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.

Quantification of Emphysema Progression at CT Using Simultaneous Volume, Noise, and Bias Lung Density Correction.

Background CT attenuation is affected by lung volume, dosage, and scanner bias, leading to inaccurate emphysema progression measurements in multicenter studies. Purpose To develop and validate a method that simultaneously corrects volume, noise, and interscanner bias for lung density change estimation in emphysema progression at CT in a longitudinal multicenter study. Materials and Methods In this secondary analysis of the prospective Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) study, lung function data were obtained from participants who completed baseline and 5-year follow-up visits from January 2008 to August 2017. CT emphysema progression was measured with volume-adjusted lung density (VALD) and compared with the joint volume-noise-bias-adjusted lung density (VNB-ALD). Reproducibility was studied under change of dosage protocol and scanner model with repeated acquisitions. Emphysema progression was visually scored in 102 randomly selected participants. A stratified analysis of clinical characteristics was performed that considered groups based on their combined lung density change measured by VALD and VNB-ALD. Results A total of 4954 COPDGene participants (mean age, 60 years ± 9 [SD]; 2511 male, 2443 female) were analyzed (1329 with repeated reduced-dose acquisition in the follow-up visit). Mean repeatability coefficients were 30 g/L ± 0.46 for VALD and 14 g/L ± 0.34 for VNB-ALD. VALD measurements showed no evidence of differences between nonprogressors and progressors (mean, -5.5 g/L ± 9.5 vs -8.6 g/L ± 9.6; P = .11), while VNB-ALD agreed with visual readings and showed a difference (mean, -0.67 g/L ± 4.8 vs -4.2 g/L ± 5.5; P < .001). Analysis of progression showed that VNB-ALD progressors had a greater decline in forced expiratory volume in 1 second (-42 mL per year vs -32 mL per year; Tukey-adjusted P = .002). Conclusion Simultaneously correcting volume, noise, and interscanner bias for lung density change estimation in emphysema progression at CT improved repeatability analyses and agreed with visual readings. It distinguished between progressors and nonprogressors and was associated with a greater decline in lung function metrics. Clinical trial registration no. NCT00608764 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Goo in this issue.

Genome-wide association study of preserved ratio impaired spirometry (PRISm).

BACKGROUND: Preserved ratio impaired spirometry (PRISm) is defined as a forced expiratory volume in 1 s (FEV1) <80% predicted and FEV1/forced vital capacity ≥0.70. PRISm is associated with respiratory symptoms and comorbidities. Our objective was to discover novel genetic signals for PRISm and see if they provide insight into the pathogenesis of PRISm and associated comorbidities. METHODS: We undertook a genome-wide association study (GWAS) of PRISm in UK Biobank participants (Stage 1), and selected single nucleotide polymorphisms (SNPs) reaching genome-wide significance for replication in 13 cohorts (Stage 2). A combined meta-analysis of Stage 1 and Stage 2 was done to determine top SNPs. We used cross-trait linkage disequilibrium score regression to estimate genome-wide genetic correlation between PRISm and pulmonary and extrapulmonary traits. Phenome-wide association studies of top SNPs were performed. RESULTS: 22 signals reached significance in the joint meta-analysis, including four signals novel for lung function. A strong genome-wide genetic correlation (rg) between PRISm and spirometric COPD (rg=0.62, p<0.001) was observed, and genetic correlation with type 2 diabetes (rg=0.12, p=0.007). Phenome-wide association studies showed that 18 of 22 signals were associated with diabetic traits and seven with blood pressure traits. CONCLUSION: This is the first GWAS to successfully identify SNPs associated with PRISm. Four of the signals, rs7652391 (nearest gene MECOM), rs9431040 (HLX), rs62018863 (TMEM114) and rs185937162 (HLA-B), have not been described in association with lung function before, demonstrating the utility of using different lung function phenotypes in GWAS. Genetic factors associated with PRISm are strongly correlated with risk of both other lung diseases and extrapulmonary comorbidity.

Causes of and Clinical Features Associated with Death in Tobacco Cigarette Users by Lung Function Impairment.

