Proteomic analysis of cardiorespiratory fitness for prediction of mortality and multisystem disease risks.

Despite the wide effects of cardiorespiratory fitness (CRF) on metabolic, cardiovascular, pulmonary and neurological health, challenges in the feasibility and reproducibility of CRF measurements have impeded its use for clinical decision-making. Here we link proteomic profiles to CRF in 14,145 individuals across four international cohorts with diverse CRF ascertainment methods to establish, validate and characterize a proteomic CRF score. In a cohort of around 22,000 individuals in the UK Biobank, a proteomic CRF score was associated with a reduced risk of all-cause mortality (unadjusted hazard ratio 0.50 (95% confidence interval 0.48-0.52) per 1 s.d. increase). The proteomic CRF score was also associated with multisystem disease risk and provided risk reclassification and discrimination beyond clinical risk factors, as well as modulating high polygenic risk of certain diseases. Finally, we observed dynamicity of the proteomic CRF score in individuals who undertook a 20-week exercise training program and an association of the score with the degree of the effect of training on CRF, suggesting potential use of the score for personalization of exercise recommendations. These results indicate that population-based proteomics provides biologically relevant molecular readouts of CRF that are additive to genetic risk, potentially modifiable and clinically translatable.

Utility of peripheral protein biomarkers for the prediction of incident interstitial features: a multicentre retrospective cohort study.

INTRODUCTION/RATIONALE: Protein biomarkers may help enable the prediction of incident interstitial features on chest CT. METHODS: We identified which protein biomarkers in a cohort of smokers (COPDGene) differed between those with and without objectively measured interstitial features at baseline using a univariate screen (t-test false discovery rate, FDR p<0.001), and which of those were associated with interstitial features longitudinally (multivariable mixed effects model FDR p<0.05). To predict incident interstitial features, we trained four random forest classifiers in a two-thirds random subset of COPDGene: (1) imaging and demographic information, (2) univariate screen biomarkers, (3) multivariable confirmation biomarkers and (4) multivariable confirmation biomarkers available in a separate testing cohort (Pittsburgh Lung Screening Study (PLuSS)). We evaluated classifier performance in the remaining one-third of COPDGene, and, for the final model, also in PLuSS. RESULTS: In COPDGene, 1305 biomarkers were available and 20 differed between those with and without interstitial features at baseline. Of these, 11 were associated with feature progression over a mean of 5.5 years of follow-up, and of these 4 were available in PLuSS, (angiopoietin-2, matrix metalloproteinase 7, macrophage inflammatory protein 1 alpha) over a mean of 8.8 years of follow-up. The area under the curve (AUC) of classifiers using demographics and imaging features in COPDGene and PLuSS were 0.69 and 0.59, respectively. In COPDGene, the AUC of the univariate screen classifier was 0.78 and of the multivariable confirmation classifier was 0.76. The AUC of the final classifier in COPDGene was 0.75 and in PLuSS was 0.76. The outcome for all of the models was the development of incident interstitial features. CONCLUSIONS: Multiple novel and previously identified proteomic biomarkers are associated with interstitial features on chest CT and may enable the prediction of incident interstitial diseases such as idiopathic pulmonary fibrosis.

Exploring quantitative measures in metacognition of emotion.

Metacognition of emotion (meta-emotion) refers to the ability to evaluate and identify one's emotional feelings. No previous study has defined and measured this construct through objective and quantitative procedures. We established a reliable method to measure meta-emotion. With a two-interval forced-choice procedure, participants selected which of two pictures elicited stronger positive emotion; via the Law of Comparative Judgment, their responses were used to compute individual psychological distances for the emotional responses triggered by the pictures. Then, participants were asked to judge whether a pre-exposed picture induced a stronger positive emotion than the median of that elicited by the whole picture set, followed by a confidence rating. By utilizing each individual's psychological distance, the correctness of a participant's emotional experience was quantified by d', and meta-emotion was quantified using meta-d', M-ratio, and M-diff as indices of metacognitive sensitivity and efficiency based on Signal-Detection Theory. Test-retest reliabilities, validated by Spearman correlation, were observed in meta-d', M-ratio, and marginally with M-diff, suggesting the stability of meta-emotion in the current design. This study unveils a validated procedure to quantify meta-emotion, extendable for assessing metacognition of other subjective feelings. Nevertheless, caution is warranted in interpretation, as the measured processes may be influenced by non-metacognitive factors.

Proteomic Biomarkers of Quantitative Interstitial Abnormalities in COPDGene and CARDIA Lung Study.

