Early Evidence of Chronic Obstructive Pulmonary Disease Obscured by Race-Specific Prediction Equations.

Rationale: The identification of early chronic obstructive pulmonary disease (COPD) is essential to appropriately counsel patients regarding smoking cessation, provide symptomatic treatment, and eventually develop disease-modifying treatments. Disease severity in COPD is defined using race-specific spirometry equations. These may disadvantage non-White individuals in diagnosis and care. Objectives: Determine the impact of race-specific equations on African American (AA) versus non-Hispanic White individuals. Methods: Cross-sectional analyses of the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) cohort were conducted, comparing non-Hispanic White (n = 6,766) and AA (n = 3,366) participants for COPD manifestations. Measurements and Main Results: Spirometric classifications using race-specific, multiethnic, and "race-reversed" prediction equations (NHANES [National Health and Nutrition Examination Survey] and Global Lung Function Initiative "Other" and "Global") were compared, as were respiratory symptoms, 6-minute-walk distance, computed tomography imaging, respiratory exacerbations, and St. George's Respiratory Questionnaire. Application of different prediction equations to the cohort resulted in different classifications by stage, with NHANES and Global Lung Function Initiative race-specific equations being minimally different, but race-reversed equations moving AA participants to more severe stages and especially between the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 0 and preserved ratio impaired spirometry groups. Classification using the established NHANES race-specific equations demonstrated that for each of GOLD stages 1-4, AA participants were younger, had fewer pack-years and more current smoking, but had more exacerbations, shorter 6-minute-walk distance, greater dyspnea, and worse BODE (body mass index, airway obstruction, dyspnea, and exercise capacity) scores and St. George's Respiratory Questionnaire scores. Differences were greatest in GOLD stages 1 and 2. Race-reversed equations reclassified 774 AA participants (43%) from GOLD stage 0 to preserved ratio impaired spirometry. Conclusions: Race-specific equations underestimated disease severity among AA participants. These effects were particularly evident in early disease and may result in late detection of COPD.

Returning incidentally discovered Hepatitis C RNA-seq results to COPDGene study participants.

The consequences of returning infectious pathogen test results identified incidentally in research studies have not been well-studied. Concerns include identification of an important health issue for individuals, accuracy of research test results, public health impact, potential emotional distress for participants, and need for IRB permissions. Blood RNA-sequencing analysis for non-human RNA in 3984 participants from the COPDGene study identified 228 participants with evidence suggestive for hepatitis C virus (HCV) infection. We hypothesized that incidentally discovered HCV results could be effectively returned to COPDGene participants with attention to the identified concerns. In conjunction with a COPDGene Participant Advisory Panel, we developed and obtained IRB approval for a process of returning HCV research results and an HCV Follow-Up Study questionnaire to capture information about previous HCV diagnosis and treatment information and participant reactions to return of HCV results. During phone calls following the initial HCV notification letter, 84 of 124 participants who could be contacted (67.7%) volunteered that they had been previously diagnosed with HCV infection. Thirty-one of these 124 COPDGene participants were enrolled in the HCV Follow-Up Study. Five of the 31 HCV Follow-Up Study participants did not report a previous diagnosis of HCV. For four of these participants, subsequent clinical HCV testing confirmed HCV infection. Thus, 30/31 Follow-Up Study participants had confirmed HCV diagnoses, supporting the accuracy of the HCV research test results. However, the limited number of participants in the Follow-Up Study precludes an accurate assessment of the false-positive and false-negative rates of the research RNA sequencing evidence for HCV. Most HCV Follow-Up Study participants (29/31) were supportive of returning HCV research results, and most participants found the process for returning HCV results to be informative and not upsetting. Newly diagnosed participants were more likely to be pleased to learn about a potentially curable infection (p = 0.027) and showed a trend toward being more frightened by the potential health risks of HCV (p = 0.11). We conclude that HCV results identified incidentally during transcriptomic research studies can be successfully returned to research study participants with a carefully designed process.

Findings on High Resolution Computed Tomography in Symptomatic Veterans with Deployment-Related Lung Disease.