Rationale: Cigarette smoking contributes to the risk of death through different mechanisms. Objectives: To determine how causes of and clinical features associated with death vary in tobacco cigarette users by lung function impairment. Methods: We stratified current and former tobacco cigarette users enrolled in Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) into normal spirometry, PRISm (Preserved Ratio Impaired Spirometry), Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1-2 COPD, and GOLD 3-4 COPD. Deaths were identified via longitudinal follow-up and Social Security Death Index search. Causes of death were adjudicated after a review of death certificates, medical records, and next-of-kin interviews. We tested associations between baseline clinical variables and all-cause mortality using multivariable Cox proportional hazards models. Measurements and Main Results: Over a 10.1-year median follow-up, 2,200 deaths occurred among 10,132 participants (age 59.5 ± 9.0 yr; 46.6% women). Death from cardiovascular disease was most frequent in PRISm (31% of deaths). Lung cancer deaths were most frequent in GOLD 1-2 (18% of deaths vs. 9-11% in other groups). Respiratory deaths outpaced competing causes of death in GOLD 3-4, particularly when BODE index ⩾7. St. George's Respiratory Questionnaire score ⩾25 was associated with higher mortality in all groups: Hazard ratio (HR), 1.48 (1.20-1.84) normal spirometry; HR, 1.40 (1.05-1.87) PRISm; HR, 1.80 (1.49-2.17) GOLD 1-2; HR, 1.65 (1.26-2.17) GOLD 3-4. History of respiratory exacerbations was associated with higher mortality in GOLD 1-2 and GOLD 3-4, quantitative emphysema in GOLD 1-2, and airway wall thickness in PRISm and GOLD 3-4. Conclusions: Leading causes of death vary by lung function impairment in tobacco cigarette users. Worse respiratory-related quality of life is associated with all-cause mortality regardless of lung function.

Heterogeneity and Progression of Chronic Obstructive Pulmonary Disease: Emphysema-Predominant and Non-Emphysema-Predominant Disease.

While variation in emphysema severity between patients with chronic obstructive pulmonary disease (COPD) is well-recognized, clinically applicable definitions of the emphysema-predominant disease (EPD) and non-emphysema-predominant disease (NEPD) subtypes have not been established. To study the clinical relevance of the EPD and NEPD subtypes, we tested the association of these subtypes with prospective decline in forced expiratory volume in 1 second (FEV1) and mortality among 3,427 subjects with Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometric grade 2-4 COPD at baseline in the Genetic Epidemiology of COPD (COPDGene) Study, an ongoing national multicenter study that started in 2007. NEPD was defined as airflow obstruction with less than 5% computed tomography (CT) quantitative densitometric emphysema at -950 Hounsfield units, and EPD was defined as airflow obstruction with 10% or greater CT emphysema. Mixed-effects models for FEV1 demonstrated larger average annual FEV1 loss in EPD subjects than in NEPD subjects (-10.2 mL/year; P < 0.001), and subtype-specific associations with FEV1 decline were identified. Cox proportional hazards models showed higher risk of mortality among EPD patients versus NEPD patients (hazard ratio = 1.46, 95% confidence interval: 1.34, 1.60; P < 0.001). To determine whether the NEPD/EPD dichotomy is captured by previously described COPDGene subtypes, we used logistic regression and receiver operating characteristic (ROC) curve analysis to predict NEPD/EPD membership using these previous subtype definitions. The analysis generally showed excellent discrimination, with areas under the ROC curve greater than 0.9. The NEPD and EPD COPD subtypes capture important aspects of COPD heterogeneity and are associated with different rates of disease progression and mortality.

Quantitative CT Evaluation of Emphysema Progression over 10 Years in the COPDGene Study.

