2014
Manichaikul A, Hoffman EA, Smolonska J, Gao W, Cho MH, Baumhauer H, Budoff M, Austin JHM, Washko GR, Carr JJ, Kaufman JD, Pottinger T, Powell CA, Wijmenga C, Zanen P, Groen HJM, Postma DS, Wanner A, Rouhani FN, Brantly ML, Powell R, Smith BM, Rabinowitz D, Raffel LJ, Hinckley Stukovsky KD, Crapo JD, Beaty TH, Hokanson JE, Silverman EK, Dupuis J, O'Connor GT, Boezen MH, Rich SS, Barr GR.
Genome-wide study of percent emphysema on computed tomography in the general population. The Multi-Ethnic Study of Atherosclerosis Lung/SNP Health Association Resource Study. Am J Respir Crit Care Med 2014;189(4):408-18.
AbstractRATIONALE: Pulmonary emphysema overlaps partially with spirometrically defined chronic obstructive pulmonary disease and is heritable, with moderately high familial clustering.
OBJECTIVES: To complete a genome-wide association study (GWAS) for the percentage of emphysema-like lung on computed tomography in the Multi-Ethnic Study of Atherosclerosis (MESA) Lung/SNP Health Association Resource (SHARe) Study, a large, population-based cohort in the United States.
METHODS: We determined percent emphysema and upper-lower lobe ratio in emphysema defined by lung regions less than -950 HU on cardiac scans. Genetic analyses were reported combined across four race/ethnic groups: non-Hispanic white (n = 2,587), African American (n = 2,510), Hispanic (n = 2,113), and Chinese (n = 704) and stratified by race and ethnicity.
MEASUREMENTS AND MAIN RESULTS: Among 7,914 participants, we identified regions at genome-wide significance for percent emphysema in or near SNRPF (rs7957346; P = 2.2 × 10(-8)) and PPT2 (rs10947233; P = 3.2 × 10(-8)), both of which replicated in an additional 6,023 individuals of European ancestry. Both single-nucleotide polymorphisms were previously implicated as genes influencing lung function, and analyses including lung function revealed independent associations for percent emphysema. Among Hispanics, we identified a genetic locus for upper-lower lobe ratio near the α-mannosidase-related gene MAN2B1 (rs10411619; P = 1.1 × 10(-9); minor allele frequency [MAF], 4.4%). Among Chinese, we identified single-nucleotide polymorphisms associated with upper-lower lobe ratio near DHX15 (rs7698250; P = 1.8 × 10(-10); MAF, 2.7%) and MGAT5B (rs7221059; P = 2.7 × 10(-8); MAF, 2.6%), which acts on α-linked mannose. Among African Americans, a locus near a third α-mannosidase-related gene, MAN1C1 (rs12130495; P = 9.9 × 10(-6); MAF, 13.3%) was associated with percent emphysema.
CONCLUSIONS: Our results suggest that some genes previously identified as influencing lung function are independently associated with emphysema rather than lung function, and that genes related to α-mannosidase may influence risk of emphysema.
Martinez CH, Okajima Y, Murray S, Washko GR, Martinez FJ, Silverman EK, Lee JH, Regan EA, Crapo JD, Curtis JL, Hatabu H, Han MLK.
Impact of self-reported gastroesophageal reflux disease in subjects from COPDGene cohort. Respir Res 2014;15:62.
AbstractBACKGROUND: The coexistence of gastroesophageal reflux disease (GERD) and COPD has been recognized, but there has been no comprehensive evaluation of the impact of GERD on COPD-related health status and patient-centered outcomes.
METHODS: Cross-sectional and longitudinal study of 4,483 participants in the COPDGene cohort who met GOLD criteria for COPD. Physician-diagnosed GERD was ascertained by questionnaire. Clinical features, spirometry and imaging were compared between COPD subjects without versus with GERD. We evaluated the relationship between GERD and symptoms, exacerbations and markers of microaspiration in univariate and multivariate models. Associations were additionally tested for the confounding effect of covariates associated with a diagnosis of GERD and the use of proton-pump inhibitor medications (PPIs). To determine whether GERD is simply a marker for the presence of other conditions independently associated with worse COPD outcomes, we also tested models incorporating a GERD propensity score.
RESULTS: GERD was reported by 29% of subjects with female predominance. Subjects with GERD were more likely to have chronic bronchitis symptoms, higher prevalence of prior cardiovascular events (combined myocardial infarction, coronary artery disease and stroke 21.3% vs. 13.4.0%, p < 0.0001). Subjects with GERD also had more severe dyspnea (MMRC score 2.2 vs. 1.8, p < 0.0001), and poorer quality of life (QOL) scores (St. George's Respiratory Questionnaire (SGRQ) total score 41.8 vs. 34.9, p < 0.0001; SF36 Physical Component Score 38.2 vs. 41.4, p < 0.0001). In multivariate models, a significant relationship was detected between GERD and SGRQ (3.4 points difference, p < 0.001) and frequent exacerbations at baseline (≥2 exacerbation per annum at inclusion OR 1.40, p = 0.006). During a mean follow-up time of two years, GERD was also associated with frequent (≥2/year exacerbations OR 1.40, p = 0.006), even in models in which PPIs, GERD-PPI interactions and a GERD propensity score were included. PPI use was associated with frequent exacerbator phenotype, but did not meaningfully influence the GERD-exacerbation association.