PURPOSE: Military deployment to dusty, austere environments in Southwest Asia and Afghanistan is associated with symptomatic airways diseases including asthma and bronchiolitis. The utility of chest high-resolution computed tomographic (HRCT) imaging in lung disease diagnosis in this population is poorly understood. We investigated visual assessment of HRCT for identifying deployment-related lung disease compared with healthy controls. MATERIALS AND METHODS: Chest HRCT images from 46 healthy controls and 45 symptomatic deployed military personnel with clinically confirmed asthma and/or biopsy-confirmed distal lung disease were scored by 3 independent thoracic radiologists. We compared demographic and clinical characteristics and frequency of imaging findings between deployers and controls, and between deployers with asthma and those with biopsy-confirmed distal lung disease, using χ2, Fisher exact or t tests, and logistic regression where appropriate. We also analyzed inter-rater agreement for imaging findings. RESULTS: Expiratory air trapping was the only chest CT imaging finding that was significantly more frequent in deployers compared with controls. None of the 24 deployers with biopsy-confirmed bronchiolitis and/or granulomatous pneumonitis had HRCT findings of inspiratory mosaic attenuation or centrilobular nodularity. Only 2 of 21 with biopsy-proven emphysema had emphysema on HRCT. CONCLUSIONS: Compared with surgical lung biopsy, visual assessment of HRCT showed few abnormalities in this small cohort of previously deployed symptomatic veterans with normal or near-normal spirometry.

Use of the Spirometric "Fixed-Ratio" Underdiagnoses COPD in African-Americans in a Longitudinal Cohort Study.

BACKGROUND: COPD diagnosis is tightly linked to the fixed-ratio spirometry criteria of FEV1/FVC < 0.7. African-Americans are less often diagnosed with COPD. OBJECTIVE: Compare COPD diagnosis by fixed-ratio with findings and outcomes by race. DESIGN: Genetic Epidemiology of COPD (COPDGene) (2007-present), cross-sectional comparing non-Hispanic white (NHW) and African-American (AA) participants for COPD diagnosis, manifestations, and outcomes. SETTING: Multicenter, longitudinal US cohort study. PARTICIPANTS: Current or former smokers with ≥ 10-pack-year smoking history enrolled at 21 clinical centers including over-sampling of participants with known COPD and AA. Exclusions were pre-existing non-COPD lung disease, except for a history of asthma. MEASUREMENTS: Subject diagnosis by conventional criteria. Mortality, imaging, respiratory symptoms, function, and socioeconomic characteristics, including area deprivation index (ADI). Matched analysis (age, sex, and smoking status) of AA vs. NHW within participants without diagnosed COPD (GOLD 0; FEV1 ≥ 80% predicted and FEV1/FVC ≥ 0.7). RESULTS: Using the fixed ratio, 70% of AA (n = 3366) were classified as non-COPD, versus 49% of NHW (n = 6766). AA smokers were younger (55 vs. 62 years), more often current smoking (80% vs. 39%), with fewer pack-years but similar 12-year mortality. Density distribution plots for FEV1 and FVC raw spirometry values showed disproportionate reductions in FVC relative to FEV1 in AA that systematically led to higher ratios. The matched analysis demonstrated GOLD 0 AA had greater symptoms, worse DLCO, spirometry, BODE scores (1.03 vs 0.54, p < 0.0001), and greater deprivation than NHW. LIMITATIONS: Lack of an alternative diagnostic metric for comparison. CONCLUSIONS: The fixed-ratio spirometric criteria for COPD underdiagnosed potential COPD in AA participants when compared to broader diagnostic criteria. Disproportionate reductions in FVC relative to FEV1 leading to higher FEV1/FVC were identified in these participants and associated with deprivation. Broader diagnostic criteria for COPD are needed to identify the disease across all populations.

Parameter D: New Measure of Airflow Obstruction.