Background Long-term studies of chronic obstructive pulmonary disease (COPD) can evaluate emphysema progression. Adjustment for differences in equipment and scanning protocols of individual CT examinations have not been studied extensively. Purpose To evaluate emphysema progression in current and former smokers in the COPDGene cohort over three imaging points obtained at 5-year intervals accounting for individual CT parameters. Materials and Methods Current and former cigarette smokers enrolled between 2008 and 2011 from the COPDGene study were prospectively followed for 10 years between 2008 and 2020. Extent of emphysema as adjusted lung density (ALD) from quantitative CT was measured at baseline and at 5- and 10-year follow-up. Linear mixed models adjusted for CT technical characteristics were constructed to evaluate emphysema progression. Mean annual changes in ALD over consecutive 5-year study periods were estimated by smoking status and baseline emphysema. Results Of 8431 participants at baseline (mean age, 60 years ± 9 [SD]; 3905 female participants), 4913 were at 5-year follow-up and 1544 participants were at 10-year follow-up. There were 4134 (49%) participants who were current smokers, and 4449 (53%) participants had more than trace emphysema at baseline. Current smokers with more than trace emphysema showed the largest decline in ALD, with mean annual decreases of 1.4 g/L (95% CI: 1.2, 1.5) in the first 5 years and 0.9 g/L (95% CI: 0.7, 1.2) in the second 5 years. Accounting for CT noise, field of view, and scanner model improved model fit for estimation of emphysema progression (P < .001 by likelihood ratio test). Conclusion Evaluation at CT of emphysema progression in the COPDGene study showed that, during the span of 10 years, participants with pre-existing emphysema who continued smoking had the largest decline in ALD. Adjusting for CT equipment and protocol factors improved these longitudinal estimates. Clinical trial registration no. NCT00608764 © RSNA, 2023 Supplemental material is available for this article. See the editorial by Parraga and Kirby in this issue.

Principal component analysis of flow-volume curves in COPDGene to link spirometry with phenotypes of COPD.

BACKGROUND: Parameters from maximal expiratory flow-volume curves (MEFVC) have been linked to CT-based parameters of COPD. However, the association between MEFVC shape and phenotypes like emphysema, small airways disease (SAD) and bronchial wall thickening (BWT) has not been investigated. RESEARCH QUESTION: We analyzed if the shape of MEFVC can be linked to CT-determined emphysema, SAD and BWT in a large cohort of COPDGene participants. STUDY DESIGN AND METHODS: In the COPDGene cohort, we used principal component analysis (PCA) to extract patterns from MEFVC shape and performed multiple linear regression to assess the association of these patterns with CT parameters over the COPD spectrum, in mild and moderate-severe COPD. RESULTS: Over the entire spectrum, in mild and moderate-severe COPD, principal components of MEFVC were important predictors for the continuous CT parameters. Their contribution to the prediction of emphysema diminished when classical pulmonary function test parameters were added. For SAD, the components remained very strong predictors. The adjusted R2 was higher in moderate-severe COPD, while in mild COPD, the adjusted R2 for all CT outcomes was low; 0.28 for emphysema, 0.21 for SAD and 0.19 for BWT. INTERPRETATION: The shape of the maximal expiratory flow-volume curve as analyzed with PCA is not an appropriate screening tool for early disease phenotypes identified by CT scan. However, it contributes to assessing emphysema and SAD in moderate-severe COPD.

Baseline characteristics from a 3-year longitudinal study to phenotype subjects with COPD: the FOOTPRINTS study.

