Air Pollution Exposure and Interstitial Lung Features in SPIROMICS Participants with COPD.

RATIONALE: It is unknown whether air pollution is associated with radiographic features of interstitial lung disease in individuals with chronic obstructive pulmonary disease (COPD). OBJECTIVES: To determine whether air pollution increases prevalence of interstitial lung abnormalities (ILA) or percent high-attenuation area (HAA) on computed tomography (CT) in individuals with a heavy smoking history and COPD. METHODS: We performed a cross-sectional study of SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study), focused on current or former smokers with COPD. 10-year exposure to particulate matter < 2.5 µm (PM2.5), nitrogen oxides (NOx), nitrogen dioxide (NO2), and ozone (O3) prior to enrollment CTs (completed between 2010-2015) were estimated with validated spatiotemporal models at residential addresses. We applied adjusted multivariable modified Poisson regression and linear regression to investigate associations between pollution exposure and relative risk of ILA or increased percent HAA (between -600 and -250 Hounsfield units) respectively. We assessed for effect modification by MUC5B-promoter polymorphism (GT/TT vs GG at rs3705950), smoking status, sex, and percent emphysema. RESULTS: Among 1272 participants with COPD assessed for HAA, 424 were current smokers, 249 were carriers of the variant MUC5B allele (GT/TT). 519 participants were assessed for ILA. We found no association between pollution exposure and ILA or HAA. Associations between pollutant exposures and risk of ILA were modified by the presence of MUC5B polymorphism (p-value interaction term for NOx = 0.04 and PM2.5 = 0.05) and smoking status (p-value interaction term for NOx = 0.05, NO2 = 0.01, and O3 = 0.05). With higher exposure to NOx and PM2.5, MUC5B variant carriers had increased risk of ILA (Relative Risk [RR] per 26ppb NOx 2.41; 95% Confidence Interval [CI] 0.97 to 6.0) and RR per 4 µg·m-3 PM2.5 1.43; 95% CI 0.93 to 2.2). With higher exposure to NO2, former smokers had increased risk of ILA (RR per 10ppb 1.64; 95% CI 1.0 to 2.7). CONCLUSIONS: Exposure to ambient air pollution was not associated with interstitial features on CT in this population of heavy smokers with COPD. MUC5B modified the association between pollution and ILA, suggesting that gene-environment interactions may influence prevalence of interstitial lung features in COPD.

Vessel and Airway Characteristics in One-Year CT-defined Rapid Emphysema Progression: SPIROMICS.

Rationale: Rates of emphysema progression vary in chronic obstructive pulmonary disease (COPD), and the relationship with vascular and airway pathophysiology remain unclear. Objective: We sought to determine if indices of peripheral (segmental and beyond) pulmonary arterial (PA) dilation measured via computed tomography (CT) are associated with a 1-year index of emphysema (EI: %voxels<-950HU) progression. Methods: 599 GOLD 0-3 former and never-smokers were evaluated from the SubPopulations and InterMediate Outcome Measures in COPD Study (SPIROMICS) cohort: rapid-emphysema-progressors (RP, n=188; 1-year ΔEI>1%), non-progressors (NP, n=301; 1-year ΔEI±0.5%) and never-smokers (NS: N=110). Segmental PA cross-sectional areas were standardized to associated airway luminal areas (Segmental : Pulmonary Artery-to-Airway Ratio: PAARseg). Full inspiratory CT scan-derived total (arteries + veins) pulmonary vascular volume (TPVV) was compared to vessel volume with radius smaller than 0.75mm (SVV.75/TPVV). Airway-to-lung ratios (an index of dysanapsis and COPD risk) were compared to TPVV-lung-volume-ratios. Results: Compared with NP, RP exhibited significantly larger PAARseg (0.73±0.29 vs. 0.67±0.23; p=0.001), lower TPVV-to-lung-volume ratio (3.21%±0.42% vs. 3.48%±0.38%; p=5.0 x 10-12), lower airway-to-lung-volume ratio (0.031±0.003 vs. 0.034±0.004; p=6.1 x 10-13) and larger SVV.75/TPVV (37.91%±4.26% vs. 35.53±4.89; p=1.9 x 10-7). In adjusted analyses, a 1-SD increment in PAARseg was associated with a 98.4% higher rate of severe exacerbations (95%CI: 29 to 206%; p = 0.002) and 79.3% higher in odds of being in the rapid emphysema progression group (95%CI: 24% to 157%; p = 0.001). At year-2 followup, the CT-defined RP group demonstrated a significant decline in post-bronchodilator-FEV1% predicted. Conclusion: Rapid one-year progression of emphysema was associated with indices indicative of higher peripheral pulmonary vascular resistance and a possible role played by pulmonary vascular-airway dysanapsis.

