The genetic and environmental etiology of novel frequency-driven regional parcellations of abnormal white matter.

The prevalence of white matter disease increases with age and is associated with cerebrovascular disease, cognitive decline, and risk for dementia. MRI measures of abnormal signal in the white matter (AWM) provide estimates of damage, however, regional patterns of AWM may be differentially influenced by genetic or environmental factors. With our data-driven regional parcellation approach, we created a probability distribution atlas using Vietnam Era Twin Study of Aging (VETSA) data (n = 475, mean age 67.6 years) and applied a watershed algorithm to define separate regional parcellations. We report biometrical twin modeling for five anatomically distinct regions: (1) Posterior, (2) Superior frontal and parietal, (3) Anterior and inferior frontal with deep areas, (4) Occipital, and (5) Anterior periventricular. We tested competing multivariate hypotheses to identify unique influences and to explain sources of covariance among the parcellations. Family aggregation could be entirely explained by additive genetic influences, with additive genetic variance (heritability) ranging from 0.69 to 0.79. Most genetic correlations between parcellations ranged from moderate to high (rg = 0.57-0.85), although two were small (rg = 0.35-0.39), consistent with varying degrees of unique genetic influences. This proof-of-principle investigation demonstrated the value of our novel, data-driven parcellations, with identifiable genetic and environmental differences, for future exploration.

Changes in abdominal adipose tissue depots assessed by MRI correlate with hepatic histologic improvement in non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is prevalent in adults with obesity and can progress to cirrhosis. In a secondary analysis of prospectively acquired data from the multicenter, randomized, placebo-controlled FLINT trial, we investigated the relationship between reduction in adipose tissue compartment volumes and hepatic histologic improvement. METHODS: Adult participants in the FLINT trial with paired liver biopsies and abdominal MRI exams at baseline and end-of-treatment (72 weeks) were included (n = 76). Adipose tissue compartment volumes were obtained using MRI. RESULTS: Treatment and placebo groups did not differ in baseline adipose tissue volumes, or in change in adipose tissue volumes longitudinally (p = 0.107 to 0.745). Deep subcutaneous adipose tissue (dSAT) and visceral adipose tissue volume reductions were associated with histologic improvement in NASH (i.e., NAS [non-alcoholic fatty liver disease activity score] reductions of ≥2 points, at least 1 point from lobular inflammation and hepatocellular ballooning, and no worsening of fibrosis) (p = 0.031, and 0.030, respectively). In a stepwise logistic regression procedure, which included demographics, treatment group, baseline histology, baseline and changes in adipose tissue volumes, MRI hepatic proton density fat fraction (PDFF), and serum aminotransferases as potential predictors, reductions in dSAT and PDFF were associated with histologic improvement in NASH (regression coefficient = -2.001 and -0.083, p = 0.044 and 0.033, respectively). CONCLUSIONS: In adults with NASH in the FLINT trial, those with greater longitudinal reductions in dSAT and potentially visceral adipose tissue volumes showed greater hepatic histologic improvements, independent of reductions in hepatic PDFF. CLINICAL TRIAL NUMBER: NCT01265498. IMPACT AND IMPLICATIONS: Although central obesity has been identified as a risk factor for obesity-related disorders including insulin resistance and cardiovascular disease, the role of central obesity in non-alcoholic steatohepatitis (NASH) warrants further clarification. Our results highlight that a reduction in central obesity, specifically deep subcutaneous adipose tissue and visceral adipose tissue, may be related to histologic improvement in NASH. The findings from this analysis should increase awareness of the importance of lifestyle intervention in NASH for clinical researchers and clinicians. Future studies and clinical practice may design interventions that assess the reduction of deep subcutaneous adipose tissue and visceral adipose tissue as outcome measures, rather than simply weight reduction.

A Multicenter Assessment of Interreader Reliability of LI-RADS Version 2018 for MRI and CT.