BACKGROUND: FOOTPRINTS® is a prospective, longitudinal, 3-year study assessing the association between biomarkers of inflammation/lung tissue destruction and chronic obstructive pulmonary disease (COPD) severity and progression in ex-smokers with mild-to-severe COPD. Here, we present baseline characteristics and select biomarkers of study subjects. METHODS: The methodology of FOOTPRINTS® has been published previously. The study population included ex-smokers with a range of COPD severities (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages 1-3), ex-smokers with COPD and alpha-1-antitrypsin deficiency (A1ATD) and a control group of ex-smokers without airflow limitation (EwAL). At study entry, data were collected for: demographics, disease characteristics, history of comorbidities and COPD exacerbations, symptoms, lung function and volume, exercise capacity, soluble biomarkers, and quantitative and qualitative computed tomography. Baseline data are presented with descriptive statistical comparisons for soluble biomarkers in the individual GOLD and A1ATD groups versus EwAL. RESULTS: In total, 463 subjects were enrolled. The per-protocol set comprised 456 subjects, mostly male (64.5%). The mean (standard deviation) age was 60.7 (6.9) years. At baseline, increasing pulmonary symptoms, worse lung function, increased residual volume, reduced diffusing capacity of the lung for carbon monoxide (DLco) and greater prevalence of centrilobular emphysema were observed with increasing disease severity amongst GOLD 1-3 subjects. Subjects with A1ATD (n = 19) had similar lung function parameters to GOLD 2-3 subjects, a high residual volume comparable to GOLD 3 subjects, and similar air trapping to GOLD 2 subjects. Compared with EwAL (n = 61), subjects with A1ATD had worse lung function, increased residual volume, reduced DLco, and a greater prevalence of confluent or advanced destructive emphysema. The soluble inflammatory biomarkers white blood cell count, fibrinogen, high-sensitivity C-reactive protein and plasma surfactant protein were higher in GOLD 1-3 groups than in the EwAL group. Interleukin-6 was expressed less often in EwAL subjects compared with subjects in the GOLD and A1ATD groups. Soluble receptor for advanced glycation end product was lowest in GOLD 3 subjects, indicative of more severe emphysema. CONCLUSIONS: These findings provide context for upcoming results from FOOTPRINTS®, which aims to establish correlations between biomarkers and disease progression in a representative COPD population. TRIAL REGISTRATION NUMBER: NCT02719184, study start date 13/04/2016.

X chromosome associations with chronic obstructive pulmonary disease and related phenotypes: an X chromosome-wide association study.

BACKGROUND: The association between genetic variants on the X chromosome to risk of COPD has not been fully explored. We hypothesize that the X chromosome harbors variants important in determining risk of COPD related phenotypes and may drive sex differences in COPD manifestations. METHODS: Using X chromosome data from three COPD-enriched cohorts of adult smokers, we performed X chromosome specific quality control, imputation, and testing for association with COPD case-control status, lung function, and quantitative emphysema. Analyses were performed among all subjects, then stratified by sex, and subsequently combined in meta-analyses. RESULTS: Among 10,193 subjects of non-Hispanic white or European ancestry, a variant near TMSB4X, rs5979771, reached genome-wide significance for association with lung function measured by FEV1/FVC ([Formula: see text] 0.020, SE 0.004, p 4.97 × 10-08), with suggestive evidence of association with FEV1 ([Formula: see text] 0.092, SE 0.018, p 3.40 × 10-07). Sex-stratified analyses revealed X chromosome variants that were differentially trending in one sex, with significantly different effect sizes or directions. CONCLUSIONS: This investigation identified loci influencing lung function, COPD, and emphysema in a comprehensive genetic association meta-analysis of X chromosome genetic markers from multiple COPD-related datasets. Sex differences play an important role in the pathobiology of complex lung disease, including X chromosome variants that demonstrate differential effects by sex and variants that may be relevant through escape from X chromosome inactivation. Comprehensive interrogation of the X chromosome to better understand genetic control of COPD and lung function is important to further understanding of disease pathology. Trial registration Genetic Epidemiology of COPD Study (COPDGene) is registered at ClinicalTrials.gov, NCT00608764 (Active since January 28, 2008). Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints Study (ECLIPSE), GlaxoSmithKline study code SCO104960, is registered at ClinicalTrials.gov, NCT00292552 (Active since February 16, 2006). Genetics of COPD in Norway Study (GenKOLS) holds GlaxoSmithKline study code RES11080, Genetics of Chronic Obstructive Lung Disease.

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.

Evidence of Spaceflight-Induced Adverse Effects on Photoreceptors and Retinal Function in the Mouse Eye.

