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This paper is a survey of existing estimation methods for pharmacokinetic/pharmacodynamic (PK/PD) models based on stochastic differential equations (SDEs). Most parametric estimation methods proposed for SDEs require high frequency data and are often poorly suited for PK/PD data which are usually sparse. Moreover, PK/PD experiments generally include not a single individual but a group of subjects, leading to a population estimation approach. This review concentrates on estimation methods which have been applied to PK/PD data, for SDEs observed with and without measurement noise, with a standard or a population approach. Besides, the adopted methodologies highly differ depending on the existence or not of an explicit transition density of the SDE solution.

Modelling relationships between individuals is a classical question in social sciences and clustering individuals according to the observed patterns of interactions allows us to uncover a latent structure in the data. The stochastic block model is a popular approach for grouping individuals with respect to their social comportment. When several relationships of various types can occur jointly between individuals, the data are represented by multiplex networks where more than one edge can exist between the nodes. We extend stochastic block models to multiplex networks to obtain a clustering based on more than one kind of relationship. We propose to estimate the parameters-such as the marginal probabilities of assignment to groups (blocks) and the matrix of probabilities of connections between groups-through a variational expectation-maximization procedure. Consistency of the estimates is studied. The number of groups is chosen by using the integrated completed likelihood criterion, which is a penalized likelihood criterion. Multiplex stochastic block models arise in many situations but our applied example is motivated by a network of French cancer researchers. The two possible links (edges) between researchers are a direct connection or a connection through their laboratories. Our results show strong interactions between these two kinds of connection and the groups that are obtained are discussed to emphasize the common features of researchers grouped together.

Growth curve data consist of repeated measurements of a continuous growth process over time in a population of individuals. These data are classically analyzed by nonlinear mixed models. However, the standard growth functions used in this context prescribe monotone increasing growth and can fail to model unexpected changes in growth rates. We propose to model these variations using stochastic differential equations (SDEs) that are deduced from the standard deterministic growth function by adding random variations to the growth dynamics. A Bayesian inference of the parameters of these SDE mixed models is developed. In the case when the SDE has an explicit solution, we describe an easily implemented Gibbs algorithm. When the conditional distribution of the diffusion process has no explicit form, we propose to approximate it using the Euler-Maruyama scheme. Finally, we suggest validating the SDE approach via criteria based on the predictive posterior distribution. We illustrate the efficiency of our method using the Gompertz function to model data on chicken growth, the modeling being improved by the SDE approach.

Abstract. Non-linear mixed models defined by stochastic differential equations (SDEs) are considered: the parameters of the diffusion process are random variables and vary among the individuals. A maximum likelihood estimation method based on the Stochastic Approximation EM algorithm, is proposed. This estimation method uses the Euler-Maruyama approximation of the diffusion, achieved using latent auxiliary data introduced to complete the diffusion process between each pair of measurement instants. A tuned hybrid Gibbs algorithm based on conditional Brownian bridges simulations of the unobserved process paths is included in this algorithm. The convergence is proved and the error induced on the likelihood by the Euler-Maruyama approximation is bounded as a function of the step size of the approximation. Results of a pharmacokinetic simulation study illustrate the accuracy of this estimation method. The analysis of the Theophyllin real dataset illustrates the relevance of the SDE approach relative to the deterministic approach.