Using numerical simulations and model-to-models tests, we found that reduced, 3-parameter models provide more precise and accurateMBF estimates than model-independent methods or models with more than three free parameters when considering MPI-CT acquisition conditions and physiologic conditions. Models with four or more free parameters had poor MBF precision and/or significant bias.Biaswasmorepronouncedattheshortesttestedimagingduration,30s,formodel- based methods than at the longer imaging

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... tions, 40 s and 50 s, indicating that MPI- CT acquisitions ≥40 s should be preferred. Model-independent LSVD and maximum- upslope provided relatively precise MBF estimates but, in general, greatly underestimated MBF. Considering precision and bias for MBF estimation using model-based methods, reducing temporal sampling and reducing exposure per image frame appears to be preferable to reducing imaging duration for dose reduction. We recommend reduced, 3- parameter models that incorporate prior information of physiology and contrast agent extraction for typical MPI-CT datasets. The two proposed robust physiologic models, RPM1 and RPM2, and the single compartment model were found to be best for MBF estimation in MPI-CT, with little overall bias, ≤11%, and precise MBF estimates, ≤10%, over the tested conditions. This work provides a foundation for the development and application of analysis methods, as well as optimization of acquisition protocols, for precise and accurate MBF estimation in MPI-CT.