title: Domain-specific model selection for structural identification of the Rab5-Rab7 dynamics in endocytosis.
abstract: BACKGROUND
  Given its recent rapid development and the central role that modeling plays in the discipline, systems biology clearly needs methods for automated modeling of dynamical systems. Process-based modeling focuses on explanatory models of dynamical systems; it constructs such models from measured time-course data and formalized modeling knowledge. In this paper, we apply process-based modeling to the practically relevant task of modeling the Rab5-Rab7 conversion switch in endocytosis. The task is difficult due to the limited observability of the system variables and the noisy measurements, which pose serious challenges to the process of model selection. To address these issues, we propose a domain-specific model selection criteria that take into account knowledge about the necessary properties of the simulated model behavior.
  
  
  RESULTS
  In a series of modeling experiments, we compare the results of process-based modeling obtained with different model selection criteria. The first is the standard maximum likelihood criterion based solely on least-squares model error. The second one is a parsimony-based criterion that also takes into account model complexity. We also introduce three domain-specific criteria based on domain expert expectations about the simulated behavior of an endocytosis model. According to the first criterion, 90 of the candidate models are indistinguishable. Furthermore, taking into account the complexity of the model does not lead to better model selection. However, the use of domain-specific criteria results in a remarkable improvement over the other two model selection criteria.
  
  
  CONCLUSIONS
  We demonstrate the applicability of process-based modeling to the task of modeling the Rab5-Rab7 dynamics in endocytosis. Our experiments show that the domain-specific criteria outperform the standard domain-independent criteria for model selection. We also find that some of the model structures discarded as implausible in previous studies lead to the expected Rab5-Rab7 switch behavior.
authors.affiliation: Jožef Stefan Institute, Jamova cesta 39, Ljubljana, 1000, Slovenia. jovan.tanevski@ijs.si.|Jožef Stefan International Postgraduate School, Jamova cesta 39, Ljubljana, 1000, Slovenia. jovan.tanevski@ijs.si.
authors.forename: Jovan
authors.initials: J
authors.lastname: Tanevski
authors.affiliation: University of Ljubljana, Gosarjeva ulica 5, Ljubljana, 1000, Slovenia. ljupco.todorovski@fu.uni-lj.si.
authors.forename: Ljupčo
authors.initials: L
authors.lastname: Todorovski
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauer Straße 108, Dresden, 01308, Germany. kalaidzi@mpi-cbg.de.
authors.forename: Yannis
authors.initials: Y
authors.lastname: Kalaidzidis
authors.affiliation: Jožef Stefan Institute, Jamova cesta 39, Ljubljana, 1000, Slovenia. saso.dzeroski@ijs.si.
authors.forename: Sašo
authors.initials: S
authors.lastname: Džeroski
mesh_terms: D004705:Endocytosis; D008954:Models, Biological; D017434:Protein Structure, Tertiary; D020691:rab GTP-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D020696:rab5 GTP-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D000090802:rab7 GTP-Binding Proteins
chemical_list: D000090802:rab7 GTP-Binding Proteins; D020691:rab GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins