Publications by authors named "Gregory L Kinney"

88 Publications

10 Year Follow-up of Lung Function, Respiratory Symptoms, and Functional Capacity in the COPDGene Study.

Ann Am Thorac Soc 2021 Aug 30. Epub 2021 Aug 30.

National Jewish Health, 2930, Denver, Colorado, United States.

Rationale: The course of lung function, respiratory symptoms, and functional status over time in people who smoke cigarettes is still incompletely understood. The Genetic Epidemiology of COPD (COPDGene) study provides a unique cohort to examine these trajectories, and now 10 year follow-up data are available.

Objectives: This study aims to provide insight into the progression of spirometric parameters, respiratory symptoms, and functional capacity over 10 years in current and former cigarette smokers.

Methods: We analyzed available longitudinal data for COPDGene participants who did not change smoking status over 3 visits spanning approximately 10 years of follow-up. Change in post-bronchodilator forced expiratory volume in one second (FEV1), St. George's Respiratory Questionnaire (SGRQ), and six-minute walk distance (6MWD) from Phase 1 to Phase 3 were examined using linear mixed models. Terms were included in the models to estimate mean progression separately for current and former cigarette smokers. Models were stratified by baseline GOLD spirometry stages as well as by new 2019 COPDGene Classification.

Results: Mean age at enrollment of the 9,103 participants in this analysis was 59.8 years (SD=9.2 years); 46.4% were women, and 32.6% were African American. In all GOLD COPD groups, including participants with normal spirometry, as well as all groups categorized by 2019 COPDGene Classification, FEV1 decreased, SGRQ increased (indicating higher symptom burden), and 6MWD decreased over the 10 year follow-up period. Current smokers exhibited a greater mean loss of FEV1 over the study period than former smokers for all groups except those with preserved ratio impaired spirometry (PRISm). For both SGRQ and 6MWD, rates of progression tended to be similar for former and current smokers except for 6MWD in the highest severity groups, where former smokers had greater progression. However, this could be impacted by some current smokers with faster progression that had quit smoking and were dropped from analyses.

Conclusions: Progression in FEV1, SGRQ, and 6MWD overall appears to be slow, and the change over time in groups traditionally characterized as not having disease closely mirrors that of the groups with COPD at all GOLD stages. Current cigarette smokers had greater loss of FEV1 than former smokers, while SGRQ and 6MWD changes were more similar between current and former cigarette smokers.
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http://dx.doi.org/10.1513/AnnalsATS.202007-873OCDOI Listing
August 2021

Haemoglobin as a biomarker for clinical outcomes in chronic obstructive pulmonary disease.

ERJ Open Res 2021 Jul 26;7(3). Epub 2021 Jul 26.

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA.

In COPD, anaemia is associated with increased morbidity, but the relationship between haemoglobin over its entire observed range and morbidity is poorly understood. Such an understanding could guide future therapeutic targeting of haemoglobin in COPD management. Leveraging the COPDGene study, we conducted a cross-sectional analysis of haemoglobin from COPD participants, examining symptoms, quality of life, functional performance, and acute exacerbations of COPD (AECOPD). Haemoglobin was analysed both as a continuous variable and categorised into anaemia, normal haemoglobin, and polycythaemia groups. Fractional polynomial modelling was used for continuous analyses; categorical models were multivariable linear or negative binomial regressions. Covariates included demographics, comorbidities, emphysema, diffusing capacity, and airflow obstruction. From 2539 participants, 366 (14%) were identified as anaemic and 125 (5%) as polycythaemic. Compared with normal haemoglobin, anaemia was significantly associated with increased symptoms (COPD Assessment Test score: p=0.006, modified Medical Research Council (mMRC) Dyspnoea Score: p=0.001); worse quality of life (St. George's Respiratory Questionnaire (SGRQ) score: p<0.001; Medical Outcomes Study Short Form 36-item Questionnaire (SF-36) General Health: p=0.002; SF-36 Physical Health: p<0.001), decreased functional performance (6-min walk distance (6MWD): p<0.001), and severe AECOPD (p=0.01), while polycythaemia was not. Continuous models, however, demonstrated increased morbidity at both ends of the haemoglobin distribution (p<0.01 for mMRC, SGRQ, SF-36 Physical Health, 6MWD, and severe AECOPD). Evaluating interactions, both diffusing capacity and haemoglobin were independently associated with morbidity. We present novel findings that haemoglobin derangements towards either extreme of the observed range are associated with increased morbidity in COPD. Further investigation is necessary to determine whether haemoglobin derangement drives morbidity or merely reflects systemic inflammation, and whether correcting haemoglobin towards the normal range improves morbidity.
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http://dx.doi.org/10.1183/23120541.00068-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311135PMC
July 2021

Small Airway Disease and Emphysema Are Associated with Future Exacerbations in Smokers with CT-derived Bronchiectasis and COPD: Results from the COPDGene Cohort.

Radiology 2021 09 22;300(3):706-714. Epub 2021 Jun 22.

From the Division of Pulmonary Diseases and Critical Care, the University of Texas Health Science Center at San Antonio, San Antonio, Tex (D.J.M., A.A., M.I.R.); Department of Radiology, University of California, San Diego, Calif (A.Y.); Division of Sleep Medicine and Circadian Disorders (W.W.), Division of Pulmonary and Critical Care Medicine, Department of Medicine (W.R.D., A.A.D.), and Department of Radiology (R.S.J.E.), Brigham and Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115; Department of Radiology, St. Luke's International Hospital, Chuo-ku, Tokyo, Japan (Y.O.); Quinnipiac University School of Medicine, Hamden, Conn (C.M.); South Texas Veterans Health Care System, San Antonio, Tex (A.A., M.I.R.); Pulmonary Disease and Critical Care Medicine, Mayo Clinic, Rochester, Minn (T.R.A.); Division of Pulmonary, Critical Care & Sleep Medicine, New York University School of Medicine, New York, NY (A.B.); Department of Pathophysiology and Transplantation, University of Milan Internal Medicine, and Respiratory Unit and Cystic Fibrosis Adult Center, Milan, Italy (S.A.); Department of Epidemiology, Colorado School of Public Health, University of Colorado, Aurora, Colo (K.A.Y., G.L.K.); Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Ala (J.M.W.); and Department of Radiology, National Jewish Health, Denver, Colo (D.A.L.).

