Biomedical subjects

R Graham Barr

Publications and source records attributed to R Graham Barr.

8 recordsLinked to original sources

PubMed2026

Systemic Platelet Activation and Respiratory Exacerbations, Pulmonary Symptoms, and Mortality among Current and Former Smokers in SPIROMICS.

RATIONALE: Platelet activation is elevated in chronic obstructive pulmonary disease (COPD) and associated with self-reported respiratory symptoms. Observational studies link the antiplatelet drug aspirin to lower exacerbation rates and fewer symptoms. However, it is unknown if platelet activation predicts incident respiratory exacerbations or mortality. OBJECTIVE: Is systemic platelet activation prospectively associated with respiratory exacerbations and mortality among ever-smokers with or at risk for COPD? METHODS: We measured two systemic platelet activation biomarkers, urinary 11-dehydro-thromboxane B2 (11dTxB2) and plasma soluble CD40 ligand (sCD40L), at baseline in self-reported aspirin non-users in the longitudinal SPIROMICS cohort. Adjusted generalized negative binomial and linear mixed-effects models assessed associations between these biomarkers and prospective rates of total and severe exacerbations, plus cross-sectional and longitudinal respiratory health (St. George's Respiratory Questionnaire, COPD Assessment Test, modified Medical Research Council questionnaire, and six minute walk distance). Cox proportional hazard and competing risk models evaluated associations between platelet activation biomarkers and all-cause and cause-specific mortality. RESULTS: Among 2,711 participants, 1,572 (58.0%) reported aspirin non-use; of these, 1,433 and 1,437 had 11dTxB2 and sCD40L measured, respectively. Over a median 6.6 years, a two-fold higher baseline 11dTxB2 was associated with increased rates of total (8.8%; 95%CI: 0.4-17.8%) and severe (18.1%; 95%CI: 5.1-32.6%) exacerbations. Although there were no significant interactions, there was a trend toward higher severe exacerbation rates among current cigarettes smokers and those with COPD. There were no significant results for sCD40L. Among aspirin non-users, higher 11dTxB2, but not sCD40L, was associated with worse cross-sectional respiratory health and modestly increased all-cause mortality over a median 8.2 years (adjusted hazard ratio 1.11; 95%CI: 1.00-1.24). After covariate adjustment, there were no associations with longitudinal respiratory health or cause-specific mortality. CONCLUSIONS: Systemic platelet activation, measured by urinary 11dTxB2, is a statistically significant but modest predictor of respiratory exacerbations and all-cause mortality in individuals with or at risk for COPD, suggesting its potential utility as a prognostic and predictive biomarker for antiplatelet therapy trials. CLINICAL TRIAL REGISTRATION: NCT01969344.

aspirin↗

PubMed2026

Lung function after randomization to metformin, lifestyle intervention or placebo in the Diabetes Prevention Program Outcomes Study (DPPOS).

INTRODUCTION: Metformin and physical activity have been suggested as beneficial for chronic lung disease; however, there are no prior randomized trials. METHODS: The Diabetes Prevention Program (DPP) was a 3-year trial that randomized 3234 individuals at risk for diabetes to metformin, lifestyle intervention or placebo. After the DPP, 88% of participants enrolled in the DPP Outcomes Study that offered lifestyle intervention to all and open-label continuation of metformin. Spirometry was performed at approximately 19 and 22 years post-randomization. Lung function measures were compared in an intention-to-treat (ITT) analysis by original randomization group. Models were unadjusted and adjusted for demographics, body size, smoking and sitting/standing at spirometry. Additional analyses tested prevalence of obstruction (FEV1/FVC <70%), restrictive pattern (FVC < LLN and FEV1/FVC ≥70%), preserved ratio impaired spirometry (PRISm: FEV1 <80% predicted, FEV1/FVC ≥70%) and symptoms (COPD Assessment Test [CAT] score ≥10). RESULTS: The 1888 participants with spirometry were a mean (±SD) age of 68.2 ± 9.3 years, 70% female and 6% currently smoked and 33% had previously smoked cigarettes. Mean follow-up time was 19.0 ± 0.8 years. The mean FEV1 was 2.14 ± 0.60 L, FVC 2.74 ± 0.74 L, FEV1/FVC 78.4 ± 6.4%, mean BMI was 32.4 ± 6.7 kg/m2 and 58% had diabetes. In both unadjusted and adjusted ITT analyses, randomization group was not associated with FEV1, FVC or FEV1/FVC. Likewise, rates of obstruction, restrictive pattern, PRISm or symptoms did not differ by randomization group. CONCLUSIONS: In this long-term follow-up after a randomized trial, we found no significant associations between randomization to metformin or lifestyle intervention and lung function or respiratory symptoms.

