Deep Functional Phenotyping of the ALA Lung Health Cohort

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Project Summary/Abstract An individual can progress from ideal lung health, to an intermediate phenotype of impaired lung health, to chronic respiratory disease, yet this transition is poorly understood. A consequence of this knowledge gap is the lack of robust strategies to prevent chronic lung disease. The Lung Health Cohort (LHC) study (NHLBI 5U01HL146408) will recruit healthy participants across the US to have their lung health evaluated through questionnaires, biospecimen analysis, spirometry, and computerized tomography (CT), and relate these features to an array of anthropomorphic and environmental factors thought to influence lung health. In this Ancillary study application, we propose to extend the phenotyping of the LHC to include detailed measures of lung structure and function to obtain a more robust understanding of the influence of modifiable exposures and risk factors on lung health. We postulate that a key aspect of both current and future lung health is “dysanapsis”, which is thought to occur when dyssynchronous growth of airways and lung parenchyma such that the airways are small relative to lung size. Dysanapsis has been associated in children with obesity, airways hyperresponsiveness and asthma, and in adults, with COPD; however, a comprehensive characterization and validation of dysanapsis by both more specific functional and structural measures has not been assessed in healthy young adults nor shown to be a longitudinal risk factor. Our timely and innovative approach will combine structural information by CT with functional, state-of the-art assessment of spirometry, lung volumes, and oscillometry and gas exchange. We hypothesize that modifiable exposures and risk factors influence lung health by their effects on structural and functional dysanapsis of the airway, parenchyma and pulmonary vasculature and gas exchange. In particular, we will assess the associations of modifiable environmental factors such as tobacco, air pollution, marijuana and electronic cigarettes, in addition to age, sex, ethnicity, BMI, prematurity, allergic rhinitis, and history of COVID-19, as these factors relate to airway and vascular dysanapsis, cardiac morphology and gas exchange. The plausible mechanistic hypothesis that underlies the proposal is that there is mismatching of airways and blood vessels to parenchyma both in terms of structure (CT) and function (PFTs); we posit that this dysanapsis is a silent marker of early and progressive lung disease. This ancillary study will leverage the infrastructure and endpoints of the parent LHC study, as we will extend the LHC investigation in a number of significant ways to fill knowledge gaps that determine both the reserve and susceptibility of the lung to disease. This “deep phenotyping” of the baseline lung function and cardiac and pulmonary vascular structure will provide a more detailed understanding of the influence of modifiable exposures and risk factors of both current and future lung disease.