A} } @article {1433686, title = {Understanding the contribution of native tracheobronchial structure to lung function: CT assessment of airway morphology in never smokers}, journal = {Respir Res}, volume = {16}, number = {1}, year = {2015}, month = {2015 Feb 14}, pages = {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.}, keywords = {Aged, Bronchi, Bronchography, Female, Forced Expiratory Volume, Humans, Imaging, Three-Dimensional, Lung Volume Measurements, Male, Maximal Midexpiratory Flow Rate, Middle Aged, Multivariate Analysis, Radiographic Image Interpretation, Computer-Assisted, Regression Analysis, Tomography, X-Ray Computed, Total Lung Capacity, Trachea, United States, Vital Capacity}, issn = {1465-993X}, doi = {10.1186/s12931-015-0181-y}, author = {Diaz, Alejandro A and Rahaghi, Farbod N and Ross, James C and Harmouche, Rola and Tschirren, Juerg and San Jos{\'e} Est{\'e}par, Raul and Washko, George R} } @article {1433659, title = {Undiagnosed Obstructive Lung Disease in the United States. Associated Factors and Long-term Mortality}, journal = {Ann Am Thorac Soc}, volume = {12}, number = {12}, year = {2015}, month = {2015 Dec}, pages = {1788-95}, abstract = {RATIONALE: Understanding factors associated with undiagnosed obstructive lung disease and its impact on mortality could inform the ongoing discussions about benefits and risks of screening and case finding. OBJECTIVES: To define factors associated with undiagnosed obstructive lung disease and its long-term mortality. METHODS: Cross-sectional analysis of participants, aged 20 to 79 years, in two National Health and Nutritional Examination Surveys (NHANES), NHANES III (1988-1994) and NHANES 2007-2012, with longitudinal follow-up of NHANES III participants. MEASUREMENTS AND MAIN RESULTS: We classified participants with spirometry-confirmed obstructive disease, based on the fixed ratio definition (FEV1/FVC < 0.7), as "diagnosed" (physician diagnosis of either asthma or chronic obstructive pulmonary disease), and "undiagnosed" (no recorded physician diagnosis). For the longitudinal analysis of NHANES III participants, mortality was the outcome of interest. We tested the contribution of self-reported health status and comorbidity burden (exposure) to the odds of being undiagnosed using logistic models adjusted for demographics, smoking status, and lung function. We estimated hazard ratios (HRs) for all-cause mortality for diagnosed and undiagnosed subjects participating in NHANES III who had spirometry using Cox- proportional regression analysis. Among those with spirometry-defined obstruction, 71.2\% (SE, 1.8) in NHANES III and 72.0\% (SE, 1.9) in NHANES 2007-2012 were undiagnosed. In multivariate models, undiagnosed obstructive disease was consistently associated in both surveys with self-reported good/excellent health status, lower comorbidity burden, higher lung function, and being of racial/ethnic minority. Among NHANES III participants (median follow up, 14.5 yr), both undiagnosed (HR, 1.23; 95\% confidence interval, 1.08-1.40) and correctly diagnosed participants (HR, 1.74; 95\% confidence interval, 1.45-2.09) had higher risk for all-cause mortality than participants without obstruction. CONCLUSIONS: Undiagnosed obstructive lung disease is common among American adults and remained unchanged over 2 decades. Although undiagnosed subjects appear healthier than those with a diagnosis, their risk of death was increased compared with subjects without obstruction. These findings need to be considered when judging the implications of case-finding programs for obstructive lung disease.