Humans↗

PubMed2026

A Quantitative Lung Mucin Score to Identify Chronic Bronchitis.

BACKGROUND: We previously demonstrated that sputum total mucin concentration is an objective marker for chronic bronchitis (CB). This current study introduces a novel Mucin Quantitative Score (MUCQ) that combines total mucin concentration and mucin composition to improve the assessment of risk, onset of clinically diagnosed disease, and progression of muco-obstructive lung diseases. METHODS: Patients from the SPIROMICS (SubPopulations and InteRmediate Outcome Measures in COPD Study) cohort were classified as having CB, or not, based on clinical questionnaires. Using the measured total mucin, MUC5AC, and MUC5B concentrations in sputum samples, we calculated MUCQ as [Total mucin]×([MUC5AC]÷[MUC5B])÷100 μg/ml, which is a unitless, weighted concentration score. Our primary outcome was the net reclassification of patients with a diagnosis of CB, or not, based on total mucin concentrations in their sputum compared with using the MUCQ score. Participants were first classified as CB- positive or -negative using a total mucin concentration threshold of 2306 μg/ml, then reclassified using the MUCQ threshold of 4.30. Associated z statistics and a P value for the primary outcome are reported. RESULTS: Among 164 patients in the SPIROMICS cohort with clinically defined CB, using the MUCQ score up-classified 18 patients who were currently smoking to a diagnosis of CB and down-classified 5 patients who were currently smoking and 3 control participants who had never smoked, compared with the classification of CB was based on total mucin concentrations alone (P=0.001). In addition, MUCQ correlated with other clinical and pathological indices of chronic airway disease and airway obstruction. CONCLUSIONS: The MUCQ metric was superior in distinguishing patients with CB compared to a total mucin concentration. Trials are needed to ascertain the prospective use of MUCQ metrics in research and clinical settings for assessment, management, and tracking therapeutic responses in CB and potentially other muco-obstructive conditions. (Funded by the National Institutes of Health and others.).

Humans↗

PubMed2025

Proteomic discovery analysis of quantitatively assessed emphysema in the general population. The MESA Lung Study.

BACKGROUND: Pulmonary emphysema occurs frequently in older adults, often without airflow limitation. Its presence predicts symptoms, respiratory hospitalizations and deaths, and all-cause mortality. Proteomics may provide further insights into emphysema pathogenesis and inform therapeutic targets. OBJECTIVE: We performed a proteomic discovery analysis of percent emphysema on computed tomography (CT) in a population-based, multiethnic sample from the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study. Replication was performed in two chronic obstructive pulmonary disease (COPD)-based studies, the SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS) and the Genetic Epidemiology of COPD (COPDGene) Study. METHODS: MESA recruited participants from the general population in 2000-02. The MESA Lung Study performed full-lung CT scans in 2010-12. Percent emphysema was defined as the percentage of lung voxels < -950 Hounsfield units. Over 7,200 plasma aptamers were measured via SomaScan. Cross-sectional linear and least absolute shrinkage and selection operator (LASSO) regression models were adjusted for demographics, anthropometrics, smoking, renal function, and scanner parameters. Statistical significance was defined as a false discovery rate p-value < 0.05. Gene Ontology (GO)/Reactome enrichment analyses were performed. LASSO-selected proteins' predictive performance was evaluated. RESULTS: Among 2,504 participants in the MESA Lung Study, mean age was 69.4 years, 1,291 had ever smoked, and median percent emphysema-like lung was 1.4%. In total, 1,234 aptamers were significantly associated with percent emphysema in the MESA Lung Study, and 35 replicated in the SPIROMICS and COPDGene Studies. Novel associations included protein family with sequence similarity (FAM) 177A1, syntenin-2, ubiquitin carboxyl-terminal hydrolase 25, and uncharacterized protein C20orf173. Previously identified emphysema-associated proteins included soluble advanced glycosylation end product-specific receptor (sRAGE), protein S100-A12, high mobility group protein B1, and roundabout homolog 2. Enrichment analyses identified 40 GO biological processes, including chemokine production and regulation and cell-cell adhesion and regulation, and two Reactome pathways, including RAGE signaling. In tenfold cross-validation, novel proteins were largely retained by LASSO (R2 = 5.4%), improved overall model performance (R2 = 24.8%), and uniquely explained greater variance in percent emphysema. CONCLUSIONS: This analysis in a general population sample identified novel and previously characterized proteins whose functional roles were validated by GO/Reactome enriched pathways, offering new insights into emphysema pathophysiology and therapeutics.