The goal of the present study was to characterize acute oxidative damage in ocular structure and retinal function after exposure to spaceflight, and to evaluate the efficacy of an antioxidant in reducing spaceflight-induced changes in the retina. Ten-week-old adult C57BL/6 male mice were flown aboard the ISS on Space-X 24 over 35 days, and returned to Earth alive. The mice received a weekly injection of a superoxide dismutase mimic, MnTnBuOE-2-PyP 5+ (BuOE), before launch and during their stay onboard the ISS. Ground control mice were maintained on Earth under identical environmental conditions. Before the launch, intraocular pressure (IOP) was measured using a handheld tonometer and retinal function was evaluated using electroretinogram (ERG). ERG signals were recorded when the mouse eye was under dark-adapted conditions in response to ultraviolet monochromatic light flashes. Within 20 h after splashdown, IOP and ERG assessments were repeated before euthanasia. There were significant increases in body weight for habitat control groups post-flight compared to pre-flight measurements. However, the body weights were similar among flight groups before launch and after splashdown. The IOP measurements were similar between pre- and post-flight groups with no significant differences between BuOE-treated and saline controls. Immunofluorescence evaluation showed increases in retinal oxidative stress and apoptotic cell death after spaceflight. BuOE treatment significantly decreased the level of the oxidative stress biomarker. ERG data showed that the average amplitudes of the a- and b-wave were significantly decreased (39% and 32% by spaceflight, respectively) compared to that of habitat ground controls. These data indicate that spaceflight conditions induce oxidative stress in the retina, which may lead to photoreceptor cell damage and retinal function impairment.

Spaceflight-Induced Gene Expression Profiles in the Mouse Brain Are Attenuated by Treatment with the Antioxidant BuOE.

The demands of deep space pose a health risk to the central nervous system that has long been a concern when sending humans to space. While little is known about how spaceflight affects transcription spatially in the brain, a greater understanding of this process has the potential to aid strategies that mitigate the effects of spaceflight on the brain. Therefore, we performed GeoMx Digital Spatial Profiling of mouse brains subjected to either spaceflight or grounded controls. Four brain regions were selected: Cortex, Frontal Cortex, Corunu Ammonis I, and Dentate Gyrus. Antioxidants have emerged as a potential means of attenuating the effects of spaceflight, so we treated a subset of the mice with a superoxide dismutase mimic, MnTnBuOE-2-PyP 5+ (BuOE). Our analysis revealed hundreds of differentially expressed genes due to spaceflight in each of the four brain regions. Both common and region-specific transcriptomic responses were observed. Metabolic pathways and pathways sensitive to oxidative stress were enriched in the four brain regions due to spaceflight. These findings enhance our understanding of brain regional variation in susceptibility to spaceflight conditions. BuOE reduced the transcriptomic effects of spaceflight at a large number of genes, suggesting that this compound may attenuate oxidative stress-induced brain damage caused by the spaceflight environment.

Emphysema Progression at CT by Deep Learning Predicts Functional Impairment and Mortality: Results from the COPDGene Study.

Background Visual assessment remains the standard for evaluating emphysema at CT; however, it is time consuming, is subjective, requires training, and is affected by variability that may limit sensitivity to longitudinal change. Purpose To evaluate the clinical and imaging significance of increasing emphysema severity as graded by a deep learning algorithm on sequential CT scans in cigarette smokers. Materials and Methods A secondary analysis of the prospective Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) study participants was performed and included baseline and 5-year follow-up CT scans from 2007 to 2017. Emphysema was classified automatically according to the Fleischner emphysema grading system at baseline and 5-year follow-up using a deep learning model. Baseline and change in clinical and imaging parameters at 5-year follow-up were compared in participants whose emphysema progressed versus those who did not. Kaplan-Meier analysis and multivariable Cox regression were used to assess the relationship between emphysema score progression and mortality. Results A total of 5056 participants (mean age, 60 years ± 9 [SD]; 2566 men) were evaluated. At 5-year follow-up, 1293 of the 5056 participants (26%) had emphysema progression according to the Fleischner grading system. This group demonstrated progressive airflow obstruction (forced expiratory volume in 1 second [percent predicted]: -3.4 vs -1.8), a greater decline in 6-minute walk distance (-177 m vs -124 m), and greater progression in quantitative emphysema extent (adjusted lung density: -1.4 g/L vs 0.5 g/L; percentage of lung voxels with CT attenuation less than -950 HU: 0.6 vs 0.2) than those with nonprogressive emphysema (P < .001 for each). Multivariable Cox regression analysis showed a higher mortality rate in the group with emphysema progression, with an estimated hazard ratio of 1.5 (95% CI: 1.2, 1.8; P < .001). Conclusion An increase in Fleischner emphysema grade on sequential CT scans using an automated deep learning algorithm was associated with increased functional impairment and increased risk of mortality. ClinicalTrials.gov registration no. NCT00608764 © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Grenier in this issue.