The Effect of Chronic Altitude Exposure on COPD Outcomes in the SPIROMICS Cohort.

RATIONALE: Individuals with COPD have airflow obstruction and maldistribution of ventilation. For those living at high altitude, any gas exchange abnormality is compounded by reduced partial pressures of inspired oxygen. OBJECTIVES: Does residence at higher-altitude exposure affect COPD outcomes, including lung function, imaging characteristics, symptoms, health status, functional exercise capacity, exacerbations, or mortality? METHODS: From the SPIROMICS cohort, we identified individuals with COPD living below 1,000 ft (305 m) elevation (n= 1,367) versus above 4,000 ft (1,219 m) elevation (n= 288). Multivariable regression models were used to evaluate associations of exposure to high altitude with COPD-related outcomes. MEASUREMENTS AND MAIN RESULTS: Living at higher altitude was associated with reduced functional exercise capacity as defined by 6MWD (-32.3 m, (-55.7 to -28.6)). There were no differences in patient-reported outcomes as defined by symptoms (CAT, mMRC), or health status (SGRQ). Higher altitude was not associated with a different rate of FEV1 decline. Higher altitude was associated with lower odds of severe exacerbations (IRR 0.65, (0.46 to 0.90)). There were no differences in small airway disease, air trapping, or emphysema. In longitudinal analyses, higher altitude was associated with increased mortality (HR 1.25, (1.0 to 1.55)); however, this association was no longer significant when accounting for air pollution. CONCLUSIONS: Chronic altitude exposure is associated with reduced functional exercise capacity in individuals with COPD, but this did not translate into differences in symptoms or health status. Additionally, chronic high-altitude exposure did not affect progression of disease as defined by longitudinal changes in spirometry.

Exploiting meta-analysis of genome-wide interaction with serum 25-hydroxyvitamin D to identify novel genetic loci associated with pulmonary function.

BACKGROUND: Higher 25-hydroxyvitamin D (25(OH)D) concentrations in serum has a positive association with pulmonary function. Investigating genome-wide interactions with 25(OH)D may reveal new biological insights into pulmonary function. OBJECTIVES: We aimed to identify novel genetic variants associated with pulmonary function by accounting for 25(OH)D interactions. METHODS: We included 211,264 participants from the observational United Kingdom Biobank study with pulmonary function tests (PFTs), genome-wide genotypes, and 25(OH)D concentrations from 4 ancestral backgrounds-European, African, East Asian, and South Asian. Among PFTs, we focused on forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) because both were previously associated with 25(OH)D. We performed genome-wide association study (GWAS) analyses that accounted for variant×25(OH)D interaction using the joint 2 degree-of-freedom (2df) method, stratified by participants' smoking history and ancestry, and meta-analyzed results. We evaluated interaction effects to determine how variant-PFT associations were modified by 25(OH)D concentrations and conducted pathway enrichment analysis to examine the biological relevance of our findings. RESULTS: Our GWAS meta-analyses, accounting for interaction with 25(OH)D, revealed 30 genetic variants significantly associated with FEV1 or FVC (P2df <5.00×10-8) that were not previously reported for PFT-related traits. These novel variant signals were enriched in lung function-relevant pathways, including the p38 MAPK pathway. Among variants with genome-wide-significant 2df results, smoking-stratified meta-analyses identified 5 variants with 25(OH)D interactions that influenced FEV1 in both smoking groups (never smokers P1df interaction<2.65×10-4; ever smokers P1df interaction<1.71×10-5); rs3130553, rs2894186, rs79277477, and rs3130929 associations were only evident in never smokers, and the rs4678408 association was only found in ever smokers. CONCLUSION: Genetic variant associations with lung function can be modified by 25(OH)D, and smoking history can further modify variant×25(OH)D interactions. These results expand the known genetic architecture of pulmonary function and add evidence that gene-environment interactions, including with 25(OH)D and smoking, influence lung function.

Airway tree caliber heterogeneity and airflow obstruction among older adults.

