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© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/., Smoking is the most well-established cause of chronic airflow obstruction (CAO) but particulate air pollution and poverty have also been implicated. We regressed sex-specific prevalence of CAO from 41 Burden of Obstructive Lung Disease study sites against smoking prevalence from the same study, the gross national income per capita and the local annual mean level of ambient particulate matter (PM2.5) using negative binomial regression. The prevalence of CAO was not independently associated with PM2.5 but was strongly associated with smoking and was also associated with poverty. Strengthening tobacco control and improved understanding of the link between CAO and poverty should be prioritised., Supported by Wellcome Trust grant 085790/Z/08/Z for the BOLD (Burden of Obstructive Lung Disease) Study. The initial BOLD programprogramme was funded in part by unrestricted educational grants to the Operations CenterCentre in Portland, Oregon from Altana, Aventis, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Merck, Novartis, Pfizer, Schering-Plough, Sepracor, and the University of Kentucky (Lexington, KY). A full list of local funders can be found at https://www.boldstudy.org.

Background: Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone.Research Question: What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma?Study Design and Methods: We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 × 10–6) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2).Results: We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 × 10–8) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent.Interpretation: We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.

Background: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes. Methods: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC 1

Background There are several reports on underdiagnosis of COPD, while little is known about COPD overdiagnosis and overtreatment. We describe the overdiagnosis and the prevalence of spirometrically defined false positive COPD, as well as their relationship with overtreatment across 23 population samples in 20 countries participating in the BOLD Study between 2003 and 2012. Methods A false positive diagnosis of COPD was considered when participants reported a doctor's diagnosis of COPD, but postbronchodilator spirometry was unobstructed (FEV1/FVC > LLN). Additional analyses were performed using the fixed ratio criterion (FEV1/FVC Results Among 16,177 participants, 919 (5.7%) reported a previous medical diagnosis of COPD. Postbronchodilator spirometry was unobstructed in 569 subjects (61.9%): false positive COPD. A similar rate of overdiagnosis was seen when using the fixed ratio criterion (55.3%). In a subgroup analysis excluding participants who reported a diagnosis of "chronic bronchitis" or "emphysema" (n = 220), 37.7% had no airflow limitation. The site-specific prevalence of false positive COPD varied greatly, from 1.9% in low- to middle-income countries to 4.9% in high-income countries. In multivariate analysis, overdiagnosis was more common among women, and was associated with higher education; former and current smoking; the presence of wheeze, cough, and phlegm; and concomitant medical diagnosis of asthma or heart disease. Among the subjects with false positive COPD, 45.7% reported current use of respiratory medication. Excluding patients with reported asthma, 34.4% of those with normal spirometry still used a respiratory medication. Conclusions False positive COPD is frequent. This might expose nonobstructed subjects to possible adverse effects of respiratory medication.

Rationale The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 is based on an ABCD assessment tool of symptoms and exacerbation history and grade 1-4 of airflow limitation severity, facilitating classification either into 4 groups (ABCD) or 16 groups (1A-4D). We aimed to compare the GOLD 2011, GOLD 2017 ABCD, and GOLD 2017 1A-4D classifications in terms of their distribution and prediction of mortality and hospitalizations. Methods In the GenKOLS study, 912 COPD patients with FEV1 less than 80% of the predicted answered questionnaires and performed lung function testing in 2003-2005. The patients were recruited from a hospital patient registry (n=662) and from the general population (n=250), followed up until 2011 with respect to all-cause and respiratory mortality, and all-cause and respiratory hospitalizations. We performed logistic regression and receiver operating curve (ROC) analyses for the different classifications with estimations of area under the curve (AUC) for comparisons. Results Mean age at baseline was 60 years (SD 11), 55% were male. Mean duration of follow-up was 91 months. By GOLD 2011, 21% were classified as group A, 29% group B, 6% group C, and 43% as group D, corresponding percentages for GOLD 2017 were: 25%, 52%, 3%, and 20%. The GOLD 2011 classification had higher AUC values than the GOLD 2017 group ABCD classification for respiratory mortality and hospitalization, but after inclusion of airflow limitation severity in GOLD 2017 groups 2A-4D, AUC values were significantly higher with GOLD 2017. Conclusion In a clinically relevant sample of COPD patients, the GOLD 2017 classification doubles the prevalence of group B and halves the prevalence of groups C and D as compared to the GOLD 2011 classification. The prediction of respiratory mortality and respiratory hospitalization was better for GOLD 2017 2A-4D taking airflow limitation severity into account, as compared to GOLD 2017 ABCD and GOLD 2011.