Background Chronic obstructive pulmonary disease (COPD) and bronchiectasis can overlap and share pathologic features, such as small airway disease (SAD). Whether the presence of SAD and emphysema in smokers with CT-derived bronchiectasis is associated with exacerbations is unknown. Purpose To assess whether SAD and emphysema in smokers with CT-derived bronchiectasis are associated with future exacerbations. Materials and Methods SAD and emphysema were quantified using the parametric response map method in former and current heavy smokers with and without bronchiectasis at CT from the COPDGene Study (from July 2009 to July 2018). Exacerbations were prospectively assessed through biannual follow-up. An exacerbation was defined as an increase in or new onset of respiratory symptoms treated with antibiotics and/or corticosteroids. Severe exacerbations were defined as those that required hospitalization. The association of a high burden of SAD (≥15.6%) and high burden of emphysema (≥5%) at CT with exacerbations was assessed with generalized linear mixed models. Results Of 737 participants, 387 (median age, 64 years [interquartile range, 58-71 years]; 223 women) had CT-derived bronchiectasis. During a 9-year follow-up, after adjustment for age, sex, race, body mass index, current smoking status, pack-years, exacerbations before study entry, forced expiratory volume in 1 second, or FEV, and bronchiectasis severity CT score, high burden of SAD and high burden of emphysema were associated with a higher number of exacerbations per year (relative risk [RR], 1.89 [95% CI: 1.54, 2.33] and 1.37 [95% CI: 1.13, 1.66], respectively; ≤ .001 for both). Results were comparable among participants with bronchiectasis meeting criteria for COPD ( = 197) (RR, 1.67 [95% CI: 1.23, 2.27] for high burden of SAD and 1.51 [95% CI: 1.20, 1.91] for high burden of emphysema; ≤ .001 for both). Conclusion In smokers with CT-derived bronchiectasis and chronic obstructive pulmonary disease, structural damage to lung parenchyma and small airways was associated with a higher number of exacerbations per year. Clinical trial registration no. NCT00608764 © RSNA, 2021.
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http://dx.doi.org/10.1148/radiol.2021204052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409101PMC
September 2021

Quantification of prenatal marijuana use: evaluation of the correlation between self-report, serum, urine and umbilical cord assays among women delivering at two urban Colorado hospitals.

Addiction 2021 Jun 17. Epub 2021 Jun 17.

University of Colorado School of Medicine, Aurora, CO, USA.

Background And Aims: To estimate during pregnancy correlations between frequency of self-reported use of marijuana and quantified marijuana metabolite in biospecimens including urine, sera and umbilical cord homogenate.

Design: Prospective cohort.

Setting: Two urban hospitals in Colorado with legal recreational and medicinal marijuana.

Participants: Pregnant women (<16 weeks gestation) self-reporting marijuana use.

Measurements: Participants completed a written self-report survey and provided biospecimens at <16 weeks gestation (n = 46), 18 to 22 weeks gestation (n = 43), 32 to 36 weeks gestation (n = 39), and delivery (n = 37). Self-reported marijuana use frequency was calculated based on past-month days of use multiplied by number of daily uses. Maternal urine and sera were tested for presence (>5 ng/mL) of 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (THC-COOH). Liquid chromatography tandem mass spectrometry quantified THC-COOH in umbilical cord homogenate (ng/g). Last marijuana use by any measure was recorded to evaluate the time frame over which THC-COOH remains detectable (>0.10 ng/g) in cord.

Findings: From December 2017 through May 2019, 51 pregnant women enrolled, and 46 were included in analyses (2 withdrew and 3 had a spontaneous abortion). The majority were normal weight, White or Black race, and insured by Medicaid. At the time of enrollment between 7 to 15 weeks' gestation, 87% had ongoing use by self-report, or positive urine or serum. The majority (33 [66%]) stopped using before delivery. Sera and urine results were strongly correlated with self-reported use frequency (Spearman correlation coefficient [r] range 0.70-0.87 across visits, P < 0.001), and with each other. There was only one positive cord result when use stopped before 22 weeks. Frequency of self-reported marijuana use at delivery had strong correlation with quantified cord THC-COOH (r = 0.80, 95% CI = 0.62-0.89).

Conclusions: Quantified umbilical cord THC-COOH appears to strongly correlate with frequency of maternal marijuana use in the last month of pregnancy. Earlier use can be measured by either quantitative urine or serum assay.
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http://dx.doi.org/10.1111/add.15606DOI Listing
June 2021

Emphysema Progression and Lung Function Decline Among Angiotensin Converting Enzyme Inhibitors and Angiotensin-Receptor Blockade Users in the COPDGene Cohort.

Chest 2021 Oct 21;160(4):1245-1254. Epub 2021 May 21.

Division of Pulmonary and Critical Care, Johns Hopkins University, Baltimore, MD.

Background: Attenuation of transforming growth factor β by blocking angiotensin II has been shown to reduce emphysema in a murine model. General population studies have demonstrated that the use of angiotensin converting enzyme inhibitors (ACEis) and angiotensin-receptor blockers (ARBs) is associated with reduction of emphysema progression in former smokers and that the use of ACEis is associated with reduction of FEV progression in current smokers.

Research Question: Is use of ACEi and ARB associated with less progression of emphysema and FEV decline among individuals with COPD or baseline emphysema?

Methods: Former and current smokers from the Genetic Epidemiology of COPD Study who attended baseline and 5-year follow-up visits, did not change smoking status, and underwent chest CT imaging were included. Adjusted linear mixed models were used to evaluate progression of adjusted lung density (ALD), percent emphysema (%total lung volume <-950 Hounsfield units [HU]), 15th percentile of the attenuation histogram (attenuation [in HU] below which 15% of voxels are situated plus 1,000 HU), and lung function decline over 5 years between ACEi and ARB users and nonusers in those with spirometry-confirmed COPD, as well as all participants and those with baseline emphysema. Effect modification by smoking status also was investigated.

Results: Over 5 years of follow-up, compared with nonusers, ACEi and ARB users with COPD showed slower ALD progression (adjusted mean difference [aMD], 1.6; 95% CI, 0.34-2.9). Slowed lung function decline was not observed based on phase 1 medication (aMD of FEV % predicted, 0.83; 95% CI, -0.62 to 2.3), but was when analysis was limited to consistent ACEi and ARB users (aMD of FEV % predicted, 1.9; 95% CI, 0.14-3.6). No effect modification by smoking status was found for radiographic outcomes, and the lung function effect was more pronounced in former smokers. Results were similar among participants with baseline emphysema.

Interpretation: Among participants with spirometry-confirmed COPD or baseline emphysema, ACEi and ARB use was associated with slower progression of emphysema and lung function decline.

Trial Registry: ClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2021.05.007DOI Listing
October 2021

The Association Between Lung Hyperinflation and Coronary Artery Disease in Smokers.

Chest 2021 Sep 8;160(3):858-871. Epub 2021 May 8.

Department of Medicine, University of Pittsburgh, Pittsburgh, PA. Electronic address:

Background: Smokers manifest varied phenotypes of pulmonary impairment.

Research Question: Which pulmonary phenotypes are associated with coronary artery disease (CAD) in smokers?

Study Design And Methods: We analyzed data from the University of Pittsburgh COPD Specialized Center for Clinically Oriented Research (SCCOR) cohort (n = 481) and the Genetic Epidemiology of COPD (COPDGene) cohort (n = 2,580). Participants were current and former smokers with > 10 pack-years of tobacco exposure. Data from the two cohorts were analyzed separately because of methodologic differences. Lung hyperinflation was assessed by plethysmography in the SCCOR cohort and by inspiratory and expiratory CT scan lung volumes in the COPDGene cohort. Subclinical CAD was assessed as the coronary artery calcium score, whereas clinical CAD was defined as a self-reported history of CAD or myocardial infarction (MI). Analyses were performed in all smokers and then repeated in those with airflow obstruction (FEV to FVC ratio, < 0.70).

