R. Graham Barr

Performance of American Thoracic Society-Recommended Spirometry Reference Values in a Multiethnic Sample of Adults: The Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study

BACKGROUND The American Thoracic Society recommends race-specific spirometric reference values from the National Health and Nutrition Survey (NHANES) III for clinical evaluation of pulmonary function in whites, African-Americans, and Mexican-Americans in the United States and a correction factor of 0.94 for Asian-Americans. We aimed to validate the NHANES III reference equations and the correction factor for Asian-Americans in an independent, multiethnic sample of US adults. METHODS The Multi-Ethnic Study of Atherosclerosis (MESA) recruited self-identified non-Hispanic white, African-American, Hispanic, and Asian-American participants aged 45 to 84 years at six US sites. The MESA-Lung Study assessed prebronchodilator spirometry among 3,893 MESA participants who performed acceptable tests, of whom 1,068 were asymptomatic healthy nonsmokers who performed acceptable spirometry. RESULTS The 1,068 participants were mean age 65 +/- 10 years, 60% female, 25% white, 20% African-American, 23% Hispanic, and 32% Asian-American. Observed values of FEV(1), FEV(6), and FVC among whites, African-Americans, and Hispanics of Mexican origin in MESA-Lung were slightly lower than predicted values based on NHANES III. Observed values among Hispanics of non-Mexican origin were consistently lower. Agreement in classification of participants with airflow obstruction based on lower limit of normal criteria was good (overall kappa = 0.88). For Asian-Americans, a correction factor of 0.88 was more accurate than 0.94. CONCLUSIONS The NHANES III reference equations are valid for use among older adults who are white, African-American, or Hispanic of Mexican origin. Comparison of white and Asian-American participants suggests that a correction factor of 0.88, applied to the predicted and lower limits of normal values, is more appropriate than the currently recommended value of 0.94.

Cluster analysis in the COPDGene study identifies subtypes of smokers with distinct patterns of airway disease and emphysema

Background There is notable heterogeneity in the clinical presentation of patients with COPD. To characterise this heterogeneity, we sought to identify subgroups of smokers by applying cluster analysis to data from the COPDGene study. Methods We applied a clustering method, k-means, to data from 10 192 smokers in the COPDGene study. After splitting the sample into a training and validation set, we evaluated three sets of input features across a range of k (user-specified number of clusters). Stable solutions were tested for association with four COPD-related measures and five genetic variants previously associated with COPD at genome-wide significance. The results were confirmed in the validation set. Findings We identified four clusters that can be characterised as (1) relatively resistant smokers (ie, no/mild obstruction and minimal emphysema despite heavy smoking), (2) mild upper zone emphysema-predominant, (3) airway disease-predominant and (4) severe emphysema. All clusters are strongly associated with COPD-related clinical characteristics, including exacerbations and dyspnoea (p<0.001). We found strong genetic associations between the mild upper zone emphysema group and rs1980057 near HHIP, and between the severe emphysema group and rs8034191 in the chromosome 15q region (p<0.001). All significant associations were replicated at p<0.05 in the validation sample (12/12 associations with clinical measures and 2/2 genetic associations). Interpretation Cluster analysis identifies four subgroups of smokers that show robust associations with clinical characteristics of COPD and known COPD-associated genetic variants.

Relation of cardiovascular risk factors to right ventricular structure and function as determined by magnetic resonance imaging (results from the multi-ethnic study of atherosclerosis).

The effect of cardiovascular risk factors on the left ventricle is well known but their effect on right ventricle has not been studied using advanced imaging techniques. The purpose of the present study was to determine the relation between the cardiovascular risk factors and right ventricular (RV) structure and function and its interaction with the left ventricle. Cardiac magnetic resonance images from 4,204 participants free of clinical cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis were analyzed. Multivariate linear regression models were used to study the cross-sectional association between individual RV parameters and risk factors. All RV parameters, except for ejection fraction, decreased with age (p <0.0001). The RV mass was positively associated with systolic blood pressure (+0.4 g, p <0.0001) and high-density lipoprotein cholesterol (+0.2 g, p <0.0001). It was inversely related with diastolic blood pressure (-0.3 g, p <0.0001) and total cholesterol (-0.2 g, p <0.01). The RV end-diastolic volume was positively associated with systolic blood pressure (+1.6 ml, p <0.01) and high-density lipoprotein cholesterol (+1.8 ml, p <0.0001). It was inversely related with diastolic blood pressure (-2.2 ml, p <0.01), total cholesterol (-1.4 ml, p <0.0001), current smoking (-2.7 ml, p <0.05), and diabetes mellitus (-3.1 ml, p <0.01). The RV ejection fraction was positively associated with systolic blood pressure (+1.0%, p <0.0001), high-density lipoprotein cholesterol (+0.4%, p <0.0001) and inversely with diastolic blood pressure (-0.7%, p <0.0001). In conclusion, the mass and volumes of the right ventricle decrease with age. Cardiovascular risk factors, especially blood pressure and high-density lipoprotein cholesterol, are associated with subclinical changes in the RV mass and volume.