Optimism is associated with respiratory symptoms and functional status in chronic obstructive pulmonary disease.

BACKGROUND: Optimism is the general belief that good things will occur in the future; optimism is modifiable by cognitive behavioral therapy (CBT). Previous studies have associated higher optimism with improved health outcomes and lower all-cause mortality. RESEARCH QUESTION: Investigate association between optimism and disease-related characteristics in chronic obstructive pulmonary disease (COPD). STUDY DESIGN AND METHODS: Current and former smokers with/without COPD and Preserved Ratio Impaired Spirometry (PRISm) from the 10-year follow-up visit for the Genetic Epidemiology of COPD (COPDGene) study were included. Optimism was assessed at the 10-year visit using the Life Orientation Test-Revised. Models of optimism as a predictor of lung function, COPD-associated phenotypes including exacerbations, and functional assessments, were adjusted for demographic confounders, smoking status, and comorbidities. RESULTS: Among 1967 subjects, higher optimism was significantly associated with older age, non-Hispanic white race, marital status, quitting smoking status, absence of COPD, and absence of depression. In multivariable analysis, higher optimism was independently associated with fewer prior exacerbations of COPD (coef = - 0.037, P < 0.001). Higher optimism was also related to better MMRC scores (coef = - 0.041, P < 0.001), CAT scores (coef = - 0.391, P < 0.001), SGRQ scores (coef = - 0.958, P < 0.001), BODE index (coef = - 0.059, P < 0.001), and longer 6-min walk distance (coef = 10.227, P < 0.001). After stratification by severity of COPD, these associations with optimism were still significant in all groups. No significant association was observed for cross-sectional FEV1 (%) or FVC (%) with optimism score. INTERPRETATION: Fewer exacerbations and less severe respiratory symptoms and higher functional capacity were associated with higher optimism, which may impact health outcomes in current and former smokers with and without COPD. Optimism is a modifiable trait and these results may further support a role for CBT to improve outcomes in COPD.

A rapidly changing understanding of COPD: World COPD Day from the COPD Foundation.

World COPD Day raises awareness about chronic obstructive pulmonary disease (COPD). COPD accounts for over 150,000 US deaths per year. A major challenge is that COPD receives only a fraction of the research funding provided to other major diseases. Control of COPD is dependent on developing new approaches to diagnose the disease earlier with a recognition of either pre-COPD or established COPD based on symptoms, lung structural change and/or loss of lung function that occurs before meeting long established criteria for a population-based definition of obstruction. Optimization of current therapies improves lung function, exercise capacity, quality of life, and survival. New pathways of disease progression are being identified creating new opportunities for development of therapies that could stop or cure this disease.

Whole exome sequencing analysis in severe chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD), one of the leading causes of death worldwide, is substantially influenced by genetic factors. Alpha-1 antitrypsin deficiency demonstrates that rare coding variants of large effect can influence COPD susceptibility. To identify additional rare coding variants in patients with severe COPD, we conducted whole exome sequencing analysis in 2543 subjects from two family-based studies (Boston Early-Onset COPD Study and International COPD Genetics Network) and one case-control study (COPDGene). Applying a gene-based segregation test in the family-based data, we identified significant segregation of rare loss of function variants in TBC1D10A and RFPL1 (P-value < 2x10-6), but were unable to find similar variants in the case-control study. In single-variant, gene-based and pathway association analyses, we were unable to find significant findings that replicated or were significant in meta-analysis. However, we found that the top results in the two datasets were in proximity to each other in the protein-protein interaction network (P-value = 0.014), suggesting enrichment of these results for similar biological processes. A network of these association results and their neighbors was significantly enriched in the transforming growth factor beta-receptor binding and cilia-related pathways. Finally, in a more detailed examination of candidate genes, we identified individuals with putative high-risk variants, including patients harboring homozygous mutations in genes associated with cutis laxa and Niemann-Pick Disease Type C. Our results likely reflect heterogeneity of genetic risk for COPD along with limitations of statistical power and functional annotation, and highlight the potential of network analysis to gain insight into genetic association studies.

