Publications by Year: 2017

2017
Dransfield MT, Kunisaki KM, Strand MJ, Anzueto A, Bhatt SP, Bowler RP, Criner GJ, Curtis JL, Hanania NA, Nath H, Putcha N, Roark SE, Wan ES, Washko GR, Wells MJ, Wendt CH, Make BJ. Acute Exacerbations and Lung Function Loss in Smokers with and without Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2017;195(3):324-330.Abstract
RATIONALE: Acute exacerbations of chronic obstructive pulmonary disease (COPD) increase the risk of death and drive healthcare costs, but whether they accelerate loss of lung function remains controversial. Whether exacerbations in subjects with mild COPD or similar acute respiratory events in smokers without airflow obstruction affect lung function decline is unknown. OBJECTIVES: To determine the association between acute exacerbations of COPD (and acute respiratory events in smokers without COPD) and the change in lung function over 5 years of follow-up. METHODS: We examined data on the first 2,000 subjects who returned for a second COPDGene visit 5 years after enrollment. Baseline data included demographics, smoking history, and computed tomography emphysema. We defined exacerbations (and acute respiratory events in those without established COPD) as acute respiratory symptoms requiring either antibiotics or systemic steroids, and severe events by the need for hospitalization. Throughout the 5-year follow-up period, we collected self-reported acute respiratory event data at 6-month intervals. We used linear mixed models to fit FEV decline based on reported exacerbations or acute respiratory events. MEASUREMENTS AND MAIN RESULTS: In subjects with COPD, exacerbations were associated with excess FEV decline, with the greatest effect in Global Initiative for Chronic Obstructive Lung Disease stage 1, where each exacerbation was associated with an additional 23 ml/yr decline (95% confidence interval, 2-44; P = 0.03), and each severe exacerbation with an additional 87 ml/yr decline (95% confidence interval, 23-151; P = 0.008); statistically significant but smaller effects were observed in Global Initiative for Chronic Obstructive Lung Disease stage 2 and 3 subjects. In subjects without airflow obstruction, acute respiratory events were not associated with additional FEV decline. CONCLUSIONS: Exacerbations are associated with accelerated lung function loss in subjects with established COPD, particularly those with mild disease. Trials are needed to test existing and novel therapies in subjects with early/mild COPD to potentially reduce the risk of progressing to more advanced lung disease. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).
Martinez CH, Diaz AA, Meldrum C, Curtis JL, Cooper CB, Pirozzi C, Kanner RE, Paine R, Woodruff PG, Bleecker ER, Hansel NN, Barr GR, Marchetti N, Criner GJ, Kazerooni EA, Hoffman EA, Ross BD, Galban CJ, Cigolle CT, Martinez FJ, Han MLK. Age and Small Airway Imaging Abnormalities in Subjects with and without Airflow Obstruction in SPIROMICS. Am J Respir Crit Care Med 2017;195(4):464-472.Abstract
RATIONALE: Aging is associated with reduced FEV to FVC ratio (FEV/FVC), hyperinflation, and alveolar enlargement, but little is known about how age affects small airways. OBJECTIVES: To determine if chest computed tomography (CT)-assessed functional small airway would increase with age, even among asymptomatic individuals. METHODS: We used parametric response mapping analysis of paired inspiratory/expiratory CTs to identify functional small airway abnormality (PRM) and emphysema (PRM) in the SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) cohort. Using adjusted linear regression models, we analyzed associations between PRM and age in subjects with or without airflow obstruction. We subdivided participants with normal spirometry based on respiratory-related impairment (6-minute-walk distance <350 m, modified Medical Research Council ≥2, chronic bronchitis, St. George's Respiratory Questionnaire >25, respiratory events requiring treatment [antibiotics and/or steroids or hospitalization] in the year before enrollment). MEASUREMENTS AND MAIN RESULTS: Among 580 never- and ever-smokers without obstruction or respiratory impairment, PRM increased 2.7% per decade, ranging from 3.6% (ages 40-50 yr) to 12.7% (ages 70-80 yr). PRM increased nonsignificantly (0.1% [ages 40-50 yr] to 0.4% [ages 70-80 yr]; P = 0.34). Associations were similar among nonobstructed individuals with respiratory-related impairment. Increasing PRM in subjects without airflow obstruction was associated with increased FVC (P = 0.004) but unchanged FEV (P = 0.94), yielding lower FEV/FVC ratios (P < 0.001). Although emphysema was also significantly associated with lower FEV/FVC (P = 0.04), its contribution relative to PRM in those without airflow obstruction was limited by its low burden. CONCLUSIONS: In never- and ever-smokers without airflow obstruction, aging is associated with increased FVC and CT-defined functional small airway abnormality regardless of respiratory symptoms.