Rationale: Currently used spirometry measures of airflow obstruction are influenced by demographics, predominantly by age, complicating selection of diagnostic thresholds for the presence of airflow obstruction. Objectives: To develop diagnostic thresholds for Parameter D, a new metric for detection of airflow obstruction, which quantifies the rate of rise of expiratory volume over time. Methods: We analyzed spirometry data of normal subjects enrolled in the 2007-2008, 2009-2010, and 2011-2012 NHANES (National Health and Nutrition Examination Survey) cohorts and calculated Parameter D using the expiratory volume-time curve. Relationships between demographics and lung function (forced expiratory volume in 1 second [FEV1], FEV1/forced vital capacity [FVC], and Parameter D) were tested using generalized linear models in NHANES and UK Biobank. The variation in lung function explained by demographics was estimated using R2. A diagnostic threshold was developed for Parameter D using population-based percentiles. Based on concordance between the lower limit of normal (LLN) for FEV1/FVC and the Parameter D threshold, four groups were identified: normal (no airflow obstruction by either criterion), D+chronic obstructive pulmonary disease (D+COPD; positive by Parameter D only), D-COPD (positive by LLN only), and COPD (positive by both criteria), and associations with structural lung disease, exacerbations, and mortality were tested using multivariable analyses. Results: In contrast to FEV1 and FEV1/FVC, demographics cumulatively explained only 9% of the variance in Parameter D in NHANES (n = 4,945) and 3% in UK BioBank (n = 109,623). In COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) (n = 9,542), a diagnostic threshold of -3.15 resulted in the identification of an additional 10.8% of participants with airflow obstruction. A total of 3.7% had FEV1/FVC < LLN but were missed by the Parameter D threshold. Compared with subjects in the normal group, after adjustment for age, sex, race, body mass index, pack-years of smoking, and current smoking status, D+COPD was associated with worse structural lung disease (odds ratio [OR] for ⩾5% emphysema, 1.71; 95% confidence interval [CI], 1.37-2.12; OR for functional small airway disease ⩾ 15%, 2.1; 95% CI, 1.79-2.67) and significant symptoms (OR for modified Medical Research Council dyspnea score ⩾ 2, 1.25; 95% CI, 1.07-1.47; OR for St. George's respiratory questionnaire ⩾ 25, 1.31; 95% CI, 1.13-1.53), a greater frequency of exacerbations (incidence rate ratio, 1.26; 95% CI, 1.10-1.46), and higher mortality (hazard ratio, 1.32; 95% CI, 1.10-1.57). Over 5 years, 28% of the D+COPD group versus 8% of normal group progressed to COPD by traditional criteria. Conclusions: Parameter D is not affected by age, and a normal population-based diagnostic threshold results in the early identification of additional individuals with airflow obstruction with a substantial amount of structural lung disease and respiratory symptoms.

Sex Differences in Airways at Chest CT: Results from the COPDGene Cohort.