Results: Pulmonary phenotypes, including airflow limitation, emphysema, lung hyperinflation, diffusion capacity, and radiographic measures of airway remodeling, showed weak to moderate correlations (r < 0.7) with each other. In multivariate models adjusted for pulmonary phenotypes and CAD risk factors, lung hyperinflation was the only phenotype associated with calcium score, history of clinical CAD, or history of MI (per 0.2 higher expiratory and inspiratory CT scan lung volume; coronary calcium: OR, 1.2; 95% CI, 1.1-1.5; P = .02; clinical CAD: OR, 1.6; 95% CI, 1.1-2.3; P = .01; and MI in COPDGene: OR, 1.7; 95% CI, 1.0-2.8; P = .05). FEV and emphysema were associated with increased risk of CAD (P < .05) in models adjusted for CAD risk factors; however, these associations were attenuated on adjusting for lung hyperinflation. Results were the same in those with airflow obstruction and were present in both cohorts.

Interpretation: Lung hyperinflation is associated strongly with clinical and subclinical CAD in smokers, including those with airflow obstruction. After lung hyperinflation was accounted for, FEV and emphysema no longer were associated with CAD. Subsequent studies should consider measuring lung hyperinflation and examining its mechanistic role in CAD in current and former smokers.
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http://dx.doi.org/10.1016/j.chest.2021.04.066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449003PMC
September 2021

Self-Reported Cannabis Use and Markers of Inflammation in Men Who Have Sex With Men With and Without HIV.

Cannabis Cannabinoid Res 2021 04 15;6(2):165-173. Epub 2021 Apr 15.

Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.

Chronic inflammation contributes to aging and organ dysfunction in the general population, and is a particularly important determinant of morbidity and mortality among people with HIV (PWH). The effect of cannabis use on chronic inflammation is not well understood among PWH, who use cannabis more frequently than the general population. We evaluated participants in the Multicenter AIDS Cohort Study (MACS) beginning in 2004 with available data on cannabis use and inflammatory biomarkers. Associations of current cannabis use with plasma concentrations of inflammatory markers were adjusted for hepatitis C, tobacco smoking, and comorbidities. Markers were analyzed individually and in exploratory factor analysis (EFA). We included 1352 men within the MACS. Twenty-seven percent of HIV-negative men, 41% of HIV viremic men, and 35% of virologically suppressed men reported cannabis use at baseline. Among cannabis users, 20-25% in all groups defined by HIV serostatus were daily users, and the same proportion reported weekly use. The remaining ∼50% of users in all groups reported monthly or less frequent use. Four biomarker groupings were identified by EFA: : immune activation markers; : proinflammatory cytokines; : Th1- and Th2-promoting cytokines; and : inflammatory chemokines. In EFA, daily users had 30% higher levels of Factor 2 biomarkers than nonusers (=0.03); this was the only statistically significant difference by cannabis use status. Among individual markers, concentrations of IL-1β, IL-2, IL-6, and IL-8 (Factor 2); IL-10 (Factor 3); and BAFF (Factor 1) were higher (<0.05) among daily cannabis users than among nonusers, after adjusting for HIV serostatus and other covariates. Associations between daily cannabis use and proinflammatory biomarker levels did not differ by HIV serostatus. Further prospective studies with measured cannabis components are needed to clarify the impact of these compounds on inflammation. Our findings can facilitate for hypothesis generation and selection of biomarkers to include in such studies.
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http://dx.doi.org/10.1089/can.2019.0083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064959PMC
April 2021

Collaborative Cohort of Cohorts for COVID-19 Research (C4R) Study: Study Design.

medRxiv 2021 Mar 20. Epub 2021 Mar 20.

The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults at risk for coronavirus disease 2019 (COVID-19) comprising 14 established United States (US) prospective cohort studies. For decades, C4R cohorts have collected extensive data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R will link this pre-COVID phenotyping to information on SARS-CoV-2 infection and acute and post-acute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and broadly reflects the racial, ethnic, socioeconomic, and geographic diversity of the US. C4R is ascertaining severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations, and high-quality events surveillance. Extensive pre-pandemic data minimize referral, survival, and recall bias. Data are being harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these will be pooled and shared widely to expedite collaboration and scientific findings. This unique resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including post-acute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term trajectories of health and aging.
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http://dx.doi.org/10.1101/2021.03.19.21253986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987050PMC
March 2021

Metformin use and respiratory outcomes in asthma-COPD overlap.

Respir Res 2021 Feb 26;22(1):70. Epub 2021 Feb 26.

Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, 1830 E. Monument St. 5th Floor, Baltimore, MD, 21205, USA.

Background: Metformin is associated with improved respiratory outcomes in asthma; however, metformin in COPD and asthma-COPD overlap (ACO) remains unexplored.

Objective: To determine the association between metformin use and respiratory outcomes in COPD and ACO.

Study Design And Methods: Participants with COPD (FEV1/FVC < 0.70) in the Genetic Epidemiology of COPD study (COPDGene®) were categorized as ACO (n = 510), defined as concurrent physician-diagnosed asthma before age 40 years, or COPD alone (n = 3459). We estimated the association of baseline metformin use with (1) rate of total and severe respiratory exacerbations during follow-up, (2) cross-sectional St. George's Respiratory Questionnaire (SGRQ) score, six-minute walk distance (6MWD), and post-bronchodilator FEV1 percent predicted (FEV1pp), and (3) 5-year change in SGRQ, 6MWD, and FEV1pp. We also examined change in SGRQ, 6MWD and FEV1pp among participants who initiated metformin during follow-up (n = 108) compared to persistent metformin non-users (n = 2080). Analyses were adjusted for sociodemographic factors, medications, and comorbidities.

Results: Among participants with ACO, metformin use was associated with lower rate of total (adjusted incidence rate ratio [aIRR] 0.3; 95% confidence interval [95%CI] 0.11, 0.77) and severe exacerbations (aIRR 0.29; 95%CI 0.10, 0.89). Among participants with COPD alone, there was no association between metformin use with total (aIRR 0.98; 95%CI 0.62, 1.5) or severe exacerbations (aIRR 1.3; 95% CI 0.68, 2.4) (p-interaction < 0.05). Metformin use was associated with lower baseline SGRQ score (adjusted mean difference [aMD] - 2.7; 95%CI - 5.3, - 0.2) overall. Metformin initiation was associated with improved SGRQ score (aMD -10.0; 95% CI - 18.7, - 1.2) among participants with ACO but not COPD alone (p-interaction < 0.05). There was no association between metformin use and 6MWD or FEV1pp in any comparison.

Conclusions: Metformin use was associated with fewer respiratory exacerbations and improved quality of life among individuals with ACO but not COPD alone. Results suggest a potential role for metformin in ACO which requires further prospective study.

Trial Registry: NCT00608764.
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http://dx.doi.org/10.1186/s12931-021-01658-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908718PMC
February 2021

Co-Morbidity Patterns Identified Using Latent Class Analysis of Medications Predict All-Cause Mortality Independent of Other Known Risk Factors: The COPDGene Study.

Clin Epidemiol 2020 27;12:1171-1181. Epub 2020 Oct 27.

Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Purpose: Medication patterns include all medications in an individual's clinical profile. We aimed to identify chronic co-morbidity treatment patterns through medication use among COPDGene participants and determine whether these patterns were associated with mortality, acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and quality of life.