CONCLUSIONS: In COPD the presence of physician-diagnosed GERD is associated with increased symptoms, poorer QOL and increased frequency of exacerbations at baseline and during follow-up. These associations are maintained after controlling for PPI use. The PPI-exacerbations association could result from confounding-by-indication.
Kinsey MC, Estepar RSJ, Zhao Y, Yu X, Diao N, Heist RS, Wain JC, Mark EJ, Washko G, Christiani DC.
Invasive adenocarcinoma of the lung is associated with the upper lung regions. Lung Cancer 2014;84(2):145-50.
AbstractOBJECTIVES: We postulated that ventilation-perfusion (V/Q) relationships within the lung might influence where lung cancer occurs. To address this hypothesis we evaluated the location of lung adenocarcinoma, by both tumor lobe and superior-inferior regional distribution, and associated variables such as emphysema.
MATERIALS AND METHODS: One hundred fifty-nine cases of invasive adenocarcinoma and adenocarcinoma with lepidic features were visually evaluated to identify lobar or regional tumor location. Regions were determined by automated division of the lungs into three equal volumes: (upper region, middle region, or lower region). Automated densitometry was used to measure radiographic emphysema.
RESULTS: The majority of invasive adenocarcinomas occurred in the upper lobes (69%), with 94% of upper lobe adenocarcinomas occurring in the upper region of the lung. The distribution of adenocarcinoma, when classified as upper or lower lobe, was not different between invasive adenocarcinoma and adenocarcinoma with lepidic features (formerly bronchioloalveolar cell carcinoma, P = 0.08). Regional distribution of tumor was significantly different between invasive adenocarcinoma and adenocarcinoma with lepidic features (P = 0.001). Logistic regression analysis with the outcome of invasive adenocarcinoma histology was used to adjust for confounders. Tumor region continued to be a significant predictor (OR 8.5, P = 0.008, compared to lower region), whereas lobar location of tumor was not (P = 0.09). In stratified analysis, smoking was not associated with region of invasive adenocarcinoma occurrence (P = 0.089). There was no difference in total emphysema scores between invasive adenocarcinoma cases occurring in each of the three regions (P = 0.155). There was also no difference in the distribution of region of adenocarcinoma occurrence between quartiles of emphysema (P = 0.217).
CONCLUSION: Invasive adenocarcinoma of the lung is highly associated with the upper lung regions. This association is not related to smoking, history of COPD, or total emphysema. The regional distribution of invasive adenocarcinoma may be due to V/Q relationships or other local factors.
Mizumura K, Cloonan SM, Nakahira K, Bhashyam AR, Cervo M, Kitada T, Glass K, Owen CA, Mahmood A, Washko GR, Hashimoto S, Ryter SW, Choi AMK.
Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD. J Clin Invest 2014;124(9):3987-4003.
AbstractThe pathogenesis of chronic obstructive pulmonary disease (COPD) remains unclear, but involves loss of alveolar surface area (emphysema) and airway inflammation (bronchitis) as the consequence of cigarette smoke (CS) exposure. Previously, we demonstrated that autophagy proteins promote lung epithelial cell death, airway dysfunction, and emphysema in response to CS; however, the underlying mechanisms have yet to be elucidated. Here, using cultured pulmonary epithelial cells and murine models, we demonstrated that CS causes mitochondrial dysfunction that is associated with a reduction of mitochondrial membrane potential. CS induced mitophagy, the autophagy-dependent elimination of mitochondria, through stabilization of the mitophagy regulator PINK1. CS caused cell death, which was reduced by administration of necrosis or necroptosis inhibitors. Genetic deficiency of PINK1 and the mitochondrial division/mitophagy inhibitor Mdivi-1 protected against CS-induced cell death and mitochondrial dysfunction in vitro and reduced the phosphorylation of MLKL, a substrate for RIP3 in the necroptosis pathway. Moreover, Pink1(-/-) mice were protected against mitochondrial dysfunction, airspace enlargement, and mucociliary clearance (MCC) disruption during CS exposure. Mdivi-1 treatment also ameliorated CS-induced MCC disruption in CS-exposed mice. In human COPD, lung epithelial cells displayed increased expression of PINK1 and RIP3. These findings implicate mitophagy-dependent necroptosis in lung emphysematous changes in response to CS exposure, suggesting that this pathway is a therapeutic target for COPD.
Diaz AA, Come CE, Mannino DM, Pinto-Plata V, Divo MJ, Bigelow C, Celli B, Washko GR.
Obstructive lung disease in Mexican Americans and non-Hispanic whites: an analysis of diagnosis and survival in the National Health and Nutritional Examination Survey III Follow-up Study. Chest 2014;145(2):282-289.
