Sources of Long-term Variability in Measurements of Lung Function: Implications for Interpretation and Clinical Trial Design

摘要

Background: The objective of the study was to characterize the biological and technicalncomponents of variability associated with longitudinal measurements of FEV1 and carbonnmonoxide diffusing capacity (DLCO). Variability was apportioned to subject and instrument fornfive commercially available pulmonary function testing (PFT) systems: Collins CPL (FerrarisnRespiratory; Louisville, CO); Morgan Transflow Test PFT System (Morgan Scientific; Haverhill,nMA); SensorMedics Vmax 22D (VIASYS Healthcare; Yorba Linda, CA); Jaeger USA MasterscreennDiffusion TP (VIASYS Healthcare; Yorba Linda, CA); and Medical Graphics Profiler DX Systemn(Medical Graphics Corporation; St. Paul, MN).nMethods: This was a randomized, replicated cross-over, single-center methodology study in 11nhealthy subjects aged 20 to 65 years. Spirometry and DLCO measurements were performed atnbaseline, 3 months, and 6 months. Repetitive simulations of FEV1 and DLCO were performed onnthe same instruments on four occasions over a 90-day period using a spirometry waveformngenerator and a DLCO simulator.nResults: The coefficient of variation associated with repetitive measurements of FEV1 or DLCO innsubjects was consistently larger than that associated with repetitive simulated waveforms acrossnthe five instruments. Instrumentation accounted for 13 to 58% of the total FEV1 and 36 to 70%nof the total DLCO variability observed in subjects. Sample size estimates of hypothetical studiesndesigned to detect treatment group differences of 0.050 L in FEV1 and 0.5 mL/min/mm Hg innDLCO varied as much as four times depending on the instrument utilized.nConclusions: These results provide a semiquantitative assessment of the biological and technicalncomponents of PFT variability in a highly standardized setting. They illustrate how instrumentnchoice and test variability can impact sample size determinations in clinical studies that use FEV1nand DLCO as end points.