Genome-wide association studies (GWAS) have identified multiple associations with emphysema apicobasal distribution (EABD), but the biological functions of these variants are unknown. To characterize the functions of EABD-associated variants, we integrated GWAS results with 1) expression quantitative trait loci (eQTL) from the Genotype Tissue Expression (GTEx) project and subjects in the COPDGene (Genetic Epidemiology of COPD) study and 2) cell type epigenomic marks from the Roadmap Epigenomics project. On the basis of these analyses, we selected a variant near ACVR1B (activin A receptor type 1B) for functional validation. SNPs from 168 loci with P values less than 5 × 10(−5) in the largest GWAS meta-analysis of EABD were analyzed. Eighty-four loci overlapped eQTL, with 12 of these loci showing greater than 80% likelihood of harboring a single, shared GWAS and eQTL causal variant. Seventeen cell types were enriched for overlap between EABD loci and Roadmap Epigenomics marks (permutation P

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent patient populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never-smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD., Editorial summary: A genome-wide association study in over 400,000 individuals identifies 139 new signals for lung function. These variants can predict chronic obstructive pulmonary disease in independent, trans-ethnic cohorts.

Rationale: The Global Burden of Disease program identified smoking and ambient and household air pollution as the main drivers of death and disability from chronic obstructive pulmonary disease (COPD). Objective: To estimate the attributable risk of chronic airflow obstruction (CAO), a quantifiable characteristic of COPD, due to several risk factors. Methods: The Burden of Obstructive Lung Disease study is a cross-sectional study of adults, aged ≥40, in a globally distributed sample of 41 urban and rural sites. Based on data from 28,459 participants, we estimated the prevalence of CAO, defined as a postbronchodilator FEV1-to-FVC ratio less than the lower limit of normal, and the relative risks associated with different risk factors. Local relative risks were estimated using a Bayesian hierarchical model borrowing information from across sites. From these relative risks and the prevalence of risk factors, we estimated local population attributable risks. Measurements and Main Results: The mean prevalence of CAO was 11.2% in men and 8.6% in women. The mean population attributable risk for smoking was 5.1% in men and 2.2% in women. The next most influential risk factors were poor education levels, working in a dusty job for ≥10 years, low body mass index, and a history of tuberculosis. The risk of CAO attributable to the different risk factors varied across sites. Conclusions: Although smoking remains the most important risk factor for CAO, in some areas, poor education, low body mass index, and passive smoking are of greater importance. Dusty occupations and tuberculosis are important risk factors at some sites.

Some individuals have characteristics of both asthma and COPD (asthma-COPD overlap, ACO), and evidence suggests they experience worse outcomes than those with either condition alone. Improved knowledge of the genetic architecture would contribute to understanding whether determinants of risk in this group differ from those in COPD or asthma.We conducted a genome-wide association study in 8,068 cases and 40,360 controls of European ancestry from UK Biobank (stage 1). After excluding variants only associated with asthma or COPD we selected 31 variants for further investigation in 12 additional cohorts (stage 2), and discovered eight novel signals for ACO in a meta-analysis of stage 1 and 2 studies.Our signals include an intergenic signal on chromosome 5 not previously associated with asthma, COPD or lung function, and suggest a spectrum of shared and distinct genetic influences in asthma, COPD and ACO. A number of signals may represent loci that predispose to serious long-term consequences in people with asthma.

Objectives To estimate treatment- and productivity-related costs associated with COPD in two different samples, and to analyse the association between the costs and moderate and severe exacerbations. Methods We performed a baseline visit and four telephone-interviews during a one-year follow-up of 81 COPD cases and 132 controls recruited from a population-based sample, and of 205 hospital-recruited COPD patients. COPD was defined by post-bronchodilator spirometry. Total costs consisted of treatment related costs and costs of productivity losses. Exacerbation-related costs were estimated by multivariate median regression. Results The average annual disease-related costs for a COPD patient from the hospital sample was nearly twice as high as for a COPD case from the population sample (€26,518 vs €15,021), and nearly four times as high as for a control subject (€6740). For both sampling sources, the average annual costs of productivity losses were substantially higher than the treatment related costs (€17,014 vs €9,504, €11,192 vs €3,829, and €4494 vs €2,246, for the hospital COPD patients, the population-based COPD cases, and the controls, respectively). Severe exacerbations were an important cost driver for the treatment related costs in both COPD groups. Moderate exacerbations explained all the costs of productivity losses in the population-based COPD cases, but did not affect the costs of productivity losses in the hospital-recruited COPD patients. Conclusion We found that there were significant incremental costs associated with COPD, and the treatment related costs were significantly affected by exacerbations. The costs of productivity losses substantially exceeded the treatment related costs in both sampling sources.

