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RATIONALE - Adiposity is associated with low lung function, but the longitudinal relationship between lung function and adiposity is inadequately studied.
OBJECTIVE - To examine the bidirectional longitudinal associations between rapid decline in lung function and adiposity phenotypes in healthy adults.
METHODS - This secondary analysis used a 25-year longitudinal dataset from the Coronary Artery Risk Development in Young Adults (CARDIA) study that enrolled 5115 participants.
MEASUREMENTS - In the first analysis, metabolic syndrome at or before CARDIA year (Y) 10 (Y10) was the predictor, and subsequent rapid decline in forced vital capacity (FVC) or forced expiratory volume in 1 s (FEV) between Y10 and Y20 was the outcome. In the second analysis, rapid decline was the predictor, and incident metabolic syndrome at Y20 and/or Y25 was the outcome. In the third analysis, rapid decline was the predictor, and subsequent CT-assessed regional fat depots at Y25 were the outcome.
RESULTS - Metabolic syndrome at or before Y10 is temporally associated with rapid decline in FVC between Y10 and Y20 (adjusted p=0.04), but this association was explained by body mass index (BMI) at Y10. Rapid decline in FVC or FEV is temporally associated with greater incident metabolic syndrome at Y20 and/or Y25 (adjusted OR 2.10 (1.69, 2.61); p<0.001, and 1.56 (1.26, 1.94); p<0.001, respectively) and greater CT-assessed intrathoracic visceral adiposity at Y25 (adjusted standardised β 0.09; p<0.001 for both analyses). These associations were not explained by BMI levels prior to the outcome measurement.
CONCLUSIONS - Healthy adults with rapid decline in lung function are at risk for developing metabolic syndrome and for disproportionate accumulation of intrathoracic visceral fat. Metabolic abnormalities may be an early extrapulmonary manifestation of lung impairment that may be preventable by improving lung health.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
Cardiopulmonary disease is the leading cause of mortality in adults with sickle cell disease (SCD). Elevated tricuspid regurgitant jet velocity (TRJV) and reduced forced expiratory volume in 1 second (FEV ) %predicted are associated with early mortality in SCD; however their relationship and combined effect on survival is unknown. We investigated the relationship between TRJV and FEV %predicted, and their combined effect on mortality, in a retrospective cohort of 189 adults with SCD who underwent both pulmonary function testing and echocardiography. Nineteen (9.9%) of 189 patients died over a median follow-up of 1.4 years; cardiopulmonary disease was the major cause of death in 52.6%. FEV %predicted was negatively associated with TRJV (Spearman rho, -0.34, P < 0.001). Individuals with FEV %predicted ≤70% were more likely to have an elevated TRJV ≥2.5 m/second, compared to those with FEV %predicted >70% [45.8% versus 17.1%; odds ratio (OR) 4.1 (95% Confidence interval ([CI] 2.1-8.0); P = 0.001]. In a multivariable cox regression model, the combination of TRJV ≥2.5 m/second and FEV %predicted ≤70% predicted earlier mortality [hazard ratio (HR) 4.97 (95% CI 1.30-18.91; P = 0.019)] after adjusting for age, sex, and nephropathy. Both FEV %predicted ≤70% and TRJV ≥2.5 m/second were independently associated with nephropathy [OR 4.48 (95% CI 1.51-13.31); P = 0.004] and [OR 3.27 (95% CI 1.19-9.00); P = 0.017], respectively. In conclusion, pulmonary and cardiac impairment are associated with, and contribute to mortality in SCD. Therapies aimed at improving reduced FEV %predicted and elevated TRJV could improve survival in patients with SCD. Am. J. Hematol. 92:125-130, 2017. © 2016 Wiley Periodicals, Inc.
© 2016 Wiley Periodicals, Inc.
BACKGROUND - The Lung Cancer Risk Test (LCRT) trial is a prospective cohort study comparing lung cancer incidence among persons with a positive or negative value for the LCRT, a 15 gene test measured in normal bronchial epithelial cells (NBEC). The purpose of this article is to describe the study design, primary endpoint, and safety; baseline characteristics of enrolled individuals; and establishment of a bio-specimen repository.
METHODS/DESIGN - Eligible participants were aged 50-90 years, current or former smokers with 20 pack-years or more cigarette smoking history, free of lung cancer, and willing to undergo bronchoscopic brush biopsy for NBEC sample collection. NBEC, peripheral blood samples, baseline CT, and medical and demographic data were collected from each subject.