Woodruff PG, van den Berge M, Boucher RC, Brightling C, Burchard EG, Christenson SA, Han MLK, Holtzman MJ, Kraft M, Lynch DA, Martinez FD, Reddel HK, Sin DD, Washko GR, Wenzel SE, Punturieri A, Freemer MM, Wise RA. American Thoracic Society/National Heart, Lung, and Blood Institute Asthma-Chronic Obstructive Pulmonary Disease Overlap Workshop Report. Am J Respir Crit Care Med 2017;196(3):375-381.Abstract
Asthma and chronic obstructive pulmonary disease (COPD) are highly prevalent chronic obstructive lung diseases with an associated high burden of disease. Asthma, which is often allergic in origin, frequently begins in infancy or childhood with variable airflow obstruction and intermittent wheezing, cough, and dyspnea. Patients with COPD, in contrast, are usually current or former smokers who present after the age of 40 years with symptoms (often persistent) including dyspnea and a productive cough. On the basis of age and smoking history, it is often easy to distinguish between asthma and COPD. However, some patients have features compatible with both diseases. Because clinical studies typically exclude these patients, their underlying disease mechanisms and appropriate treatment remain largely uncertain. To explore the status of and opportunities for research in this area, the NHLBI, in partnership with the American Thoracic Society, convened a workshop of investigators in San Francisco, California on May 14, 2016. At the workshop, current understanding of asthma-COPD overlap was discussed among clinicians, pathologists, radiologists, epidemiologists, and investigators with expertise in asthma and COPD. They considered knowledge gaps in our understanding of asthma-COPD overlap and identified strategies and research priorities that will advance its understanding. This report summarizes those discussions.
Yip SSF, Parmar C, Blezek D, Estepar RSJ, Pieper S, Kim J, Aerts HJWL. Application of the 3D slicer chest imaging platform segmentation algorithm for large lung nodule delineation. PLoS One 2017;12(6):e0178944.Abstract
PURPOSE: Accurate segmentation of lung nodules is crucial in the development of imaging biomarkers for predicting malignancy of the nodules. Manual segmentation is time consuming and affected by inter-observer variability. We evaluated the robustness and accuracy of a publically available semiautomatic segmentation algorithm that is implemented in the 3D Slicer Chest Imaging Platform (CIP) and compared it with the performance of manual segmentation. METHODS: CT images of 354 manually segmented nodules were downloaded from the LIDC database. Four radiologists performed the manual segmentation and assessed various nodule characteristics. The semiautomatic CIP segmentation was initialized using the centroid of the manual segmentations, thereby generating four contours for each nodule. The robustness of both segmentation methods was assessed using the region of uncertainty (δ) and Dice similarity index (DSI). The robustness of the segmentation methods was compared using the Wilcoxon-signed rank test (pWilcoxon<0.05). The Dice similarity index (DSIAgree) between the manual and CIP segmentations was computed to estimate the accuracy of the semiautomatic contours. RESULTS: The median computational time of the CIP segmentation was 10 s. The median CIP and manually segmented volumes were 477 ml and 309 ml, respectively. CIP segmentations were significantly more robust than manual segmentations (median δCIP = 14ml, median dsiCIP = 99% vs. median δmanual = 222ml, median dsimanual = 82%) with pWilcoxon~10-16. The agreement between CIP and manual segmentations had a median DSIAgree of 60%. While 13% (47/354) of the nodules did not require any manual adjustment, minor to substantial manual adjustments were needed for 87% (305/354) of the nodules. CIP segmentations were observed to perform poorly (median DSIAgree≈50%) for non-/sub-solid nodules with subtle appearances and poorly defined boundaries. CONCLUSION: Semi-automatic CIP segmentation can potentially reduce the physician workload for 13% of nodules owing to its computational efficiency and superior stability compared to manual segmentation. Although manual adjustment is needed for many cases, CIP segmentation provides a preliminary contour for physicians as a starting point.