Rationale There is limited knowledge on the effect of acute exacerbations in chronic obstructive pulmonary disease (AECOPD) on lung cancer risk in COPD patients with and without a history of asthma. This study aims to examine whether AECOPD is associated with risk of lung cancer, and whether the effect depends on a history of asthma. Methods In the GenKOLS study of 2003–2005, 852 subjects with COPD performed spirometry, and filled out questionnaires on smoking habits, symptoms and disease history. These data were linked to lung cancer data from the Cancer Registry of Norway through 2013. AECOPD, measured at baseline was the main predictor. To quantify differences in lung cancer risk, we performed Cox-proportional hazards regression. We adjusted for sex, age, smoking variables, body mass index, and lung function. Measurements and results During follow-up, 8.8% of the subjects with, and 5.9% of the subjects without exacerbations were diagnosed with lung cancer. Cox regression showed a significant increased risk of lung cancer with one or more exacerbations in COPD patients without a history of asthma, HRR = 2.77 (95% CI 1.39–5.52). We found a significant interaction between a history of asthma and AECOPD on lung cancer. Conclusions AECOPD is associated with an increased risk of lung cancer in COPD patients without a history of asthma. publishedVersion

Objective This study assessed the association between respiratory symptoms and mortality in four cohorts of the general population in Norway aged 15–75 years and in selected subgroups in the pooled sample. Methods The study comprised 158,702 persons, who were drawn randomly from the Norwegian population register. All subjects received a standardized, self-administered questionnaire on 11 respiratory symptoms between 1972 and 1998, with follow-up of death until December 31, 2017. Analyses were performed on 114,380 respondents. Results The hazard of death was closely associated with sex, age, and education. The hazard ratios (HR) for death and the 95% confidence intervals (CI) by risk factors were similar in the four cohorts. After adjustment for demographic and environmental, modifiable factors, the HR for death was 1.90 (95% CI 1.80–2.00) for breathlessness score 3, 1.28 (1.21–1.37) for cough/phlegm score 5 and 1.09 (1.05–1.14) for attack of breathlessness/wheeze score 2 compared to the referent (no symptom), respectively. The cough/phlegm score was associated with death in current smokers but not in never smokers or ex-smokers. Breathlessness score was associated with death in men and women. Conclusion Among persons aged 45–75 years, respiratory symptoms were significant predictors of all cause mortality. Education and smoking habits influenced only the associations between coughing and mortality. The associations were independent of study sites.

