Repeatability of MRI Biomarkers in Nonalcoholic Fatty Liver Disease: The NIMBLE Consortium

Abstract

Background There is a need for reliable noninvasive methods for diagnosing and monitoring nonalcoholic fatty liver disease (NAFLD). Thus, the multidisciplinary Non-invasive Biomarkers of Metabolic Liver disease (NIMBLE) consortium was formed to identify and advance the regulatory qualification of NAFLD imaging biomarkers. Purpose To determine the different-day same-scanner repeatability coefficient of liver MRI biomarkers in patients with NAFLD at risk for steatohepatitis. Materials and Methods NIMBLE 1.2 is a prospective, observational, single-center short-term cross-sectional study (October 2021 to June 2022) in adults with NAFLD across a spectrum of low, intermediate, and high likelihood of advanced fibrosis as determined according to the fibrosis based on four factors (FIB-4) index. Participants underwent up to seven MRI examinations across two visits less than or equal to 7 days apart. Standardized imaging protocols were implemented with six MRI scanners from three vendors at both 1.5 T and 3 T, with central analysis of the data performed by an independent reading center (University of California, San Diego). Trained analysts, who were blinded to clinical data, measured the MRI proton density fat fraction (PDFF), liver stiffness at MR elastography (MRE), and visceral adipose tissue (VAT) for each participant. Point estimates and CIs were calculated using χ² distribution and statistical modeling for pooled repeatability measures. Results A total of 17 participants (mean age, 58 years ± 8.5 [SD]; 10 female) were included, of which seven (41.2%), six (35.3%), and four (23.5%) participants had a low, intermediate, or high likelihood of advanced fibrosis, respectively. The different-day same-scanner mean measurements were 13%-14% for PDFF, 6.6 L for VAT, and 3.15 kPa for two-dimensional MRE stiffness. The different-day same-scanner repeatability coefficients were 0.22 L (95% CI: 0.17, 0.29) for VAT, 0.75 kPa (95% CI: 0.6, 0.99) for MRE stiffness, 1.19% (95% CI: 0.96, 1.61) for MRI PDFF using magnitude reconstruction, 1.56% (95% CI: 1.26, 2.07) for MRI PDFF using complex reconstruction, and 19.7% (95% CI: 15.8, 26.2) for three-dimensional MRE shear modulus. Conclusion This preliminary study suggests that thresholds of 1.2%-1.6%, 0.22 L, and 0.75 kPa for MRI PDFF, VAT, and MRE, respectively, should be used to discern measurement error from real change in patients with NAFLD. ClinicalTrials.gov registration no. NCT05081427 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Kozaka and Matsui in this issue.

Graphical abstract

Figure 1:

Flowchart shows study enrollment. ATP = adult treatment panel, BMI = body mass index, NAFLD = nonalcoholic fatty liver disease, NASH = nonalcoholic steatohepatitis.

Figure 2:

Schematic shows study procedures, including randomization to different blocks to ensure spread of participant data across all vendors and field strengths relatively equally. Each participant also underwent vibration-controlled transient elastography (VCTE) as part of the study. Imaging examinations were performed at approximately the same time each day and within 7 days of each other. B₀ = field strength.

Figure 3:

Schematic shows adaptive enrollment for determining the stopping rule for the interim analysis after enrollment of 12 participants, the results of which are used to determine if more participants need to be included in the final analysis. If the a priori upper bound 95% confidence threshold is met for each biomarker, no additional participants would be recruited. If a single biomarker or multiple biomarkers failed to meet the threshold, additional participants would be enrolled with another interim analysis planned upon enrollment of 21 and 24 participants. CSE = chemical shift encoding, MRE = MR elastography, PDFF = proton density fat fraction, RC_diff-day = different-day repeatability coefficient, 3D = three-dimensional, 2D = two-dimensional, VAT = visceral adipose tissue.

Figure 4:

Point estimate graph of the upper 95% confidence bounds for different-day repeatability coefficient percentages (%RC) for all imaging biomarkers shows the relative spread between biomarkers. MRE = MR elastography, PDFF = proton density fat fraction, 3D = three-dimensional, 2D = two-dimensional, VAT = visceral adipose tissue.

Figure 5:

MRI in a 65-year-old male participant with low likelihood of advanced fibrosis according to the fibrosis based on four factors (FIB-4) index. (A) Axial MRI proton density fat fraction map shows regions of interest (green circles) drawn in each Couinaud segment while avoiding any vessels or lesions, as per the study protocol. (B) Coronal image shows body composition with autosegmented visceral (pink) and subcutaneous (blue) adipose tissue. (C) Left to right: Axial elastogram, magnitude, and wave images obtained at two-dimensional MR elastography (MRE) show placement of the region of interest (dotted outline) in the region of parallel wave propagation, avoiding the outer edge of the liver. (D) Left to right: Axial elastogram, magnitude, and wave images obtained at three-dimensional MRE similarly show the region of interest (dotted outline) in a region of parallel wave propagation, avoiding the outer margin of the liver. Color bars alongside elastograms indicate a range of kilopascals from low (purple) to high (red).

Figure 6:

Axial MRI in a 57-year-old female participant with a high likelihood of advanced fibrosis according to the fibrosis based on four factors (FIB-4) index. (A) Left to right: Elastogram, magnitude, and wave images obtained at three-dimensional MR elastography (MRE) show the region of interest (dotted outline) in a region of parallel wave propagation, avoiding the outer margin of the liver. (B) Left to right: Elastogram, magnitude, and wave images obtained at two-dimensional MRE show placement of the region of interest (dotted outline) in the region of parallel wave propagation, avoiding the outer edge of the liver. (C) MRI proton density fat fraction map shows placement of regions of interest (green circles) within different segments of the liver. Color bars alongside elastograms indicate a range of kilopascals from low (purple) to high (red).