This multi-center, multi-vendor study will validate a rapid magnetic resonance-based confounder- corrected R2* mapping method as a quantitative imaging biomarker of liver iron concentration (LIC). Excessive accumulation of iron in various organs, including the liver, which affects both adult and pediatric populations, is toxic and requires treatment aimed at reducing body iron stores. Measurement of LIC is critical for detection and staging of iron overload, and for monitoring iron-reducing chelator therapies that are expensive and have side effects. Magnetic Resonance Imaging (MRI) is a widely available, accessible, and safe technology, and it is very sensitive to the presence of iron in tissue. Translation of an MRI biomarker of liver iron concentration into broad clinical use requires that i is clinically feasible, precise, robust to changes in scan parameters, calibrated to a validated reference standard of LIC, and is reproducible across sites and manufacturers. There are currently no available MRI methods that meet these requirements. R2*-MRI holds the greatest promise to meet these requirements. R2* mapping can be performed very rapidly with whole-liver 3D coverage in a single 20s breath-hold. Past work has demonstrated excellent correlation and linear calibration between R2* and LIC. However, current R2*-MRI methods are affected by three key confounding factors: [1] fat, [2] noise, and [3] magnetic field variations. A quantitativ confounder- corrected R2*-MRI method developed at the University of Wisconsin shows great promise to address the shortcomings of current R2*-MRI methods. By addressing the confounding effects of fat, noise, and magnetic field variations, this single breath-hold method is robust to changes in protocol and is precise (repeatable) with multiple measurements. Preliminary clinical data of the confounder-corrected R2* method demonstrates linear calibration with LIC with excellent correlation. Preliminary phantom studies show excellent reproducibility across sites and MRI manufacturers. However, the performance and reproducibility of this technique for in vivo liver iron quantification across different sites and platforms have yet to be validated. Therefore, the goal of this proposal is to validate rapid confounder-corrected R2*-MRI as a biomarker for liver iron overload in a multi-center study (participating sites: Stanford, UT-Southwestern, Johns Hopkins and UW-Madison), including the three main MRI vendors (GE, Siemens and Philips) at different field strengths (1.5T and 3T), in adults and pediatrics with live iron overload. Specifically, we aim to establish the [1] precision and [2] robustness of confounder-corrected R2*-MRI, [3] to calibrate R2* MRI to LIC at 1.5T and 3.0T, and [4] to establish the reproducibility of R2* across manufacturer and site. Successful validation of confounder-corrected R2*-MRI is needed to translate this method into a biomarker that is independent of site, platform, and scan parameters, and would provide a universal and standardized method to assess body iron content with widespread impact and clinical applicability.

Public Health Relevance

The overall goal of this research is to validate a new, rapid, and non-invasive method to measure iron concentration in the liver with magnetic resonance imaging (MRI). Toxic levels of iron can accumulate in the liver due to many conditions such as certain hereditary diseases and in patients who receive a large number of blood transfusions. We will test the performance of the new method in patients at four different institutions, in order to translate it into widespread clinical practice and provide physicians with a validated method for diagnosis and treatment monitoring of iron overload.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Bishop, Terry Rogers
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University of Wisconsin Madison
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United States
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