INTRODUCTION: Cigarette smoking is a major environmental risk factor for many diseases, including chronic obstructive pulmonary disease (COPD). There are shared genetic influences on cigarette smoking and COPD. Genetic risk factors for cigarette smoking in cohorts enriched for COPD are largely unknown. METHODS: We performed genome-wide association analyses for average cigarettes per day (CPD) across the Genetic Epidemiology of COPD (COPDGene) non-Hispanic white (NHW) (n = 6659) and African American (AA) (n = 3260), GenKOLS (the Genetics of Chronic Obstructive Lung Disease) (n = 1671), and ECLIPSE (the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) (n = 1942) cohorts. In addition, we performed exome array association analyses across the COPDGene NHW and AA cohorts. We considered analyses across the entire cohort and stratified by COPD case–control status. RESULTS: We identified genome-wide significant associations for CPD on chromosome 15q25 across all cohorts (lowest p = 1.78 × 10(−15)), except in the COPDGene AA cohort alone. Previously reported associations on chromosome 19 had suggestive and directionally consistent associations (RAB4, p = 1.95 × 10(−6); CYP2A7, p = 7.50 × 10(−5); CYP2B6, p = 4.04 × 10(−4)). When we stratified by COPD case–control status, single nucleotide polymorphisms on chromosome 15q25 were nominally associated with both NHW COPD cases (β = 0.11, p = 5.58 × 10(−4)) and controls (β = 0.12, p = 3.86 × 10(−5)) For the gene-based exome array association analysis of rare variants, there were no exome-wide significant associations. For these previously replicated associations, the most significant results were among COPDGene NHW subjects for CYP2A7 (p = 5.2 × 10(−4)). CONCLUSIONS: In a large genome-wide association study of both common variants and a gene-based association of rare coding variants in ever-smokers, we found genome-wide significant associations on chromosome 15q25 with CPD for common variants, but not for rare coding variants. These results were directionally consistent among COPD cases and controls. IMPLICATIONS: We examined both common and rare coding variants associated with CPD in a large population of heavy smokers with and without COPD of NHW and AA descent. We replicated genome-wide significant associations on chromosome 15q25 with CPD for common variants among NHW subjects, but not for rare variants. We demonstrated for the first time that common variants on chromosome 15q25 associated with CPD are similar among COPD cases and controls. Previously reported associations on chromosome 19 showed suggestive and directionally consistent associations among common variants (RAB4, CYP2A7, and CYP2B6) and for rare variants (CYP2A7) among COPDGene NHW subjects. Although the genetic effect sizes for these single nucleotide polymorphisms on chromosome 15q25 are modest, we show that this creates a substantial smoking burden over the lifetime of a smoker.

Rationale: Evidence supporting the association of chronic obstructive pulmonary disease or airflow obstruction with use of solid fuels is conflicting and inconsistent. Objectives: To assess the association of airflow obstruction with self-reported use of solid fuels for cooking or heating. Methods: We analyzed 18,554 adults from the BOLD (Burden of Obstructive Lung Disease) study, who had provided acceptable post-bronchodilator spirometry measurements, and information on use of solid fuels. The association of airflow obstruction with use of solid fuels for cooking or heating was assessed by sex, within each site, using regression analysis. Estimates were stratified by national income and meta-analyzed. We performed similar analyses for spirometric restriction, chronic cough, and chronic phlegm. Measurements and Main Results: We found no association between airflow obstruction and use of solid fuels for cooking or heating (odds ratio [OR] for men, 1.20 [95% confidence interval (CI), 0.94–1.53]; OR for women, 0.88 [95% CI, 0.67–1.15]). This was true for low-/middle- and high-income sites. Among never-smokers, there was also no evidence of an association of airflow obstruction with use of solid fuels (OR for men, 1.00 [95% CI, 0.57–1.76]; OR for women, 1.00 [95% CI, 0.76–1.32]). Overall, we found no association of spirometric restriction, chronic cough, or chronic phlegm with the use of solid fuels. However, we found that chronic phlegm was more likely to be reported among female never-smokers and those who had been exposed for 20 years or longer. Conclusions: Airflow obstruction assessed from post-bronchodilator spirometry was not associated with use of solid fuels for cooking or heating.

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide(1). We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P

Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (similar to 6 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 x 10(-49)), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.

Dl(CO) is a widely used pulmonary function test in clinical practice and a particularly useful measure for assessing patients with chronic obstructive pulmonary disease (COPD). We hypothesized that elucidating genetic determinants of Dl(CO) could lead to better understanding of the genetic architecture of COPD. We estimated the heritability of Dl(CO) using common genetic variants and performed genome-wide association analyses in four cohorts enriched for subjects with COPD (COPDGene [Genetic Epidemiology of COPD], NETT [National Emphysema Treatment Trial], GenKOLS [Genetics of Chronic Obstructive Lung Disease study], and TESRA [Treatment of Emphysema With a Gamma-Selective Retinoid Agonist study]) using a combined European ancestry white dataset and a COPDGene African American dataset. We assessed our genome-wide significant and suggestive associations for Dl(CO) in previously reported genome-wide association studies of COPD and related traits. We also characterized associations of known COPD-associated variants and Dl(CO). We estimated the SNP-based heritability of Dl(CO) in the European ancestry white population to be 22% (P = 0.0004). We identified three genome-wide significant associations with Dl(CO): variants near TGFB2, CHRNA3, and PDE11A loci (P