Background The prevalence of chronic obstructive pulmonary disease (COPD) in women is fast approaching that in men, and women experience greater symptom burden. Although sex differences in emphysema have been reported, differences in airways have not been systematically characterized. Purpose To evaluate whether structural differences in airways may underlie some of the sex differences in COPD prevalence and clinical outcomes. Materials and Methods In a secondary analyses of a multicenter study of never-, current-, and former-smokers enrolled from January 2008 to June 2011 and followed up longitudinally until November 2020, airway disease on CT images was quantified using seven metrics: airway wall thickness, wall area percent, and square root of the wall thickness of a hypothetical airway with internal perimeter of 10 mm (referred to as Pi10) for airway wall; and lumen diameter, airway volume, total airway count, and airway fractal dimension for airway lumen. Least-squares mean values for each airway metric were calculated and adjusted for age, height, ethnicity, body mass index, pack-years of smoking, current smoking status, total lung capacity, display field of view, and scanner type. In ever-smokers, associations were tested between each airway metric and postbronchodilator forced expiratory volume in 1 second (FEV1)-to-forced vital capacity (FVC) ratio, modified Medical Research Council dyspnea scale, St George's Respiratory Questionnaire score, and 6-minute walk distance. Multivariable Cox proportional hazards models were created to evaluate the sex-specific association between each airway metric and mortality. Results In never-smokers (n = 420), men had thicker airway walls than women as quantified on CT images for segmental airway wall area percentage (least-squares mean, 47.68 ± 0.61 [standard error] vs 45.78 ± 0.55; difference, -1.90; P = .02), whereas airway lumen dimensions were lower in women than men after accounting for height and total lung capacity (segmental lumen diameter, 8.05 mm ± 0.14 vs 9.05 mm ± 0.16; difference, -1.00 mm; P < .001). In ever-smokers (n = 9363), men had greater segmental airway wall area percentage (least-squares mean, 52.19 ± 0.16 vs 48.89 ± 0.18; difference, -3.30; P < .001), whereas women had narrower segmental lumen diameter (7.80 mm ± 0.05 vs 8.69 mm ± 0.04; difference, -0.89; P < .001). A unit change in each of the airway metrics (higher wall or lower lumen measure) resulted in lower FEV1-to-FVC ratio, more dyspnea, poorer respiratory quality of life, lower 6-minute walk distance, and worse survival in women compared with men (all P < .01). Conclusion Airway lumen sizes quantified at chest CT were smaller in women than in men after accounting for height and lung size, and these lower baseline values in women conferred lower reserves against respiratory morbidity and mortality for equivalent changes compared with men. © RSNA, 2022 Online supplemental material is available for this article.

Structural airway imaging metrics are differentially associated with persistent chronic bronchitis.

BACKGROUND: Chronic bronchitis (CB) is strongly associated with cigarette smoking, but not all smokers develop CB. We aimed to evaluate whether measures of structural airway disease on CT are differentially associated with CB. METHODS: In smokers between ages 45 and 80 years, and with Global Initiative for Obstructive Lung Disease stages 0-4, CB was defined by the classic definition. Airway disease on CT was quantified by (i) wall area percent (WA%) of segmental airways; (ii) Pi10, the square root of the wall area of a hypothetical airway with 10 mm internal perimeter; (iii) total airway count (TAC) and (iv) airway fractal dimension (AFD), a measure of the complex branching pattern and remodelling of airways. CB was also assessed at the 5-year follow-up visit. MEASUREMENTS AND MAIN RESULTS: Of 8917 participants, 1734 (19.4%) had CB at baseline. Airway measures were significantly worse in those with CB compared with those without CB: WA% 54.5 (8.8) versus 49.8 (8.3); Pi10 2.58 (0.67) versus 2.28 (0.59) mm; TAC 156.7 (81.6) versus 177.8 (91.1); AFD 1.477 (0.091) versus 1.497 (0.092) (all p<0.001). On follow-up of 5517 participants at 5 years, 399 (7.2%) had persistent CB. With adjustment for between-visits changes in smoking status and lung function, greater WA% and Pi10 were associated with significantly associated with persistent CB, adjusted OR per SD change 1.75, 95% CI 1.56 to 1.97; p<0.001 and 1.66, 95% CI 1.42 to 1.86; p<0.001, respectively. Higher AFD and TAC were associated with significantly lower odds of persistent CB, adjusted OR per SD change 0.76, 95% CI 0.67 to 0.86; p<0.001 and 0.69, 95% CI 0.60 to 0.80; p<0.001, respectively. CONCLUSIONS: Higher baseline AFD and TAC are associated with a lower risk of persistent CB, irrespective of changes in smoking status, suggesting preserved airway structure can confer a reserve against CB.

Deep neural network analyses of spirometry for structural phenotyping of chronic obstructive pulmonary disease.

