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Optimal flow rate sampling designs for studies with extended exhaled nitric oxide analysis

Introduction. The fractional concentration of exhaled nitric oxide (FeNO) is a biomarker of airway inflammation. Repeat FeNO maneuvers at multiple fixed exhalation flow rates (extended NO analysis) can be used to estimate parameters quantifying proximal and distal sources of NO in mathematical models of lower respiratory tract NO. A growing number of studies use extended NO analysis, but there is no official standard flow rate sampling protocol. In this paper, we provide information for study planning by deriving theoretically optimal flow rate sampling designs. Methods. First, we reviewed previously published designs. Then, under a nonlinear regression framework for estimating NO parameters in the steady-state two compartment model of NO, we identified unbiased optimal four flow rate designs (within the range of 10–400 ml s−1) using theoretical derivations and simulation studies. Optimality criteria included NO parameter standard errors (SEs). A simulation study was used to estimate sample sizes required to detect associations with NO parameters estimated from studies with different designs. Results. Most designs (77%) were unbiased. NO parameter SEs were smaller for designs with: more target flows, more replicate maneuvers per target flow, and a larger range of target flows. High flows were most important for estimating alveolar NO concentration, while low flows were most important for the proximal NO parameters. The Southern California Children’s Health Study design (30, 50, 100 and 300 ml s−1) had ≥1.8 fold larger SEs and required 1.1–3.2 fold more subjects to detect the association of a determinant with each NO parameter as compared to an optimal design of 10, 50, 100 and 400 ml s−1. Conclusions. There is a class of reasonable flow rate sampling designs with good theoretical performance. In practice, designs should be selected to balance the tradeoffs between optimality and feasibility of the flow range and total number of maneuvers.