Benck LR, Cuttica MJ, Colangelo LA, Sidney S, Dransfield MT, Mannino DM, Jacobs DR, Lewis CE, Zhu N, Washko GR, Liu K, Carnethon MR, Kalhan R. Association between Cardiorespiratory Fitness and Lung Health from Young Adulthood to Middle Age. Am J Respir Crit Care Med 2017;195(9):1236-1243.Abstract
RATIONALE: Beyond the risks of smoking, there are limited data on factors associated with change in lung function over time. OBJECTIVES: To determine whether cardiorespiratory fitness was longitudinally associated with preservation of lung health. METHODS: Prospective data were collected from 3,332 participants in the Coronary Artery Risk Development in Young Adults study aged 18-30 in 1985 who underwent treadmill exercise testing at baseline visit, and 2,735 participants with a second treadmill test 20 years later. The association between cardiorespiratory fitness and covariate adjusted decline in lung function was evaluated. MEASUREMENTS AND MAIN RESULTS: Higher baseline fitness was associated with less decline in lung function. When adjusted for age, height, race-sex group, peak lung function, and years from peak lung function, each additional minute of treadmill duration was associated with 1.00 ml/yr less decline in FEV (P < 0.001) and 1.55 ml/yr less decline in FVC (P < 0.001). Greater decline in fitness was associated with greater annual decline in lung function. Each 1-minute decline in treadmill duration between baseline and Year 20 was associated with 2.54 ml/yr greater decline in FEV (P < 0.001) and 3.27 ml/yr greater decline in FVC (P < 0.001). Both sustaining higher and achieving relatively increased levels of fitness over 20 years were associated with preservation of lung health. CONCLUSIONS: Greater cardiopulmonary fitness in young adulthood, less decline in fitness from young adulthood to middle age, and achieving increased fitness from young adulthood to middle age are associated with less decline in lung health over time. Clinical trial registered with www.clinicaltrials.gov (NCT 00005130).
Ross JC, Castaldi PJ, Cho MH, Chen J, Chang Y, Dy JG, Silverman EK, Washko GR, Estepar RSJ. A Bayesian Nonparametric Model for Disease Subtyping: Application to Emphysema Phenotypes. IEEE Trans Med Imaging 2017;36(1):343-354.Abstract
We introduce a novel Bayesian nonparametric model that uses the concept of disease trajectories for disease subtype identification. Although our model is general, we demonstrate that by treating fractions of tissue patterns derived from medical images as compositional data, our model can be applied to study distinct progression trends between population subgroups. Specifically, we apply our algorithm to quantitative emphysema measurements obtained from chest CT scans in the COPDGene Study and show several distinct progression patterns. As emphysema is one of the major components of chronic obstructive pulmonary disease (COPD), the third leading cause of death in the United States [1], an improved definition of emphysema and COPD subtypes is of great interest. We investigate several models with our algorithm, and show that one with age , pack years (a measure of cigarette exposure), and smoking status as predictors gives the best compromise between estimated predictive performance and model complexity. This model identified nine subtypes which showed significant associations to seven single nucleotide polymorphisms (SNPs) known to associate with COPD. Additionally, this model gives better predictive accuracy than multiple, multivariate ordinary least squares regression as demonstrated in a five-fold cross validation analysis. We view our subtyping algorithm as a contribution that can be applied to bridge the gap between CT-level assessment of tissue composition to population-level analysis of compositional trends that vary between disease subtypes.
Diaz AA, Young TP, Maselli DJ, Martinez CH, Maclean ES, Yen A, Dass C, Simpson SA, Lynch DA, Kinney GL, Hokanson JE, Washko GR, San José Estépar R. Bronchoarterial ratio in never-smokers adults: Implications for bronchial dilation definition. Respirology 2017;22(1):108-113.Abstract
BACKGROUND AND OBJECTIVE: Bronchiectasis manifests as recurrent respiratory infections and reduced lung function. Airway dilation, which is measured as the ratio of the diameters of the bronchial lumen (B) and adjacent pulmonary artery (A), is a defining radiological feature of bronchiectasis. A challenge to equating the bronchoarterial (BA) ratio to disease severity is that the diameters of airway and vessel in health are not established. We sought to explore the variability of BA ratio in never-smokers without pulmonary disease and its associations with lung function. METHODS: Objective measurements of the BA ratio on volumetric computed tomography (CT) scans and pulmonary function data were collected in 106 never-smokers. The BA ratio was measured in the right upper lobe apical bronchus (RB1) and the right lower lobe basal posterior bronchus. The association between the BA ratio and forced expiratory volume in 1 s (FEV ) was assessed using regression analysis. RESULTS: The BA ratio was 0.79 ± 0.16 and was smaller in more peripheral RB1 bronchi (P < 0.0001). The BA ratio was >1, a typical threshold for bronchiectasis, in 10 (8.5%) subjects. Subjects with a BA ratio >1 versus ≤1 had smaller artery diameters (P < 0.0001) but not significantly larger bronchial lumens. After adjusting for age, gender, race and height, the BA ratio was directly related to FEV (P = 0.0007). CONCLUSION: In never-smokers, the BA ratio varies by airway generation and is associated with lung function. A BA ratio >1 is driven by small arteries. Using artery diameter as reference to define bronchial dilation seems inappropriate.