Materials And Methods: Participants analyzed here completed Phase 1 (P1) and/or Phase 2 (P2) of COPDGene. Latent class analysis (LCA) was used to identify medication patterns and assign individuals into unobserved LCA classes. Mortality, AECOPD, and the St. George's Respiratory Questionnaire (SGRQ) health status were compared in different LCA classes through survival analysis, logistic regression, and Kruskal-Wallis test, respectively.

Results: LCA identified 8 medication patterns from 32 classes of chronic comorbid medications. A total of 8110 out of 10,127 participants with complete covariate information were included. Survival analysis adjusted for covariates showed, compared to a low medication use class, mortality was highest in participants with hypertension+diabetes+statin+antiplatelet medication group. Participants in hypertension+SSRI+statin medication group had the highest odds of AECOPD and the highest SGRQ score at both P1 and P2.

Conclusion: Medication pattern can serve as a good indicator of an individual's comorbidities profile and improves models predicting clinical outcomes.
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http://dx.doi.org/10.2147/CLEP.S279075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602898PMC
October 2020

A Risk Prediction Model for Mortality Among Smokers in the COPDGene® Study.

Chronic Obstr Pulm Dis 2020 Oct;7(4):346-361

University of Pittsburgh, Pittsburgh, Pennsylvania.

Background: Risk factor identification is a proven strategy in advancing treatments and preventive therapy for many chronic conditions. Quantifying the impact of those risk factors on health outcomes can consolidate and focus efforts on individuals with specific high-risk profiles. Using multiple risk factors and longitudinal outcomes in 2 independent cohorts, we developed and validated a risk score model to predict mortality in current and former cigarette smokers.

Methods: We obtained extensive data on current and former smokers from the COPD Genetic Epidemiology (COPDGene) study at enrollment. Based on physician input and model goodness-of-fit measures, a subset of variables was selected to fit final Weibull survival models separately for men and women. Coefficients and predictors were translated into a point system, allowing for easy computation of mortality risk scores and probabilities. We then used the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) cohort for external validation of our model.

Results: Of 9867 COPDGene participants with standard baseline data, 17.6% died over 10 years of follow-up, and 9074 of these participants had the full set of baseline predictors (standard plus 6-minute walk distance and computed tomography variables) available for full model fits. The average age of participants in the cohort was 60 for both men and women, and the average predicted 10-year mortality risk was 18% for women and 25% for men. Model time-integrated area under the receiver operating characteristic curve statistics demonstrated good predictive model accuracy (0.797 average), validated in the external cohort (0.756 average). Risk of mortality was impacted most by 6-minute walk distance, forced expiratory volume in 1 second and age, for both men and women.

Conclusions: Current and former smokers exhibited a wide range of mortality risk over a 10- year period. Our models can identify higher risk individuals who can be targeted for interventions to reduce risk of mortality, for participants with or without chronic obstructive pulmonary disease (COPD) using current Global initiative for obstructive Lung Disease (GOLD) criteria.
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http://dx.doi.org/10.15326/jcopdf.7.4.2020.0146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883903PMC
October 2020

Smaller Left Ventricle Size at Noncontrast CT Is Associated with Lower Mortality in COPDGene Participants.

Radiology 2020 07 5;296(1):208-215. Epub 2020 May 5.

From the Division of Pulmonary and Critical Care, Department of Medicine, Applied Chest Imaging Laboratory (G.R.W., S.Y.A., F.N.R., C.E.C., C.L.P., A.A.D.), Department of Radiology, Applied Chest Imaging Laboratory (P.N., G.V.S.F., J.C.R., R.S.J.E.), Department of Anesthesia (G.Q.R.), and Division of Cardiology (A.M.S.), Brigham and Women's Hospital, 1249 Boylston St, Boston, MA 02215; Lung Health Center, University of Alabama at Birmingham, Birmingham, Ala (M.T.D., S.P.B., J.M.W.); Asthma and COPD Program, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill (R.K.); Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Mich (M.K.H.); BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (S.R.), Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Neb (S.R.); Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, Colo (K.Y., G.L.K., J.E.H.); and Respiratory Institute, Hospital Clinic, August Pi i Sunyer Biomedical Research Institute, Centro de Investigación Biomédica en Red Enfermedades Respiratorias, University of Barcelona, Barcelona, Spain (A.A.).

Background Smokers with chronic obstructive pulmonary disease (COPD) have smaller left ventricles (LVs) due to reduced preload. Skeletal muscle wasting is also common in COPD, but less is known about its contribution to LV size. Purpose To explore the relationships between CT metrics of emphysema, venous vascular volume, and sarcopenia with the LV epicardial volume (LV) (myocardium and chamber) estimated from chest CT images in participants with COPD and then to determine the clinical relevance of the LV in multivariable models, including sex and anthropomorphic metrics. Materials and Methods The COPDGene study (ClinicalTrials.gov identifier: NCT00608764) is an ongoing prospective longitudinal observational investigation that began in 2006. LV, distal pulmonary venous blood volume for vessels smaller than 5 mm in cross section (BV5), CT emphysema, and pectoralis muscle area were retrospectively extracted from 3318 nongated, unenhanced COPDGene CT scans. Multivariable linear and Cox regression models were used to explore the association between emphysema, venous BV5, pectoralis muscle area, and LV as well as the association of LV with health status using the St George's Respiratory Questionnaire, 6-minute walk distance, and all-cause mortality. Results The median age of the cohort was 64 years (interquartile range, 57-70 years). Of the 2423 participants, 1806 were men and 617 were African American. The median LV between Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 and GOLD 4 COPD was reduced by 13.9% in women and 17.7% in men ( < .001 for both). In fully adjusted models, higher emphysema percentage (β = -4.2; 95% confidence interval [CI]: -5.0, -3.4; < .001), venous BV5 (β = 7.0; 95% CI: 5.7, 8.2; < .001), and pectoralis muscle area (β = 2.7; 95% CI: 1.2, 4.1; < .001) were independently associated with reduced LV. Reductions in LV were associated with improved health status (β = 0.3; 95% CI: 0.1, 0.4) and 6-minute walk distance (β = -12.2; 95% CI: -15.2, -9.3). These effects were greater in women than in men. The effect of reduced LV on mortality (hazard ratio: 1.07; 95% CI: 1.05, 1.09) did not vary by sex. Conclusion In women more than men with chronic obstructive pulmonary disease, a reduction in the estimated left ventricle epicardial volume correlated with a loss of pulmonary venous vasculature, greater pectoralis muscle sarcopenia, and lower all-cause mortality. © RSNA, 2020
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http://dx.doi.org/10.1148/radiol.2020191793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299752PMC
July 2020

Machine Learning Characterization of COPD Subtypes: Insights From the COPDGene Study.

Chest 2020 05 28;157(5):1147-1157. Epub 2019 Dec 28.

Department of Epidemiology, University of Colorado, Denver, Aurora, CO.

