Sequential Parameter Estimation for Mammalian Cell Model Based on In Silico Design of Experiments

Due to the complicated metabolism of mammalian cells, the corresponding dynamic mathematical models usually consist of large sets of differential and algebraic equations with a large number of parameters to be estimated. On the other hand, the measured data for estimating the model parameters are limited. Consequently, the parameter estimates may converge to a local minimum far from the optimal ones, especially when the initial guesses of the parameter values are poor. The methodology presented in this paper provides a systematic way for estimating parameters sequentially that generates better initial guesses for parameter estimation and improves the accuracy of the obtained metabolic model. The model parameters are first classified into four subsets of decreasing importance, based on the sensitivity of the model's predictions on the parameters' assumed values. The parameters in the most sensitive subset, typically a small fraction of the total, are estimated first. When estimating the remaining parameters with next most sensitive subset, the subsets of parameters with higher sensitivities are estimated again using their previously obtained optimal values as the initial guesses. The power of this sequential estimation approach is illustrated through a case study on the estimation of parameters in a dynamic model of CHO cell metabolism in fed-batch culture. We show that the sequential parameter estimation approach improves model accuracy and that using limited data to estimate low-sensitivity parameters can worsen model performance.