Sources of long-term variability in measurements of lung function - Implications for interpretation and clinical trial design

Background: The objective of the study was to characterize the biological and technical components of variability associated with longitudinal measurements of FEV1 and carbon monoxide diffusing capacity (DLCO). Variability was apportioned to subject and instrument for five commercially available pulmonary function testing (PFT) systems: Collins CPL (Ferraris Respiratory; Louisville, CO); Morgan Transflow Test PFT System (Morgan Scientific; Haverhill, MA); SensorMedics Vmax 22D (VIASYS Healthcare; Yorba Linda, CA); Jaeger USA Masterscreen Diffusion TP (VIASYS Healthcare; Yorba Linda, CA); and Medical Graphics Profiler DX System (Medical Graphics Corporation; St. Paul, MN). Methods: This was a randomized, replicated cross-over, single-center methodology study in 11 healthy subjects aged 20 to 65 years. Spirometry and DLCO measurements were performed at baseline, 3 months, and 6 months. Repetitive simulations of FEV1 and DLCO were performed on the same instruments on four occasions over a 90-day period using a spirometry waveform generator and a DLCO simulator. Results: The coefficient of variation associated with repetitive measurements of FEV1,or DLCO in subjects was consistently larger than that associated with repetitive simulated waveforms across the five instruments. Instrumentation accounted for 13 to 58% of the total FEV1, and 36 to 70% of the total DLCO variability observed in subjects. Sample size estimates of hypothetical studies designed to detect treatment group differences of 0.050 L in FEV1 and 0.5 mL/min/min Hg in DLCO varied as much as four times depending on the instrument utilized. Conclusions: These results provide a semiquantitative assessment of the biological and technical components of PFT variability in a highly standardized setting. They illustrate how instrument choice and test variability can impact sample size determinations in clinical studies that use FEV1 and DLCo as end points.