INTRODUCTION: Smaller mean airway tree caliber is associated with airflow obstruction and chronic obstructive pulmonary disease (COPD). We investigated whether airway tree caliber heterogeneity was associated with airflow obstruction and COPD. METHODS: Two community-based cohorts (MESA Lung, CanCOLD) and a longitudinal case-control study of COPD (SPIROMICS) performed spirometry and computed tomography measurements of airway lumen diameters at standard anatomic locations and total lung volume. Percent-predicted airway lumen diameters were calculated using sex-specific reference equations accounting for age, height and lung volume. The association of airway tree caliber heterogeneity, quantified as the standard deviation (SD) of percent-predicted airway lumen diameters, with baseline forced expired volume in 1-second (FEV1), FEV1/forced vital capacity (FEV1/FVC) and COPD, as well as longitudinal spirometry, were assessed using regression models adjusted for age, sex, height, race-ethnicity, and mean airway tree caliber. RESULTS: Among 2,505 MESA Lung participants (mean±SD age: 69±9 years; 53% female, mean airway tree caliber: 99±10% predicted, airway tree caliber heterogeneity: 14±5%; median follow-up: 6.1 years), participants in the highest quartile of airway tree caliber heterogeneity exhibited lower FEV1 (adjusted mean difference: -125 ml, 95%CI:-171,-79), lower FEV1/FVC (adjusted mean difference: -0.01, 95%CI:-0.02,-0.01), and higher odds of COPD (adjusted OR 1.42, 95%CI:1.01-2.02) when compared with the lowest quartile, whereas longitudinal changes in FEV1 and FEV1/FVC did not differ significantly. Observations in CanCOLD and SPIROMICS were consistent. CONCLUSION: Among older adults, airway tree caliber heterogeneity was associated with airflow obstruction and COPD at baseline but was not associated with longitudinal changes in spirometry.

Peripheral Blood Mononuclear Cell Gene Expression Associated with Pulmonary Microvascular Perfusion: The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease Study.

Rationale Chronic obstructive pulmonary disease (COPD) and emphysema are associated with endothelial damage and altered pulmonary microvascular perfusion. Molecular mechanisms underlying these changes are poorly understood in patients due, in part, to the inaccessibility of the pulmonary vasculature. Peripheral blood mononuclear cells (PBMC) interact with the pulmonary endothelium. Objective To test the association between gene expression in PBMCs and pulmonary microvascular perfusion in COPD. Methods The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited two independent samples of COPD cases and controls with 10 or more pack-years. In both samples, pulmonary microvascular blood flow, pulmonary microvascular blood volume (PMBV), and mean transit time were assessed on contrast-enhanced MRI, and PBMC gene expression was assessed by microarray. Additional replication was performed in a third sample with PMBV measures on contrast-enhanced, dual-energy CT. Differential expression analyses were adjusted for age, gender, race-ethnicity, educational attainment, height, weight, smoking status, and pack-years. Results The 79 participants in the discovery sample had mean age of 69±6 years, 44% were female, 25% were non-white, 34% were current smokers and 66% had COPD. There were large PBMC gene expression signatures associated with pulmonary microvascular perfusion traits, with several replicated in the replication sets with MRI (n=47) or dual-energy CT scan (n=157) measures. Many of the identified genes are involved in inflammatory processes, including NF-κB and chemokine signaling pathways. Conclusions PBMC gene expression in NF-κB, inflammatory and chemokine signaling pathways was associated pulmonary microvascular perfusion in COPD, potentially offering new targetable candidates for novel therapies.

Airway Tree Caliber and Susceptibility to Pollution-associated Emphysema: MESA Air and Lung Studies.

RATIONALE: Airway tree morphology varies in the general population and may modify the distribution and uptake of inhaled pollutants. OBJECTIVES: We hypothesized that smaller airway caliber would be associated with emphysema progression and would increase susceptibility to air pollutant-associated emphysema progression. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) is a general population cohort of adults 45-84 years old from six U.S. communities. Airway tree caliber was quantified as the mean of airway lumen diameters measured from baseline cardiac computed tomography (CT) (2000-02). Percent emphysema, defined as percentage of lung pixels below -950 Hounsfield units, was assessed up to 5 times per participant via cardiac CT scan (2000-07) and equivalent regions on lung CT scan (2010-18). Long-term outdoor air pollutant concentrations (PM2.5, NOx, O3) were estimated at residential address with validated spatio-temporal models. Linear mixed models estimated the association between airway tree caliber and emphysema progression; modification of pollutant-associated emphysema progression was assessed using multiplicative interaction terms. MAIN RESULTS: Among 6,793 participants (mean±SD age: 62±10 years), baseline airway tree caliber was 3.95±1.1 mm and median (interquartile range) of percent emphysema was 2.88 (1.21-5.68). In adjusted analyses, 10-year emphysema progression rate was 0.75 percentage points (95%CI 0.54-0.96%) higher in the smallest compared to largest airway tree caliber quartile. Airway tree caliber also modified air pollutant-associated emphysema progression. CONCLUSIONS: Smaller airway tree caliber was associated with accelerated emphysema progression and modified air pollutant-associated emphysema progression. A better understanding of mechanisms of airway-alveolar homeostasis and air pollutant deposition are needed.