AbstractBACKGROUND: Although obstructive lung disease (OLD), which includes COPD, affects all the populations, Hispanics seem to be protected against COPD development and progression. Whether this advantage translates into a survival benefit for this population is unknown. We aimed to determine the risk for OLD in Mexican Americans, the largest US Hispanic subgroup, compared with non-Hispanic whites and to assess all-cause mortality in subjects with OLD.
METHODS: We assessed the relationships between Mexican American ethnicity and spirometric OLD and risk of death among 6,456 US adults aged ≥ 40 years who participated in the Third National Health and Nutritional Examination Survey Follow-up Study. We used logistic and Cox regression analyses to estimate the OR for OLD among Mexican Americans and the hazard ratio (HR) for all-cause mortality among Mexican Americans with OLD, respectively.
RESULTS: After adjustment for demographic factors, socioeconomic status, and COPD risk factors, Mexican Americans had decreased odds of OLD diagnosis compared with whites (OR, 0.72 [95% CI, 0.54-0.95]). Among the 1,734 participants with OLD, 1,054 (60.8%) died during median follow-up of 12 years. In an adjusted model, Mexican Americans had no advantage in mortality from all causes (HR, 0.88 [95% CI, 0.69-1.13]). After accounting for the fact that some Mexican Americans may have moved back to Mexico and died there (thus, had no US death certificate), there was still no difference in mortality between these groups.
CONCLUSIONS: Although Mexican Americans appear to have lower risk for OLD, subjects of this ethnicity with OLD do not seem to have a survival advantage.
Hobbs BD, Foreman MG, Bowler R, Jacobson F, Make BJ, Castaldi PJ, San José Estépar R, Silverman EK, Hersh CP.
Pneumothorax risk factors in smokers with and without chronic obstructive pulmonary disease. Ann Am Thorac Soc 2014;11(9):1387-94.
AbstractRATIONALE: The demographic, physiological, and computed tomography (CT) features associated with pneumothorax in smokers with and without chronic obstructive pulmonary disease (COPD) are not clearly defined.
OBJECTIVES: We evaluated the hypothesis that pneumothorax in smokers is associated with male sex, tall and thin stature, airflow obstruction, and increased total and subpleural emphysema.
METHODS: The study included smokers with and without COPD from the COPDGene Study, with quantitative chest CT analysis. Pleural-based emphysema was assessed on the basis of local histogram measures of emphysema. Pneumothorax history was defined by subject self-report.
MEASUREMENTS AND MAIN RESULTS: Pneumothorax was reported in 286 (3.2%) of 9,062 participants. In all participants, risk of prior pneumothorax was significantly higher in men (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.08-2.22) and non-Hispanic white subjects (OR, 1.90; 95% CI, 1.34-2.69). Risk of prior pneumothorax was associated with increased percent CT emphysema in all participants and participants with COPD (OR, 1.04 for each 1% increase in emphysema; 95% CI, 1.03-1.06). Increased pleural-based emphysema was independently associated with risk of past pneumothorax in all participants (OR, 1.05 for each 1% increase; 95% CI, 1.01-1.10). In smokers with normal spirometry, risk of past pneumothorax was associated with non-Hispanic white race and lifetime smoking intensity (OR, 1.20 for every 10 pack-years; 95% CI, 1.09-1.33).
CONCLUSIONS: Among smokers, pneumothorax is associated with male sex, non-Hispanic white race, and increased percentage of total and subpleural CT emphysema. Pneumothorax was not independently associated with height or lung function, even in participants with COPD. Clinical trial registered with
www.clinicaltrials.gov (NCT00608764).
Bowler RP, Kim V, Regan E, Williams AAA, Santorico SA, Make BJ, Lynch DA, Hokanson JE, Washko GR, Bercz P, Soler X, Marchetti N, Criner GJ, Ramsdell J, Han MLK, Demeo D, Anzueto A, Comellas A, Crapo JD, Dransfield M, Wells MJ, Hersh CP, MacIntyre N, Martinez F, Nath HP, Niewoehner D, Sciurba F, Sharafkhaneh A, Silverman EK, van Beek EJR, Wilson C, Wendt C, Wise RA.
Prediction of acute respiratory disease in current and former smokers with and without COPD. Chest 2014;146(4):941-950.
AbstractBACKGROUND: The risk factors for acute episodes of respiratory disease in current and former smokers who do not have COPD are unknown.
METHODS: Eight thousand two hundred forty-six non-Hispanic white and black current and former smokers in the Genetic Epidemiology of COPD (COPDGene) cohort had longitudinal follow-up (LFU) every 6 months to determine acute respiratory episodes requiring antibiotics or systemic corticosteroids, an ED visit, or hospitalization. Negative binomial regression was used to determine the factors associated with acute respiratory episodes. A Cox proportional hazards model was used to determine adjusted hazard ratios (HRs) for time to first episode and an acute episode of respiratory disease risk score.
