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Sources of Long-term Variability in Measurements of Lung Function^*

Implications for Interpretation and Clinical Trial Design

^* From LDS Hospital and University of Utah (Drs. Jensen and Crapo, and Ms. Howell), Salt Lake City, UT; and Pfizer Global Research and Development (Drs. Teeter, England, White, and Pickering), Groton, CT.

Correspondence to: Robert L. Jensen, PhD, Pulmonary Laboratory, LDS Hospital and University of Utah, Eighth Ave and C St, Salt Lake City, UT 84143; e-mail: ldrjens1{at}ihc.com

Abstract

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/mm 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.

Key Words: clinical trial design • diffusing capacity • diffusing capacity simulator • pulmonary function testing • pulmonary waveform generator • spirometry • variability

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Instrument Accuracy and Reproducibility in Measurements of Pulmonary Function

Robert L. Jensen, John G. Teeter, Richard D. England, Heather J. White, Eve H. Pickering, and Robert O. Crapo
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