COPD is a heterogeneous syndrome. Many COPD subtypes have been proposed, but there is not yet consensus on how many COPD subtypes there are and how they should be defined. The COPD Genetic Epidemiology Study (COPDGene), which has generated 10-year longitudinal chest imaging, spirometry, and molecular data, is a rich resource for relating COPD phenotypes to underlying genetic and molecular mechanisms. In this article, we place COPDGene clustering studies in context with other highly cited COPD clustering studies, and summarize the main COPD subtype findings from COPDGene. First, most manifestations of COPD occur along a continuum, which explains why continuous aspects of COPD or disease axes may be more accurate and reproducible than subtypes identified through clustering methods. Second, continuous COPD-related measures can be used to create subgroups through the use of predictive models to define cut-points, and we review COPDGene research on blood eosinophil count thresholds as a specific example. Third, COPD phenotypes identified or prioritized through machine learning methods have led to novel biological discoveries, including novel emphysema genetic risk variants and systemic inflammatory subtypes of COPD. Fourth, trajectory-based COPD subtyping captures differences in the longitudinal evolution of COPD, addressing a major limitation of clustering analyses that are confounded by disease severity. Ongoing longitudinal characterization of subjects in COPDGene will provide useful insights about the relationship between lung imaging parameters, molecular markers, and COPD progression that will enable the identification of subtypes based on underlying disease processes and distinct patterns of disease progression, with the potential to improve the clinical relevance and reproducibility of COPD subtypes.
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http://dx.doi.org/10.1016/j.chest.2019.11.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242638PMC
May 2020

Surface Detection of THC Attributable to Vaporizer Use in the Indoor Environment.

Sci Rep 2019 12 9;9(1):18587. Epub 2019 Dec 9.

Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

The number of cannabis users increased up to 188 million users worldwide in 2017. Smoking and vaping are the most common consumption routes with formation of side-stream smoke/vapor and secondhand exposure to cannabinoids has been described in the literature. External contamination of hair by cannabis smoke has been studied but there are no studies on third-hand cannabis exposure due to deposition of smoke or vapor on surfaces. We tested whether cannabinoids could be detected on surfaces and objects in a room where cannabis is vaporized. Surface samples were collected using isopropanol imbued non-woven wipes from hard surfaces and objects. Each surface was swabbed three times with standardized swabbing protocol including three different patterns. Samples were analyzed using LC-ESI-MS/MS in combination with online extraction. THC was detected on 6 samples out of the 15 collected in the study room at quantifiable levels ranging 348-4882 ng/m. Negative control samples collected from areas outside the study room were all negative. We demonstrated that surfaces exposed to side-stream cannabis vapor are positive for THC at quantifiable levels. This study represents a first step in understanding how side-stream cannabis vapor deposits in the environment and potentially results in a tertiary exposure for users and non-users.
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http://dx.doi.org/10.1038/s41598-019-55151-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901575PMC
December 2019

Pulmonary Subtypes Exhibit Differential Global Initiative for Chronic Obstructive Lung Disease Spirometry Stage Progression: The COPDGene® Study.

Chronic Obstr Pulm Dis 2019 Nov;6(5):414-429

Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora.

Rationale: We classified individuals into pulmonary disease subtypes based on 2 underlying pathophysiologic disease axes (airway-predominant and emphysema-predominant) and their increased mortality risk. Our next objective was to determine whether some subcomponents of these subtypes are additionally associated with unique patterns of Global initiative for chronic Obstructive Lung Disease (GOLD) spirometry stage progression.

Methods: After accounting for intra-individual measurement variability in spirometry measures between baseline (Phase 1) and the 5-year follow up (Phase 2) of the COPD Genetic Epidemiology (COPDGene) study, 4615 individuals had complete data that would characterize patterns of disease progression over 5 years (2033 non-Hispanic whites; 827 African Americans; 48% female). Individuals could express increased risk for mortality on one or both of the primary subtype axes (airway-predominant or emphysema-predominant) and thus they were further classified into 6 groups: high-risk airway-predominant disease only (APD-only), moderate-risk airway-predominant disease only (MR-APD-only), high-risk emphysema-predominant disease only (EPD-only), combined high-risk airway- and emphysema-predominant disease (combined APD-EPD), combined moderate-risk airway- and emphysema-predominant disease (combined MR-APD-EPD), and no high-risk pulmonary subtype. Outcomes were dichotomized for GOLD spirometry stage progression from Phase 1 to Phase 2. Logistic regression of the progression outcomes on the pulmonary subtypes were adjusted for age, sex, race, and change in smoking status.

Results: The MR-APD-only group was associated with conversion from GOLD 0 to preserved ratio-impaired spirometry (PRISm) status (odds ratio [OR] 11.3, 95% confidence interval [CI] 5.7-22.1) and GOLD 0 to GOLD 2-4 (OR 6.0, 95% CI 2.0-18.0). The EPD-only group was associated with conversion from GOLD 0 to GOLD 1 (OR 2.4, 95% CI 1.2-4.6), and GOLD 1 to GOLD 2-4 (OR 2.6, 95% CI 1.0-6.9). Conversion between PRISm and GOLD 2-4 (31%-38%) occurred in both the APD-only and the MR-APD-only groups.

Conclusion: Differential conversion occurs from GOLD 0 to PRISm and GOLD 0 to GOLD 1 based on groups expressing airway-predominant disease or emphysema-predominant disease independently or in combination. Airway-predominant and emphysema-predominant subtypes are highly important in determining patterns of early disease progression.
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http://dx.doi.org/10.15326/jcopdf.6.5.2019.0155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020848PMC
November 2019

Subtypes of COPD Have Unique Distributions and Differential Risk of Mortality.

Chronic Obstr Pulm Dis 2019 Nov;6(5):400-413

Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora.

Background: Previous attempts to explore the heterogeneity of chronic obstructive pulmonary disease (COPD) clustered individual patients using clinical, demographic, and disease features. We developed continuous multidimensional disease axes based on radiographic and spirometric variables that split into an airway-predominant axis and an emphysema-predominant axis.

Methods: The COPD Genetic Epidemiology study (COPDGene) is a cohort of current and former smokers, > 45 years, with at least 10 pack years of smoking history. Spirometry measures, blood pressure and body mass were directly measured. Mortality was assessed through continuing longitudinal follow-up and cause of death was adjudicated. Among 8157 COPDGene participants with complete spirometry and computed tomography (CT) measures, the top 2 deciles of the airway-predominant and emphysema-predominant axes previously identified were used to categorize individuals into 3 groups having the highest risk for mortality using Cox proportional hazard ratios. These groups were also assessed for causal mortality. Biomarkers of COPD (fibrinogen, soluble receptor for advanced glycation end products [sRAGE], C-reactive protein [CRP], clara cell secretory protein [CC16], surfactant-D [SP-D]) were compared by group.

Findings: High-risk subtype classification was defined for 2638 COPDGene participants who were in the highest 2 deciles of either the airway-predominant and/or emphysema-predominant axis (32% of the cohort). These high-risk participants fell into 3 groups: airway-predominant disease only (APD-only), emphysema-predominant disease only (EPD-only) and combined APD-EPD. There was 26% mortality for the APD-only group, 21% mortality for the EPD-only group, and 54% mortality for the combined APD-EPD group. The APD-only group (n=1007) was younger, had a lower forced expiratory volume in 1 second (FEV) percent (%) predicted and a strong association with the preserved ratio-impaired spirometry (PRISm) quadrant. The EPD-only group (n=1006) showed a relatively higher FEV % predicted and included largely GOLD stage 0, 1 and 2 partipants. Individuals in each of the 3 high-risk groups were at greater risk for respiratory mortality, while those in the APD-only group were additionally at greater risk for cardiovascular mortality. Biomarker analysis demonstrated a significant association of the APD-only group with CRP, and sRAGE demonstrated greatest significance with both the EPD-only and the combined APD-EPD groups.