DISCUSSION - Over a two-year span (2010-2012), 403 subjects were enrolled at 12 sites. At baseline 384 subjects remained in study and mean age and smoking history were 62.9 years and 50.4 pack-years respectively, with 34% current smokers. Obstructive lung disease (FEV1/FVC <0.7) was present in 157 (54%). No severe adverse events were associated with bronchoscopic brushing. An NBEC and matched peripheral blood bio-specimen repository was established. The demographic composition of the enrolled group is representative of the population for which the LCRT is intended. Specifically, based on baseline population characteristics we expect lung cancer incidence in this cohort to be representative of the population eligible for low-dose Computed Tomography (LDCT) lung cancer screening. Collection of NBEC by bronchial brush biopsy/bronchoscopy was safe and well-tolerated in this population. These findings support the feasibility of testing LCRT clinical utility in this prospective study. If validated, the LCRT has the potential to significantly narrow the population of individuals requiring annual low-dose helical CT screening for early detection of lung cancer and delay the onset of screening for individuals with results indicating low lung cancer risk. For these individuals, the small risk incurred by undergoing once in a lifetime bronchoscopic sample collection for LCRT may be offset by a reduction in their CT-related risks. The LCRT biospecimen repository will enable additional studies of genetic basis for COPD and/or lung cancer risk.
TRIAL REGISTRATION - The LCRT Study, NCT 01130285, was registered with Clinicaltrials.gov on May 24, 2010.
BACKGROUND - The COPD assessment test (CAT) score is a key component of the multifactorial assessment of COPD in the Global initiative for chronic Obstructive Lung Disease (GOLD) guidelines of 2014. Nevertheless, little is known regarding the differences among COPD categories in terms of clinical parameters such as pulmonary function or radiological findings. Thus, our aims in this study were to evaluate the associations between CAT scores and pulmonary clinical parameters, and to investigate factors that could discriminate between a "less symptomatic group" (categories A and C) and a "more symptomatic group" (categories B and D) among stable COPD patients.
METHODS - We enrolled 200 outpatients at Chiba University Hospital. Study subjects were assessed by CAT, pulmonary function testing, and multidetector computed tomography (MDCT). We assessed possible correlations between these indices.
RESULTS - CAT scores were negatively correlated with percentage of the forced expiratory volume in 1 second predicted value (FEV1 %predicted) and percentage of the diffusing capacity for carbon monoxide per liter of lung volume predicted value (DLCO/VA [%predicted]) results and positively correlated with low attenuation volume percentage (LAV%) and residual volume to total lung capacity ratios (RV/TLC). In the "more symptomatic group" (category B or D), the mean DLCO/VA (%predicted) was significantly lower and the mean LAV% and RV/TLC was significantly higher than those in the "less symptomatic group" (category A or C), respectively. Interestingly, those in category B had higher mean LAV% compared to those in category C.
CONCLUSION - CAT scores were significantly correlated with pulmonary function parameters and emphysematous changes on MDCT. The new GOLD classification system would be a step toward a phenotypic approach, especially taking into account the degree of emphysema and hyperinflation.
BACKGROUND - Interstitial lung disease is common in patients with sickle cell anemia (SCA). Fibrocytes are circulating cells implicated in the pathogenesis of pulmonary fibrosis and airway remodeling in asthma. In this study, we tested the hypotheses that fibrocyte levels are: (1) increased in children with SCA compared to healthy controls, and (2) associated with pulmonary disease.
PROCEDURE - Cross-sectional cohort study of children with SCA who participated in the Sleep Asthma Cohort Study.
RESULTS - Fibrocyte levels were obtained from 45 children with SCA and 24 controls. Mean age of SCA cases was 14 years and 53% were female. In children with SCA, levels of circulating fibrocytes were greater than controls (P < 0.01). The fibrocytes expressed a hierarchy of chemokine receptors, with CXCR4 expressed on the majority of cells and CCR2 and CCR7 expressed on a smaller subset. Almost half of fibrocytes demonstrated α-smooth muscle actin activation. Increased fibrocyte levels were associated with a higher reticulocyte count (P = 0.03) and older age (P = 0.048) in children with SCA. However, children with increased levels of fibrocytes were not more likely to have asthma or lower percent predicted forced expiratory volume in 1 sec/forced vital capacity (FEV1 /FVC) or FEV1 than those with lower fibrocyte levels.
CONCLUSIONS - Higher levels of fibrocytes in children with SCA compared to controls may be due to hemolysis. Longitudinal studies may be able to better assess the relationship between fibrocyte level and pulmonary dysfunction.