Bhatt SP, Vegas-Sánchez-Ferrero G, Rahaghi FN, Maclean ES, Gonzalez-Serrano G, Come CE, Kinney GL, Hokanson JE, Budoff MJ, Cuttica MJ, Wells MJ, San José Estépar R, Washko GR. Cardiac Morphometry on Computed Tomography and Exacerbation Reduction with β-Blocker Therapy in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2017;196(11):1484-1488.
McDonald M-LN, Diaz AA, Rutten E, Lutz SM, Harmouche R, Estepar RSJ, Kinney G, Hokanson JE, Gower BA, Wouters EFM, Rennard SI, Hersh CP, Casaburi R, Dransfield MT, Silverman EK, Washko GR. Chest computed tomography-derived low fat-free mass index and mortality in COPD. Eur Respir J 2017;50(6)Abstract
Low fat-free mass index (FFMI) is an independent risk factor for mortality in chronic obstructive pulmonary disease (COPD) not typically measured during routine care. In the present study, we aimed to derive fat-free mass from the pectoralis muscle area (FFM) and assess whether low FFMI is associated with all-cause mortality in COPD cases. We used data from two independent COPD cohorts, ECLIPSE and COPDGene.Two equal sized groups of COPD cases (n=759) from the ECLIPSE study were used to derive and validate an equation to calculate the FFM measured using bioelectrical impedance from PMA. We then applied the equation in COPD cases (n=3121) from the COPDGene cohort, and assessed survival. Low FFMI was defined, using the Schols classification (FFMI <16 in men, FFMI <15 in women) and the fifth percentile normative values of FFMI from the UK Biobank.The final regression model included PMA, weight, sex and height, and had an adjusted R of 0.92 with fat-free mass (FFM) as the outcome. In the test group, the correlation between FFM and FFM remained high (Pearson correlation=0.97). In COPDGene, COPD cases with a low FFMI had an increased risk of death (HR 1.6, p<0.001).We demonstrated COPD cases with a low FFMI have an increased risk of death.
Ash SY, Harmouche R, Putman RK, Ross JC, Diaz AA, Hunninghake GM, Onieva Onieva J, Martinez FJ, Choi AM, Lynch DA, Hatabu H, Rosas IO, Estepar RSJ, Washko GR. Clinical and Genetic Associations of Objectively Identified Interstitial Changes in Smokers. Chest 2017;152(4):780-791.Abstract
BACKGROUND: Smoking-related lung injury may manifest on CT scans as both emphysema and interstitial changes. We have developed an automated method to quantify interstitial changes and hypothesized that this measurement would be associated with lung function, quality of life, mortality, and a mucin 5B (MUC5B) polymorphism. METHODS: Using CT scans from the Genetic Epidemiology of COPD Study, we objectively labeled lung parenchyma as a tissue subtype. We calculated the percentage of the lung occupied by interstitial subtypes. RESULTS: A total of 8,345 participants had clinical and CT scanning data available. A 5% absolute increase in interstitial changes was associated with an absolute decrease in FVC % predicted of 2.47% (P < .001) and a 1.36-point higher St. George's Respiratory Questionnaire score (P < .001). Among the 6,827 participants with mortality data, a 5% increase in interstitial changes was associated with a 29% increased risk of death (P < .001). These associations were present in a subgroup without visually defined interstitial lung abnormalities, as well as in those with normal spirometric test results, and in those without chronic respiratory symptoms. In non-Hispanic whites, for each copy of the minor allele of the MUC5B promoter polymorphism, there was a 0.64% (P < .001) absolute increase in the percentage of lung with interstitial changes. CONCLUSIONS: Objective interstitial changes on CT scans were associated with impaired lung function, worse quality of life, increased mortality, and more copies of a MUC5B promoter polymorphism, suggesting that these changes may be a marker of susceptibility to smoking-related lung injury, detectable even in those who are healthy by other measures.