Loss of Airway Phylogenetic Diversity Is Associated with Clinical and Pathobiological Markers of Disease Development in COPD.

RATIONALE: The airway microbiome has the potential to shape COPD pathogenesis, but its relationship to outcomes in milder disease is unestablished. OBJECTIVES: Identify sputum microbiome characteristics associated with markers of COPD in participants of the SubPopulations and InteRmediate Outcome Measures of COPD Study (SPIROMICS). METHODS: Sputum DNA from 877 participants were analyzed using 16S rRNA gene sequencing. Relationships between baseline airway microbiota composition and clinical, radiographic and muco-inflammatory markers, including longitudinal lung function trajectory, were examined. MEASUREMENTS AND MAIN RESULTS: Participant data represented predominantly milder disease (GOLD 0-2: N=732/877). Phylogenetic diversity (range of different species within a sample) correlated positively with baseline lung function, declined with higher GOLD stage, and correlated negatively with symptom burden, radiographic markers of airway disease, and total mucin concentrations (p<0.001). In co-variate adjusted regression models, organisms robustly associated with better lung function included members of Alloprevotella, Oribacterium, and Veillonella. Conversely, lower lung function, greater symptoms and radiographic measures of small airway disease associated with enrichment in members of Streptococcus, Actinobacillus, Actinomyces, and other genera. Baseline sputum microbiota features also associated with lung function trajectory during SPIROMICS follow up (stable/improved, decliner, or rapid decliner). The 'stable/improved' group (slope of FEV1 regression ≥ 66th percentile) had higher bacterial diversity at baseline, associated with enrichment in Prevotella, Leptotrichia, and Neisseria. In contrast, the 'rapid decliner' group (FEV1 slope ≤ 33rd percentile) had significantly lower baseline diversity, associated with enrichment in Streptococcus. CONCLUSIONS: In SPIROMICS baseline airway microbiota features demonstrate divergent associations with better or worse COPD-related outcomes.

Interaction molecular QTL mapping discovers cellular and environmental modifiers of genetic regulatory effects.

Bulk-tissue molecular quantitative trait loci (QTLs) have been the starting point for interpreting disease-associated variants, and context-specific QTLs show particular relevance for disease. Here, we present the results of mapping interaction QTLs (iQTLs) for cell type, age, and other phenotypic variables in multi-omic, longitudinal data from the blood of individuals of diverse ancestries. By modeling the interaction between genotype and estimated cell-type proportions, we demonstrate that cell-type iQTLs could be considered as proxies for cell-type-specific QTL effects, particularly for the most abundant cell type in the tissue. The interpretation of age iQTLs, however, warrants caution because the moderation effect of age on the genotype and molecular phenotype association could be mediated by changes in cell-type composition. Finally, we show that cell-type iQTLs contribute to cell-type-specific enrichment of diseases that, in combination with additional functional data, could guide future functional studies. Overall, this study highlights the use of iQTLs to gain insights into the context specificity of regulatory effects.

Lung Structure and Risk of Sleep Apnea in SPIROMICS.