Interpretation: Among current and former smokers, individuals in the highest 2 deciles for mortality risk on the airway-predominant axis and the emphysema-predominant axis have unique associations to spirometric patterns, different imaging characteristics, biomarkers and causal mortality.
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http://dx.doi.org/10.15326/jcopdf.6.5.2019.0150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020845PMC
November 2019

COPDGene 2019: Redefining the Diagnosis of Chronic Obstructive Pulmonary Disease.

Chronic Obstr Pulm Dis 2019 Nov;6(5):384-399

Northeastern University, Boston, Massachusetts.

Background: Chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality. Present-day diagnostic criteria are largely based solely on spirometric criteria. Accumulating evidence has identified a substantial number of individuals without spirometric evidence of COPD who suffer from respiratory symptoms and/or increased morbidity and mortality. There is a clear need for an expanded definition of COPD that is linked to physiologic, structural (computed tomography [CT]) and clinical evidence of disease. Using data from the COPD Genetic Epidemiology study (COPDGene), we hypothesized that an integrated approach that includes environmental exposure, clinical symptoms, chest CT imaging and spirometry better defines disease and captures the likelihood of progression of respiratory obstruction and mortality.

Methods: Four key disease characteristics - environmental exposure (cigarette smoking), clinical symptoms (dyspnea and/or chronic bronchitis), chest CT imaging abnormalities (emphysema, gas trapping and/or airway wall thickening), and abnormal spirometry - were evaluated in a group of 8784 current and former smokers who were participants in COPDGene Phase 1. Using these 4 disease characteristics, 8 categories of participants were identified and evaluated for odds of spirometric disease progression (FEV > 350 ml loss over 5 years), and the hazard ratio for all-cause mortality was examined.

Results: Using smokers without symptoms, CT imaging abnormalities or airflow obstruction as the reference population, individuals were classified as Possible COPD, Probable COPD and Definite COPD. Current Global initiative for obstructive Lung Disease (GOLD) criteria would diagnose 4062 (46%) of the 8784 study participants with COPD. The proposed COPDGene 2019 diagnostic criteria would add an additional 3144 participants. Under the new criteria, 82% of the 8784 study participants would be diagnosed with Possible, Probable or Definite COPD. These COPD groups showed increased risk of disease progression and mortality. Mortality increased in patients as the number of their COPD characteristics increased, with a maximum hazard ratio for all cause-mortality of 5.18 (95% confidence interval [CI]: 4.15-6.48) in those with all 4 disease characteristics.

Conclusions: A substantial portion of smokers with respiratory symptoms and imaging abnormalities do not manifest spirometric obstruction as defined by population normals. These individuals are at significant risk of death and spirometric disease progression. We propose to redefine the diagnosis of COPD through an integrated approach using environmental exposure, clinical symptoms, CT imaging and spirometric criteria. These expanded criteria offer the potential to stimulate both current and future interventions that could slow or halt disease progression in patients before disability or irreversible lung structural changes develop.
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http://dx.doi.org/10.15326/jcopdf.6.5.2019.0149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020846PMC
November 2019

Cannabis Use Is Associated With Increased Risk for Diabetic Ketoacidosis in Adults With Type 1 Diabetes: Findings From the T1D Exchange Clinic Registry.

Diabetes Care 2020 01 18;43(1):247-249. Epub 2019 Oct 18.

Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO.

Objective: We examined the frequency of diabetic ketoacidosis (DKA) in cannabis users compared with nonusers in the T1D Exchange clinic registry (T1DX).

Research Design And Methods: The association between cannabis use by total substance score for cannabis (TSC) and DKA in the past 12 months was examined using a logistic regression model adjusted for potential confounders among adults in the T1DX.

Results: Of 932 adults with type 1 diabetes, 61 had a TSC >4, which classified them as moderate cannabis users. Adjusting for sex, age at study visit, and HbA, cannabis use was associated with a twofold increase in risk for DKA among adults with type 1 diabetes (odds ratio 2.5 [95% CI 1.0-5.9]).

Conclusions: Cannabis use was associated with an increased risk for DKA among adults in the T1DX. Providers should inform their patients of the potential risk of DKA with cannabis use.
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http://dx.doi.org/10.2337/dc19-0365DOI Listing
January 2020

The Prevalence of Type 1 Diabetes in Hispanic/Latino Populations in the United States: Findings from the Hispanic Community Health Study/Study of Latinos.

Epidemiology 2020 01;31(1):e7-e8

Department of Epidemiology, Colorado School of Public Health, University of Colorado, Aurora, Colorado, Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania Collaborative Studies Coordinating Center, Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, New York University of California, San Francisco, California Graduate School of Public Health, San Diego State University, San Diego, California University of North Carolina, Chapel Hill, North Carolina Institute of Minority Health Research, University of Illinois at Chicago, Chicago, Illinois.

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http://dx.doi.org/10.1097/EDE.0000000000001125DOI Listing
January 2020

Identifying Smoking-Related Disease on Lung Cancer Screening CT Scans: Increasing the Value.

Chronic Obstr Pulm Dis 2019 Jul;6(3):233-245

Division of Pulmonary Medicine National Jewish Health, Denver, Colorado.

Background: Lung cancer screening (LCS) via chest computed tomography (CT) scans can save lives by identifying early-stage tumors. However, most smokers die of comorbid smoking-related diseases. LCS scans contain information about smoking-related conditions that is not currently systematically assessed. Identifying these common comorbid diseases on CT could increase the value of screening with minimal impact on LCS programs. We determined the prevalence of 3 comorbid diseases from LCS eligible scans and quantified related adverse outcomes.

Methods: We studied COPD Genetic Epidemiology study (COPDGene) participants (n=4078) who met criteria for LCS screening at enrollment (age > 55 years, and < 80 years, > 30 pack years smoking, current smoker or former smoker within 15 years of smoking cessation). CT scans were assessed for coronary artery calcification (CAC), emphysema, and vertebral bone density. We tracked the following clinically significant events: myocardial infarctions (MIs), strokes, pneumonia, respiratory exacerbations, and hip and vertebral fractures.

Results: Overall, 77% of eligible CT scans had one or more of these diagnoses identified. CAC (> 100 mg) was identified in 51% of scans, emphysema in 44%, and osteoporosis in 54%. Adverse events related to the underlying smoking-related diseases were common, with 50% of participants reporting at least one. New diagnoses of cardiovascular disease, emphysema and osteoporosis were made in 25%, 7% and 46%, of participants respectively. New diagnosis of disease was associated with significantly more adverse events than in participants who did not have CT diagnoses for both osteoporosis and cardiovascular risk.

Conclusions: Expanded analysis of LCS CT scans identified individuals with evidence of previously undiagnosed cardiovascular disease, emphysema or osteoporosis that corresponded with adverse events. LCS CT scans can potentially facilitate diagnoses of these smoking-related diseases and provide an opportunity for treatment or prevention.
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http://dx.doi.org/10.15326/jcopdf.6.3.2018.0142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872218PMC
July 2019

Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes.

J Clin Invest 2019 07 11;129(10):4165-4179. Epub 2019 Jul 11.