Washko GR, Coxson HO, O'Donnell DE, Aaron SD. CT imaging of chronic obstructive pulmonary disease: insights, disappointments, and promise. Lancet Respir Med 2017;5(11):903-908.Abstract
CT imaging is a readily quantifiable tool that can provide in-vivo assessments of lung structure in conditions such as chronic obstructive pulmonary disease (COPD). The information extracted from these data has been used in many clinical, epidemiological, and genetic investigations for patient stratification and prognostication, and to determine intermediate endpoints for clinical trials. Although these efforts have informed our understanding of the heterogeneity of pulmonary disease in smokers, they have not yet translated into new treatments for COPD or the personalisation of patient care. There are a multitude of potential reasons for this, including the lack of insight that static imaging provides for lung function and dysfunction, the limited resolution of clinical CT scanning for microscopic changes to the lung architecture, and the challenges that the biomedical community faces when trying to translate discovery to therapy. Such limitations might be addressed through novel image analysis techniques, up-and-coming CT-based and MRI-based technologies, closer ties between academia and industry, and an expanded endeavour to share data across the biomedical community.
Ash SY, Harmouche R, Vallejo DLL, Villalba JA, Ostridge K, Gunville R, Come CE, Onieva Onieva J, Ross JC, Hunninghake GM, El-Chemaly SY, Doyle TJ, Nardelli P, Sanchez-Ferrero GV, Goldberg HJ, Rosas IO, Estepar RSJ, Washko GR. Densitometric and local histogram based analysis of computed tomography images in patients with idiopathic pulmonary fibrosis. Respir Res 2017;18(1):45.Abstract
BACKGROUND: Prior studies of clinical prognostication in idiopathic pulmonary fibrosis (IPF) using computed tomography (CT) have often used subjective analyses or have evaluated quantitative measures in isolation. This study examined associations between both densitometric and local histogram based quantitative CT measurements with pulmonary function test (PFT) parameters and mortality. In addition, this study sought to compare risk prediction scores that incorporate quantitative CT measures with previously described systems. METHODS: Forty six patients with biopsy proven IPF were identified from a registry of patients with interstitial lung disease at Brigham and Women's Hospital in Boston, MA. CT scans for each subject were visually scored using a previously published method. After a semi-automated method was used to segment the lungs from the surrounding tissue, densitometric measurements including the percent high attenuating area, mean lung density, skewness and kurtosis were made for the entirety of each patient's lungs. A separate, automated tool was used to detect and quantify the percent of lung occupied by interstitial lung features. These analyses were used to create clinical and quantitative CT based risk prediction scores, and the performance of these was compared to the performance of clinical and visual analysis based methods. RESULTS: All of the densitometric measures were correlated with forced vital capacity and diffusing capacity, as were the total amount of interstitial change and the percentage of interstitial change that was honeycombing measured using the local histogram method. Higher percent high attenuating area, higher mean lung density, lower skewness, lower kurtosis and a higher percentage of honeycombing were associated with worse transplant free survival. The quantitative CT based risk prediction scores performed similarly to the clinical and visual analysis based methods. CONCLUSIONS: Both densitometric and feature based quantitative CT measures correlate with pulmonary function test measures and are associated with transplant free survival. These objective measures may be useful for identifying high risk patients and monitoring disease progression. Further work will be needed to validate these measures and the quantitative imaging based risk prediction scores in other cohorts.
Diaz AA, Rahaghi FN, Doyle TJ, Young TP, Maclean ES, Martinez CH, San José Estépar R, Guerra S, Tesfaigzi Y, Rosas IO, Washko GR, Wilson DO. Differences in Respiratory Symptoms and Lung Structure Between Hispanic and Non-Hispanic White Smokers: A Comparative Study. Chronic Obstr Pulm Dis 2017;4(4):297-304.Abstract
Prior studies have demonstrated that U.S. Hispanic smokers have a lower risk of decline in lung function and chronic obstructive pulmonary disease (COPD) compared with non-Hispanic whites (NHW). This suggests there might be racial-ethnic differences in susceptibility in cigarette smoke-induced respiratory symptoms, lung parenchymal destruction, and airway and vascular disease, as well as in extra-pulmonary manifestations of COPD. Therefore, we aimed to explore respiratory symptoms, lung function, and pulmonary and extra-pulmonary structural changes in Hispanic and NHW smokers. We compared respiratory symptoms, lung function, and computed tomography (CT) measures of emphysema-like tissue, airway disease, the branching generation number (BGN) to reach a 2-mm-lumen-diameter airway, and vascular pruning as well as muscle and fat mass between 39 Hispanic and 39 sex-, age- and smoking exposure-matched NHW smokers. Hispanic smokers had higher odds of dyspnea than NHW after adjustment for COPD and asthma statuses (odds ratio[OR] = 2.96; 95% confidence interval [CI] 1.09-8.04), but no significant differences were found in lung function and CT measurements. While lung function and CT measures of the lung structure were similar, dyspnea is reported more frequently by Hispanic than matched-NHW smokers. It seems to be an impossible puzzle but it's easy to solve a Rubik' Cube using a few algorithms.