Rationale: The SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS) is a prospective cohort study that enrolled 2981 participants with the goal of identifying new chronic obstructive pulmonary disease (COPD) subgroups and intermediate markers of disease progression. Individuals with COPD and obstructive sleep apnea (OSA) experience impaired quality of life and more frequent exacerbations. COPD severity also associates with computed tomography scan-based emphysema and alterations in airway dimensions. Objectives: The objective was to determine whether the combination of lung function and structure influences the risk of OSA among current and former smokers. Methods: Using 2 OSA risk scores, the Berlin Sleep Questionnaire (BSQ), and the DOISNORE50 (Diseases, Observed apnea, Insomnia, Snoring, Neck circumference > 18 inches, Obesity with body mass index [BMI] > 32, R = are you male, Excessive daytime sleepiness, 50 = age ≥ 50) (DIS), 1767 current and former smokers were evaluated for an association of lung structure and function with OSA risk. Measurements and Main Results: The study cohort's mean age was 63 years, BMI was 28 kg/m2, and forced expiratory volume in 1 second (FEV1) was 74.8% predicted. The majority were male (55%), White (77%), former smokers (59%), and had COPD (63%). A high-risk OSA score was reported in 36% and 61% using DIS and BSQ respectively. There was a 9% increased odds of a high-risk DIS score (odds ratio [OR]=1.09, 95% confidence interval [CI]:1.03-1.14) and nominally increased odds of a high-risk BSQ score for every 10% decrease in FEV1 %predicted (OR=1.04, 95%CI: 0.998-1.09). Lung function-OSA risk associations persisted after additionally adjusting for lung structure measurements (%emphysema, %air trapping, parametric response mapping for functional small airways disease, , mean segmental wall area, tracheal %wall area, dysanapsis) for DIS (OR=1.12, 95%CI:1.03-1.22) and BSQ (OR=1.09, 95%CI:1.01-1.18). Conclusions: Lower lung function independently associates with having high risk for OSA in current and former smokers. Lung structural elements, especially dysanapsis, functional small airways disease, and tracheal %wall area strengthened the effects on OSA risk.

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

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

Predictive Value of Deep Learning-derived CT Pectoralis Muscle and Adipose Measurements for Incident Heart Failure: Multi-Ethnic Study of Atherosclerosis.

Purpose: To develop a deep learning algorithm capable of extracting pectoralis muscle and adipose measurements and to longitudinally investigate associations between these measurements and incident heart failure (HF) in participants from the Multi-Ethnic Study of Atherosclerosis (MESA). Materials and Methods: MESA is a prospective study of subclinical cardiovascular disease characteristics and risk factors for progression to clinically overt disease approved by institutional review boards of six participating centers (ClinicalTrials.gov identifier: NCT00005487). All participants with adequate imaging and clinical data from the fifth examination of MESA were included in this study. Hence, in this secondary analysis, manual segmentations of 600 chest CT examinations (between the years 2010 and 2012) were used to train and validate a convolutional neural network, which subsequently extracted pectoralis muscle and adipose (intermuscular adipose tissue (IMAT), perimuscular adipose tissue (PAT), extramyocellular lipids and subcutaneous adipose tissue) area measurements from 3031 CT examinations using individualized thresholds for adipose segmentation. Next, 1781 participants without baseline HF were longitudinally investigated for associations between baseline pectoralis muscle and adipose measurements and incident HF using crude and adjusted Cox proportional hazards models. The full models were adjusted for variables in categories of demographic (age, race, sex, income), clinical/laboratory (including physical activity, BMI, and smoking), CT (coronary artery calcium score), and cardiac MRI (left ventricular ejection fraction and mass (% of predicted)) data. Results: In 1781 participants (median age, 68 (IQR,61, 75) years; 907 [51%] females), 41 incident HF events occurred over a median 6.5-year follow-up. IMAT predicted incident HF in unadjusted (hazard ratio [HR]:1.14; 95% CI: 1.03-1.26) and fully adjusted (HR:1.16, 95% CI: 1.03-1.31) models. PAT also predicted incident HF in crude (HR:1.19; 95% CI: 1.06-1.35) and fully adjusted (HR:1.25; 95% CI: 1.07-1.46) models. Conclusion: The study demonstrates that fast and reliable deep learning-derived pectoralis muscle and adipose measurements are obtainable from conventional chest CT, which may be predictive of incident HF.©RSNA, 2023.

CT-derived pectoralis composition and incident pneumonia hospitalization using fully automated deep-learning algorithm: multi-ethnic study of atherosclerosis.