© 2015 Wiley Periodicals, Inc.
RATIONALE - Most genomic studies of lung function have used phenotypic data derived from a single time-point (e.g., presence/absence of disease) without considering the dynamic progression of a chronic disease.
OBJECTIVES - To characterize lung function change over time in subjects with asthma and identify genetic contributors to a longitudinal phenotype.
METHODS - We present a method that models longitudinal FEV1 data, collected from 1,041 children with asthma who participated in the Childhood Asthma Management Program. This longitudinal progression model was built using population-based nonlinear mixed-effects modeling with an exponential structure and the determinants of age and height.
MEASUREMENTS AND MAIN RESULTS - We found ethnicity was a key covariate for FEV1 level. Budesonide-treated children with asthma had a slight but significant effect on FEV1 when compared with those treated with placebo or nedocromil (P < 0.001). A genome-wide association study identified seven single-nucleotide polymorphisms nominally associated with longitudinal lung function phenotypes in 581 white Childhood Asthma Management Program subjects (P < 10(-4) in the placebo ["discovery"] and P < 0.05 in the nedocromil treatment ["replication"] group). Using ChIP-seq and RNA-seq data, we found that some of the associated variants were in strong enhancer regions in human lung fibroblasts and may affect gene expression in human lung tissue. Genetic mapping restricted to genome-wide enhancer single-nucleotide polymorphisms in lung fibroblasts revealed a highly significant variant (rs6763931; P = 4 × 10(-6); false discovery rate < 0.05).
CONCLUSIONS - This study offers a strategy to explore the genetic determinants of longitudinal phenotypes, provide a comprehensive picture of disease pathophysiology, and suggest potential treatment targets.
BACKGROUND - Cigarette smoking is the major cause of chronic obstructive pulmonary disease and emphysema. Recent studies suggest that susceptibility to cigarette smoke may vary by race/ethnicity; however, they were generally small and relied on self-reported race/ethnicity.
OBJECTIVE - To test the hypothesis that relationships of smoking to lung function and per cent emphysema differ by genetic ancestry and self-reported race/ethnicity among Caucasians, African-Americans, Hispanics and Chinese-Americans.
DESIGN - Cross-sectional population-based study of adults age 45-84 years in the USA.
MEASUREMENTS - Principal components of genetic ancestry and continental ancestry estimated from one million genome-wide single nucleotide polymorphisms; pack-years of smoking; spirometry measured for 3344 participants; and per cent emphysema on computed tomography for 8224 participants.
RESULTS - The prevalence of ever-smoking was: Caucasians, 57.6%; African-Americans, 56.4%; Hispanics, 46.7%; and Chinese-Americans, 26.8%. Every 10 pack-years was associated with -0.73% (95% CI -0.90% to -0.56%) decrement in the forced expiratory volume in 1 s to forced vital capacity (FEV1 to FVC) and a 0.23% (95% CI 0.08% to 0.38%) increase in per cent emphysema. There was no evidence that relationships of pack-years to the FEV1 to FVC, airflow obstruction and per cent emphysema varied by genetic ancestry (all p>0.10), self-reported race/ethnicity (all p>0.10) or, among African-Americans, African ancestry. There were small differences in relationships of pack-years to the FEV1 among male Chinese-Americans and to the FEV1 to FVC ratio with African and Native American ancestry among male Hispanics only.
CONCLUSIONS - In this large cohort, there was little to no evidence that the associations of smoking to lung function and per cent emphysema differed by genetic ancestry or self-reported race/ethnicity.
The analysis of longitudinal trajectories usually focuses on evaluation of explanatory factors that are either associated with rates of change, or with overall mean levels of a continuous outcome variable. In this article, we introduce valid design and analysis methods that permit outcome dependent sampling of longitudinal data for scenarios where all outcome data currently exist, but a targeted substudy is being planned in order to collect additional key exposure information on a limited number of subjects. We propose a stratified sampling based on specific summaries of individual longitudinal trajectories, and we detail an ascertainment corrected maximum likelihood approach for estimation using the resulting biased sample of subjects. In addition, we demonstrate that the efficiency of an outcome-based sampling design relative to use of a simple random sample depends highly on the choice of outcome summary statistic used to direct sampling, and we show a natural link between the goals of the longitudinal regression model and corresponding desirable designs. Using data from the Childhood Asthma Management Program, where genetic information required retrospective ascertainment, we study a range of designs that examine lung function profiles over 4 years of follow-up for children classified according to their genotype for the IL 13 cytokine.
© 2013, The International Biometric Society.