Background Various limitations have impacted research evaluating reader agreement for Liver Imaging Reporting and Data System (LI-RADS). Purpose To assess reader agreement of LI-RADS in an international multicenter multireader setting using scrollable images. Materials and Methods This retrospective study used deidentified clinical multiphase CT and MRI and reports with at least one untreated observation from six institutions and three countries; only qualifying examinations were submitted. Examination dates were October 2017 to August 2018 at the coordinating center. One untreated observation per examination was randomly selected using observation identifiers, and its clinically assigned features were extracted from the report. The corresponding LI-RADS version 2018 category was computed as a rescored clinical read. Each examination was randomly assigned to two of 43 research readers who independently scored the observation. Agreement for an ordinal modified four-category LI-RADS scale (LR-1, definitely benign; LR-2, probably benign; LR-3, intermediate probability of malignancy; LR-4, probably hepatocellular carcinoma [HCC]; LR-5, definitely HCC; LR-M, probably malignant but not HCC specific; and LR-TIV, tumor in vein) was computed using intraclass correlation coefficients (ICCs). Agreement was also computed for dichotomized malignancy (LR-4, LR-5, LR-M, and LR-TIV), LR-5, and LR-M. Agreement was compared between research-versus-research reads and research-versus-clinical reads. Results The study population consisted of 484 patients (mean age, 62 years ± 10 [SD]; 156 women; 93 CT examinations, 391 MRI examinations). ICCs for ordinal LI-RADS, dichotomized malignancy, LR-5, and LR-M were 0.68 (95% CI: 0.61, 0.73), 0.63 (95% CI: 0.55, 0.70), 0.58 (95% CI: 0.50, 0.66), and 0.46 (95% CI: 0.31, 0.61) respectively. Research-versus-research reader agreement was higher than research-versus-clinical agreement for modified four-category LI-RADS (ICC, 0.68 vs 0.62, respectively; P = .03) and for dichotomized malignancy (ICC, 0.63 vs 0.53, respectively; P = .005), but not for LR-5 (P = .14) or LR-M (P = .94). Conclusion There was moderate agreement for LI-RADS version 2018 overall. For some comparisons, research-versus-research reader agreement was higher than research-versus-clinical reader agreement, indicating differences between the clinical and research environments that warrant further study. © RSNA, 2023 Supplemental material is available for this article. See also the editorials by Johnson and Galgano and Smith in this issue.

MR elastography in nonalcoholic fatty liver disease: inter-center and inter-analysis-method measurement reproducibility and accuracy at 3T.

OBJECTIVES: To assess reproducibility and fibrosis classification accuracy of magnetic resonance elastography (MRE)-determined liver stiffness measured manually at two different centers, and by automated analysis software in adults with nonalcoholic fatty liver disease (NAFLD), using histopathology as a reference standard. METHODS: This retrospective, cross-sectional study included 91 adults with NAFLD who underwent liver MRE and biopsy. MRE-determined liver stiffness was measured independently for this analysis by an image analyst at each of two centers using standardized manual analysis methodology, and separately by an automated analysis. Reproducibility was assessed pairwise by intraclass correlation coefficient (ICC) and Bland-Altman analysis. Diagnostic accuracy was assessed by receiver operating characteristic (ROC) analyses. RESULTS: ICC of liver stiffness measurements was 0.95 (95% CI: 0.93, 0.97) between center 1 and center 2 analysts, 0.96 (95% CI: 0.94, 0.97) between the center 1 analyst and automated analysis, and 0.94 (95% CI: 0.91, 0.96) between the center 2 analyst and automated analysis. Mean bias and 95% limits of agreement were 0.06 ± 0.38 kPa between center 1 and center 2 analysts, 0.05 ± 0.32 kPa between the center 1 analyst and automated analysis, and 0.11 ± 0.41 kPa between the center 2 analyst and automated analysis. The area under the ROC curves for the center 1 analyst, center 2 analyst, and automated analysis were 0.834, 0.833, and 0.847 for distinguishing fibrosis stage 0 vs. ≥ 1, and 0.939, 0.947, and 0.940 for distinguishing fibrosis stage ≤ 2 vs. ≥ 3. CONCLUSION: MRE-determined liver stiffness can be measured with high reproducibility and fibrosis classification accuracy at different centers and by an automated analysis. KEY POINTS: • Reproducibility of MRE liver stiffness measurements in adults with nonalcoholic fatty liver disease is high between two experienced centers and between manual and automated analysis methods. • Analysts at two centers had similar high diagnostic accuracy for distinguishing dichotomized fibrosis stages. • Automated analysis provides similar diagnostic accuracy as manual analysis for advanced fibrosis.

Establishing Institutional Scores With the Rigor and Transparency Index: Large-scale Analysis of Scientific Reporting Quality.