BACKGROUND: Pneumonia-related hospitalization may be associated with advanced skeletal muscle loss due to aging (i.e., sarcopenia) or chronic illnesses (i.e., cachexia). Early detection of muscle loss may now be feasible using deep-learning algorithms applied on conventional chest CT. OBJECTIVES: To implement a fully automated deep-learning algorithm for pectoralis muscle measures from conventional chest CT and investigate longitudinal associations between these measures and incident pneumonia hospitalization according to Chronic Obstructive Pulmonary Disease (COPD) status. MATERIALS AND METHODS: This analysis from the Multi-Ethnic Study of Atherosclerosis included participants with available chest CT examinations between 2010 and 2012. We implemented pectoralis muscle composition measures from a fully automated deep-learning algorithm (Mask R-CNN, built on the Faster Region Proposal Network (R-) Convolutional Neural Network (CNN) with an extension for mask identification) for two-dimensional segmentation. Associations between CT-derived measures and incident pneumonia hospitalizations were evaluated using Cox proportional hazards models adjusted for multiple confounders which include but are not limited to age, sex, race, smoking, BMI, physical activity, and forced-expiratory-volume-at-1 s-to-functional-vital-capacity ratio. Stratification analyses were conducted based on baseline COPD status. RESULTS: This study included 2595 participants (51% female; median age: 68 (IQR: 61, 76)) CT examinations for whom we implemented deep learning-derived measures for longitudinal analyses. Eighty-six incident pneumonia hospitalizations occurred during a median 6.67-year follow-up. Overall, pectoralis muscle composition measures did not predict incident pneumonia. However, in fully-adjusted models, only among participants with COPD (N = 507), CT measures like extramyocellular fat index (hazard ratio: 1.98, 95% CI: 1.22, 3.21, p value: 0.02), were independently associated with incident pneumonia. CONCLUSION: Reliable deep learning-derived pectoralis muscle measures could predict incident pneumonia hospitalization only among participants with known COPD. CLINICAL RELEVANCE STATEMENT: Pectoralis muscle measures obtainable at zero additional cost or radiation exposure from any chest CT may have independent predictive value for clinical outcomes in chronic obstructive pulmonary disease patients. KEY POINTS: •Identification of independent and modifiable risk factors of pneumonia can have important clinical impact on patients with chronic obstructive pulmonary disease. •Opportunistic CT measures of adipose tissue within pectoralis muscles using deep-learning algorithms can be quickly obtainable at zero additional cost or radiation exposure. •Deep learning-derived pectoralis muscle measurements of intermuscular fat and its subcomponents are independently associated with subsequent incident pneumonia hospitalization.

Returning incidentally discovered Hepatitis C RNA-seq results to COPDGene study participants.

The consequences of returning infectious pathogen test results identified incidentally in research studies have not been well-studied. Concerns include identification of an important health issue for individuals, accuracy of research test results, public health impact, potential emotional distress for participants, and need for IRB permissions. Blood RNA-sequencing analysis for non-human RNA in 3984 participants from the COPDGene study identified 228 participants with evidence suggestive for hepatitis C virus (HCV) infection. We hypothesized that incidentally discovered HCV results could be effectively returned to COPDGene participants with attention to the identified concerns. In conjunction with a COPDGene Participant Advisory Panel, we developed and obtained IRB approval for a process of returning HCV research results and an HCV Follow-Up Study questionnaire to capture information about previous HCV diagnosis and treatment information and participant reactions to return of HCV results. During phone calls following the initial HCV notification letter, 84 of 124 participants who could be contacted (67.7%) volunteered that they had been previously diagnosed with HCV infection. Thirty-one of these 124 COPDGene participants were enrolled in the HCV Follow-Up Study. Five of the 31 HCV Follow-Up Study participants did not report a previous diagnosis of HCV. For four of these participants, subsequent clinical HCV testing confirmed HCV infection. Thus, 30/31 Follow-Up Study participants had confirmed HCV diagnoses, supporting the accuracy of the HCV research test results. However, the limited number of participants in the Follow-Up Study precludes an accurate assessment of the false-positive and false-negative rates of the research RNA sequencing evidence for HCV. Most HCV Follow-Up Study participants (29/31) were supportive of returning HCV research results, and most participants found the process for returning HCV results to be informative and not upsetting. Newly diagnosed participants were more likely to be pleased to learn about a potentially curable infection (p = 0.027) and showed a trend toward being more frightened by the potential health risks of HCV (p = 0.11). We conclude that HCV results identified incidentally during transcriptomic research studies can be successfully returned to research study participants with a carefully designed process.

Associations between eGFR and albuminuria with right ventricular measures: the MESA-Right Ventricle study.