RESULTS: At enrollment, 4,442 subjects did not have COPD, 658 had mild COPD, and 3,146 had moderate or worse COPD. Nine thousand three hundred three acute episodes of respiratory disease and 2,707 hospitalizations were reported in LFU (3,044 acute episodes of respiratory disease and 827 hospitalizations in those without COPD). Major predictors included acute episodes of respiratory disease in year prior to enrollment (HR, 1.20; 95% CI, 1.15-1.24 per exacerbation), airflow obstruction (HR, 0.94; 95% CI, 0.91-0.96 per 10% change in % predicted FEV1), and poor health-related quality of life (HR, 1.07; 95% CI, 1.06-1.08 for each 4-unit increase in St. George's Respiratory Questionnaire score). Risks were similar for those with and without COPD.
CONCLUSIONS: Although acute episode of respiratory disease rates are higher in subjects with COPD, risk factors are similar, and at a population level, there are more episodes in smokers without COPD.
Rahaghi FN, Lazea D, Dihya S, San José Estépar R, Bueno R, Sugarbaker D, Frendl G, Washko GR.
Preoperative pulmonary vascular morphology and its relationship to postpneumonectomy hemodynamics. Acad Radiol 2014;21(6):704-10.
AbstractRATIONALE AND OBJECTIVES: Pulmonary edema and pulmonary hypertension are postsurgical complications of pneumonectomy that may represent the remaining pulmonary vasculature's inability to accommodate the entirety of the cardiac output. Quantification of the aggregate pulmonary vascular cross-sectional area (CSA) has been used to study the development of pulmonary vascular disease in smokers. In this study, we applied this technique to demonstrate the potential utility of pulmonary vascular quantification in surgical risk assessment. Our hypothesis was that those subjects with the lowest aggregate vascular CSA in the nonoperative lung would be most likely to have elevated pulmonary vascular pressures in the postoperative period.
MATERIALS AND METHODS: A total of 61 subjects with postoperative hemodynamics and adequate imaging were identified from 159 patients undergoing pneumonectomies for mesothelioma. The total CSA of blood vessels perpendicular to the plane of computed tomographic (CT) scan slices was computed for blood vessels <5 mm(2) (CSA 5 mm). This measurement expressed as a percentage of lung parenchyma area (CSA 5%) was compared to postoperative hemodynamic measurements obtained by right heart catheterization.
RESULTS: In patients where a contrasted CT scan was used (n = 26), CSA 5% was correlated with postoperative day 0 minimum cardiac index (R = 0.37, P = .03) but not with the maximum pulmonary arterial pressures. In patients with noncontrast CT scans (n = 35), CSA 5% was inversely correlated with postoperative day 0 maximum pulmonary arterial pressures (R = 0.43, P = .03) but not with the minimum cardiac index. The preoperative perfusion fraction of the nonsurgical lung did not correlate with postoperative hemodynamics.
CONCLUSIONS: CSA of pulmonary vasculature with an area ≤5 mm(2) has potential in estimating the ability of pulmonary vascular bed to accommodate postsurgical changes in pneumonectomy.
Díaz AA, Tringler MF.
Prevalence of hypertension in rural populations from Ibero-America and the Caribbean. Rural Remote Health 2014;14:2591.
AbstractINTRODUCTION: Hypertension and cardiovascular risk factors are widespread in developing countries, but little is known about cardiovascular risk profiles in rural communities from Ibero-America and the Caribbean. The aim of the present study was to evaluate the peer-reviewed literature published from 1990 to 2012 relating to the prevalence of hypertension in rural populations from Ibero-America and the Caribbean.
METHODS: A bibliographic search was conducted in MEDLINE, SCIELO and LILACS databases. Included were population-based studies in which prevalence of hypertension in adults was reported.
RESULTS: A total of 30 peer-reviewed publications were identified that reported the prevalence of hypertension in 33 143 patients. The crude hypertension prevalence reported from rural Ibero-America was 32.6% (95% confidence interval: 31.4-32.5%; range: 1.8-52%). The prevalence of hypertension was lower in aboriginal populations than in other rural communities (19.5% vs 36%). Only nine studies assessed the awareness, treatment, and level of control of hypertension (means 54%, 57%, and 14% respectively). The most prevalent cardiovascular risk factors were abdominal obesity (39%) and overweight (39%).
CONCLUSIONS: Hypertension is of public health importance in rural Ibero-America and the Caribbean, with evidence of considerable under-diagnosis, treatment, and control. There is an urgent need to develop strategies to prevent, detect, treat, and control hypertension effectively in this region.
McDonald M-LN, Diaz AA, Ross JC, Estepar RSJ, Zhou L, Regan EA, Eckbo E, Muralidhar N, Come CE, Cho MH, Hersh CP, Lange C, Wouters E, Casaburi RH, Coxson HO, MacNee W, Rennard SI, Lomas DA, Agusti A, Celli BR, Black-Shinn JL, Kinney GL, Lutz SM, Hokanson JE, Silverman EK, Washko GR.