Background: Studies on costs of COPD exacerbations from general populations are scarce. Objectives: To compare direct costs (treatment-related) and indirect costs (productivity-related) associated with COPD in population based and hospital-recruited samples, and to estimate the components related to moderate and severe exacerbations. Methods: We performed 4 telephone interviews with 81 COPD cases and 132 controls from a population-based survey and 205 hospital-recruited COPD-patients. A moderate exacerbation was defined by use of antibiotics or corticosteroids due to respiratory disease, and severe exacerbations by hospitalisation due to respiratory disease. The sum of direct and indirect costs gave the total costs. Initial analyses compared costs across the three groups, and multivariate quantile regression estimated the costs attributed to exacerbations. Results: The crude, annual mean total disease-related costs were €26518, €15021, and €6740 per person for the patients, cases, and controls (p Conclusion: The annual total health-related costs for a hospital-recruited COPD-patient were nearly twice that of a general population-based COPD-case. The most important cost driver was severe exacerbations.

SummaryChronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide novel insights into disease pathogenesis. To broaden COPD genetic risk loci discovery and identify cell type and phenotype associations we performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci with P value < 5×10−8; 47 were previously described in association with either COPD or population-based lung function. Of the remaining 35 novel loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified enrichment for loci in lung tissue, smooth muscle and alveolar type II cells. We found 9 shared genomic regions between COPD and asthma and 5 between COPD and pulmonary fibrosis. COPD genetic risk loci clustered into groups of quantitative imaging features and comorbidity associations. Our analyses provide further support to the genetic susceptibility and heterogeneity of COPD.

Reduced lung function predicts mortality and is key to the diagnosis of COPD. In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, one-half of which are new. In combination these variants strongly predict COPD in deeply-phenotyped patient populations. Furthermore, the combined effect of these variants showed generalisability across smokers and never-smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.

INTRODUCTION Based on the National Lung Cancer Screening Trial (NLST), guidelines on screening programs for lung cancer have recommended low-dose computed tomography (LDCT). De Torres et al made a score for COPD patients (COPD-LUCSS) to improve their selection criteria. OBJECTIVE To examine and compare the discriminating value of both scores in a community-based cohort of COPD patients. METHODS Four hundred and twenty-two ever-smokers with COPD from the GenKOLS study in Bergen were merged with the Cancer Registry of Norway. We divided the patients into groups of high and low risk according to the COPD-LUCSS and the NLST criteria. Cox regression and logistic regression were used to analyse the associations between the scores and lung cancer. We used Harrell's C and area under the curve (AUC) to estimate discriminating values and to compare the models. RESULTS Hazard ratio for the high risk vs the low risk in the COPD-LUCSS was 3.0 (1.4-6.5 95% CI), P

Background Evidence from several studies show poor guideline adherence to COPD treatment, but no such study has been undertaken in Norway. The objectives of this study, was to estimate and compare the guideline adherence to COPD treatment in general population-based and hospital-recruited COPD patients, and find possible predictors of guideline adherence. Methods From the prospective, observational EconCOPD-study, we analysed guideline adherence for 90 population-based COPD cases compared to 245 hospital-recruited COPD patients. Overall guideline adherence was defined as correct pharmacological treatment, and influenza vaccination the preceding year, and having received smoking cessation advice. Multivariate logistic regression analysis was performed with the dichotomous outcome overall guideline adherence adjusting for relevant variables. Results The overall guideline adherence for population-based COPD cases was 6.7%, significantly lower than the 29.8% overall guideline-adherence amongst hospital-recruited COPD patients. Adherence to pharmacological treatment guidelines was 10.0 and 35.5%, for the two recruitment sources, respectively. GOLD-stage 3 to 4 was associated with significantly better guideline adherence compared to GOLD-stage 2 (OR (95% CI) 18.9 (8.37,42.7)). The unadjusted difference between the two recruitment sources was completely explained by degree of airflow obstruction. Conclusion Overall guideline adherence was very low for both recruitment sources. We call for increased attention from authorities and healthcare personnel to improve the quality of care given to this patient group. Electronic supplementary material The online version of this article (10.1186/s12890-018-0756-8) contains supplementary material, which is available to authorized users.

