Optimized blood sampling protocols and sequential design of kinetic experiments.

Design of optimal blood sampling protocols for kinetic experiments is discussed and evaluated, with the aid of several examples--including an endocrine system case study. The criterion of optimality is maximum accuracy of kinetic model parameter estimates. A simple example illustrates why a sequential experiment approach is required; optimal designs depend on the true model parameter values, knowledge of which is usually a primary objective of the experiment, as well as the structure of the model and the measurement error (e.g., assay) variance. The methodology is evaluated from the results of a series of experiments designed to quantify the dynamics of distribution and metabolism of three iodothyronines, T3, T4, and reverse-T3. This analysis indicates that 1) the sequential optimal experiment approach can be effective and efficient in the laboratory, 2) it works in the presence of reasonably controlled biological variation, producing sufficiently robust sampling protocols, and 3) optimal designs can be highly efficient designs in practice, requiring for maximum accuracy a number of blood samples equal to the number of independently adjustable model parameters, no more or less.