Martin M, Almeras N, Després J-P, Coxson HO, Washko GR, Vivodtzev I, Wouters EFM, Rutten E, Williams MC, Murchison JT, MacNee W, Sin DD, Maltais F. Ectopic fat accumulation in patients with COPD: an ECLIPSE substudy. Int J Chron Obstruct Pulmon Dis 2017;12:451-460.Abstract
BACKGROUND: Obesity is increasingly associated with COPD, but little is known about the prevalence of ectopic fat accumulation in COPD and whether this can possibly be associated with poor clinical outcomes and comorbidities. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) substudy tested the hypothesis that COPD is associated with increased ectopic fat accumulation and that this would be associated with COPD-related outcomes and comorbidities. METHODS: Computed tomography (CT) images of the thorax obtained in ECLIPSE were used to quantify ectopic fat accumulation at L2-L3 (eg, cross-sectional area [CSA] of visceral adipose tissue [VAT] and muscle tissue [MT] attenuation, a reflection of muscle fat infiltration) and CSA of MT. A dose-response relationship between CSA of VAT, MT attenuation and CSA of MT and COPD-related outcomes (6-minute walking distance [6MWD], exacerbation rate, quality of life, and forced expiratory volume in 1 second [FEV] decline) was addressed with the Cochran-Armitage trend test. Regression models were used to investigate possible relationships between CT body composition indices and comorbidities. RESULTS: From the entire ECLIPSE cohort, we identified 585 subjects with valid CT images at L2-L3 to assess body composition. CSA of VAT was increased (<0.0001) and MT attenuation was reduced (indicating more muscle fat accumulation) in patients with COPD (<0.002). Progressively increasing CSA of VAT was not associated with adverse clinical outcomes. The probability of exhibiting low 6MWD and accelerated FEV decline increased with progressively decreasing MT attenuation and CSA of MT. In COPD, the probability of having diabetes (=0.024) and gastroesophageal reflux (=0.0048) at baseline increased in parallel with VAT accumulation, while the predicted MT attenuation increased the probability of cardiovascular comorbidities (=0.042). Body composition parameters did not correlate with coronary artery scores or with survival. CONCLUSION: Ectopic fat accumulation is increased in COPD, and this was associated with relevant clinical outcomes and comorbidities.
Morrow JD, Zhou X, Lao T, Jiang Z, DeMeo DL, Cho MH, Qiu W, Cloonan S, Pinto-Plata V, Celli B, Marchetti N, Criner GJ, Bueno R, Washko GR, Glass K, Quackenbush J, Choi AMK, Silverman EK, Hersh CP. Functional interactors of three genome-wide association study genes are differentially expressed in severe chronic obstructive pulmonary disease lung tissue. Sci Rep 2017;7:44232.Abstract
In comparison to genome-wide association studies (GWAS), there has been poor replication of gene expression studies in chronic obstructive pulmonary disease (COPD). We performed microarray gene expression profiling on a large sample of resected lung tissues from subjects with severe COPD. Comparing 111 COPD cases and 40 control smokers, 204 genes were differentially expressed; none were at significant GWAS loci. The top differentially expressed gene was HMGB1, which interacts with AGER, a known COPD GWAS gene. Differentially expressed genes showed enrichment for putative interactors of the first three identified COPD GWAS genes IREB2, HHIP, and FAM13A, based on gene sets derived from protein and RNA binding studies, RNA-interference, a murine smoking model, and expression quantitative trait locus analyses. The gene module most highly associated for COPD in Weighted Gene Co-Expression Network Analysis (WGCNA) was enriched for B cell pathways, and shared seventeen genes with a mouse smoking model and twenty genes with previous emphysema studies. As in other common diseases, genes at COPD GWAS loci were not differentially expressed; however, using a combination of network methods, experimental studies and careful phenotype definition, we found differential expression of putative interactors of these genes, and we replicated previous human and mouse microarray results.