Introduction There are few data available on the optimal number of lung cancer patients needed to generate and compare estimates of quality between units managing lung cancer. The number of lung cancer patients per management unit varies considerably in Norway, where there are 42 hospitals that treated between 1 and 454 lung cancer patients in 2011. Aims To estimate the differences in quality indicators that are of sufficient importance to change a pulmonary physician's lung cancer management program, and to estimate the size of the patient samples necessary to detect such differences. Method Twenty-six physicians were asked about the relative differences from a national average of quality indicators that would change their own lung cancer management program. Sample sizes were calculated to give valid estimates of quality of a management unit based on prevalence of quality indicators and minimally important differences (MID). Results The average MID in quality indicators that would cause a change in management varied from 18% to 24% among 26 chest physicians, depending on the indicator. Conclusions To generate precise estimates for quality control of lung cancer care in Norway, the number of management units must be reduced. Given the present willingness of chest physicians to change their procedures for management of lung cancer according to the results of quality control indicators, we recommend a maximum of 10 units with a minimum of 200 incident lung cancer patients per year for each management center.

The heritability of chronic obstructive pulmonary disease (COPD) cannot be fully explained by recognized genetic risk factors identified as achieving genome-wide significance. In addition, the combined contribution of genetic variation to COPD risk has not been fully explored. We sought to determine: (1) whether studies of variants from previous studies of COPD or lung function in a larger sample could identify additional associated variants, particularly for severe COPD; and (2) the impact of genetic risk scores on COPD. We genotyped 3,346 single-nucleotide polymorphisms (SNPs) in 2,588 cases (1,803 severe COPD) and 1,782 control subjects from four cohorts, and performed association testing with COPD, combining these results with existing genotyping data from 6,633 cases (3,497 severe COPD) and 5,704 control subjects. In addition, we developed genetic risk scores from SNPs associated with lung function and COPD and tested their discriminatory power for COPD-related measures. We identified significant associations between SNPs near PPIC (P = 1.28 X 10(-8)) and PPP4R4/SERPINA1 (P = 1.01 X 10(-8)) and severe COPD; the latter association may be driven by recognized variants in SERPINA1. Genetic risk scores based on SNPs previously associated with COPD and lung function had a modest ability to discriminate COPD (area under the curve, similar to 0.6), and accounted for a mean 0.9-1.9% lower forced expiratory volume in 1 second percent predicted for each additional risk allele. In a large genetic association analysis, we identified associations with severe COPD near PPIC and SERPINA1. A risk score based on combining genetic variants had modest, but significant, effects on risk of COPD and lung function.

Chronic obstructive pulmonary disease (COPD) is caused by a complex interaction of environmental exposures, most commonly cigarette smoke, and genetic factors. Chronic cigarette smoke exposure in the mouse is a commonly used animal model of COPD. We aimed to expand our knowledge about the variable susceptibility of inbred strains to this model and test for genetic variants associated with this trait. To that end, we sought to measure differential susceptibility to cigarette smoke–induced emphysema in the mouse, identify genetic loci associated with this quantitative trait, and find homologous human genes associated with COPD. Alveolar chord length (CL) in 34 inbred strains of mice was measured after 6 months of exposure to cigarette smoke. After testing for association, we connected a murine candidate locus to a published meta-analysis of moderate-to-severe COPD. We identified deleterious mutations in a candidate gene in silico and measured gene expression in extreme strains. A/J was the most susceptible strain in our survey (Δ CL 7.0 ± 2.2 μm) and CBA/J was the least susceptible (Δ CL −0.3 ± 1.2 μm). By integrating mouse and human genome-wide scans, we identified the candidate gene Abi3bp. CBA/J mice harbor predicted deleterious variants in Abi3bp, and expression of the gene differs significantly between CBA/J and A/J mice. This is the first report of susceptibility to cigarette smoke–induced emphysema in 34 inbred strains of mice, and Abi3bp is identified as a potential contributor to this phenotype.