Visual Emphysema at Chest CT in GOLD Stage 0 Cigarette Smokers Predicts Disease Progression: Results from the COPDGene Study.

Background The clinical significance of visually evident emphysema on CT images in individuals without spirometric evidence of chronic obstructive pulmonary disease (COPD) by current diagnostic criteria is, to the knowledge of the authors, unknown. Purpose To evaluate whether participants with visually evident emphysema at CT were more likely to have progressive disease and increased mortality at 5 years compared with those without visual emphysema. Materials and Methods This secondary analysis of the prospective Genetic Epidemiology of COPD study evaluated current or former smokers enrolled between 2008 and 2011 who did not meet current criteria for COPD (defined as Global Initiative for Obstructive Lung Disease stage 0). Statistical analysis was performed by using linear mixed models to estimate mean physiologic, imaging, and clinical outcomes for those with and without visual emphysema. Hazard ratios for mortality were calculated by using Cox regression models with emphysema as the main predictor. Results Of the 4095 participants, 48.3% (1979 participants; 1096 men and 883 women; mean age, 57 years ± 8 [standard deviation]) had trace or greater visual emphysema at CT and 51.7% (2116 participants; 1068 men and 1048 women; mean age, 56 years ± 8) had no emphysema at CT. At 5 years, participants with visual emphysema at CT demonstrated progressive airflow obstruction with lower values of ratio of forced expiratory volume in 1 second (FEV1)-to-functional vital capacity (FVC) ratio (-1.7 vs -0.7) and greater progression in quantitative emphysema measured by 15th percentile lung density (-3.3 vs -0.3 HU), adjusted lung density (-3.1 vs -0.2 g/L), and percentage of lung voxels with CT attenuation less than -950 HU (0.17 vs -0.20) than participants without emphysema (P < .001 for each). The rate of quantitative emphysema progression increased with greater grades of emphysema severity within the emphysema group. Conclusion The presence of visual emphysema at CT in current and former Global Initiative for Obstructive Lung Disease stage 0 smokers predicted structural and physiologic disease progression. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Grenier in this issue.

Deep Learning Enables Automatic Classification of Emphysema Pattern at CT.

BackgroundPattern of emphysema at chest CT, scored visually by using the Fleischner Society system, is associated with physiologic impairment and mortality risk.PurposeTo determine whether participant-level emphysema pattern could predict impairment and mortality when classified by using a deep learning method.Materials and MethodsThis retrospective analysis of Genetic Epidemiology of COPD (COPDGene) study participants enrolled between 2007 and 2011 included those with baseline CT, visual emphysema scores, and survival data through 2018. Participants were partitioned into nonoverlapping sets of 2407 for algorithm training, 100 for validation and parameter tuning, and 7143 for testing. A deep learning algorithm using convolutional neural network and long short-term memory architectures was trained to classify pattern of emphysema according to Fleischner criteria. Deep learning scores were compared with visual scores and clinical parameters including pulmonary function tests. Cox proportional hazard models were used to evaluate relationships between emphysema scores and survival. The algorithm was also tested by using CT and clinical data in 1962 participants enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) study.ResultsA total of 7143 COPDGene participants (mean age ± standard deviation, 59.8 years ± 8.9; 3734 men and 3409 women) were evaluated. Deep learning emphysema classifications were associated with impaired pulmonary function tests, 6-minute walk distance, and St George's Respiratory Questionnaire at univariate analysis (P < .001 for each). Testing in the ECLIPSE cohort showed similar associations (P < .001). In the COPDGene test cohort, deep learning emphysema classification improved the fit of linear mixed models in the prediction of these clinical parameters compared with visual scoring (P < .001). Compared with participants without emphysema, mortality was greater in participants classified by the deep learning algorithm as having any grade of emphysema (adjusted hazard ratios were 1.5, 1.7, 2.9, 5.3, and 9.7, respectively, for trace, mild, moderate, confluent, and advanced destructive emphysema; P < .05).ConclusionDeep learning automation of the Fleischner grade of emphysema at chest CT is associated with clinical measures of pulmonary insufficiency and the risk of mortality.© RSNA, 2019Online supplemental material is available for this article.