}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Child, Cross-Sectional Studies, Diagnostic Errors, Female, Follow-Up Studies, Health Status, Humans, Male, Middle Aged, Nutrition Surveys, Prevalence, Pulmonary Disease, Chronic Obstructive, Risk Factors, Spirometry, Survival Rate, Time Factors, Tomography, X-Ray Computed, United States, Young Adult}, issn = {2325-6621}, doi = {10.1513/AnnalsATS.201506-388OC}, author = {Martinez, Carlos H and Mannino, David M and Jaimes, Fabian A and Curtis, Jeffrey L and Han, MeiLan K and Hansel, Nadia N and Diaz, Alejandro A} } @article {472956, title = {Lung Cancer Workshop XI}, journal = {Journal of Thoracic OncologyJournal of Thoracic Oncology}, volume = {10}, year = {2015}, month = {Jun}, pages = {762-767}, abstract = {The Prevent Cancer Foundation Lung Cancer Workshop XI: Tobacco-Induced Disease: Advances in Policy, Early Detection and Management was held in New York, NY on May 16 and 17, 2014. The two goals of the Workshop were to define strategies to drive innovation in precompetitive quantitative research on the use of imaging to assess new therapies for management of early lung cancer and to discuss a process to implement a national program to provide high quality computed tomography imaging for lung cancer and other tobacco-induced disease. With the central importance of computed tomography imaging for both early detection and volumetric lung cancer assessment, strategic issues around the development of imaging and ensuring its quality are critical to ensure continued progress against this most lethal cancer.}, author = {Mulshine, James L and Avila, Rick and Yankelevitz, David and Baer, Thomas M and San Jose Est{\'e}par, Ra{\'u}l and Ambrose, Laurie Fenton and Aldige, Carolyn R} } @article {472931, title = {Regional Emphysema of a Non-Small Cell Tumor Is Associated with Larger Tumors and Decreased Survival}, journal = {Annals ATSAnnals ATS}, year = {2015}, month = {Jul 03}, publisher = {American Thoracic Society - AJRCCM}, abstract = {RATIONALE:COPD is associated with a worse overall survival in NSCLC. Lung emphysema is one component of COPD. We hypothesized that emphysema of the tumor region may result in larger tumors and a poorer overall survival.METHODS:We evaluated 304 cases of NSCLC from a prospectively enrolled cohort. The lung was divided into equal volumetric thirds (upper, middle, or lower region). Emphysema was defined as percentage of low attenuation areas less than -950 Hounsfield units (\%LAA-950) and measured for each region. Whole-lung \%LAA-950 was defined as the emphysema score of the entire lung parenchyma while regional \%LAA-950 was the score within that particular region (upper, middle, or lower). The emphysema score of the region in which the tumor occurred was defined as the tumor \%LAA-950. Tumor diameter was measured while blinded to characteristics of the lung parenchyma. A proportional hazards model was used to control for multiple factors associated with survival.RESULTS:Increasing tumor \%LAA-950 was associated with larger tumors (P=0.024). Survival, stratified by stage, was significantly worse in those with tumor \%LAA-950 greater than or equal to the 50th percentile vs. less than the 50th percentile (P=0.046). Whole-lung \%LAA-950 and regional \%LAA-950 (e.g. regional emphysema without tumor occurring in the region) were not significantly associated with survival. There were no differences in presenting symptoms or locations of mediastinal or distant metastasis by emphysema score. Increasing tumor \%LAA-950 was associated with an increased risk of death (HRadj 1.36 [1.09, 1.68], P=0.006) after adjustment for age, sex, smoking status, histology, stage, performance status, chemotherapy, radiation, and surgery. Sensitivity analyses revealed no significant difference in the effect size or test of significance for each of the following conditions: 1) exclusion of cases with central tumor location, 2) exclusion of cases where surgery was performed, 3) exclusion of cases where radiation therapy was performed, 4) exclusion of cases where epidermal growth factor receptor tyrosine kinase inhibitors were administered, and 5) inclusion of only stage IV disease.CONCLUSIONS:Increasing emphysema of the region in which a NSCLC tumor occurs is associated with increasing tumor size and worse overall survival.