Quantitative Evaluation of Hyperpolarized Helium-3 Magnetic Resonance Imaging of Lung Function Variability in Cystic Fibrosis

Rationale and Objectives

To better understand imaging measurement precision and reproducibility and to provide guidance for measurements in individual cystic fibrosis (CF) subjects, we evaluated CF adults on two occasions 7 ± 2 days apart using spirometry, plethysmography, and hyperpolarized helium-3 ( 3 He) magnetic resonance imaging (MRI).

Materials and Methods

Twelve CF subjects underwent spirometry, plethysmography, and 3 He MRI twice within 7 ± 2 days, reporting 3 He ventilation defect volume (VDV) and ventilation defect percent (VDP).

Results

Based on measurement variability, the smallest detectable difference (SDD) for 3 He VDV and VDP was determined to be 120 mL and 2%, respectively. Although no significant difference in spirometry or plethysmography was detected after 7 days, there was a significant difference in mean 3 He VDV (130 mL ± 250 mL, P < .0001) and VDP (3% ± 4%, P < .0001), although baseline and 7-day measurements were highly correlated (VDV: r = .85, P = .001; VDP: r = .94, P < .0001). We estimated the sample sizes required to detect a 5%/7%/10% change in 3 He VDP as 60/15/5 subjects per group.

Conclusion

Hyperpolarized 3 He MRI VDP measurement precision resulted in an SDD for individual CF subjects of 2%, indicating that changes greater than this can be attributed to lung functional changes and not measurement error. After 7 days, significant changes in mean 3 He VDV and VDP were detected and these changes were not reflected by changes in pulmonary function measurements. These findings demonstrate the high sensitivity and reproducibility of 3 He MRI functional imaging that permits the use of relatively small samples sizes in CF interventional studies.

High-resolution computed tomography (HRCT) is currently the gold standard imaging method for providing quantitative morphological measurements of lung abnormalities associated with cystic fibrosis (CF). Scoring systems have been developed for radiological interpretation of various pulmonary abnormalities, including bronchiectasis, mucous plugging, airway wall thickening, and air trapping. Such scoring systems correlate with chest radiograph scores , pulmonary function tests , and clinical findings and have been shown to be more sensitive than spirometry for detecting disease worsening . Despite these important advantages, the risk associated from repeated radiation exposure, particularly in monitoring disease progression and serial imaging in therapy studies, limits the use of CT in CF. In addition, the relationship between lung functional changes and the structural, anatomical, and morphological changes reflected by quantitative HRCT is still not completely understood.

Hyperpolarized helium-3 ( 3 He) magnetic resonance imaging (MRI) provides high spatial and temporal resolution images of both lung structure and function without ionizing radiation. Regional ventilation abnormalities can be clearly visualized as decreased or absent 3 He signal in the lung that can be evaluated using quantitative scoring systems or volumetric approaches . These measurements are sensitive to the pathological changes that accompany CF , have high same-day reproducibility in pediatric CF patients , and changes are clearly visible despite clinically normal spirometry results . Because of previous same-day reproducibility and treatment studies in CF patients, we hypothesized that 3 He MRI would provide the necessary and sufficient spatial and temporal sensitivity to detect day-to-day changes in lung function.

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Methods and materials

Subjects

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Pulmonary Function Tests

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Image Acquisition

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Image Analysis

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Statistical Methods

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SDD≥zα2SEMintra−−−−−−−−−√ S

≥

int

where zα z

α is 1.96 corresponding to a significance level of α α = .05 and SEMintra S

int

a is the standard error of measurement from intraobserver variability and is calculated as shown in Equation 2 :

SEMintra=σ∧2e−−√ S

int

∧

where σ∧2e σ

∧

2 is the intraobserver repeated measures variance. Multivariate analysis of variance was performed for comparison of baseline and 7-day pulmonary function measurements using SPSS 16.00 (SPSS Inc., Chicago, IL; LEAD Technologies, Inc., Chicago, IL). For 3 He MRI measurements, a three-way mixed design repeated measures analysis of variance was used to determine the interactions between time-point (baseline and 7-day), repetition (four repeated measurements) and subject using SPSS 16.00. The agreement between time-points for both pulmonary function and 3 He MRI measurements was evaluated using Bland-Altman plots generated using GraphPad Prism version 4.00 (GraphPad Software Inc, San Diego, CA). Linear regression ( r 2 ) and Spearman correlation coefficients ( r ) were used to determine the relationship between pulmonary function and 3 He MRI measurements using SPSS 16.00. A sample size ( n ) calculation was also performed to determine the number of subjects required in a controlled trial to detect a significant difference ( δ ) for VDP between baseline and follow-up with 95% confidence (α = 0.05, zα=1.96 z

1.96 ) and 80% power ( β=0.20 β

0.20 , zβ=0.84 z

0.84 ), according to Equation 3 :

n=2(Zα+Zβ)2SD2Diffδ2 n

(

)

where SDDiff S

f is the standard deviation of the difference between baseline and follow-up. In all statistical analyses, results were considered significant when the probability of making a type I error was less than 5% ( P < .05).

