Section: Research Program
Parametrization of complex systems
Projectteam positioning
Clinical data are often sparse: we have few data per patient. The number of data is of the order of the number of parameters. In this context, a natural way to parametrize complex models with real world clinical data is to use a Bayesian approach, namely to try to find the distribution of the model parameters in the population, rather than to try to identify the parameters of every single patient. This approach has been pioneered in the 90's by the Nonmem software, and has been much improved thanks to Marc Lavielle in the 2000's. Refined statistical methods, called SAEM, have been tuned and implemented in commercial softwares like Monolix.
Recent results
The main problem when we try to parametrize clinical data using complex systems is the computational time. One single evaluation of the model can be costly, in particular if this model involves partial differential equations, and SAEM algorithm requires hundreds of thousands of single evaluations. The time cost is then too large, in particular because SAEM may not be parallelized.
To speed up the evaluation of the complex model, we replace it by an approximate one, or so called metamodel, constructed by interpolation of a small number of its values. We therefore combine the classical SAEM algorithm with an interpolation step, leading to a strong acceleration. Interpolation can be done through a precomputation step on a fixed grid, or through a more efficient kriging step. The interpolation grid or the kriging step may be improved during SAEM algorithm in an iterative way in order to get accurate evaluations of the complex system only in the domain of interest, namely near the clinical values [14],[15].
We applied these new algorithms to synthetic data and are currently using them on glioma data. We are also currently trying to prove the convergence of the corresponding algorithms. We will develop glioma applications in the next section.
Moreover E. Ollier in his phD developed new strategies to distinguish various populations within a SAEM algorithm [23].
We have two long standing collaborations with Sanofi and Servier on parametrization issues:

Servier: during a four years contract, we modelled the pkpd of new drugs and also study the combination and optimization of chimiotherapies.

Sanofi: during a eight years contract, Emmanuel Grenier wrote a complete software devoted to the study of the degradation of vaccine. This software is used worldwide by Sanofi R&D teams in order to investigate the degradation of existing or new vaccines and to study their behavior when they are heated. This software has been used on flu, dengue and various other diseases.
Collaborations

Academic collaborations: A. Leclerc Samson (Grenoble University)

Medical collaborations: Dr Ducray (Centre Léon Bérard, Lyon) and Dr Sujobert (Lyon Sud Hospital)

Industrial contracts: we used parametrization and treatment improvement techniques for Servier (four years contract, on cancer drug modeling and optimization) and Sanofi (long standing collaboration)