Department of Medicine, UW Medicine Diabetes Institute, University of Washington, Seattle, Washington, USA.

Type 1 diabetes mellitus (T1DM) increases the risk of atherosclerotic cardiovascular disease (CVD) in humans by poorly understood mechanisms. Using mouse models of T1DM-accelerated atherosclerosis, we found that relative insulin deficiency rather than hyperglycemia elevated levels of apolipoprotein C3 (APOC3), an apolipoprotein that prevents clearance of triglyceride-rich lipoproteins (TRLs) and their remnants. We then showed that serum APOC3 levels predict incident CVD events in subjects with T1DM in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study. To explore underlying mechanisms, we investigated the impact of Apoc3 antisense oligonucleotides (ASOs) on lipoprotein metabolism and atherosclerosis in a mouse model of T1DM. Apoc3 ASO treatment abolished the increased hepatic Apoc3 expression in diabetic mice - resulting in lower levels of TRLs - without improving glycemic control. APOC3 suppression also prevented arterial accumulation of APOC3-containing lipoprotein particles, macrophage foam cell formation, and the accelerated atherosclerosis in diabetic mice. Our observations demonstrate that relative insulin deficiency increases APOC3 and that this results in elevated levels of TRLs and accelerated atherosclerosis in a mouse model of T1DM. Because serum levels of APOC3 predicted incident CVD events in the CACTI study, inhibiting APOC3 might reduce CVD risk in T1DM patients.
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http://dx.doi.org/10.1172/JCI127308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763229PMC
July 2019

Subjects with diffuse idiopathic skeletal hyperostosis have an increased burden of coronary artery disease: An evaluation in the COPDGene cohort.

Atherosclerosis 2019 08 30;287:24-29. Epub 2019 May 30.

National Jewish Health, Denver CO, Division of Rheumatology, USA.

Background And Aims: Diffuse idiopathic skeletal hyperostosis (DISH) is a common incidental finding on medical imaging and often thought to be benign. Our objective was to investigate whether DISH is associated with coronary artery disease as measured with the coronary artery calcification (CAC) score in a large cohort of current and former smokers.

Methods: In a subset of subjects from the COPDGene study, DISH was scored by a minimum of two independent readers if there were four adjacent levels of flowing osteophytes and a third reader adjudicated discrepancies. CAC was calculated using a modified Agatston method. Associations of DISH with the presence and extent of CAC were analyzed with and without adjustment for COPD and known atherosclerotic risk factors, including age, sex, race, diabetes, hypertension, high cholesterol, body mass index and smoking.

Results: DISH was present in 361 subjects (13.2%) from a total group of 2728. Median (interquartile range) Agatston was 81 (0-329) in DISH subjects compared to 0 (0-94 in subjects without DISH (p < 0.001). DISH prevalence was 8.8% in CAC = 0, 12.8% in CAC1-100, 20.0% in CAC100-400 and 24.7% in CAC.400. Subjects with DISH had a significantly higher risk of having coronary artery calcifications; OR [CI95%] 1.37[1.05-1.78] (p=0.019) after correction for age, gender, race, COPD and atherosclerotic risk factors.

Conclusions: Subjects with DISH, a common musculoskeletal disorder involving bone formation anterior to the spine, have an increased burden of coronary artery disease, and therefore DISH may be a more relevant incidental finding than commonly thought.
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http://dx.doi.org/10.1016/j.atherosclerosis.2019.05.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041152PMC
August 2019

Clinical Epidemiology of COPD: Insights From 10 Years of the COPDGene Study.

Chest 2019 08 30;156(2):228-238. Epub 2019 May 30.

Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO. Electronic address:

The Genetic Epidemiology of COPD (COPDGene) study is a noninterventional, multicenter, longitudinal analysis of > 10,000 subjects, including smokers with a ≥ 10 pack-year history with and without COPD and healthy never smokers. The goal was to characterize disease-related phenotypes and explore associations with susceptibility genes. The subjects were extensively phenotyped with the use of comprehensive symptom and comorbidity questionnaires, spirometry, CT scans of the chest, and genetic and biomarker profiling. The objective of this review was to summarize the major advances in the clinical epidemiology of COPD from the first 10 years of the COPDGene study. We highlight the influence of age, sex, and race on the natural history of COPD, and the impact of comorbid conditions, chronic bronchitis, exacerbations, and asthma/COPD overlap.
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http://dx.doi.org/10.1016/j.chest.2019.04.135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198872PMC
August 2019

Symptoms of anxiety and depression and use of anxiolytic-hypnotics and antidepressants in current and former smokers with and without COPD - A cross sectional analysis of the COPDGene cohort.

J Psychosom Res 2019 03 7;118:18-26. Epub 2019 Jan 7.

Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA; Iowa Neuroscience Institute, Carver College of Medicine, University of Iowa, Iowa City, IA, USA; Department of Pulmonary, Critical Care, and Sleep Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA. Electronic address:

Objectives: To compare the frequency of anxiety/depressive symptoms and use of anxiolytic-hypnotics/antidepressants in smokers with and without COPD and to identify characteristics associated with having unmedicated symptoms.

Methods: Cross-sectional analysis of ambulatory, current/former smokers ≥10 pack years enrolled in the COPDGene study. We measured anxiety/depressive symptoms using the Hospital Anxiety and Depression Scale (subscales ≥8), recorded anxiolytic-hypnotic/antidepressant use, and defined unmedicated symptoms as elevated anxiety/depressive symptoms and not on medications. Regression analysis identified characteristics associated with having unmedicated symptoms.

Key Results: Of 5331 current/former smokers (45% with and 55% without COPD), 1332 (25.0%) had anxiety/depressive symptoms. Anxiety symptoms were similar in frequency in smokers with and without COPD (19.7% overall), while depressive symptoms were most frequent in severe-very severe COPD at 20.7% (13.1% overall). In the entire cohort, 1135 (21.2%) were on medications. Anxiolytic-hypnotic use was highest in severe-very severe COPD (range 7.6%-12.0%), while antidepressant use showed no significant variation in smokers with and without COPD (range 14.7%-17.1%). Overall, 881 (66% of those with symptoms) had unmedicated symptoms, which was associated with African American race (adjusted OR 2.95, 95% CI 2.25-3.87), male gender (adjusted OR 1.93, 95% CI 1.57-2.36), no health insurance (adjusted OR 2.38, 95% CI 1.30-4.35), severe-very severe COPD (adjusted OR 1.48, 95% CI 1.04-2.11), and higher respiratory symptoms/exacerbation history (adjusted OR 2.21, 95% CI 1.62-3.02).

Conclusions: Significant unmet mental health care needs exist in current and former smokers with and without COPD. One in five have unmedicated symptoms, identified by key demographic and clinical characteristics.

Primary Funding Source: National Institutes of Health and The COPD Foundation.
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http://dx.doi.org/10.1016/j.jpsychores.2019.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383809PMC
March 2019

Arterial Vascular Pruning, Right Ventricular Size, and Clinical Outcomes in Chronic Obstructive Pulmonary Disease. A Longitudinal Observational Study.

Am J Respir Crit Care Med 2019 08;200(4):454-461

2Applied Chest Imaging Laboratory, Department of Radiology.