Humans↗

PubMed2025

Association of Lung Quantitative CT Scan Textures With Systemic Inflammation and Mortality in COPD.

BACKGROUND: COPD is characterized by persistent inflammation that is responsible for remodeling the bronchovascular bundles (BVBs), which may lead to poor quality of life. Quantitative CT (QCT) scan textures of the lung can capture local disease patterns of inflammation and related respiratory morbidity. RESEARCH QUESTION: Are BVB textures, obtained from the adaptive multiple feature method, associated with systemic inflammation, morbidity, and mortality in COPD? STUDY DESIGN AND METHODS: We analyzed data from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS; n = 2,981) and the Genetic Epidemiology of COPD (COPDGene) study (n = 10,305). The predictors included 2 QCT scan biomarkers, the BVB and CT density gradient (CTDG) textures, age, sex, BMI, race, smoking status, pack-years of smoking, CT scan-detected emphysema, and square root of the wall area of a hypothetical airway with a 10-mm lumen perimeter (Pi10). Outcomes included plasma biomarker concentrations from Meso Scale Discovery proteomics assays and CBC counts, both as markers of inflammation, along with FEV1, FEV1 to FVC ratio, St. George's Respiratory Questionnaire score, 6-minute walk distance, and modified Medical Research Council dyspnea scale score. Associations of these QCT scan textures with FEV1 decline and all-cause mortality also were investigated. RESULTS: Increased BVB texture was associated significantly with elevated neutrophil and monocyte counts and the neutrophil to lymphocyte ratio, independent of clinical covariates, CT scan-detected emphysema, and Pi10. Elevated CTDG was associated with increased neutrophil count, NLR, and tumor necrosis factor α. Increased CTDG and BVB textures also were associated with a lower FEV1 and 6-minute walk distance. CTDG at baseline was also associated with decline in FEV1 at the 5-year follow-up in the COPDGene study. We observed a significant association of both BVB texture (SPIROMICS: hazard ratio [HR], 1.084 [95% CI, 1.035-1.135; P < .001]; COPDGene: HR, 1.106 [95% CI, 1.080-1.131; P < .001]) and CTDG texture (SPIROMICS: HR, 1.033 [95% CI, 1.003-1.064; P = .03]; COPDGene: HR, 1.079 [95% CI, 1.061-1.096; P < .001]) with all-cause mortality independent of CT scan-detected emphysema and Pi10. INTERPRETATION: QCT scan textures may provide imaging evidence of the spatial heterogeneity of lung inflammation and overall disease burden in COPD. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; Nos.: NCT01969344 (SPIROMICS) and NCT00608764 (COPDGene); URL: www. CLINICALTRIALS: gov.

Humans↗

PubMed2025

Associations of High Attenuation Area-Related Proteomic Biomarkers with Fibrotic or Subpleural Interstitial Lung Abnormalities.