Alternate Healthy Eating Index 2010 and risk of chronic obstructive pulmonary disease among US women and men: prospective study

Objective To investigate the association between the Alternate Healthy Eating Index 2010 (AHEI-2010)—a measure of diet quality—and the risk of chronic obstructive pulmonary disease (COPD). Design Prospective cohort study. Setting Participants in the Nurses’ Health Study and the Health Professionals Follow-up Study, United States. Participants 73 228 female nurses from 1984 to 2000 and 47 026 men from 1986 to 1998, who completed biennial questionnaires. Main outcome measures The primary outcome was the self report of newly diagnosed COPD. Multivariable Cox proportional hazards models were adjusted for age, physical activity, body mass index, total energy intake, smoking, second hand tobacco exposure (only in the Nurses’ Health Study), race/ethnicity, physician visits, US region, spouse’s highest educational attainment (only in the Nurses’ Health Study), and menopausal status (only in the Nurses’ Health Study). Results Over the study period, 723 cases of newly diagnosed COPD occurred in women and 167 in men. In the pooled analysis, a significant negative association was seen between the risk of newly diagnosed COPD and fifths of the AHEI-2010: hazard ratios were 0.81 (95% confidence interval 0.51 to 1.29) for the second fifth, 0.98 (0.80 to 1.18) for the third fifth, 0.74 (0.59 to 0.92) for the fourth fifth, and 0.67 (0.53 to 0.85) for participants who ate the healthiest diet according to the AHEI-2010 (that is, were in the highest fifth), compared with those who ate the less healthy diet (participants in the lowest fifth). Similar findings were observed among ex-smokers and current smokers. Conclusions A higher AHEI-2010 diet score (reflecting high intakes of whole grains, polyunsaturated fatty acids, nuts, and long chain omega-3 fats and low intakes of red/processed meats, refined grains, and sugar sweetened drinks) was associated with a lower risk of COPD in both women and men. These findings support the importance of a healthy diet in multi-interventional programs to prevent COPD.

Percent Emphysema and Right Ventricular Structure and Function: The Multi-Ethnic Study of Atherosclerosis-Lung and Multi-Ethnic Study of Atherosclerosis-Right Ventricle Studies

BACKGROUND Severe COPD can lead to cor pulmonale and emphysema and is associated with impaired left ventricular (LV) filling. We evaluated whether emphysema and airflow obstruction would be associated with changes in right ventricular (RV) structure and function and whether these associations would differ by smoking status. METHODS The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac MRI on 5,098 participants without clinical cardiovascular disease aged 45 to 84 years. RV and emphysema measures were available for 4,188 participants. Percent emphysema was defined as the percentage of voxels below -910 Hounsfield units in the lung windows on cardiac CT scans. Generalized additive models were used to control for confounders and adjust for respective LV parameters. RESULTS Participants consisted of 13% current smokers, 36% former smokers, and 52% never smokers. Percent emphysema was inversely associated with RV end-diastolic volume, stroke volume, cardiac output, and mass prior to adjustment for LV measures. After adjustment for LV end-diastolic volume, greater percent emphysema was associated with greater RV end-diastolic volume (+1.5 mL, P=.03) among current smokers, smaller RV end-diastolic volume (-0.8 mL, P=.02) among former smokers, and similar changes among never smokers. CONCLUSIONS Percent emphysema was associated with smaller RV volumes and lower mass. The relationship of emphysema to cardiac function is complex but likely involves increased pulmonary vascular resistance, predominantly with reduced cardiac output, pulmonary hyperinflation, and accelerated cardiopulmonary aging.