Cor pulmonale (right ventricular [RV] dilation) and cor pulmonale parvus (RV shrinkage) are both described in chronic obstructive pulmonary disease (COPD). The identification of emphysema as a shared risk factor suggests that additional disease characterization is needed to understand these widely divergent cardiac processes. To explore the relationship between computed tomography measures of emphysema and distal pulmonary arterial morphology with RV volume, and their association with exercise capacity and mortality in ever-smokers with COPD enrolled in the COPDGene Study. Epicardial (myocardium and chamber) RV volume (RV), distal pulmonary arterial blood vessel volume (arterial BV5: vessels <5 mm in cross-section), and objective measures of emphysema were extracted from 3,506 COPDGene computed tomography scans. Multivariable linear and Cox regression models and the log-rank test were used to explore the association between emphysema, arterial BV5, and RV with exercise capacity (6-min-walk distance) and all-cause mortality. The RV was approximately 10% smaller in Global Initiative for Chronic Obstructive Lung Disease stage 4 versus stage 1 COPD ( < 0.0001). In multivariable modeling, a 10-ml decrease in arterial BV5 (pruning) was associated with a 1-ml increase in RV. For a given amount of emphysema, relative preservation of the arterial BV5 was associated with a smaller RV. An increased RV was associated with reduced 6-minute-walk distance and in those with arterial pruning an increased mortality. Pulmonary arterial pruning is associated with clinically significant increases in RV volume in smokers with COPD and is related to exercise capacity and mortality in COPD.Clinical trial registered with www.clinicaltrials.gov (NCT00608764).
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http://dx.doi.org/10.1164/rccm.201811-2063OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701031PMC
August 2019

Race and Gender Disparities are Evident in COPD Underdiagnoses Across all Severities of Measured Airflow Obstruction.

Chronic Obstr Pulm Dis 2018 Jul 2;5(3):177-184. Epub 2018 Jul 2.

Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine, Temple University Health System, Philadelphia, Pennsylvania.

The COPD Genetic Epidemiology (COPDGene®) study provides a rich cross-sectional dataset of patients with substantial tobacco smoke exposure, varied by race, gender, chronic obstructive pulmonary disease (COPD) diagnosis, and disease. We aimed to determine the influence of race, gender and Global initiative for chronic Obstructive Lung Disease (GOLD) stage on prevalence of prior COPD diagnosis at COPDGene® enrollment. Data from the complete phase 1 cohort of 10,192 participants were analyzed. Participants were non-Hispanic white and African-American, ≥45 years of age with a minimum of 10 pack years of cigarette smoking. Characterization upon enrollment included spirometry, demographics and history of COPD diagnosis determined by questionnaire. We evaluated the effects of race and gender on the likelihood of prior diagnosis of COPD and the interaction of race and GOLD stage, and gender and GOLD stage, as determined at study enrollment, on likelihood of prior diagnosis of COPD. We evaluated the 3-way interaction of race, gender and GOLD stage on prior diagnosis. African-Americans had higher odds of not having a prior COPD diagnosis at all GOLD stages of airflow obstruction versus non-Hispanic whites (<0.0001). Women had higher odds of having a prior COPD diagnosis at all GOLD stages versus men (<0.0001). Three-way interaction of race, gender and GOLD stage was not significant. African-Americans were less likely to have prior COPD regardless of the severity of airflow obstruction determined at study enrollment. Women were more likely to have a prior COPD diagnosis regardless of the severity of measured airflow obstruction. Race and gender are associated with significant disparities in COPD diagnosis.
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http://dx.doi.org/10.15326/jcopdf.5.3.2017.0145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296789PMC
July 2018

Prenatal Marijuana Use by Self-Report and Umbilical Cord Sampling in a State With Marijuana Legalization.

Obstet Gynecol 2019 01;133(1):98-104

University of Utah Health and ARUP Laboratories, Salt Lake City, Utah; the University of Colorado Denver, the University of Colorado School of Medicine, and Children's Hospital Colorado, Aurora, and the Institute for Health Research, Kaiser Permanente Colorado, Denver, Colorado.

Objective: To compare self-reported maternal marijuana use with quantitative biological sampling for a marijuana metabolite, 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid, in umbilical cord homogenate in a state with legalized marijuana.

Methods: We conducted a cross-sectional study of women approached at the time of admission for delivery with live, singleton pregnancies at 24 weeks of gestation or greater at two urban medical centers in Colorado. Maternal marijuana use was estimated by 1) report to a health care provider on admission history and physical, 2) survey of self-reported use, and 3) liquid chromatography-tandem mass spectrometry analysis of umbilical cord homogenate for 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid. Women were categorized by survey-reported last use (30 days ago or less, 30 days to 1 year, more than 1 year, never) and proportion of women with cord results above the limit of detection and limit of quantification for 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid was reported for each group. Comparisons between groups were made using contingency tables. Correlation between survey-reported frequency of use and quantitative 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid cord homogenate results was evaluated.

Results: We included 116 women with self-report surveys linked to cord assay results. Six percent (95% CI 2.5-12.0%) of participants reported use in the past 30 days on survey and 2.6% (95% CI 0.5-7.4%) of participants reported marijuana use to health care providers. On umbilical cord assay, 22.4% (95% CI 15.2-31.1%) had detectable 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid. The proportion of women with detectable 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid increased with more recent self-reported use. Survey-reported frequency of use in the past 30 days had moderate correlation with quantified umbilical cord 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid (correlation coefficient 0.44, 95% CI 0.28-0.58, P<.001).

Conclusion: Umbilical cord sampling results in higher estimates of prenatal marijuana use than self-report even in the setting of legalization. Umbilical cord assays for 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid demonstrate promise for quantifying use. Future studies should examine how the use of biological sampling informs the association between marijuana use and perinatal outcomes.
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http://dx.doi.org/10.1097/AOG.0000000000003028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370297PMC
January 2019

Pulmonary vascular pruning in smokers with bronchiectasis.

ERJ Open Res 2018 Oct 23;4(4). Epub 2018 Nov 23.

Dept of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

There are few studies looking at the pulmonary circulation in subjects with bronchiectasis. We aimed to evaluate the intraparenchymal pulmonary vascular structure, using noncontrast chest computed tomography (CT), and its clinical implications in smokers with radiographic bronchiectasis. Visual bronchiectasis scoring and quantitative assessment of the intraparenchymal pulmonary vasculature were performed on CT scans from 486 smokers. Clinical, lung function and 6-min walk test (6MWT) data were also collected. The ratio of blood vessel volume in vessels <5 mm in cross-section (BV5) to total blood vessel volume (TBV) was used as measure of vascular pruning, with lower values indicating more pruning. Whole-lung and lobar BV5/TBV values were determined, and regression analyses were used to assess the differences in BV5/TBV between subjects with and without bronchiectasis. 155 (31.9%) smokers had bronchiectasis, which was, on average, mild in severity. Compared to subjects without bronchiectasis, those with lower-lobe bronchiectasis had greater vascular pruning in adjusted models. Among subjects with bronchiectasis, those with vascular pruning had lower forced expiratory volume in 1 s and 6MWT distance compared to those without vascular pruning. Smokers with mild radiographic bronchiectasis appear to have pruning of the distal pulmonary vasculature and this pruning is associated with measures of disease severity.
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http://dx.doi.org/10.1183/23120541.00044-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6250564PMC
October 2018
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