Rationale: High-attenuation area (HAA) is a computed tomography (CT) tool that correlates with lung inflammation and fibrosis. Systemic molecular correlates of HAA (e.g., plasma proteins) may inform biological processes involved in interstitial lung disease. Objectives: To identify plasma proteins that associate with HAA and correlate with a higher probability of developing new-onset fibrotic or subpleural interstitial lung abnormalities (ILAs). Methods: Plasma protein levels were measured using a semiquantitative aptamer-based platform in MESA (the Multi-Ethnic Study of Atherosclerosis; N = 5,486) and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study; N = 1,781). Linear regression models identified HAA-associated proteins after adjustment for demographic and socioeconomic factors, CT scanner parameters, study center, and batch. Associations of HAA-related proteins with new-onset fibrotic or subpleural ILAs were examined in MESA participants with ILA assessments on full-lung CT 10 years later. Immunohistochemical staining of select proteins was performed in lung tissue from pulmonary fibrosis cases. Measurements and Main Results: There were 75 proteins detected that were significantly associated with HAA in MESA and SPIROMICS. Gene Ontology analysis of these proteins identified processes involved in immune cell chemotaxis and cellular growth and apoptosis. Seven proteins were associated with a higher probability of new-onset fibrotic or subpleural ILAs in MESA, and two of these, junctional adhesion molecule-like protein and GTP cyclohydrolase 1 feedback regulatory protein, stained in areas of fibrosis in lung tissue from patients with interstitial lung disease. Conclusions: Plasma proteins associated with more HAA are involved in immune and cellular processes and associate with new-onset fibrotic-subpleural ILA.

Humans↗

PubMed2024

Design of the SPIROMICS Study of Early COPD Progression: SOURCE Study.

BACKGROUND: The biological mechanisms leading some tobacco-exposed individuals to develop early-stage chronic obstructive pulmonary disease (COPD) are poorly understood. This knowledge gap hampers development of disease-modifying agents for this prevalent condition. OBJECTIVES: Accordingly, with National Heart, Lung and Blood Institute support, we initiated the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) Study of Early COPD Progression (SOURCE), a multicenter observational cohort study of younger individuals with a history of cigarette smoking and thus at-risk for, or with, early-stage COPD. Our overall objectives are to identify those who will develop COPD earlier in life, characterize them thoroughly, and by contrasting them to those not developing COPD, define mechanisms of disease progression. METHODS/DISCUSSION: SOURCE utilizes the established SPIROMICS clinical network. Its goal is to enroll n=649 participants, ages 30-55 years, all races/ethnicities, with ≥10 pack-years cigarette smoking, in either Global initiative for chronic Obstructive Lung Disease (GOLD) groups 0-2 or with preserved ratio-impaired spirometry; and an additional n=40 never-smoker controls. Participants undergo baseline and 3-year follow-up visits, each including high-resolution computed tomography, respiratory oscillometry and spirometry (pre- and postbronchodilator administration), exhaled breath condensate (baseline only), and extensive biospecimen collection, including sputum induction. Symptoms, interim health care utilization, and exacerbations are captured every 6 months via follow-up phone calls. An embedded bronchoscopy substudy involving n=100 participants (including all never-smokers) will allow collection of lower airway samples for genetic, epigenetic, genomic, immunological, microbiome, mucin analyses, and basal cell culture. CONCLUSION: SOURCE should provide novel insights into the natural history of lung disease in younger individuals with a smoking history, and its biological basis.

SPIROMICS↗

PubMed2023

A blood and bronchoalveolar lavage protein signature of rapid FEV1 decline in smoking-associated COPD.

Accelerated progression of chronic obstructive pulmonary disease (COPD) is associated with increased risks of hospitalization and death. Prognostic insights into mechanisms and markers of progression could facilitate development of disease-modifying therapies. Although individual biomarkers exhibit some predictive value, performance is modest and their univariate nature limits network-level insights. To overcome these limitations and gain insights into early pathways associated with rapid progression, we measured 1305 peripheral blood and 48 bronchoalveolar lavage proteins in individuals with COPD [n = 45, mean initial forced expiratory volume in one second (FEV1) 75.6 ± 17.4% predicted]. We applied a data-driven analysis pipeline, which enabled identification of protein signatures that predicted individuals at-risk for accelerated lung function decline (FEV1 decline ≥ 70 mL/year) ~ 6 years later, with high accuracy. Progression signatures suggested that early dysregulation in elements of the complement cascade is associated with accelerated decline. Our results propose potential biomarkers and early aberrant signaling mechanisms driving rapid progression in COPD.

Humans↗