}, author = {Kinsey, C Matthew and San Jose Est{\'e}par, Ra{\'u}l and Wei, Yongyue and Washko, George R and Christiani, David C} } @article {472976, title = {Smart stylet: the development and use of a bedside external ventricular drain image-guidance system.}, journal = {Stereotactic and functional neurosurgeryStereotactic and functional neurosurgery}, volume = {93}, year = {2015}, pages = {50-58}, abstract = {BACKGROUND:Placement accuracy of ventriculostomy catheters is reported in a wide and variable range. Development of an efficient image-guidance system may improve physician performance and patient safety.OBJECTIVE:We evaluate the prototype of Smart Stylet, a new electromagnetic image-guidance system for use during bedside ventriculostomy.METHODS:Accuracy of the Smart Stylet system was assessed. System operators were evaluated for their ability to successfully target the ipsilateral frontal horn in a phantom model.RESULTS:Target registration error across 15 intracranial targets ranged from 1.3 to 4.6 mm (mean 3.1 mm). Using Smart Stylet guidance, a test operator successfully passed a ventriculostomy catheter to a shifted ipsilateral frontal horn 20/20 (100\%) times from the frontal approach in a skull phantom. Without Smart Stylet guidance, the operator was successful 4/10 (40\%) times from the right frontal approach and 6/10 (60\%) times from the left frontal approach. In a separate experiment, resident operators were successful 2/4 (50\%) times when targeting the shifted ipsilateral frontal horn with Smart Stylet guidance and 0/4 (0\%) times without image guidance using a skull phantom.CONCLUSIONS:Smart Stylet may improve the ability to successfully target the ventricles during frontal ventriculostomy. {\textcopyright} 2015 S. Karger AG, Basel.}, author = {Vaibhav Patil and Rajiv Gupta and San Jose Est{\'e}par, Ra{\'u}l and Lacson, Ronilda and Cheung, Arnold and Wong, Judith M and Popp, A John and Golby, Alexandra and Ogilvy, Christopher and Kirby G. Vosburgh} } @article {472986, title = {Abdominal Visceral Adipose Tissue is Associated with Myocardial Infarction in Patients with COPD.}, journal = {Chronic obstructive pulmonary diseases (Miami, Fla.)Chronic obstructive pulmonary diseases (Miami, Fla.)}, volume = {2}, year = {2015}, pages = {8-16}, abstract = {BACKGROUND:Cardiovascular diseases are frequent and a major cause of death in patients with chronic obstructive pulmonary disease (COPD). In the general population, various fat depots including abdominal visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and liver fat have been linked to increased risk of cardiovascular diseases. We hypothesize that these adipose tissue compartments are associated with myocardial infarction (MI) in patients with COPD.METHODS:We collected measures of VAT and SAT areas and liver attenuation on the computed tomography scan of the chest from 1267 patients with COPD. MI was a self-reported physician-diagnosed outcome. The association between fat depots and self-reported history of MI was assessed by logistic regression analysis in which the patients within the 2 lowest tertiles of VAT and SAT areas were the reference group.RESULTS:Eighty three patients (6.6\%) reported a history of MI at the time of enrollment. Compared to patients who did not have an MI episode, those who had a prior MI had a higher VAT area (mean {\textpm} SD, 303.4 {\textpm} 208.5 vs. 226.8 {\textpm} 172.6 cm(2); P=0.002) with no differences in SAT area and liver fat. After adjustment for age, gender, obesity, pack years of smoking, hypertension, high cholesterol, and diabetes, patients within the upper tertile (vs. those in the lower tertiles) of VAT area had increased odds of MI (odds ratio [OR] 1.86, 95\% confidence interval [CI] 1.02 - 3.41).CONCLUSION:Increased abdominal visceral fat is independently associated with a history of MI in individuals with COPD.