Manichaikul A, Wang X-Q, Sun L, Dupuis J, Borczuk AC, Nguyen JN, Raghu G, Hoffman EA, Onengut-Gumuscu S, Farber EA, Kaufman JD, Rabinowitz D, Stukovsky KHD, Kawut SM, Hunninghake GM, Washko GR, O'Connor GT, Rich SS, Barr GR, Lederer DJ. Genome-wide association study of subclinical interstitial lung disease in MESA. Respir Res 2017;18(1):97.Abstract
BACKGROUND: We conducted a genome-wide association study (GWAS) of subclinical interstitial lung disease (ILD), defined as high attenuation areas (HAA) on CT, in the population-based Multi-Ethnic Study of Atherosclerosis Study. METHODS: We measured the percentage of high attenuation areas (HAA) in the lung fields on cardiac CT scan defined as voxels with CT attenuation values between -600 and -250 HU. Genetic analyses were performed in MESA combined across race/ethnic groups: non-Hispanic White (n = 2,434), African American (n = 2,470), Hispanic (n = 2,065) and Chinese (n = 702), as well as stratified by race/ethnicity. RESULTS: Among 7,671 participants, regions at genome-wide significance were identified for basilar peel-core ratio of HAA in FLJ35282 downstream of ANRIL (rs7852363, P = 2.1x10) and within introns of SNAI3-AS1 (rs140142658, P = 9.6x10) and D21S2088E (rs3079677, P = 2.3x10). Within race/ethnic groups, 18 additional loci were identified at genome-wide significance, including genes related to development (FOXP4), cell adhesion (ALCAM) and glycosylation (GNPDA2, GYPC, GFPT1 and FUT10). Among these loci, SNP rs6844387 near GNPDA2 demonstrated nominal evidence of replication in analysis of n = 1,959 participants from the Framingham Heart Study (P = 0.029). FOXP4 region SNP rs2894439 demonstrated evidence of validation in analysis of n = 228 White ILD cases from the Columbia ILD Study compared to race/ethnicity-matched controls from MESA (one-sided P = 0.007). In lung tissue from 15 adults with idiopathic pulmonary fibrosis compared to 15 adults without lung disease. ANRIL (P = 0.001), ALCAM (P = 0.03) and FOXP4 (P = 0.046) were differentially expressed. CONCLUSIONS: Our results suggest novel roles for protein glycosylation and cell cycle disinhibition by long non-coding RNA in the pathogenesis of ILD.
Boueiz A, Lutz SM, Cho MH, Hersh CP, Bowler RP, Washko GR, Halper-Stromberg E, Bakke P, Gulsvik A, Laird NM, Beaty TH, Coxson HO, Crapo JD, Silverman EK, Castaldi PJ, DeMeo DL. Genome-Wide Association Study of the Genetic Determinants of Emphysema Distribution. Am J Respir Crit Care Med 2017;195(6):757-771.Abstract
RATIONALE: Emphysema has considerable variability in the severity and distribution of parenchymal destruction throughout the lungs. Upper lobe-predominant emphysema has emerged as an important predictor of response to lung volume reduction surgery. Yet, aside from alpha-1 antitrypsin deficiency, the genetic determinants of emphysema distribution remain largely unknown. OBJECTIVES: To identify the genetic influences of emphysema distribution in non-alpha-1 antitrypsin-deficient smokers. METHODS: A total of 11,532 subjects with complete genotype and computed tomography densitometry data in the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]; non-Hispanic white and African American), ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints), and GenKOLS (Genetics of Chronic Obstructive Lung Disease) studies were analyzed. Two computed tomography scan emphysema distribution measures (difference between upper-third and lower-third emphysema; ratio of upper-third to lower-third emphysema) were tested for genetic associations in all study subjects. Separate analyses in each study population were followed by a fixed effect metaanalysis. Single-nucleotide polymorphism-, gene-, and pathway-based approaches were used. In silico functional evaluation was also performed. MEASUREMENTS AND MAIN RESULTS: We identified five loci associated with emphysema distribution at genome-wide significance. These loci included two previously reported associations with COPD susceptibility (4q31 near HHIP and 15q25 near CHRNA5) and three new associations near SOWAHB, TRAPPC9, and KIAA1462. Gene set analysis and in silico functional evaluation revealed pathways and cell types that may potentially contribute to the pathogenesis of emphysema distribution. CONCLUSIONS: This multicohort genome-wide association study identified new genomic loci associated with differential emphysematous destruction throughout the lungs. These findings may point to new biologic pathways on which to expand diagnostic and therapeutic approaches in chronic obstructive pulmonary disease. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).