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Results

Subject Demographics

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Table 1

Subject Demographics

Subjects (± SD) (range) ( n = 12) Age, y 26 (8) (18–41) Male sex 5 BMI kg∙m −2 24 (4) (18–30) FEV 1 L 2.68 (0.66) (1.70–3.58) FEV 1 % pred 72 (14) (50–96) FVC L 3.87 (0.97) (2.87–5.65) FVC % pred 87 (12) (74–103) FEV 1 /FVC % 70 (12) (45–87) FEV 1 /FVC % pred 84 (13) (54–99) TLC L 6.52 (1.22) (5.15–8.95) ∗ TLC % pred 108 (12) (96–128) IC L 2.98 (0.63) (1.88–3.67) ∗ IC % pred 101 (20) (80–149) ∗ FRC L 3.60 (1.04) (2.05–4.71) † FRC % pred 116 (28) (77–156) † RV L 2.51 (0.79) (1.51–3.82) ∗ RV % pred 168 (41) (122–232) † D LCO 30.64 (6.39) (21.49–40) † D LCO % pred 105 (18) (87–138) †

BMI, body mass index; D LCO , carbon monoxide diffusion capacity of the lung; FEV 1 , forced expiratory volume in 1 second; FRC, functional residual capacity; FVC, forces vital capacity; IC, inspiratory capacity; % pred , percent predicted; RV, reserve volume; SD, standard deviation; TLC, total lung capacity.

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Table 2

Subject Listing of Baseline and 7-day Pulmonary Function and Hyperpolarized 3 He MRI Measurements

Subject 1 2 3 4 5 6 7 8 9 10 11 12 Mean (± SD) Pulmonary function measurements Baseline FEV 1 (L) 2.11 3.55 1.70 2.53 2.83 3.58 3.56 2.79 2.22 2.28 1.93 3.04 2.68 (0.66) FEV 1 % pred 50 78 54 74 79 81 79 82 69 55 61 96 72 (14) FVC (L) 3.41 4.87 3.06 2.92 3.55 5.65 4.88 3.52 2.87 5.02 2.96 3.77 3.87 (0.97) FVC% pred 65 89 79 75 87 103 90 90 74 103 81 103 87 (12) 7-day FEV 1 (L) 2.17 3.39 2.2 2.7 2.66 3.46 3.4 2.69 2.36 2.32 1.85 3.04 2.69 (0.54) FEV 1 % pred 51 74 69 79 75 78 75 79 73 56 58 96 72 (12) FVC (L) 3.69 4.75 3.39 3.05 3.49 5.31 4.82 3.34 3.05 4.87 2.83 3.76 3.86 (0.85) FVC% pred 70 87 87 78 85 96 89 86 79 100 77 102 86 (10) 3 He MRI measurements Baseline VDV (L) 1.70 1.49 1.15 0.52 0.62 1.79 0.87 0.38 0.98 1.38 1.71 0.15 1.06 (0.56) VDP (%) 30 24 22 13 13 27 17 10 21 24 34 3 20 (9) 7-day VDV (L) 1.80 1.16 1.61 0.30 0.46 1.31 0.52 0.33 0.65 1.36 1.51 0.14 0.93 (0.59) VDP (%) 30 18 27 7 10 25 10 8 11 22 31 3 17 (10)

FEV 1 , forced expiratory volume in 1 second; FVC, forced vital capacity; % pred , percent predicted; VDP, ventilation defect percent; VDV, ventilation defect volume.

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Baseline and 7-day Measurements

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Table 3

Baseline and 7-day Pulmonary Function and 3 He MRI Measurements

Parameter Baseline ( n = 12) 7-day ( n = 12) Mean Difference ( P ) ∗ Pulmonary function measurements FEV 1 (L) (± SD) 2.68 (0.66) 2.69 (0.54) −0.01(.19)(NS) FEV 1 % pred (± SD) 72 (14) 72 (12) 0 (6) (NS) FVC % pred (± SD) 87 (12) 86 (10) 0 (4) (NS) FEV 1 /FVC (± SD) 70 (12) 71 (11) −1(4)(NS) TLC % pred (± SD) 108(12) † 113 (16) † −5(7)(NS) IC % pred (± SD) 101 (20) † 103 (19) † −2(14)(NS) FRC % pred (± SD) 116 (29) † 125 (32) † −9(7)(NS) RV % pred (± SD) 168 (41) † 176 (58) † −8(37)(NS) D L CO (% pred ) (± SD) 106 (18) ‡ 111 (13) ‡ −5(8)(NS) Hyperpolarized 3 He MRI VDV L (± SD) 1.06 (0.56) 0.93 (.59) ∗ 0.13 (0.25) (<.0001) VDP % (± SD) 20 (9) 17 (10) ∗ 3 (4) (<.0001)

D LCO , carbon monoxide diffusion capacity of the lung; FEV 1 , forced expiratory volume in 1 second; FRC, functional residual capacity; FVC, forced vital capacity; IC, inspiratory capacity; % pred , percent predicted; RV, reserve volume; SD, standard deviation; TLC, total lung capacity; VDP, ventilation defect percent; VDV, ventilation defect volume.

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Correlations

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Table 4

Correlation between the Baseline and 7-day Pulmonary Function and 3 He MRI Measurements

Spearman Correlation Coefficient (p) VDV L VDP % FEV 1 L −0.34 (0.12) −0.41 (0.05) FEV 1 % pred −0.65 (0.001) −0.68 (<0.0001) FVC L 0.14 (0.52) 0.04 (0.86) FVC % pred −0.17 (0.43) −0.25 (0.24)

FEV 1 , forced expiratory volume in 1s; FVC, forced vital vapacity; % pred , percent predicted; VDP, ventilation defect percent; VDV, ventilation defect volume.

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Sample Size Calculations

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Discussion

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References

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Quantitative Evaluation of Hyperpolarized Helium-3 Magnetic Resonance Imaging of Lung Function Variability in Cystic Fibrosis

Rationale and Objectives

Materials and Methods

Results

Conclusion

Methods and materials

Subjects

Pulmonary Function Tests

Image Acquisition

Image Analysis

Statistical Methods

Results

Subject Demographics

Baseline and 7-day Measurements

Correlations

Sample Size Calculations

Discussion

References

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