}, author = {Diaz, Alejandro A and Young, Tom P and Kurugol, Sila and Eckbo, Erick and Muralidhar, Nina and Chapman, Joshua K and Kinney, Gregory L and Ross, James C and San Jose Est{\'e}par, Ra{\'u}l and Harmouche, Rola and Black-Shinn, Jennifer L and Budoff, Matthew and Bowler, Russell P and Hokanson, John and Washko, George R and COPDGene investigators} } @article {472981, title = {Automated axial right ventricle to left ventricle diameter ratio computation in computed tomography pulmonary angiography.}, journal = {PloS onePloS one}, volume = {10}, year = {2015}, pages = {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{\textpm}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.}, author = {Gonz{\'a}lez, Germ{\'a}n and Jimenez-Carretero, Daniel and Rodr{\'\i}guez-L{\'o}pez, Sara and Kumamaru, Kanako K and George, Elizabeth and San Jose Est{\'e}par, Ra{\'u}l and Rybicki, Frank J. and Ledesma-Carbayo, Maria J} } @article {472941, title = {A Feature-Based Approach to Big Data Analysis of Medical Imaging}, journal = {Information processing in medical imaging : proceedings of the ... conferenceInformation processing in medical imaging : proceedings of the ... conference}, volume = {24}, year = {2015}, month = {Jul}, pages = {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.}, author = {Toews, Matthew and Wachinger, Christian and San Jose Est{\'e}par, Ra{\'u}l and Wells, William M}, editor = {Ourselin, S{\'e}bastien and Alexander, Daniel C and Westin, Carl-Frederik and Cardoso, M Jorge} } @article {472946, title = {Generative Method to Discover Genetically Driven Image Biomarkers}, journal = {Information processing in medical imaging : proceedings of the ... conferenceInformation processing in medical imaging : proceedings of the ... conference}, volume = {24}, year = {2015}, month = {Jul}, pages = {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.\  }, author = {Batmanghelich, Nematollah K and Saeedi, Ardavan and Cho, Michael H and San Jose Est{\'e}par, Ra{\'u}l and Golland, Polina}, editor = {Ourselin, S{\'e}bastien and Alexander, Daniel C and Westin, Carl-Frederik and Cardoso, M Jorge} } @article {472936, title = {A Genome-wide Association Study of Emphysema and Airway Quantitative Imaging Phenotypes}, journal = {American journal of respiratory and critical care medicineAmerican journal of respiratory and critical care medicine}, year = {2015}, month = {Jul 01}, publisher = {American Thoracic Society - AJRCCM}, 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. .}, author = {Cho, Michael H and Castaldi, Peter J and Hersh, Craig P and Hobbs, Brian D and Barr, R Graham and Tal-Singer, Ruth and Bakke, Per and Gulsvik, Amund and San Jose Est{\'e}par, Ra{\'u}l and van Beek, Edwin J R and Coxson, Harvey O and Lynch, David A and Washko, George R and Laird, Nan M and Crapo, James D and Beaty, Terri H and Silverman, Edwin K} } @article {472951, title = {Multi-atlas and label fusion approach for patient-specific MRI based skull estimation}, journal = {Magnetic Resonance in MedicineMagnetic Resonance in Medicine}, year = {2015}, month = {Jun 18}, pages = {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 {\textpm} 6.99\%), a clinical CT-MR dataset (maximum overlap of 78.31 {\textpm} 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. {\textcopyright} 2015 Wiley Periodicals, Inc.