International audience; Chronic obstructive pulmonary disease (COPD) is a complex disease with strong environmental and genetic influences and sexually dimorphic features. Although genetic risk factors for COPD have been identified, much of the heritability remains unexplained. Sex-based genetic association studies may uncover additional COPD genetic risk factors. We studied current and former smokers from COPD case-control cohorts (COPDGene non-Hispanic whites and African Americans, Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points, and Genetics of Chronic Obstructive Lung Disease). COPD was defined as post-bronchodilator forced expiratory volume in 1 second/forced vital capacity less than 0.70 and forced expiratory volume in 1 second percent predicted less than 80. Testing was performed across all cohorts and combined in a meta-analysis adjusted for age, pack-years, and genetic ancestry. We first performed genome-wide single-nucleotide polymorphism (SNP)-by-sex interaction testing on the outcome of COPD affection status. We performed sex-stratified association testing for SNPs with interaction P less than 10-6. We examined over 8 million SNPs in four populations, including 6,260 subjects with COPD (40.6% female) and 5,269 smoking control subjects (47.3% female). The SNP rs9615358 in the cadherin gene CELSR1 approached genome-wide significance for an interaction with sex (P = 1.24 × 10-7). In the sex-stratified meta-analysis, this SNP was associated with COPD among females (odds ratio, 1.37 [95% confidence interval, 1.25-1.49]; P = 3.32 × 10-7) but not males (odds ratio, 0.90 [95% confidence interval, 0.79-1.01]; P = 0.06). CELSR1 is involved in fetal lung development. In a human fetal lung tissue dataset, we observed greater CELSR1 expression in female compared with male samples. This SNP-by-sex genome-wide association analysis identified the fetal lung development gene, CELSR1, as a potential sex-specific risk factor for COPD. Identifying sex-specific genetic risk factors may reveal new insights into sexually dimorphic features of COPD.

The predictors of autopsy and the accuracy of European short list (E) codes of respiratory diseases lack recent knowledge.A 10% random sample (n=6811) of inhabitants of Bergen, Norway, aged 20–70 years, was invited to participate in a survey in 1965–1971 (participation rate 83%).By December 31, 2005, 4387 (64%) participants had died and 1163 (27% of the deceased) had been given an autopsy. Causes of death were tuberculosis (E02, 0.2%), lung malignancy (E15, 3.5%), influenza (E38, 0.2%), pneumonia (E39, 6.5%) and chronic lower respiratory diseases (E40, 3.2%). Male sex, early deaths in the surveillance period and E15 were positive predictors of an autopsy examination, whereas old age and E39 were strong negative predictors. Among those referred for apost mortemexamination, the cause of death was verified as tuberculosis in 0.3%, lung cancer in 8.1%, acute pneumonia in 2.0% and chronic obstructive lung diseases in 4.9%. Cohen’s kappa coefficients (E codesversusautopsy) were 0.91 (95% CI 0.86–0.96) for E15, 0.37 (95% CI 0.20–0.54) for E39 and 0.65 (95% CI 0.54–0.76) for E40.These findings matter when deaths from respiratory diseases are used as end-points in epidemiological association studies and clinical trials.

The Asp358Ala variant in the interleukin-6 receptor (IL-6R) gene has been implicated in asthma, autoimmune and cardiovascular disorders, but its role in other respiratory conditions such as chronic obstructive pulmonary disease (COPD) has not been investigated. The aims of this study were to evaluate whether there is an association between Asp358Ala and COPD or asthma risk, and to explore the role of the Asp358Ala variant in sIL-6R shedding from neutrophils and its pro-inflammatory effects in the lung. We undertook logistic regression using data from the UK Biobank and the ECLIPSE COPD cohort. Results were meta-analyzed with summary data from a further three COPD cohorts (7,519 total cases and 35,653 total controls), showing no association between Asp358Ala and COPD (OR = 1.02 [95% CI: 0.96, 1.07]). Data from the UK Biobank showed a positive association between the Asp358Ala variant and atopic asthma (OR = 1.07 [1.01, 1.13]). In a series of in vitro studies using blood samples from 37 participants, we found that shedding of sIL-6R from neutrophils was greater in carriers of the Asp358Ala minor allele than in non-carriers. Human pulmonary artery endothelial cells cultured with serum from homozygous carriers showed an increase in MCP-1 release in carriers of the minor allele, with the difference eliminated upon addition of tocilizumab. In conclusion, there is evidence that neutrophils may be an important source of sIL-6R in the lungs, and the Asp358Ala variant may have pro-inflammatory effects in lung cells. However, we were unable to identify evidence for an association between Asp358Ala and COPD.