BACKGROUND: Improving rigor and transparency measures should lead to improvements in reproducibility across the scientific literature; however, the assessment of measures of transparency tends to be very difficult if performed manually. OBJECTIVE: This study addresses the enhancement of the Rigor and Transparency Index (RTI, version 2.0), which attempts to automatically assess the rigor and transparency of journals, institutions, and countries using manuscripts scored on criteria found in reproducibility guidelines (eg, Materials Design, Analysis, and Reporting checklist criteria). METHODS: The RTI tracks 27 entity types using natural language processing techniques such as Bidirectional Long Short-term Memory Conditional Random Field-based models and regular expressions; this allowed us to assess over 2 million papers accessed through PubMed Central. RESULTS: Between 1997 and 2020 (where data were readily available in our data set), rigor and transparency measures showed general improvement (RTI 2.29 to 4.13), suggesting that authors are taking the need for improved reporting seriously. The top-scoring journals in 2020 were the Journal of Neurochemistry (6.23), British Journal of Pharmacology (6.07), and Nature Neuroscience (5.93). We extracted the institution and country of origin from the author affiliations to expand our analysis beyond journals. Among institutions publishing >1000 papers in 2020 (in the PubMed Central open access set), Capital Medical University (4.75), Yonsei University (4.58), and University of Copenhagen (4.53) were the top performers in terms of RTI. In country-level performance, we found that Ethiopia and Norway consistently topped the RTI charts of countries with 100 or more papers per year. In addition, we tested our assumption that the RTI may serve as a reliable proxy for scientific replicability (ie, a high RTI represents papers containing sufficient information for replication efforts). Using work by the Reproducibility Project: Cancer Biology, we determined that replication papers (RTI 7.61, SD 0.78) scored significantly higher (P<.001) than the original papers (RTI 3.39, SD 1.12), which according to the project required additional information from authors to begin replication efforts. CONCLUSIONS: These results align with our view that RTI may serve as a reliable proxy for scientific replicability. Unfortunately, RTI measures for journals, institutions, and countries fall short of the replicated paper average. If we consider the RTI of these replication studies as a target for future manuscripts, more work will be needed to ensure that the average manuscript contains sufficient information for replication attempts.

Magnetic resonance elastography biomarkers for detection of histologic alterations in nonalcoholic fatty liver disease in the absence of fibrosis.

OBJECTIVES: To investigate associations between histology and hepatic mechanical properties measured using multiparametric magnetic resonance elastography (MRE) in adults with known or suspected nonalcoholic fatty liver disease (NAFLD) without histologic fibrosis. METHODS: This was a retrospective analysis of 88 adults who underwent 3T MR exams including hepatic MRE and MR imaging to estimate proton density fat fraction (MRI-PDFF) within 180 days of liver biopsy. Associations between MRE mechanical properties (mean shear stiffness (|G*|) by 2D and 3D MRE, and storage modulus (G'), loss modulus (G″), wave attenuation (α), and damping ratio (ζ) by 3D MRE) and histologic, demographic and anthropometric data were assessed. RESULTS: In univariate analyses, patients with lobular inflammation grade ≥ 2 had higher 2D |G*| and 3D G″ than those with grade ≤ 1 (p = 0.04). |G*| (both 2D and 3D), G', and G″ increased with age (rho = 0.25 to 0.31; p ≤ 0.03). In multivariable regression analyses, the association between inflammation grade ≥ 2 remained significant for 2D |G*| (p = 0.01) but not for 3D G″ (p = 0.06); age, sex, or BMI did not affect the MRE-inflammation relationship (p > 0.20). CONCLUSIONS: 2D |G*| and 3D G″ were weakly associated with moderate or severe lobular inflammation in patients with known or suspected NAFLD without fibrosis. With further validation and refinement, these properties might become useful biomarkers of inflammation. Age adjustment may help MRE interpretation, at least in patients with early-stage disease. KEY POINTS: • Moderate to severe lobular inflammation was associated with hepatic elevated shear stiffness and elevated loss modulus (p =0.04) in patients with known or suspected NAFLD without liver fibrosis; this suggests that with further technical refinement these MRE-assessed mechanical properties may permit detection of inflammation before the onset of fibrosis in NAFLD. • Increasing age is associated with higher hepatic shear stiffness, and storage and loss moduli (rho = 0.25 to 0.31; p ≤ 0.03); this suggests that age adjustment may help interpret MRE results, at least in patients with early-stage NAFLD.

Prospective comparison of longitudinal change in hepatic proton density fat fraction (PDFF) estimated by magnitude-based MRI (MRI-M) and complex-based MRI (MRI-C).