}, author = {Torrado-Carvajal, Angel and Herraiz, Joaquin L and Hernandez-Tamames, Juan A and San Jose Est{\'e}par, Ra{\'u}l and Eryaman, Yigitcan and Rozenholc, Yves and Adalsteinsson, Elfar and Wald, Lawrence L and Malpica, Norberto} } @report {472971, title = {Providing Guidance on Lung Cancer Screening to Patients and Physicians}, year = {2015}, institution = {American Lung Association}, author = {Samet, Jonathan and Crowell, Richard and San Jose Est{\'e}par, Ra{\'u}l and McKee, Andrea B and Mulshine, James L and Powe, Neil and Rand, Cynthia and Yung, Rex} } @article {472961, title = {Pulmonary artery enlargement is associated with right ventricular dysfunction and loss of blood volume in small pulmonary vessels in chronic obstructive pulmonary disease.}, journal = {Circulation. Cardiovascular imagingCirculation. Cardiovascular imaging}, volume = {8}, year = {2015}, month = {May}, 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{\textpm}7\% versus 60{\textpm}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.}, author = {Wells, J Michael and Iyer, Anand S and Rahaghi, Farbod N and Bhatt, Surya P and Gupta, Himanshu and Denney, Thomas S and Lloyd, Steven G and Dell\'Italia, Louis J and Nath, Hrudaya and San Jose Est{\'e}par, Ra{\'u}l and Washko, George R and Dransfield, Mark T} } @article {472966, title = {Understanding the contribution of native tracheobronchial structure to lung function: CT assessment of airway morphology in never smokers}, journal = {Respiratory researchRespiratory research}, volume = {16}, year = {2015}, month = {Mar}, pages = {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.}, author = {Diaz, Alejandro A and Rahaghi, Farbod N and Ross, James C and Harmouche, Rola and Tschirren, Juerg and San Jose Est{\'e}par, Ra{\'u}l and Washko, George R} } @article {470066, title = {Genetic control of gene expression at novel and established chronic obstructive pulmonary disease loci.}, journal = {Hum Mol Genet}, volume = {24}, number = {4}, year = {2015}, month = {2015 Feb 15}, pages = {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.}, issn = {1460-2083}, doi = {10.1093/hmg/ddu525}, author = {Castaldi, Peter J and Cho, Michael H and Zhou, Xiaobo and Qiu, Weiliang and McGeachie, Michael and Celli, Bartolome and Bakke, Per and Gulsvik, Amund and Lomas, David A and Crapo, James D and Beaty, Terri H and Rennard, Stephen and Harshfield, Benjamin and Lange, Christoph and Singh, Dave and Tal-Singer, Ruth and Riley, John H and Quackenbush, John and Raby, Benjamin A and Carey, Vincent J and Silverman, Edwin K and Hersh, Craig P} } @article {470311, title = {Loss of Lung Health from Young Adulthood and Cardiac Phenotypes in Middle Age.}, journal = {Am J Respir Crit Care Med}, volume = {192}, number = {1}, year = {2015}, month = {2015 Jul 1}, pages = {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.}, issn = {1535-4970}, doi = {10.1164/rccm.201501-0116OC}, author = {Kalhan, Ravi and Cuttica, Michael J and Colangelo, Laura A and Shah, Sanjiv J and Lima, Joao and Kishi, Satoru and Arynchyn, Alexander and Jacobs, David R and Thyagarajan, Bharat and Liu, Kiang and Lloyd-Jones, Donald} } @article {450451, title = {Pulmonary artery enlargement is associated with right ventricular dysfunction and loss of blood volume in small pulmonary vessels in chronic obstructive pulmonary disease}, journal = {Circ Cardiovasc Imaging}, volume = {8}, number = {4}, year = {2015}, month = {2015 Apr}, 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{\textpm}7\% versus 60{\textpm}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.}, keywords = {Aged, Blood Volume, Female, Humans, Hypertension, Pulmonary, Magnetic Resonance Imaging, Male, Middle Aged, Pulmonary Artery, Pulmonary Disease, Chronic Obstructive, Ventricular Dysfunction, Right}, issn = {1942-0080}, doi = {10.1161/CIRCIMAGING.114.002546}, author = {Wells, J Michael and Iyer, Anand S and Rahaghi, Farbod N and Bhatt, Surya P and Gupta, Himanshu and Denney, Thomas S and Lloyd, Steven G and Dell{\textquoteright}Italia, Louis J and Nath, Hrudaya and Estepar, Raul San Jose and Washko, George R and Dransfield, Mark T} }