Quantitative computed tomography measures of pectoralis muscle area and disease severity in chronic obstructive pulmonary disease. A cross-sectional study. Ann Am Thorac Soc 2014;11(3):326-34.
AbstractRATIONALE: Muscle wasting in chronic obstructive pulmonary disease (COPD) is associated with a poor prognosis and is not readily assessed by measures of body mass index (BMI). BMI does not discriminate between relative proportions of adipose tissue and lean muscle and may be insensitive to early pathologic changes in body composition. Computed tomography (CT)-based assessments of the pectoralis muscles may provide insight into the clinical significance of skeletal muscles in smokers.
OBJECTIVES: We hypothesized that objective assessment of the pectoralis muscle area on chest CT scans provides information that is clinically relevant and independent of BMI.
METHODS: Data from the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) Study (n = 73) were used to assess the relationship between pectoralis muscle area and fat-free mass. We then used data in a subset (n = 966) of a larger cohort, the COPDGene (COPD Genetic Epidemiology) Study, to explore the relationship between pectoralis muscle area and COPD-related traits.
MEASUREMENTS AND MAIN RESULTS: We first investigated the correlation between pectoralis muscle area and fat-free mass, using data from a subset of participants in the ECLIPSE Study. We then further investigated pectoralis muscle area in COPDGene Study participants and found that higher pectoralis muscle area values were associated with greater height, male sex, and younger age. On subsequent clinical correlation, compared with BMI, pectoralis muscle area was more significantly associated with COPD-related traits, including spirometric measures, dyspnea, and 6-minute-walk distance (6MWD). For example, on average, each 10-cm(2) increase in pectoralis muscle area was associated with a 0.8-unit decrease in the BODE (Body mass index, Obstruction, Dyspnea, Exercise) index (95% confidence interval, -1.0 to -0.6; P < 0.001). Furthermore, statistically significant associations between pectoralis muscle area and COPD-related traits remained even after adjustment for BMI.
CONCLUSIONS: CT-derived pectoralis muscle area provides relevant indices of COPD morbidity that may be more predictive of important COPD-related traits than BMI. However, the relationship with clinically relevant outcomes such as hospitalization and death requires additional investigation. Pectoralis muscle area is a convenient measure that can be collected in the clinical setting in addition to BMI.
Criner GJ, Connett JE, Aaron SD, Albert RK, Bailey WC, Casaburi R, Cooper AJD, Curtis JL, Dransfield MT, Han MLK, Make B, Marchetti N, Martinez FJ, Niewoehner DE, Scanlon PD, Sciurba FC, Scharf SM, Sin DD, Voelker H, Washko GR, Woodruff PG, Lazarus SC.
Simvastatin for the prevention of exacerbations in moderate-to-severe COPD. N Engl J Med 2014;370(23):2201-10.
AbstractBACKGROUND: Retrospective studies have shown that statins decrease the rate and severity of exacerbations, the rate of hospitalization, and mortality in chronic obstructive pulmonary disease (COPD). We prospectively studied the efficacy of simvastatin in preventing exacerbations in a large, multicenter, randomized trial.
METHODS: We designed the Prospective Randomized Placebo-Controlled Trial of Simvastatin in the Prevention of COPD Exacerbations (STATCOPE) as a randomized, controlled trial of simvastatin (at a daily dose of 40 mg) versus placebo, with annual exacerbation rates as the primary outcome. Patients were eligible if they were 40 to 80 years of age, had COPD (defined by a forced expiratory volume in 1 second [FEV1] of less than 80% and a ratio of FEV1 to forced vital capacity of less than 70%), and had a smoking history of 10 or more pack-years, were receiving supplemental oxygen or treatment with glucocorticoids or antibiotic agents, or had had an emergency department visit or hospitalization for COPD within the past year. Patients with diabetes or cardiovascular disease and those who were taking statins or who required statins on the basis of Adult Treatment Panel III criteria were excluded. Participants were treated from 12 to 36 months at 45 centers.
RESULTS: A total of 885 participants with COPD were enrolled for approximately 641 days; 44% of the patients were women. The patients had a mean (±SD) age of 62.2±8.4 years, an FEV1 that was 41.6±17.7% of the predicted value, and a smoking history of 50.6±27.4 pack-years. At the time of study closeout, the low-density lipoprotein cholesterol levels were lower in the simvastatin-treated patients than in those who received placebo. The mean number of exacerbations per person-year was similar in the simvastatin and placebo groups: 1.36±1.61 exacerbations and 1.39±1.73 exacerbations, respectively (P=0.54). The median number of days to the first exacerbation was also similar: 223 days (95% confidence interval [CI], 195 to 275) and 231 days (95% CI, 193 to 303), respectively (P=0.34). The number of nonfatal serious adverse events per person-year was similar, as well: 0.63 events with simvastatin and 0.62 events with placebo. There were 30 deaths in the placebo group and 28 in the simvastatin group (P=0.89).
