Potential problems arising from restricting the fitting algorithm in MR spectroscopy to a limited parameter space of physically meaningful values are investigated via Monte-Carlo approach and theoretical considerations. Three parameter-space configurations are compared to evaluate potential bias in the estimated mean cohort concentration for a simulated cohort study typical for conditions for MRS of hippocampus. The bias found for restrictions to positive concentration values can be ameliorated based on an estimate of the distribution width, e.g., based on Cramer-Rao bounds. Loosening parameter space restrictions can also eliminate bias while maintaining the benefit of parameter restrictions for the search algorithm.
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