Extending an established simulation: Exploration of the possible effects using a case study in experimental autoimmune encephalomyelitis

Investigation of a biological domain through simulation can naturally lead to the desire to extend the simulation as new areas of the domain are explored. Such extension may entail the incorporation of additional cell types, molecules or entire molecular pathways. The addition of these extensions can have a profound influence on simulation behaviour, and where the biological domain is not well characterised, a structured development methodology must be employed to ensure that the extended simulation is well aligned with its predecessor. The paper presents such a methodology, relying on iterated development and sensitivity analysis, by extending an existing simulation of Experimental Autoimmune Encephalomyelitis (EAE), a disease model for Multiple Sclerosis, via inclusion of an additional regulatory pathway. We reflect on the implications of extensions which alter simulation behaviour on pre-extension results.