CONCLUSIONS: Simvastatin at a daily dose of 40 mg did not affect exacerbation rates or the time to a first exacerbation in patients with COPD who were at high risk for exacerbations. (Funded by the National Heart, Lung, and Blood Institute and the Canadian Institutes of Health Research; STATCOPE ClinicalTrials.gov number, NCT01061671.).
Ross JC, Diaz AA, Okajima Y, Wassermann D, Washko GR, Dy J, San Jose Estépar R.
Airway labeling using a Hidden Markov Tree Model. In: Biomedical Imaging (ISBI), 2014 IEEE 11th International Symposium onBiomedical Imaging (ISBI), 2014 IEEE 11th International Symposium on. 2014 p. 554-558.
AbstractWe present a novel airway labeling algorithm based on a Hidden Markov Tree Model (HMTM). We obtain a collection of discrete points along the segmented airway tree using particles sampling [1] and establish topology using Kruskal's minimum spanning tree algorithm. Following this, our HMTM algorithm probabilistically assigns labels to each point. While alternative methods label airway branches out to the segmental level, we describe a general method and demonstrate its performance out to the subsubsegmental level (two generations further than previously published approaches). We present results on a collection of 25 computed tomography (CT) datasets taken from a Chronic Obstructive Pulmonary Disease (COPD) study.
Wasserman D, Ross JC, Washko GR, Wells WM, San Jose Estépar R.
Deformable Registration of Feature-Endowed Point Sets Based on Tensor Fields. In: Computer Vision and Pattern Recognition (CVPR), 2014 IEEE Conference onComputer Vision and Pattern Recognition (CVPR), 2014 IEEE Conference on. 2014 p. 2729-2735.
AbstractThe main contribution of this work is a framework to register anatomical structures characterized as a point set where each point has an associated symmetric matrix. These matrices can represent problem-dependent characteristics of the registered structure. For example, in airways, matrices can represent the orientation and thickness of the structure. Our framework relies on a dense tensor field representation which we implement sparsely as a kernel mixture of tensor fields. We equip the space of tensor fields with a norm that serves as a similarity measure. To calculate the optimal transformation between two structures we minimize this measure using an analytical gradient for the similarity measure and the deformation field, which we restrict to be a diffeomorphism. We illustrate the value of our tensor field model by comparing our results with scalar and vector field based models. Finally, we evaluate our registration algorithm on synthetic data sets and validate our approach on manually annotated airway trees.
San Jose Estépar R, Vosburgh KG.
Multimodality Guidance in Endoscopic and Laparoscopic Abdominal Procedures. In:
Jolesz FA Intraoperative Imaging and Image-Guided Therapy. New York, NY: Springer New York; 2014 p. 767-778-778.
AbstractInterventions in the body increase markedly in difficulty when the instrument body and distal tip cannot be seen from an outside vantage point. Thus most endoscopic applications, including cystoscopy, neuroendoscopy, bronchoscopy, upper GI endoscopy, and colonoscopy, require long training periods to attain proficiency, and even experts may find themselves disoriented during a procedure. As well, retroperitoneal laparoscopy, where the distal tip of the laparoscope is not seen directly from the pneumoperitoneal space, faces similar challenges. In the following, we will discuss “endoscopy” with the understanding that the techniques may also be applied to laparoscopy.
Kurugol S, Washko GR, San Jose Estépar R.
Ranking and classification of monotonic emphysema patterns with a multi-class hierarchical approach. In: Biomedical Imaging (ISBI), 2014 IEEE 11th International Symposium onBiomedical Imaging (ISBI), 2014 IEEE 11th International Symposium on. 2014 p. 1031-1034.
AbstractEmphysema has distinct and well-defined visually apparent CT patterns called centrilobular and panlobular emphysema. Existing studies concentrated on the classification of these patterns but they have not looked at the complete evolution of this disease as the destruction of lung parenchyma progresses from normal lung tissue to mild, moderate, and severe disease with complete effacement of the lung architecture. In this paper, we discretize this continuous process into five classes of increasing disease severity and construct a training set of 1161 CT patches. We exploit three solutions to this monotonic multi-class classification problem: a global rankSVM for ranking, hierarchical SVM for classification and a combination of these two, which we call a hierarchical rankSVM. Results showed that both hierarchical approaches were computationally efficient. The classification accuracies were slightly better for hierarchical SVM. However, in addition to classification, ranking approaches also provided a ranking of patterns, which can be utilized as a continuous disease progression score. In terms of the classification accuracy and ratio of pair-wise constraints satisfied, hierarchical rankSVM outperformed the global rankSVM.
Diaz AA, Hardin ME, Come CE, San Jose Estépar R, Ross JC, Kurugol S, Okajima Y, Han MLK, Kim V, Ramsdell J, Silverman EK, Crapo JD, Lynch DA, Make B, Barr GR, Hersh CP, Washko GR.
Childhood-Onset Asthma in Smokers. Association between CT Measures of Airway Size, Lung Function, and Chronic Airflow Obstruction. Annals ATSAnnals ATS 2014;11:1371-1378.
