Publications

2015
Kinsey MC, San José Estépar R, Wei Y, Washko GR, Christiani DC. Regional Emphysema of a Non-Small Cell Tumor Is Associated with Larger Tumors and Decreased Survival Rates. Ann Am Thorac Soc 2015;12(8):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.
Gjerdevik M, Grydeland TB, Washko GR, Coxson HO, Silverman EK, Gulsvik A, Bakke PS. The Relationship of Educational Attainment with Pulmonary Emphysema and Airway Wall Thickness. Ann Am Thorac Soc 2015;12(6):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.
Patil V, Gupta R, San José Estépar R, Lacson R, Cheung A, Wong JM, Popp JA, Golby A, Ogilvy C, Vosburgh KG. Smart stylet: the development and use of a bedside external ventricular drain image-guidance system. Stereotact Funct Neurosurg 2015;93(1):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.
Martinez CH, Mannino DM, Curtis JL, Han MLK, Diaz AA. 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. Chest 2015;148(1):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 (FEV₁/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.
Diaz AA, Rahaghi FN, Ross JC, Harmouche R, Tschirren J, San José Estépar R, Washko GR. Understanding the contribution of native tracheobronchial structure to lung function: CT assessment of airway morphology in never smokers. Respir Res 2015;16:23.Abstract
BACKGROUND: Computed tomographic (CT) airway lumen narrowing is associated with lower lung function. Although volumetric CT measures of airways (wall volume [WV] and lumen volume [LV]) compared to cross sectional measures can more accurately reflect bronchial morphology, data of their use in never smokers is scarce. We hypothesize that native tracheobronchial tree morphology as assessed by volumetric CT metrics play a significant role in determining lung function in normal subjects. We aimed to assess the relationships between airway size, the projected branching generation number (BGN) to reach airways of <2mm lumen diameter -the site for airflow obstruction in smokers- and measures of lung function including forced expiratory volume in 1 second (FEV1) and forced expiratory flow between 25% and 75% of vital capacity (FEF 25-75). METHODS: We assessed WV and LV of segmental and subsegmental airways from six bronchial paths as well as lung volume on CT scans from 106 never smokers. We calculated the lumen area ratio of the subsegmental to segmental airways and estimated the projected BGN to reach a <2mm-lumen-diameter airway assuming a dichotomized tracheobronchial tree model. Regression analysis was used to assess the relationships between airway size, BGN, FEF 25-75, and FEV1. RESULTS: We found that in models adjusted for demographics, LV and WV of segmental and subsegmental airways were directly related to FEV1 (P <0.05 for all the models). In adjusted models for age, sex, race, LV and lung volume or height, the projected BGN was directly associated with FEF 25-75 and FEV1 (P = 0.001) where subjects with lower FEV1 had fewer calculated branch generations between the subsegmental bronchus and small airways. There was no association between airway lumen area ratio and lung volume. CONCLUSION: We conclude that in never smokers, those with smaller central airways had lower airflow and those with lower airflow had less parallel airway pathways independent of lung size. These findings suggest that variability in the structure of the tracheobronchial tree may influence the risk of developing clinically relevant smoking related airway obstruction.
Martinez CH, Mannino DM, Jaimes FA, Curtis JL, Han MLK, Hansel NN, Diaz AA. Undiagnosed Obstructive Lung Disease in the United States. Associated Factors and Long-term Mortality. Ann Am Thorac Soc 2015;12(12):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.
Mulshine JL, Avila R, Yankelevitz D, Baer TM, San Jose Estépar R, Ambrose LF, Aldige CR. Lung Cancer Workshop XI. Journal of Thoracic OncologyJournal of Thoracic Oncology 2015;10:762-767.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.
Kinsey MC, San Jose Estépar R, Wei Y, Washko GR, Christiani DC. Regional Emphysema of a Non-Small Cell Tumor Is Associated with Larger Tumors and Decreased Survival. Annals ATSAnnals ATS 2015;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.
Patil V, Gupta R, San Jose Estépar R, Lacson R, Cheung A, Wong JM, Popp JA, Golby A, Ogilvy C, Vosburgh KG. Smart stylet: the development and use of a bedside external ventricular drain image-guidance system. Stereotactic and functional neurosurgeryStereotactic and functional neurosurgery 2015;93:50-58.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. © 2015 S. Karger AG, Basel.
Diaz AA, Young TP, Kurugol S, Eckbo E, Muralidhar N, Chapman JK, Kinney GL, Ross JC, San Jose Estépar R, Harmouche R, Black-Shinn JL, Budoff M, Bowler RP, Hokanson J, Washko GR, Washko GR. Abdominal Visceral Adipose Tissue is Associated with Myocardial Infarction in Patients with COPD. Chronic obstructive pulmonary diseases (Miami, Fla.)Chronic obstructive pulmonary diseases (Miami, Fla.) 2015;2:8-16.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 ± SD, 303.4 ± 208.5 vs. 226.8 ± 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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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