Motivation: For samples of unrelated individuals, we propose a general analysis framework in which hundred thousands of genetic loci can be tested simultaneously for association with complex phenotypes. The approach is built on spatial-clustering methodology, assuming that genetic loci that are associated with the target phenotype cluster in certain genomic regions. In contrast to standard methodology for multilocus analysis, which has focused on the dimension reduction of the data, our multilocus association-clustering test profits from the availability of large numbers of genetic loci by detecting clusters of loci that are associated with the phenotype. Results: The approach is computationally fast and powerful, enabling the simultaneous association testing of large genomic regions. Even the entire genome or certain chromosomes can be tested simultaneously. Using simulation studies, the properties of the approach are evaluated. In an application to a genome-wide association study for chronic obstructive pulmonary disease, we illustrate the practical relevance of the proposed method by simultaneously testing all genotyped loci of the genome-wide association study and by testing each chromosome individually. Our findings suggest that statistical methodology that incorporates spatial-clustering information will be especially useful in whole-genome sequencing studies in which millions or billions of base pairs are recorded and grouped by genomic regions or genes, and are tested jointly for association. Availability and implementation: Implementation of the approach is available upon request. Contact: daq412@mail.harvard.edu Supplementary information: Supplementary data are available at Bioinformatics online.

The GOLD (Global Initiative for Chronic Obstructive Lung Disease) 2011 update on chronic obstructive pulmonary disease (COPD) bases disease classification on level of dyspnea, exacerbation history, and FEV1, whereas the previous GOLD categorized disease severity according to FEV1 only. Information on how the new classification predicts long-term hospitalizations and mortality is limited.To examine how GOLD 2011 predicts hospitalizations and mortality over an 8-year period and to assess differences in predictive ability between GOLD 2011 and GOLD 2007.In the GenKOLS study, 912 patients with COPD (FEV1/FVC0.7 and FEV180% predicted) aged 40 to 91 years were clinically examined. Patients answered questionnaires and performed lung function testing in 2003-2005. The population was followed for 8 years regarding hospitalizations (all-cause, respiratory) and mortality (all-cause, respiratory, cardiovascular). We performed logistic regression and receiver operating curve analyses for GOLD 2007 and GOLD 2011 with estimations of area under the curve (AUC) to compare the different classifications.Twenty percent of patients were classified as GOLD 2011 group A (mild), 30% as group B, 6% group as C, and 44% as group D (very severe). Patients in GOLD 2011 group D had odds ratios of 4.1 (95% confidence interval [CI], 2.5-6.7), 9.6 (95% CI, 3.4-27.0), and 3.0 (95% CI, 0.7-13.2) relative to group A for all-cause, respiratory, and cardiovascular mortality, respectively, and 3.8 (95% CI, 2.4-5.9) and 13.0 (95% CI, 6.6-25.6) for all-cause and respiratory hospitalizations, respectively. Associations were similar also for GOLD 2007. The adjusted AUC values for GOLD 2011 and GOLD 2007 were 0.82/0.82 for respiratory mortality (P = 0.87) and 0.77/0.76 for respiratory hospitalizations (P = 0.51).The predictive ability of GOLD 2011 did not differ significantly from GOLD 2007 in terms of hospitalizations and mortality.

There is limited knowledge of the prognostic value of quantitative computed tomography (CT) measures of emphysema and airway wall thickness (AWT) on mortality.To examine 8-year mortality in relation to CT-measured emphysema and AWT, and assess if potential impact of these predictors remained after adjustment for lung function.In the Norwegian GenKOLS study of 2003-2005, 947 ever-smokers (49% with COPD) aged 40-85 years performed spirometry and CT examination. Mortality data from 2003-2011 were gathered from the Norwegian Cause of Death Registry. CT emphysema % low-attenuation areas (%LAA) and standardized measure for AWT (AWT-Pi10) were main predictors. We performed Laplace regression for survival data, estimating survival time for specified population percentiles within each emphysema category. Models were adjusted for sex, FEV1, COPD status, age, body mass index, smoking, and inflation level.During 8-year follow-up all-cause mortality rate was 15%. Although 4% of the subjects with %LAA less than 3 died, 18% with %LAA 3-10 and 44% with %LAA greater than or equal to 10 died. After adjustment, the comparable percentile subjects with medium and high emphysema had 19 months shorter survival than subjects who died in the lowest emphysema category. Subjects with %LAA greater than or equal to 10 had 33 and 37 months shorter survival than the lowest emphysema category with regard to respiratory and cardiovascular mortality, respectively. No significant associations were found between %LAA and cancer and lung cancer mortality. AWT did not predict mortality independently, but a positive interaction with emphysema was observed.AWT affected mortality with increasing degree of emphysema, whereas CT measure of emphysema was a strong independent mortality predictor.