AbstractRationale and Objectives: Asthma is associated with chronic airflow obstruction (CAO). Our goal was to assess the association of computed tomographic (CT) measures of airway wall volume (WV) and lumen volume (LV) with the forced expiratory volume in one second (FEV1) and CAO in smokers with childhood-onset asthma (CA). Methods: We analyzed clinical, lung function, and volumetric CT airway volumes data from 7,266 smokers including 590 with CA. Small WV and small LV of segmental airways were defined as measures 1 SD below the mean. We assessed the association between small WV, small LV, FEV1 and CAO (post-bronchodilator FEV1/forced vital capacity ratio <0.7) using linear and logistic models. Measurements and Main Results: CA subjects had smaller WV and LV than those without CA (mean ± SD, 371.3 ± 92.5mm3 vs. 388.7 ± 94.0mm3, P<0.0001; 230.8 ± 76.9 mm3 vs. 257.4 ± 80.9mm3, P<0.0001). Among CA subjects, those with the smallest WV and LV had the lowest FEV1 and greatest odds of CAO. A similar tendency was seen in those without CA. When comparing these 2 groups, small WV and small LV were more strongly associated with FEV1 (for WV, β [95%CI] -331ml [-488 - -174] vs. -244ml [-294 - -194]; for LV, -534ml [-669 - -398] vs. -435ml [-485 - -386] and CAO (Odds ratio 2.10 (1.27-3.46) vs. 2.02 [1.72-2.36]; 4.32 [2.64-7.08] vs. 3.55 [3.00-4.19], respectively) among CA subjects in multivariate models. Conclusion: In smokers with CA smaller airways are associated with reduced lung function and chronic airflow obstruction.
Hobbs BD, Foreman MG, Bowler R, Jacobson F, Make BJ, Castaldi PJ, San Jose Estépar R, Silverman EK, Hersh CP.
Pneumothorax Risk Factors in Smokers with and without Chronic Obstructive Pulmonary Disease. Annals ATSAnnals ATS 2014;11:1387-1394.
AbstractRationale: The demographic, physiologic, and computed tomography (CT) features associated with pneumothorax in smokers with and without chronic obstructive pulmonary disease (COPD) are not clearly defined. Objectives: We evaluated the hypothesis that pneumothorax in smokers is associated with male gender, tall and thin stature, airflow obstruction, and increased total and sub-pleural emphysema. Methods: The study included smokers with and without COPD from the COPDGene study, with quantitative chest CT analysis. Pleural-based emphysema was assessed using local histogram measures of emphysema. Pneumothorax history was defined by subject self-report. Measurements and Main Results: Pneumothorax was reported in 286 (3.2%) of 9,062 participants. In all participants, risk of prior pneumothorax was significantly higher in men (OR 1.55, 95% CI 1.08 - 2.22) and non-Hispanic whites (OR 1.90, 95% CI 1.34 - 2.69). Risk of prior pneumothorax was associated with increased percent CT emphysema in all participants and participants with COPD (OR 1.04 for each 1% increase in emphysema, 95% CI 1.03 - 1.06). Increased pleural-based emphysema was independently associated with risk of past pneumothorax in all participants (OR 1.05 for each 1% increase, 95% CI 1.01 - 1.10). In smokers with normal spirometry, risk of past pneumothorax was associated with non-Hispanic white race and lifetime smoking intensity (OR 1.20 for every 10 pack-years, 95% CI 1.09 - 1.33). Conclusions: Among smokers, pneumothorax is associated with male gender, non-Hispanic white race, and increased percentage of total and sub-pleural CT emphysema. Pneumothorax was not independently associated with height or lung function, even in participants with COPD. ClinicalTrials.gov Identifier: NCT00608764.
Diaz AA, Zhou L, Young TP, McDonald M-L, Harmouche R, Ross JC, San Jose Estépar R, Wouters EFM, Coxson HO, MacNee W, Rennard S, Maltais F, Kinney GL, Hokanson JE, Washko GR.
Chest CT Measures of Muscle and Adipose Tissue in COPD: Gender-based Differences in Content and in Relationships with Blood Biomarkers. Academic RadiologyAcademic Radiology 2014;21:1255-1261.
AbstractRationale and Objectives Computed tomography (CT) of the chest can be used to assess pectoralis muscle area (PMA) and subcutaneous adipose tissue (SAT) area. Adipose tissue content is associated with inflammatory mediators in chronic obstructive pulmonary disease (COPD) subjects. Based on gender differences in body composition, we aimed to assess the hypothesis that in subjects with COPD, the relationships between PMA, SAT, and blood biomarkers of inflammation differ by gender. Materials and Methods We compared chest CT measures of PMA and SAT on a single slice at aortic arch and supraesternal notch levels from 73 subjects (28 women) with COPD between genders. The relationships of PMA and SAT area to biomarkers were assessed using within-gender regression models. Results Women had a lesser PMA and a greater SAT area than men (difference range for PMA, 13.3–22.8 cm2; for SAT, 11.8–12.4 cm2; P < .05 for all comparisons) at both anatomic levels. These differences in PMA and SAT remained significant after adjustment for age and body mass index. Within-gender regression models adjusted for age showed that SAT was directly associated with C-reactive protein (for aortic arch level, P = .04) and fibrinogen (for both anatomic locations, P = .003) only in women, whereas PMA was not associated with any biomarkers in either gender. Conclusions It appears that in subjects with COPD, there are gender-based differences in the relationships between subcutaneous adipose tissue and inflammatory biomarkers.