Rationale: Quantitative interstitial abnormalities (QIAs) are early measures of lung injury automatically detected on chest computed tomography scans. QIAs are associated with impaired respiratory health and share features with advanced lung diseases, but their biological underpinnings are not well understood. Objectives: To identify novel protein biomarkers of QIAs using high-throughput plasma proteomic panels within two multicenter cohorts. Methods: We measured the plasma proteomics of 4,383 participants in an older, ever-smoker cohort (COPDGene [Genetic Epidemiology of Chronic Obstructive Pulmonary Disease]) and 2,925 participants in a younger population cohort (CARDIA [Coronary Artery Disease Risk in Young Adults]) using the SomaLogic SomaScan assays. We measured QIAs using a local density histogram method. We assessed the associations between proteomic biomarker concentrations and QIAs using multivariable linear regression models adjusted for age, sex, body mass index, smoking status, and study center (Benjamini-Hochberg false discovery rate-corrected P ⩽ 0.05). Measurements and Main Results: In total, 852 proteins were significantly associated with QIAs in COPDGene and 185 in CARDIA. Of the 144 proteins that overlapped between COPDGene and CARDIA, all but one shared directionalities and magnitudes. These proteins were enriched for 49 Gene Ontology pathways, including biological processes in inflammatory response, cell adhesion, immune response, ERK1/2 regulation, and signaling; cellular components in extracellular regions; and molecular functions including calcium ion and heparin binding. Conclusions: We identified the proteomic biomarkers of QIAs in an older, smoking population with a higher prevalence of pulmonary disease and in a younger, healthier community cohort. These proteomics features may be markers of early precursors of advanced lung diseases.

A Plant-Centered Diet is Inversely Associated With Radiographic Emphysema: Findings from the CARDIA Lung Study.

Background: Chronic obstructive pulmonary disease (COPD) is a significant public health concern and intercepting the development of emphysema is vital for COPD prevention. Smokers are a high-risk population for emphysema with limited prevention strategies. We aimed to determine if adherence to a nutritionally rich, plant-centered diet among young ever-smokers is associated with reduced risk of future radiographic emphysema. Methods: We studied participants from the Coronary Artery Risk Development in Young Adults (CARDIA) Lung Prospective Cohort Study who were 18-30 years old at enrollment and followed for 30 years. We analyzed 1706 adults who reported current or former smoking by year 20. Repeated measures of diet history were used to calculate A Priori Diet Quality Scores (APDQSs), and categorized into quintiles, with higher quintiles representing higher nutritionally rich plant-centered food intake. Emphysema was assessed at year 25 (n=1351) by computed tomography (CT). Critical covariates were selected, acknowledging potential residual confounding. Results: Emphysema was observed in 13.0% of the cohort, with a mean age of 50.4 ± 3.5 years. The prevalence of emphysema was 4.5% in the highest APDQS quintile (nutritionally rich), compared with 25.4% in the lowest quintile. After adjustment for multiple covariates, including smoking, greater adherence to a plant-centered diet was inversely associated with emphysema (highest versus lowest quintile odds ratio: 0.44, 95% CI 0.19-0.99, ptrend=0.008). Conclusion: Longitudinal adherence to a nutritionally rich, plant-centered diet was associated with a decreased risk of emphysema development in middle adulthood, warranting further examination of diet as a strategy for emphysema prevention in a high-risk smoking population.

Computed tomography measure of lung injury and future interstitial features: the CARDIA Lung Study.

Introduction: Visually normal areas of the lung with high attenuation on computed tomography (CT) imaging, termed CT lung injury, may represent injured but not yet remodelled lung parenchyma. This prospective cohort study examined if CT lung injury is associated with future interstitial features on CT and restrictive spirometry abnormality among participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Methods: CARDIA is a population-based cohort study. CT scans obtained at two time points were assessed objectively for amount of lung tissue characterised as CT lung injury and interstitial features. Restrictive spirometry was defined as having a forced vital capacity (FVC) <80% predicted with forced expiratory volume in 1 s/FVC ratio >70%. Results: Among 2213 participants, the median percentage of lung tissue characterised as CT lung injury at a mean age of 40 years was 3.4% (interquartile range 0.8-18.0%). After adjustment for covariates, a 10% higher amount of CT lung injury at mean age 40 years was associated with a 4.37% (95% CI 3.99-4.74%) higher amount of lung tissue characterised as interstitial features at mean age 50 years. Compared to those with the lowest quartile of CT lung injury at mean age 40 years, there were higher odds of incident restrictive spirometry at mean age 55 years in quartile 2 (OR 2.05, 95% CI 1.20-3.48), quartile 3 (OR 2.80, 95% CI 1.66-4.72) and quartile 4 (OR 3.77, 95% CI 2.24-6.33). Conclusions: CT lung injury is an early objective measure that indicates risk of future lung impairment.