BACKGROUNDCurrently recommended traditional spirometry outputs do not reflect the relative contributions of emphysema and airway disease to airflow obstruction. We hypothesized that machine-learning algorithms can be trained on spirometry data to identify these structural phenotypes.METHODSParticipants enrolled in a large multicenter study (COPDGene) were included. The data points from expiratory flow-volume curves were trained using a deep-learning model to predict structural phenotypes of chronic obstructive pulmonary disease (COPD) on CT, and results were compared with traditional spirometry metrics and an optimized random forest classifier. Area under the receiver operating characteristic curve (AUC) and weighted F-score were used to measure the discriminative accuracy of a fully convolutional neural network, random forest, and traditional spirometry metrics to phenotype CT as normal, emphysema-predominant (>5% emphysema), airway-predominant (Pi10 > median), and mixed phenotypes. Similar comparisons were made for the detection of functional small airway disease phenotype (>20% on parametric response mapping).RESULTSAmong 8980 individuals, the neural network was more accurate in discriminating predominant emphysema/airway phenotypes (AUC 0.80, 95%CI 0.79-0.81) compared with traditional measures of spirometry, FEV1/FVC (AUC 0.71, 95%CI 0.69-0.71), FEV1% predicted (AUC 0.70, 95%CI 0.68-0.71), and random forest classifier (AUC 0.78, 95%CI 0.77-0.79). The neural network was also more accurate in discriminating predominant emphysema/small airway phenotypes (AUC 0.91, 95%CI 0.90-0.92) compared with FEV1/FVC (AUC 0.80, 95%CI 0.78-0.82), FEV1% predicted (AUC 0.83, 95%CI 0.80-0.84), and with comparable accuracy with random forest classifier (AUC 0.90, 95%CI 0.88-0.91).CONCLUSIONSStructural phenotypes of COPD can be identified from spirometry using deep-learning and machine-learning approaches, demonstrating their potential to identify individuals for targeted therapies.TRIAL REGISTRATIONClinicalTrials.gov NCT00608764.FUNDINGThis study was supported by NIH grants K23 HL133438 and R21EB027891 and an American Thoracic Foundation 2018 Unrestricted Research Grant. The COPDGene study is supported by NIH grants NHLBI U01 HL089897 and U01 HL089856. The COPDGene study (NCT00608764) is also supported by the COPD Foundation through contributions made to an Industry Advisory Committee comprising AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Novartis, and Sunovion.

The Peak Index: Spirometry Metric for Airflow Obstruction Severity and Heterogeneity.

Rationale: Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation. Spirometry loops are not smooth curves and have undulations and peaks that likely reflect heterogeneity of airflow.Objectives: To assess whether the Peak Index, the number of peaks adjusted for lung size, is associated with clinical outcomes.Methods: We analyzed spirometry data of 9,584 participants enrolled in the COPDGene study and counted the number of peaks in the descending part of the expiratory flow-volume curve from the peak expiratory flow to end-expiration. We adjusted the peaks count for the volume of the lungs from peak expiratory flow to end-expiration to derive the Peak Index. Multivariable regression analyses were performed to test associations between the Peak Index and lung function, respiratory morbidity, structural lung disease on computed tomography (CT), forced expiratory volume in 1 second (FEV1) decline, and mortality.Results: The Peak Index progressively increased from Global Initiative for Chronic Obstructive Lung Disease stage 0 through 4 (P < 0.001). On multivariable analysis, the Peak Index was significantly associated with CT emphysema (adjusted ß = 0.906; 95% confidence interval [CI], 0.789 to 1.023; P < 0.001) and small airways disease (adjusted ß = 1.367; 95% CI, 1.188 to 1.545; P < 0.001), St. George's Respiratory Questionnaire score (adjusted ß = 1.075; 95% CI, 0.807 to 1.342; P < 0.001), 6-minute-walk distance (adjusted ß = -1.993; 95% CI, -3.481 to -0.506; P < 0.001), and FEV1 change over time (adjusted ß = -1.604; 95% CI, -2.691 to -0.516; P = 0.004), after adjustment for age, sex, race, body mass index, current smoking status, pack-years of smoking, and FEV1. The Peak Index was also associated with the BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index and mortality (P < 0.001).Conclusions: The Peak Index is a spirometry metric that is associated with CT measures of lung disease, respiratory morbidity, lung function decline, and mortality.Clinical trial registered with www.clinicaltrials.gov (NCT00608764).

Phenotype and response to growth hormone therapy in siblings with B4GALT7 deficiency.