High attenuation areas on chest computed tomography in community-dwelling adults: the MESA study

Evidence suggests that lung injury, inflammation and extracellular matrix remodelling precede lung fibrosis in interstitial lung disease (ILD). We examined whether a quantitative measure of increased lung attenuation on computed tomography (CT) detects lung injury, inflammation and extracellular matrix remodelling in community-dwelling adults sampled without regard to respiratory symptoms or smoking. We measured high attenuation areas (HAA; percentage of lung voxels between −600 and −250 Hounsfield Units) on cardiac CT scans of adults enrolled in the Multi-Ethnic Study of Atherosclerosis. HAA was associated with higher serum matrix metalloproteinase-7 (mean adjusted difference 6.3% per HAA doubling, 95% CI 1.3–11.5), higher interleukin-6 (mean adjusted difference 8.8%, 95% CI 4.8–13.0), lower forced vital capacity (FVC) (mean adjusted difference −82 mL, 95% CI −119–−44), lower 6-min walk distance (mean adjusted difference −40 m, 95% CI −1–−80), higher odds of interstitial lung abnormalities at 9.5 years (adjusted OR 1.95, 95% CI 1.43–2.65), and higher all cause-mortality rate over 12.2 years (HR 1.58, 95% CI 1.39–1.79). High attenuation areas are associated with biomarkers of inflammation and extracellular matrix remodelling, reduced lung function, interstitial lung abnormalities, and a higher risk of death among community-dwelling adults. Increased lung attenuation on CT may identify subclinical lung injury and inflammation in community-dwelling adults http://ow.ly/97k3300tvKX

Pulmonary CT and MRI phenotypes that help explain chronic pulmonary obstruction disease pathophysiology and outcomes

Pulmonary x‐ray computed tomographic (CT) and magnetic resonance imaging (MRI) research and development has been motivated, in part, by the quest to subphenotype common chronic lung diseases such as chronic obstructive pulmonary disease (COPD). For thoracic CT and MRI, the main COPD research tools, disease biomarkers are being validated that go beyond anatomy and structure to include pulmonary functional measurements such as regional ventilation, perfusion, and inflammation. In addition, there has also been a drive to improve spatial and contrast resolution while at the same time reducing or eliminating radiation exposure. Therefore, this review focuses on our evolving understanding of patient‐relevant and clinically important COPD endpoints and how current and emerging MRI and CT tools and measurements may be exploited for their identification, quantification, and utilization. Since reviews of the imaging physics of pulmonary CT and MRI and reviews of other COPD imaging methods were previously published and well‐summarized, we focus on the current clinical challenges in COPD and the potential of newly emerging MR and CT imaging measurements to address them. Here we summarize MRI and CT imaging methods and their clinical translation for generating reproducible and sensitive measurements of COPD related to pulmonary ventilation and perfusion as well as parenchyma morphology. The key clinical problems in COPD provide an important framework in which pulmonary imaging needs to rapidly move in order to address the staggering burden, costs, as well as the mortality and morbidity associated with COPD. J. MAGN. RESON. IMAGING 2016;43:544–557.

Opportunities and Challenges in the Genetics of COPD 2010: An International COPD Genetics Conference Report