Quantitative Interstitial Abnormality Progression and Outcomes in the Genetic Epidemiology of COPD and Pittsburgh Lung Screening Study Cohorts.

BACKGROUND: The risk factors and clinical outcomes of quantitative interstitial abnormality progression over time have not been characterized. RESEARCH QUESTIONS: What are the associations of quantitative interstitial abnormality progression with lung function, exercise capacity, and mortality? What are the demographic and genetic risk factors for quantitative interstitial abnormality progression? STUDY DESIGN AND METHODS: Quantitative interstitial abnormality progression between visits 1 and 2 was assessed from 4,635 participants in the Genetic Epidemiology of COPD (COPDGene) cohort and 1,307 participants in the Pittsburgh Lung Screening Study (PLuSS) cohort. We used multivariable linear regression to determine the risk factors for progression and the longitudinal associations between progression and FVC and 6-min walk distance, and Cox regression models for the association with mortality. RESULTS: Age at enrollment, female sex, current smoking status, and the MUC5B minor allele were associated with quantitative interstitial abnormality progression. Each percent annual increase in quantitative interstitial abnormalities was associated with annual declines in FVC (COPDGene: 8.5 mL/y; 95% CI, 4.7-12.4 mL/y; P < .001; PLuSS: 9.5 mL/y; 95% CI, 3.7-15.4 mL/y; P = .001) and 6-min walk distance, and increased mortality (COPDGene: hazard ratio, 1.69; 95% CI, 1.34-2.12; P < .001; PLuSS: hazard ratio, 1.28; 95% CI, 1.10-1.49; P = .001). INTERPRETATION: The objective, longitudinal measurement of quantitative interstitial abnormalities may help identify people at greatest risk for adverse events and most likely to benefit from early intervention.

Comparing Racial Differences in Emphysema Prevalence Among Adults With Normal Spirometry: A Secondary Data Analysis of the CARDIA Lung Study.

BACKGROUND: Computed tomography (CT) imaging complements spirometry and may provide insight into racial disparities in respiratory health. OBJECTIVE: To determine the difference in emphysema prevalence between Black and White adults with different measures of normal spirometry results. DESIGN: Observational study using clinical data and spirometry from the CARDIA (Coronary Artery Risk Development in Young Adults) study obtained in 2015 to 2016 and CT scans done in 2010 to 2011. SETTING: 4 U.S. centers. PARTICIPANTS: Population-based sample of Black and White adults. MEASUREMENTS: Self-identified race and visually identified emphysema on CT in participants with different measures of "normal" spirometry results, calculated using standard race-specific and race-neutral reference equations. RESULTS: A total of 2674 participants (485 Black men, 762 Black women, 659 White men, and 768 White women) had both a CT scan and spirometry available for analysis. Among participants with a race-specific FEV1 between 80% and 99% of predicted, 6.5% had emphysema. In this group, emphysema prevalence was 3.9-fold (95% CI, 2.1- to 7.1-fold; 15.5% vs. 4.0%) higher among Black men than White men and 1.9-fold (CI, 1.0- to 3.8-fold; 6.6% vs. 3.4%) higher among Black women than White women. Among participants with a race-specific FEV1 between 100% and 120% of predicted, 4.0% had emphysema. In this category, Black men had a 6.4-fold (CI, 2.2- to 18.7-fold; 13.9% vs. 2.2%) higher prevalence of emphysema than White men, whereas Black and White women had a similar prevalence of emphysema (2.6% and 2.0%, respectively). The use of race-neutral equations to identify participants with an FEV1 percent predicted between 80% and 120% attenuated racial differences in emphysema prevalence among men and eliminated racial differences among women. LIMITATION: No CT scans were obtained during the most recent study visit (2015 to 2016) when spirometry was done. CONCLUSION: Emphysema is often present before spirometry findings become abnormal, particularly among Black men. Reliance on spirometry alone to differentiate lung health from lung disease may result in the underrecognition of impaired respiratory health and exacerbate racial disparities. PRIMARY FUNDING SOURCE: National Institutes of Health.

Advances in the management of idiopathic pulmonary fibrosis and progressive pulmonary fibrosis.

Similarly to idiopathic pulmonary fibrosis (IPF), other interstitial lung diseases can develop progressive pulmonary fibrosis (PPF) characterized by declining lung function, a poor response to immunomodulatory therapies, and early mortality. The pathophysiology of disordered lung repair involves common downstream pathways that lead to pulmonary fibrosis in both IPF and PPF. The antifibrotic drugs, such as nintedanib, are indicated for the treatment of IPF and PPF, and new therapies are being evaluated in clinical trials. Clinical, radiographic, and molecular biomarkers are needed to identify patients with PPF and subgroups of patients likely to respond to specific therapies. This article reviews the evidence supporting the use of specific therapies in patients with IPF and PPF, discusses agents being considered in clinical trials, and considers potential biomarkers based on disease pathogenesis that might be used to provide a personalized approach to care.