B4GALT7 encodes beta-1,4-galactosyltransferase which links glycosaminoglycans to proteoglycans in connective tissues. Rare, biallelic variants in B4GALT7 have been associated with spondylodysplastic Ehlers-Danlos and Larsen of Reunion Island syndromes. Thirty patients with B4GALT7-related disorders have been reported to date with phenotypic variability. Using whole exome sequencing, we identified male and female siblings with biallelic, pathogenic B4GALT7 variants and phenotypic features of spondylodysplastic Ehlers-Danlos syndrome as well as previously unreported skeletal characteristics. We also provide detailed radiological characterization and describe the siblings' responses to growth hormone treatment. Our report extends the phenotypic spectrum of B4GALT7-associated spondylodysplastic Ehlers-Danlos syndrome and reports results of growth hormone treatment for patients with this rare disorder.

New Spirometry Indices for Detecting Mild Airflow Obstruction.

The diagnosis of chronic obstructive pulmonary disease (COPD) relies on demonstration of airflow obstruction. Traditional spirometric indices miss a number of subjects with respiratory symptoms or structural lung disease on imaging. We hypothesized that utilizing all data points on the expiratory spirometry curves to assess their shape will improve detection of mild airflow obstruction and structural lung disease. We analyzed spirometry data of 8307 participants enrolled in the COPDGene study, and derived metrics of airflow obstruction based on the shape on the volume-time (Parameter D), and flow-volume curves (Transition Point and Transition Distance). We tested associations of these parameters with CT measures of lung disease, respiratory morbidity, and mortality using regression analyses. There were significant correlations between FEV1/FVC with Parameter D (r = -0.83; p < 0.001), Transition Point (r = 0.69; p < 0.001), and Transition Distance (r = 0.50; p < 0.001). All metrics had significant associations with emphysema, small airway disease, dyspnea, and respiratory-quality of life (p < 0.001). The highest quartile for Parameter D was independently associated with all-cause mortality (adjusted HR 3.22,95% CI 2.42-4.27; p < 0.001) but a substantial number of participants in the highest quartile were categorized as GOLD 0 and 1 by traditional criteria (1.8% and 33.7%). Parameter D identified an additional 9.5% of participants with mild or non-recognized disease as abnormal with greater burden of structural lung disease compared with controls. The data points on the flow-volume and volume-time curves can be used to derive indices of airflow obstruction that identify additional subjects with disease who are deemed to be normal by traditional criteria.

CT-based Visual Classification of Emphysema: Association with Mortality in the COPDGene Study.

Purpose To determine whether visually assessed patterns of emphysema at CT might provide a simple assessment of mortality risk among cigarette smokers. Materials and Methods Of the first 4000 cigarette smokers consecutively enrolled between 2007 and 2011 in this COPDGene study, 3171 had data available for both visual emphysema CT scores and survival. Each CT scan was retrospectively visually scored by two analysts using the Fleischner Society classification system. Severity of emphysema was also evaluated quantitatively by using percentage lung volume occupied by low-attenuation areas (voxels with attenuation of -950 HU or less) (LAA-950). Median duration of follow-up was 7.4 years. Regression analysis for the relationship between imaging patterns and survival was based on the Cox proportional hazards model, with adjustment for age, race, sex, height, weight, pack-years of cigarette smoking, current smoking status, educational level, LAA-950, and (in a second model) forced expiratory volume in 1 second (FEV1). Results Observer agreement in visual scoring was good (weighted κ values, 0.71-0.80). There were 519 deaths in the study cohort. Compared with subjects who did not have visible emphysema, mortality was greater in those with any grade of emphysema beyond trace (adjusted hazard ratios, 1.7, 2.5, 5.0, and 4.1, respectively, for mild centrilobular emphysema, moderate centrilobular emphysema, confluent emphysema, and advanced destructive emphysema, P < .001). This increased mortality generally persisted after adjusting for LAA-950. Conclusion The visual presence and severity of emphysema is associated with significantly increased mortality risk, independent of the quantitative severity of emphysema. Online supplemental material is available for this article.

Paratracheal Paraseptal Emphysema and Expiratory Central Airway Collapse in Smokers.