PURPOSE: To compare longitudinal hepatic proton density fat fraction (PDFF) changes estimated by magnitude- vs. complex-based chemical-shift-encoded MRI during a weight loss surgery (WLS) program in severely obese adults with biopsy-proven nonalcoholic fatty liver disease (NAFLD). METHODS: This was a secondary analysis of a prospective dual-center longitudinal study of 54 adults (44 women; mean age 52 years; range 27-70 years) with obesity, biopsy-proven NAFLD, and baseline PDFF ≥ 5%, enrolled in a WLS program. PDFF was estimated by confounder-corrected chemical-shift-encoded MRI using magnitude (MRI-M)- and complex (MRI-C)-based techniques at baseline (visit 1), after a 2- to 4-week very low-calorie diet (visit 2), and at 1, 3, and 6 months (visits 3 to 5) after surgery. At each visit, PDFF values estimated by MRI-M and MRI-C were compared by a paired t test. Rates of PDFF change estimated by MRI-M and MRI-C for visits 1 to 3, and for visits 3 to 5 were assessed by Bland-Altman analysis and intraclass correlation coefficients (ICCs). RESULTS: MRI-M PDFF estimates were lower by 0.5-0.7% compared with those of MRI-C at all visits (p < 0.001). There was high agreement and no difference between PDFF change rates estimated by MRI-M vs. MRI-C for visits 1 to 3 (ICC 0.983, 95% CI 0.971, 0.99; bias = - 0.13%, p = 0.22), or visits 3 to 5 (ICC 0.956, 95% CI 0.919-0.977%; bias = 0.03%, p = 0.36). CONCLUSION: Although MRI-M underestimates PDFF compared with MRI-C cross-sectionally, this bias is consistent and MRI-M and MRI-C agree in estimating the rate of hepatic PDFF change longitudinally. KEY POINTS: • MRI-M demonstrates a significant but small and consistent bias (0.5-0.7%; p < 0.001) towards underestimation of PDFF compared with MRI-C at 3 T. • Rates of PDFF change estimated by MRI-M and MRI-C agree closely (ICC 0.96-0.98) in adults with severe obesity and biopsy- proven NAFLD enrolled in a weight loss surgery program. • Our findings support the use of either MRI technique (MRI-M or MRI-C) for clinical care or by individual sites or for multi-center trials that include PDFF change as an endpoint. However, since there is a bias in their measurements, the same technique should be used in any given patient for longitudinal follow-up.

Monitoring Fatty Liver Disease with MRI Following Bariatric Surgery: A Prospective, Dual-Center Study.

Purpose To longitudinally monitor liver fat before and after bariatric surgery by using quantitative chemical shift-encoded (CSE) MRI and to compare with changes in body mass index (BMI), weight, and waist circumference (WC). Materials and Methods For this prospective study, which was approved by the internal review board, a total of 126 participants with obesity who were undergoing evaluation for bariatric surgery with preoperative very low calorie diet (VLCD) were recruited from June 27, 2010, through May 5, 2015. Written informed consent was obtained from all participants. Participants underwent CSE MRI measuring liver proton density fat fraction (PDFF) before VLCD (2-3 weeks before surgery), after VLCD (1-3 days before surgery), and 1, 3, and 6-10 months following surgery. Linear regression was used to estimate rates of change of PDFF (ΔPDFF) and body anthropometrics. Initial PDFF (PDFF0), initial anthropometrics, and anthropometric rates of change were evaluated as predictors of ΔPDFF. Mixed-effects regression was used to estimate time to normalization of PDFF. Results Fifty participants (mean age, 51.0 years; age range, 27-70 years), including 43 women (mean age, 50.8 years; age range, 27-70 years) and seven men (mean age, 51.7 years; age range, 36-62 years), with mean PDFF0 ± standard deviation of 18.1% ± 8.6 and mean BMI0 of 44.9 kg/m2 ± 6.5 completed the study. By 6-10 months following surgery, mean PDFF decreased to 4.9% ± 3.4 and mean BMI decreased to 34.5 kg/m2 ± 5.4. Mean estimated time to PDFF normalization was 22.5 weeks ± 11.5. PDFF0 was the only strong predictor for both ΔPDFF and time to PDFF normalization. No body anthropometric correlated with either outcome. Conclusion Average liver proton density fat fraction (PDFF) decreased to normal (< 5%) by 6-10 months following surgery, with mean time to normalization of approximately 5 months. Initial PDFF was a strong predictor of both rate of change of PDFF and time to normalization. Body anthropometrics did not predict either outcome. Online supplemental material is available for this article. © RSNA, 2018.