Chronic obstructive pulmonary disease (COPD) is defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) as a disease state characterized by airflow limitation that is not fully reversible (1). Cigarette smoking is the most important risk factor for the development of COPD. Although the dose-response relationship between cigarette smoking and pulmonary function is well-established, there is considerable variability in the reduction in FEV1 among smokers with similar smoking exposures (2, 3). The low percentage of variance in pulmonary function explained by smoking suggests that there could be genetic differences in susceptibility to the effects of cigarette smoking (4, 5). In addition to genetic factors, other environmental determinants such as indoor biomass smoke exposure can be important risk factors for COPD (6). A small percentage of COPD patients (estimated at 1-2%) inherit severe alpha-1 antitrypsin (AAT) deficiency, which proves that genetic factors can in-fluence COPD susceptibility. The discovery of AAT deficiency was a major factor in the development of the Protease-Antiprotease Hypothesis for COPD, which has been one of the prevailing models of disease pathogenesis for more than 40 years. With the substantial impact of AAT deficiency on our understanding of COPD pathogenesis, it was natural to hope that the identification of other COPD susceptibility genes would lead to similar novel insights into COPD. Until recently, however, progress in the identification of additional genetic risk factors for COPD has been slow. To facilitate the development of such research, a meeting of COPD genetics investigators was held on July 13-14,2010 in Boston. The goals of the meeting were: To review the current state of COPD genetics research; To discuss existing study populations for COPD genetics research throughout the world; To consider opportunities for collaborations between different COPD research groups through an International COPD Genetics Consortium; To recognize challenges in building COPD genetics collaborations and to discuss them openly; and, To develop a framework for future collaborative studies. Current status of COPD genetics research Many candidate gene association studies have been performed over the past 40 years, but the results have been largely inconsistent. These inconsistencies likely relate to a variety of methodological issues, including small sample sizes, variable definitions of case and control groups, failure to adjust for multiple statistical testing, and inadequate adjustments for population stratification and smoking exposure. Most of the studies describing COPD-associated polymorphisms were performed in White populations (7). A meta-analysis of 20 polymorphisms in 12 candidate genes involved in the protease-antiprotease balance and several an-tioxidant pathways showed that, after combining independent studies, many of these candidate genes had no association with COPD (8). Another factor likely impeding the progress of identifying COPD susceptibility genes is the lack of accurate phenotypic characterization of this complex and heterogeneous disease. Airflow limitation determined by spirometry has been the most common approach to classify and monitor the disease. Structural changes of the lung including emphysema and small airway obstruction are the primary processes that affect lung function (9), but they are not easily discernable with the simple spirometric measures commonly used for phe-notyping COPD. Recent advances in characterizing pathologic changes such as emphysema and remodeling of the small and large airways by quantitative analyses of image data from multidetector computed tomography (CT), together with physiological testing, have been helpful to differentiate COPD phenotypes (emphysema-predominant, airway-predominant, or mixed)(10). Study populations that have chest CT data may help to better identify COPD-associated genetic variations (11). Other potentially relevant COPD phenotypes, such as cachexia and low exercise capacity, have not been widely analyzed in COPD genetic studies. Perhaps the greatest problem in the candidate gene era of COPD genetic studies was improper candidate gene selection, which reflects our limited understanding of COPD pathogenesis. However, the application of genome-wide association studies (GWAS), which provide an unbiased and comprehensive search throughout the genome for common susceptibility loci, has changed the landscape of COPD genetics. Based on GWAS, three genetic loci have been unequivocally associated with COPD susceptibility, located on chromosome 4 near the HHIP gene, on chromosome 4 in the FAM13A gene, and on chromosome 15 in a block of genes which contains several components of the nicotinic acetyl-choline receptor as well as the IREB2 gene. In 2009, a series of studies provided convincing support for these three genetic loci in COPD susceptibility. Pillai and colleagues found genome-wide significant associations of the CHRNA3/CHRNA5/IREB2 region to COPD (12). DeMeo and colleagues performed gene expression studies of normal vs. COPD lung tissues followed by genetic association analysis of COPD (13), suggesting that at least one of the key COPD genetic determinants in the chromosome 15 GWAS region was IREB2. In the Framingham Heart Study (14), the HHIP region was associated with FEV1/FVC at genome-wide significance with replication of the effect on FEV1/FVC demonstrated in an independent sample drawn from the Family Heart Study, and this same region nearly reached genome-wide significance with COPD susceptibility in the Pillai paper (12). Recently, two papers published in Nature Genetics from large general population samples have provided strong support for the association of HHIP SNPs with FEV1/FVC (15, 16). One of these articles, from the CHARGE Consortium, also found evidence for association of FEV1/FVC with the FAM13A locus (15), which has been strongly associated with COPD susceptibility (17). Moreover, several case-control studies from other European populations have replicated these findings by confirming significant associations to the chromosome 15q25 locus (CHRNA3/CHRNA5/IREB2) (18, 19), chromosome 4q31 locus (HHIP) (20, 21), and chromosome 4q22 locus (FAM13 A) (22). Thus, the frustration of inconsistent genetic association results in COPD from the beginning of the last decade has been replaced by optimism regarding the likely importance of the IREB2/CHRNA3/CHRNA5, HHIP, and FAM13A loci in COPD susceptibility.

Impact of DOTS expansion on tuberculosis related outcomes and costs in Haiti

BackgroundImplementation of the World Health Organizations DOTS strategy (Directly Observed Treatment Short-course therapy) can result in significant reduction in tuberculosis incidence. We estimated potential costs and benefits of DOTS expansion in Haiti from the government, and societal perspectives.MethodsUsing decision analysis incorporating multiple Markov processes (Markov modelling), we compared expected tuberculosis morbidity, mortality and costs in Haiti with DOTS expansion to reach all of the country, and achieve WHO benchmarks, or if the current situation did not change. Probabilities of tuberculosis related outcomes were derived from the published literature. Government health expenditures, patient and family costs were measured in direct surveys in Haiti and expressed in 2003 US

Hormone Replacement Therapy and Obstructive Airway Diseases

.ResultsStarting in 2003, DOTS expansion in Haiti is anticipated to cost