RATIONALE: Expiratory central airway collapse is associated with respiratory morbidity independent of underlying lung disease. However, not all smokers develop expiratory central airway collapse, and the etiology of expiratory central airway collapse in adult smokers is unclear. Paraseptal emphysema in the paratracheal location, by untethering airway walls, may predispose smokers to developing expiratory central airway collapse. OBJECTIVES: To evaluate whether paratracheal paraseptal emphysema is associated with expiratory central airway collapse. METHODS: We analyzed paired inspiratory and expiratory computed tomography scans from participants enrolled in a multicenter study (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) of smokers aged 45 to 80 years. Expiratory central airway collapse was defined as greater than or equal to 50% reduction in cross-sectional area of the trachea during expiration. In a nested case-control design, participants with and without expiratory central airway collapse were included in a 1:2 fashion, and inspiratory scans were further analyzed using the Fleischner Society criteria for presence of centrilobular emphysema, paraseptal emphysema, airway wall thickening, and paratracheal paraseptal emphysema (maximal diameter ≥ 0.5 cm). RESULTS: A total of 1,320 patients were included, 440 with and 880 without expiratory central airway collapse. Those with expiratory central airway collapse were older, had higher body mass index, and were less likely to be men or current smokers. Paratracheal paraseptal emphysema was more frequent in those with expiratory central airway collapse than control subjects (16.6 vs. 11.8%; P = 0.016), and after adjustment for age, race, sex, body mass index, smoking pack-years, and forced expiratory volume in 1 second, paratracheal paraseptal emphysema was independently associated with expiratory central airway collapse (adjusted odds ratio, 1.53; 95% confidence interval, 1.18-1.98; P = 0.001). Furthermore, increasing size of paratracheal paraseptal emphysema (maximal diameter of at least 1 cm and 1.5 cm) was associated with greater odds of expiratory central airway collapse (adjusted odds ratio, 1.63; 95% confidence interval, 1.18-2.25; P = 0.003 and 1.77; 95% confidence interval, 1.19-2.64; P = 0.005, respectively). CONCLUSIONS: Paraseptal emphysema adjacent to the trachea is associated with expiratory central airway collapse. The identification of this risk factor on inspiratory scans should prompt further evaluation for expiratory central airway collapse. Clinical trial registered with ClinicalTrials.gov (NCT 00608764).

A Survey of Licensed Acupuncturists in the San Francisco Bay Area: Prevalence of Treating Oncology Patients.

BACKGROUND: Many cancer patients seek traditional Chinese medicine (TCM), the prevalence varying with diagnosis, comorbidities, and demographics. Interventions sought include acupuncture, massage, herbs, diet, and exercise, usually combined with conventional therapies. It is not known what proportion of TCM practitioners care for cancer patients, their cancer specific training or caseload, what interventions they employ, their outcomes, and their communication patterns with conventional oncologists. METHODS: A survey was mailed to all 2213 licensed acupuncturists in the 9-county San Francisco Bay Area gathering descriptive statistics. RESULTS: A total of 472 (21%) responded by mail or web-based Research Electronic Data Capture (REDCap) tool. Most respondents (77%) reported caring for patients with cancer, with 29% reporting having 6 to 10 years of practice experience, and 44.2% having 0 to 20 hours of training specific to the needs of patients with cancer. Improving quality of life was reported by 94% as what their treatment offered cancer patients as well as the area where treatment was felt to have the greatest impact. The most useful TCM modalities were acupuncture (98%), herbs (79%), diet (72%), moxibustion (46%), and meditation instruction (44%). Absence of adverse reactions was noted by 95%. Ninety-one percent reported "never" or "hardly ever" having been contacted by patients' oncologists to discuss treatment. CONCLUSIONS: Many acupuncturists seeing cancer patients have significant clinical experience and have sought specialized training. Improved communication is needed between TCM practitioners and oncologists sharing care of cancer patients.

Alpha-1 Antitrypsin PiMZ Genotype Is Associated with Chronic Obstructive Pulmonary Disease in Two Racial Groups.