Assessment of a high-SNR chemical-shift-encoded MRI with complex reconstruction for proton density fat fraction (PDFF) estimation overall and in the low-fat range.

BACKGROUND: Improving the signal-to-noise ratio (SNR) of chemical-shift-encoded MRI acquisition with complex reconstruction (MRI-C) may improve the accuracy and precision of noninvasive proton density fat fraction (PDFF) quantification in patients with hepatic steatosis. PURPOSE: To assess the accuracy of high SNR (Hi-SNR) MRI-C versus standard MRI-C acquisition to estimate hepatic PDFF in adult and pediatric nonalcoholic fatty liver disease (NAFLD) using an MR spectroscopy (MRS) sequence as the reference standard. STUDY TYPE: Prospective. POPULATION/SUBJECTS: In all, 231 adult and pediatric patients with known or suspected NAFLD. FIELD STRENGTH/SEQUENCE: PDFF estimated at 3T by three MR techniques: standard MRI-C; a Hi-SNR MRI-C variant with increased slice thickness, decreased matrix size, and no parallel imaging; and MRS (reference standard). ASSESSMENT: MRI-PDFF was measured by image analysts using a region of interest coregistered with the MRS-PDFF voxel. STATISTICAL TESTS: Linear regression analyses were used to assess accuracy and precision of MRI-estimated PDFF for MRS-PDFF as a function of MRI-PDFF using the standard and Hi-SNR MRI-C for all patients and for patients with MRS-PDFF <10%. RESULTS: In all, 271 exams from 231 patients were included (mean MRS-PDFF: 12.6% [SD: 10.4]; range: 0.9-41.9). High agreement between MRI-PDFF and MRS-PDFF was demonstrated across the overall range of PDFF, with a regression slope of 1.035 for the standard MRI-C and 1.008 for Hi-SNR MRI-C. Hi-SNR MRI-C, compared to standard MRI-C, provided small but statistically significant improvements in the slope (respectively, 1.008 vs. 1.035, P = 0.004) and mean bias (0.412 vs. 0.673, P < 0.0001) overall. In the low-fat patients only, Hi-SNR MRI-C provided improvements in the slope (1.058 vs. 1.190, P = 0.002), mean bias (0.168 vs. 0.368, P = 0.007), intercept (-0.153 vs. -0.796, P < 0.0001), and borderline improvement in the R2 (0.888 vs. 0.813, P = 0.01). DATA CONCLUSION: Compared to standard MRI-C, Hi-SNR MRI-C provides slightly higher MRI-PDFF estimation accuracy across the overall range of PDFF and improves both accuracy and precision in the low PDFF range. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:229-238.

Hepatic R2* is more strongly associated with proton density fat fraction than histologic liver iron scores in patients with nonalcoholic fatty liver disease.

BACKGROUND: The liver R2* value is widely used as a measure of liver iron but may be confounded by the presence of hepatic steatosis and other covariates. PURPOSE: To identify the most influential covariates for liver R2* values in patients with nonalcoholic fatty liver disease (NAFLD). STUDY TYPE: Retrospective analysis of prospectively acquired data. POPULATION: Baseline data from 204 subjects enrolled in NAFLD/NASH (nonalcoholic steatohepatitis) treatment trials. FIELD STRENGTH: 1.5T and 3T; chemical-shift encoded multiecho gradient echo. ASSESSMENT: Correlation between liver proton density fat fraction and R2*; assessment for demographic, metabolic, laboratory, MRI-derived, and histological covariates of liver R2*. STATISTICAL TESTS: Pearson's and Spearman's correlations; univariate analysis; gradient boosting machines (GBM) multivariable machine-learning method. RESULTS: Hepatic proton density fat fraction (PDFF) was the most strongly correlated covariate for R2* at both 1.5T (r = 0.652, P < 0.0001) and at 3T (r = 0.586, P < 0.0001). In the GBM analysis, hepatic PDFF was the most influential covariate for hepatic R2*, with relative influences (RIs) of 61.3% at 1.5T and 47.5% at 3T; less influential covariates had RIs of up to 11.5% at 1.5T and 16.7% at 3T. Nonhepatocellular iron was weakly associated with R2* at 3T only (RI 6.7%), and hepatocellular iron was not associated with R2* at either field strength. DATA CONCLUSION: Hepatic PDFF is the most influential covariate for R2* at both 1.5T and 3T; nonhepatocellular iron deposition is weakly associated with liver R2* at 3T only. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:1456-1466.