Background: Chronic kidney disease (CKD) is associated with an increased risk of pulmonary hypertension, which may lead to right ventricular (RV) pressure overload and RV dysfunction. However, the presence of subclinical changes in RV structure or function in early CKD and the influence of these changes on mortality are not well studied. We hypothesized that early CKD, as indicated by elevated albuminuria or mild reductions in estimated glomerular filtration rate (eGFR), is associated with greater RV dilation and RV mass. Methods: We included 4063 participants (age 45-84 years) without baseline clinical cardiovascular disease from the Multi-Ethnic Study of Atherosclerosis. The associations of baseline creatinine-cystatin C-based eGFR and albuminuria with cardiac magnetic resonance-derived RV measures (2000-02) were examined cross-sectionally with linear regression models. Cox regression models were used to examine whether RV parameters modified the associations of eGFR and albuminuria with all-cause mortality. Results: Participants with reductions in eGFR primarily within the 60-89 mL/min/1.73 m2 category had smaller RV end-diastolic and end-systolic volumes and stroke volume (all adjusted P-trends <.001) than those with eGFR ≥90 mL/min/1.73 m2, an association that was predominantly seen in participants with albuminuria below 30 mg/g creatinine. Albuminuria was more strongly associated with death among those with lower RV volumes (P-values for interaction <.03). Conclusions: Among community-dwelling adults, reductions in eGFR primarily within the normal range were associated with smaller RV volumes and the association of albuminuria with worse survival was stronger among those with smaller RV volumes. Further studies are needed to elucidate the underlying mechanistic pathways that link kidney measures and RV morphology.

Multiset correlation and factor analysis enables exploration of multi-omics data.

Multi-omics datasets are becoming more common, necessitating better integration methods to realize their revolutionary potential. Here, we introduce multi-set correlation and factor analysis (MCFA), an unsupervised integration method tailored to the unique challenges of high-dimensional genomics data that enables fast inference of shared and private factors. We used MCFA to integrate methylation markers, protein expression, RNA expression, and metabolite levels in 614 diverse samples from the Trans-Omics for Precision Medicine/Multi-Ethnic Study of Atherosclerosis multi-omics pilot. Samples cluster strongly by ancestry in the shared space, even in the absence of genetic information, while private spaces frequently capture dataset-specific technical variation. Finally, we integrated genetic data by conducting a genome-wide association study (GWAS) of our inferred factors, observing that several factors are enriched for GWAS hits and trans-expression quantitative trait loci. Two of these factors appear to be related to metabolic disease. Our study provides a foundation and framework for further integrative analysis of ever larger multi-modal genomic datasets.

Longitudinal Follow-Up of Participants With Tobacco Exposure and Preserved Spirometry.

Importance: People who smoked cigarettes may experience respiratory symptoms without spirometric airflow obstruction. These individuals are typically excluded from chronic obstructive pulmonary disease (COPD) trials and lack evidence-based therapies. Objective: To define the natural history of persons with tobacco exposure and preserved spirometry (TEPS) and symptoms (symptomatic TEPS). Design, Setting, and Participants: SPIROMICS II was an extension of SPIROMICS I, a multicenter study of persons aged 40 to 80 years who smoked cigarettes (>20 pack-years) with or without COPD and controls without tobacco exposure or airflow obstruction. Participants were enrolled in SPIROMICS I and II from November 10, 2010, through July 31, 2015, and followed up through July 31, 2021. Exposures: Participants in SPIROMICS I underwent spirometry, 6-minute walk distance testing, assessment of respiratory symptoms, and computed tomography of the chest at yearly visits for 3 to 4 years. Participants in SPIROMICS II had 1 additional in-person visit 5 to 7 years after enrollment in SPIROMICS I. Respiratory symptoms were assessed with the COPD Assessment Test (range, 0 to 40; higher scores indicate more severe symptoms). Participants with symptomatic TEPS had normal spirometry (postbronchodilator ratio of forced expiratory volume in the first second [FEV1] to forced vital capacity >0.70) and COPD Assessment Test scores of 10 or greater. Participants with asymptomatic TEPS had normal spirometry and COPD Assessment Test scores of less than 10. Patient-reported respiratory symptoms and exacerbations were assessed every 4 months via phone calls. Main Outcomes and Measures: The primary outcome was assessment for accelerated decline in lung function (FEV1) in participants with symptomatic TEPS vs asymptomatic TEPS. Secondary outcomes included development of COPD defined by spirometry, respiratory symptoms, rates of respiratory exacerbations, and progression of computed tomographic-defined airway wall thickening or emphysema. Results: Of 1397 study participants, 226 had symptomatic TEPS (mean age, 60.1 [SD, 9.8] years; 134 were women [59%]) and 269 had asymptomatic TEPS (mean age, 63.1 [SD, 9.1] years; 134 were women [50%]). At a median follow-up of 5.76 years, the decline in FEV1 was -31.3 mL/y for participants with symptomatic TEPS vs -38.8 mL/y for those with asymptomatic TEPS (between-group difference, -7.5 mL/y [95% CI, -16.6 to 1.6 mL/y]). The cumulative incidence of COPD was 33.0% among participants with symptomatic TEPS vs 31.6% among those with asymptomatic TEPS (hazard ratio, 1.05 [95% CI, 0.76 to 1.46]). Participants with symptomatic TEPS had significantly more respiratory exacerbations than those with asymptomatic TEPS (0.23 vs 0.08 exacerbations per person-year, respectively; rate ratio, 2.38 [95% CI, 1.71 to 3.31], P < .001). Conclusions and Relevance: Participants with symptomatic TEPS did not have accelerated rates of decline in FEV1 or increased incidence of COPD vs those with asymptomatic TEPS, but participants with symptomatic TEPS did experience significantly more respiratory exacerbations over a median follow-up of 5.8 years.