Impaired Respiratory Health and Life Course Transitions From Health to Chronic Lung Disease.

Primary prevention and interception of chronic lung disease are essential in the effort to reduce the morbidity and mortality caused by respiratory conditions. In this review, we apply a life course approach that examines exposures across the life span to identify risk factors that are associated with not only chronic lung disease but also an intermediate phenotype between ideal lung health and lung disease, termed "impaired respiratory health." Notably, risk factors such as exposure to tobacco smoke and air pollution, as well as obesity and physical fitness, affect respiratory health across the life course by being associated with both abnormal lung growth and lung function decline. We then discuss the importance of disease interception and identifying those at highest risk of developing chronic lung disease. This work begins with understanding and detecting impaired respiratory health, and we review several promising molecular biomarkers, predictive symptoms, and early imaging findings that may lead to a better understanding of this intermediate phenotype.

Prevalence and Clinical Significance of Antineutrophil Cytoplasmic Antibodies in North American Patients With Idiopathic Pulmonary Fibrosis.

BACKGROUND: Antineutrophil cytoplasmic antibodies (ANCAs) have been reported to occur in 7% to 10% of patients with idiopathic pulmonary fibrosis (IPF), but their clinical relevance remains unclear. The aim of this study was to estimate the prevalence of ANCAs in a North American population with IPF and evaluate their clinical significance. METHODS: This was a retrospective study of two independent cohorts of patients diagnosed with IPF at the University of California San Francisco (discovery cohort) and the University of Chicago (replication cohort). Myeloperoxidase (MPO) and proteinase 3 (PR3) ANCAs were measured in all patients. Prevalence and associations of ANCAs with clinical characteristics and transplant-free survival were evaluated. RESULTS: A total of 14 of 353 (4.0%; 95% CI, 2.2-6.5) and 20 of 392 (5.1%; 95% CI, 3.1-7.8) patients with IPF were positive for ANCAs at the time of diagnosis in the discovery and replication cohorts, respectively. Among those positive for MPO antibodies, two of six (33%) in the discovery cohort and three of 12 (25%) in the replication cohort developed vasculitis. None of the patients who were PR3-positive developed vasculitis. Patients who were ANCA-positive were more likely to be women than patients who were ANCA-negative, and were more likely to have some ground-glass opacities on CT scan. In the combined cohort of 745 patients, median transplant-free survival was not significantly different in patients who were ANCA-positive vs ANCA-negative (P = .57). CONCLUSIONS: ANCA positivity is uncommon in North American patients with IPF and not associated with baseline disease severity or transplant-free survival; however, a significant proportion of patients who are MPO-positive with IPF develop clinical vasculitis.

Telomere length and genetic variant associations with interstitial lung disease progression and survival.

Leukocyte telomere length (LTL), MUC5B rs35705950 and TOLLIP rs5743890 have been associated with idiopathic pulmonary fibrosis (IPF).In this observational cohort study, we assessed the associations between these genomic markers and outcomes of survival and rate of disease progression in patients with interstitial pneumonia with autoimmune features (IPAF, n=250) and connective tissue disease-associated interstitial lung disease (CTD-ILD, n=248). IPF (n=499) was used as a comparator.The LTL of IPAF and CTD-ILD patients (mean age-adjusted log-transformed T/S of -0.05±0.29 and -0.04±0.25, respectively) is longer than that of IPF patients (-0.17±0.32). For IPAF patients, LTL <10th percentile is associated with faster lung function decline compared to LTL ≥10th percentile (-6.43% per year versus -0.86% per year; p<0.0001) and worse transplant-free survival (hazard ratio 2.97, 95% CI 1.70-5.20; p=0.00014). The MUC5B rs35705950 minor allele frequency (MAF) is greater for IPAF patients (23.2, 95% CI 18.8-28.2; p<0.0001) than controls and is associated with worse transplant-free IPAF survival (hazard ratio 1.92, 95% CI 1.18-3.13; p=0.0091). Rheumatoid arthritis (RA)-associated ILD (RA-ILD) has a shorter LTL than non-RA CTD-ILD (-0.14±0.27 versus -0.01±0.23; p=0.00055) and higher MUC5B MAF (34.6, 95% CI 24.4-46.3 versus 14.1, 95% CI 9.8-20.0; p=0.00025). Neither LTL nor MUC5B are associated with transplant-free CTD-ILD survival.LTL and MUC5B MAF have different associations with lung function progression and survival for IPAF and CTD-ILD.