Martinez CH, Diaz AA, Meldrum CA, McDonald M-LN, Murray S, Kinney GL, Hokanson JE, Curtis JL, Bowler RP, Han MLK, Washko GR, Regan EA. Handgrip Strength in Chronic Obstructive Pulmonary Disease. Associations with Acute Exacerbations and Body Composition. Ann Am Thorac Soc 2017;14(11):1638-1645.Abstract
RATIONALE: Handgrip strength (HGS) predicts mortality in the elderly, but its determinants and clinical significance in chronic obstructive pulmonary disease (COPD) has not been defined. OBJECTIVES: We tested associations of HGS with pectoralis muscle area (PMA), subcutaneous adipose tissue (SAT), imaging characteristics, and lung function in smokers with COPD, and evaluated the cross-sectional and longitudinal associations of HGS with acute respiratory events. METHODS: We analyzed demographic, clinical, spirometry, HGS, and imaging data of 272 subjects with COPD, obtaining measures of airway thickness, emphysema, PMA, and SAT from chest computed tomography scans. We tested associations of lung function and imaging characteristics with HGS, using linear models. HGS association to acute respiratory events at enrollment and during follow-up (mean, 2.6 years) was analyzed using adjusted logistic models. RESULTS: HGS correlated with PMA, SAT, forced expiratory volume, and airway thickness, but not with body mass index or emphysema severity. In adjusted regression models, HGS was directly (β, 1.5; 95% confidence interval [CI], 0.1-3.0) and inversely (β, -3.3; 95% CI, -5.1 to -0.9) associated with one standard deviation of PMA and SAT, respectively, independent of body mass index and emphysema. In regression models adjusted for age, sex, body mass index, race, pack-years smoked, current smoking, chronic bronchitis, FEV% predicted, emphysema, and airway metrics, HGS was associated with exacerbation risk; in cross-sectional analyses, there was an increment of 5% in the risk of exacerbations for each 1-kg decrement in HGS (risk ratio, 1.05; 95% CI, 1.01-1.08), and there was a similar risk during follow-up (risk ratio, 1.04; 95% CI, 1.01-1,07). CONCLUSIONS: In ever-smokers with COPD, HGS is associated with computed tomography markers of body composition and airway thickness, independent of body mass index and emphysema. Higher HGS is associated with lower exacerbation frequency.
Ash SY, Washko GR. Interstitial lung abnormalities: risk and opportunity. Lancet Respir Med 2017;5(2):95-96.
Kinsey MC, San José Estépar R, Van der Velden J, Cole BF, Christiani DC, Washko GR. Lower Pectoralis Muscle Area Is Associated with a Worse Overall Survival in Non-Small Cell Lung Cancer. Cancer Epidemiol Biomarkers Prev 2017;26(1):38-43.Abstract
BACKGROUND: Muscle wasting is a component of the diagnosis of cancer cachexia and has been associated with poor prognosis. However, recommended tools to measure sarcopenia are limited by poor sensitivity or the need to perform additional scans. We hypothesized that pectoralis muscle area (PMA) measured objectively on chest CT scan may be associated with overall survival (OS) in non-small cell lung cancer (NSCLC). METHODS: We evaluated 252 cases from a prospectively enrolling lung cancer cohort. Eligible cases had CT scans performed prior to the initiation of surgery, radiation, or chemotherapy. PMA was measured in a semi-automated fashion while blinded to characteristics of the tumor, lung, and patient outcomes. RESULTS: Men had a significantly greater PMA than women (37.59 vs. 26.19 cm, P < 0.0001). In univariate analysis, PMA was associated with age and body mass index (BMI). A Cox proportional hazards model was constructed to account for confounders associated with survival. Lower pectoralis area (per cm) at diagnosis was associated with an increased hazard of death of 2% (HR, 0.98; confidence interval, 0.96-0.99; P = 0.044) while adjusting for age, sex, smoking, chronic bronchitis, emphysema, histology, stage, chemotherapy, radiation, surgery, BMI, and ECOG performance status. CONCLUSIONS: Lower PMA measured from chest CT scans obtained at the time of diagnosis of NSCLC is associated with a worse OS. IMPACT: PMA may be a valuable CT biomarker for sarcopenia-associated lung cancer survival. Cancer Epidemiol Biomarkers Prev; 26(1); 38-43. ©2016 AACR SEE ALL THE ARTICLES IN THIS CEBP FOCUS SECTION, "THE OBESITY PARADOX IN CANCER EVIDENCE AND NEW DIRECTIONS".

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