Investigating Associations of Omega-3 Fatty Acids, Lung Function Decline, and Airway Obstruction.

Rationale: Inflammation contributes to lung function decline and the development of chronic obstructive pulmonary disease. Omega-3 fatty acids have antiinflammatory properties and may benefit lung health. Objectives: To investigate associations of omega-3 fatty acids with lung function decline and incident airway obstruction in a diverse sample of adults from general-population cohorts. Methods: Complementary study designs: 1) longitudinal study of plasma phospholipid omega-3 fatty acids and repeated FEV1 and FVC measures in the NHLBI Pooled Cohorts Study and 2) two-sample Mendelian randomization (MR) study of genetically predicted omega-3 fatty acids and lung function parameters. Measurements and Main Results: The longitudinal study found that higher omega-3 fatty acid levels were associated with attenuated lung function decline in 15,063 participants, with the largest effect sizes for the most metabolically downstream omega-3 fatty acid, docosahexaenoic acid (DHA). An increase in DHA of 1% of total fatty acids was associated with attenuations of 1.4 ml/yr for FEV1 (95% confidence interval [CI], 1.1-1.8) and 2.0 ml/yr for FVC (95% CI, 1.6-2.4) and a 7% lower incidence of spirometry-defined airway obstruction (95% CI, 0.89-0.97). DHA associations persisted across sexes and smoking histories and in Black, White, and Hispanic participants, with associations of the largest magnitude in former smokers and Hispanic participants. The MR study showed similar trends toward positive associations of genetically predicted downstream omega-3 fatty acids with FEV1 and FVC. Conclusions: The longitudinal and MR studies provide evidence supporting beneficial effects of higher levels of downstream omega-3 fatty acids, especially DHA, on lung health.

Indoor Pollution and Lung Function Decline in Current and Former Smokers: SPIROMICS AIR.

Rationale: Indoor pollutants have been associated with chronic obstructive pulmonary disease morbidity, but it is unclear whether they contribute to disease progression. Objectives: We aimed to determine whether indoor particulate matter (PM) and nitrogen dioxide (NO2) are associated with lung function decline among current and former smokers. Methods: Of the 2,382 subjects with a history of smoking in SPIROMICS AIR, 1,208 participants had complete information to estimate indoor PM and NO2, using individual-based prediction models, in relation to measured spirometry at two or more clinic visits. We used a three-way interaction model between time, pollutant, and smoking status and assessed the indoor pollutant-associated difference in FEV1 decline separately using a generalized linear mixed model. Measurements and Main Results: Participants had an average rate of FEV1 decline of 60.3 ml/yr for those currently smoking compared with 35.2 ml/yr for those who quit. The association of indoor PM with FEV1 decline differed by smoking status. Among former smokers, every 10 µg/m3 increase in estimated indoor PM was associated with an additional 10 ml/yr decline in FEV1 (P = 0.044). Among current smokers, FEV1 decline did not differ by indoor PM. The results of indoor NO2 suggest trends similar to those for PM ⩽2.5 µm in aerodynamic diameter. Conclusions: Former smokers with chronic obstructive pulmonary disease who live in homes with high estimated PM have accelerated lung function loss, and those in homes with low PM have lung function loss similar to normal aging. In-home PM exposure may contribute to variability in lung function decline in people who quit smoking and may be a modifiable exposure.