Five-year Progression of Emphysema and Air Trapping at CT in Smokers with and Those without Chronic Obstructive Pulmonary Disease: Results from the COPDGene Study.

Background CT is used to quantify abnormal changes in the lung parenchyma of smokers that might overlap chronic obstructive pulmonary disease (COPD), but studies on the progression of expiratory air trapping in smokers are scarce. Purpose To evaluate the relationship between longitudinal changes in forced expiratory volume in 1 second (FEV1) and CT-quantified emphysema and air trapping in smokers. Materials and Methods Cigarette smokers with and those without COPD participating in the multicenter observational COPDGene study were evaluated. Subjects underwent inspiratory and expiratory chest CT and spirometry at baseline and 5-year follow-up. Emphysema was quantified by using adjusted lung density (ALD). Air trapping was quantified by using mean lung density at expiratory CT and CT-measured functional residual capacity-to-total lung volume ratio. Linear models were used to regress quantitative CT measurements taken 5 years apart, and models were fit with and without adding FEV1 as a predictor. Analyses were stratified by Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage (GOLD 0, no COPD; GOLD 1, mild COPD; GOLD 2, moderate COPD; GOLD 3, severe COPD; GOLD 4, very severe COPD). Subjects with preserved FEV1-to-forced vital capacity ratio and reduced FEV1 percentage predicted were categorized as having preserved ratio impaired spirometry (PRISm). Results A total of 4211 subjects (503 with PRISm; 2034 with GOLD 0, 388 with GOLD 1, 816 with GOLD 2, 381 with GOLD 3, 89 with GOLD 4) were evaluated. ALD decreased by 1.7 g/L (95% confidence interval [CI]: -2.5, -0.9) in subjects with GOLD 0 at baseline and by 5.3 g/L (95% CI: -6.2, -4.4) in those with GOLD 1-4 (P < .001 for both). When adjusted for changes in FEV1, corresponding numbers were -2.2 (95% CI: -3.0, -1.3) and -4.6 g/L (95% CI: -5.6, -3.4) (P < .001 for both). Progression in air trapping was identified only in GOLD stage 2-4. Approximately 33%-50% of changes in air trapping in GOLD stages 2-4 were accounted for by changes in FEV1. Conclusion CT measures of emphysema and air trapping increased over 5 years in smokers. Forced expiratory volume in one second accounted for less than 10% of emphysema progression and less than 50% of air trapping progression detected at CT. © RSNA, 2020 Online supplemental material is available for this article.

Development and Reporting of Prediction Models: Guidance for Authors From Editors of Respiratory, Sleep, and Critical Care Journals.

Prediction models aim to use available data to predict a health state or outcome that has not yet been observed. Prediction is primarily relevant to clinical practice, but is also used in research, and administration. While prediction modeling involves estimating the relationship between patient factors and outcomes, it is distinct from casual inference. Prediction modeling thus requires unique considerations for development, validation, and updating. This document represents an effort from editors at 31 respiratory, sleep, and critical care medicine journals to consolidate contemporary best practices and recommendations related to prediction study design, conduct, and reporting. Herein, we address issues commonly encountered in submissions to our various journals. Key topics include considerations for selecting predictor variables, operationalizing variables, dealing with missing data, the importance of appropriate validation, model performance measures and their interpretation, and good reporting practices. Supplemental discussion covers emerging topics such as model fairness, competing risks, pitfalls of "modifiable risk factors", measurement error, and risk for bias. This guidance is not meant to be overly prescriptive; we acknowledge that every study is different, and no set of rules will fit all cases. Additional best practices can be found in the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines, to which we refer readers for further details.