Abstract
Exhaled breath biomarkers are an important emerging field. The fractional concentration of exhaled nitric oxide (FeNO) is a marker of airway inflammation with clinical and epidemiological applications (e.g., air pollution health effects studies). Systems of differential equations describe FeNO—measured non-invasively at the mouth—as a function of exhalation flow rate and parameters representing airway and alveolar sources of NO in the airway. Traditionally, NO parameters have been estimated separately for each study participant (Stage I) and then related to covariates (Stage II). Statistical properties of these two-step approaches have not been investigated. In simulation studies, we evaluated finite sample properties of existing two-step methods as well as a novel Unified Hierarchical Bayesian (U-HB) model. The U-HB is a one-step estimation method developed with the goal of properly propagating uncertainty as well as increasing power and reducing type I error for estimating associations of covariates with NO parameters. We demonstrated the U-HB method in an analysis of data from the southern California Children’s Health Study relating traffic-related air pollution exposure to airway and alveolar airway inflammation.
Highlights
Exhaled breath biomarkers are an important emerging field
In a previous publication using data from Children’s Health Study (CHS) participants[38], we investigated the association between traffic-related air pollution (TRAP) and nitric oxide (NO) parameters
TS Nonlinear Least Squares model (TS-NLS) and TS-Högman and Merilӓinen algorithm (HMA) models always converged in Stage II and their run times were typically less than 1 min (Supplementary Fig. 1), but they failed to estimate NO parameters in Stage I for some participants due to small sample size
Summary
The fractional concentration of exhaled nitric oxide (FeNO) is a marker of airway inflammation with clinical and epidemiological applications (e.g., air pollution health effects studies). Systems of differential equations describe FeNO—measured non-invasively at the mouth—as a function of exhalation flow rate and parameters representing airway and alveolar sources of NO in the airway. The fractional concentration of exhaled nitric oxide (FeNO) is a marker of airway inflammation with applications in clinical settings (e.g., a sthma2) and epidemiological research (e.g., studies of inhaled environmental exposures[3,4]). Measurement of FeNO at multiple expiratory flow rates (“multiple flow FeNO”) is a promising technique that takes advantage of the information across flow rates to non-invasively assess airway and alveolar inflammation using estimated parameters quantifying airway and alveolar source of NO. Non-invasive assessment of airway and alveolar NO has sparked interest in relating estimated airway and/ or alveolar NO to covariates, such as respiratory d iseases[13,14] and environmental exposures, including: ambient
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