RATIONALE: Alpha-1 antitrypsin deficiency, caused primarily by homozygosity for the Z allele of the SERPINA1 gene, is a well-established genetic cause of chronic obstructive pulmonary disease (COPD). Whether the heterozygous PiMZ genotype for alpha-1 antitrypsin confers increased risk for COPD has been debated. OBJECTIVES: We analyzed 8,271 subjects in the Genetic Epidemiology of COPD (COPDGene) Study, hypothesizing that PiMZ would independently associate with COPD and COPD-related phenotypes. METHODS: The COPDGene Study comprises a multiethnic, cross-sectional, observational cohort of non-Hispanic white and African American current and former smokers with at least 10 pack-years of smoking who were enrolled for detailed clinical and genetic studies of COPD and COPD-related traits. We performed multivariate logistic regression analysis for moderate to severe COPD and assessed Pi genotype with other relevant covariates in models stratified by race. We analyzed quantitative characteristics on the basis of volumetric computed tomography with generalized linear models controlling for genotype, scanner type, and similar covariates. RESULTS: White PiMZ COPDGene subjects had significantly lower lung function, FEV1 percent predicted (68 ± 28 vs. 75 ± 27; P = 0.0005), and FEV1/FVC ratio (0.59 ± 0.18 vs. 0.63 ± 0.17; P = 0.0008), as well as more radiographic emphysema (P = 0.001), than subjects without alpha-1 antitrypsin Z risk alleles. Similarly, African American PiMZ subjects had lower lung function, FEV1 percent predicted (65 ± 33 vs. 84 ± 25; P = 0.009) and FEV1/FVC (0.61 ± 0.21 vs. 0.71 ± 0.15; P = 0.03). CONCLUSIONS: In the COPDGene Study, we demonstrate that PiMZ heterozygous individuals who smoke are at increased risk for COPD and obstructive lung function impairment compared with Z-allele noncarriers, regardless of race. Although severe alpha-1 antitrypsin deficiency is uncommon in African Americans, our study adds further support for initial targeted detection of all subjects with COPD for alpha-1 antitrypsin deficiency, including African Americans. Clinical trial registered with www.clinicaltrials.gov (NCT00608784).

Visual Assessment of Chest Computed Tomographic Images Is Independently Useful for Genetic Association Analysis in Studies of Chronic Obstructive Pulmonary Disease.

RATIONALE: Automated analysis of computed tomographic (CT) lung images for epidemiologic and genetic association studies is increasingly common, but little is known about the utility of visual versus semiautomated emphysema and airway assessments for genetic association studies. OBJECTIVES: Assess the relative utility of visual versus semiautomated emphysema and airway assessments for genetic association studies. METHODS: A standardized inspection protocol was used to visually assess chest CT images for 1,540 non-Hispanic white subjects within the COPDGene Study for the presence and severity of radiographic features representing airway wall thickness and emphysema. A genome-wide association study (GWAS) was performed, and two sets of candidate single-nucleotide polymorphisms with a higher prior likelihood of association were specified a priori for separate analysis. For each visual CT examination feature, a corresponding semiautomated CT feature(s) was identified for comparison in the same subjects. MEASUREMENTS AND MAIN RESULTS: GWAS for visual features of chest CT scans identified a genome-wide significant association with visual emphysema at the 15q25 locus (P = 6.3e-9). In the a priori-specified set of 19 previously identified GWAS loci, 7 and 8 loci were associated with airway measures or emphysema measures, respectively. In the a priori-specified candidate gene set, 13 of 196 candidate genes harbored a nearby single-nucleotide polymorphism significantly associated with an emphysema phenotype. Visual CT examination associations were robust to adjustment for semiautomated correlates in many cases. CONCLUSIONS: Standardized visual assessments of emphysema and airway disease are significantly associated with genetic loci previously associated with chronic obstructive pulmonary disease susceptibility or semiautomated CT examination phenotypes in GWAS. Visual CT measures of emphysema and airways disease offer independent information for genetic association studies in relation to standard semiautomated measures.