acad_radiol_2014_diaz.pdf Rudyanto RD, Kerkstra S, van Rikxoort EM, Fetita C, Brillet P-Y, Lefevre C, Xue W, Zhu X, Liang J, Oksüz I, Unay D, Kadipaşaogˇlu K, San Jose Estépar R, Ross JC, Washko GR, Prieto J-C, Hoyos MH, Orkisz M, Meine H, Hüllebrand M, Stöcker C, Mir FL, Naranjo V, Villanueva E, Staring M, Xiao C, Stoel BC, Fabijanska A, Smistad E, Elster AC, Lindseth F, Foruzan AH, Kiros R, Popuri K, Cobzas D, Jimenez-Carretero D, Santos A, Ledesma-Carbayo MJ, Helmberger M, Urschler M, Pienn M, Bosboom DGH, Campo A, Prokop M, de Jong PA, Ortiz-de-Solorzano C, Muñoz-Barrutia A, van Ginneken B.
Comparing algorithms for automated vessel segmentation in computed tomography scans of the lung: the VESSEL12 study. Medical Image AnalysisMedical Image Analysis 2014;18:1217-1232.
AbstractAbstract The VESSEL12 (VESsel SEgmentation in the Lung) challenge objectively compares the performance of different algorithms to identify vessels in thoracic computed tomography (CT) scans. Vessel segmentation is fundamental in computer aided processing of data generated by 3D imaging modalities. As manual vessel segmentation is prohibitively time consuming, any real world application requires some form of automation. Several approaches exist for automated vessel segmentation, but judging their relative merits is difficult due to a lack of standardized evaluation. We present an annotated reference dataset containing 20 CT scans and propose nine categories to perform a comprehensive evaluation of vessel segmentation algorithms from both academia and industry. Twenty algorithms participated in the VESSEL12 challenge, held at International Symposium on Biomedical Imaging (ISBI) 2012. All results have been published at the VESSEL12 website http://vessel12.grand-challenge.org. The challenge remains ongoing and open to new participants. Our three contributions are: (1) an annotated reference dataset available online for evaluation of new algorithms; (2) a quantitative scoring system for objective comparison of algorithms; and (3) performance analysis of the strengths and weaknesses of the various vessel segmentation methods in the presence of various lung diseases.
Castaldi PJ, Cho MH, San Jose Estépar R, McDonald M-LN, Laird N, Beaty TH, Washko G, Crapo JD, Silverman EK.
Genome-Wide Association Identifies Regulatory Loci Associated with Distinct Local Histogram Emphysema Patterns. American journal of respiratory and critical care medicineAmerican journal of respiratory and critical care medicine 2014;190:399-409.
AbstractRATIONALE:Emphysema is a heritable trait that occurs in smokers with and without chronic obstructive pulmonary disease. Emphysema occurs in distinct pathologic patterns, but the genetic determinants of these patterns are unknown.OBJECTIVES:To identify genetic loci associated with distinct patterns of emphysema in smokers and investigate the regulatory function of these loci.METHODS:Quantitative measures of distinct emphysema patterns were generated from computed tomography scans from smokers in the COPDGene Study using the local histogram emphysema quantification method. Genome-wide association studies (GWAS) were performed in 9,614 subjects for five emphysema patterns, and the results were referenced against enhancer and DNase I hypersensitive regions from ENCODE and Roadmap Epigenomics cell lines.MEASUREMENTS AND MAIN RESULTS:Genome-wide significant associations were identified for seven loci. Two are novel associations (top single-nucleotide polymorphism rs379123 in MYO1D and rs9590614 in VMA8) located within genes that function in cell-cell signaling and cell migration, and five are in loci previously associated with chronic obstructive pulmonary disease susceptibility (HHIP, IREB2/CHRNA3, CYP2A6/ADCK, TGFB2, and MMP12). Five of these seven loci lay within enhancer or DNase I hypersensitivity regions in lung fibroblasts or small airway epithelial cells, respectively. Enhancer enrichment analysis for top GWAS associations (single-nucleotide polymorphisms associated at P < 5 × 10(-6)) identified multiple cell lines with significant enhancer enrichment among top GWAS loci, including lung fibroblasts.CONCLUSIONS:This study demonstrates for the first time genetic associations with distinct patterns of pulmonary emphysema quantified by computed tomography scan. Enhancer regions are significantly enriched among these GWAS results, with pulmonary fibroblasts among the cell types showing the strongest enrichment.