Petri Nets with Fuzzy Logic (PNFL) Reverse Engineering and Parametrization 英文参考文献.docVIP

PetriNetswithFuzzyLogic(PNFL):ReverseEngineering andParametrization RobertKu¨ffner*,TobiasPetri,LukasWindhager,RalfZimmer Institutfu¨rInformatik,Ludwig-Maximilians-Universita¨t, Mu¨nchen,Germany Abstract Background: The recent DREAM4 blind assessment provided a particularly realistic and challenging setting for network reverseengineeringmethods.TheinsilicopartofDREAM4solicitedtheinferenceofcycle-richgeneregulatorynetworks from heterogeneous, noisy expression data including time courses as well as knockout, knockdown and multifactorial perturbations. Methodology and Principal Findings: We inferred and parametrized simulation models based on Petri Nets with Fuzzy Logic (PNFL). This completely automated approach correctly reconstructed networks with cycles as well as oscillating networkmotifs.PNFLwasevaluatedasthebestperformeronDREAM4insiliconetworksofsize10withanareaunderthe precision-recall curve (AUPR) of 81%. Besides topology, we inferred a range of additional mechanistic details with good reliability,e.g.distinguishingactivationfrominhibitionaswellasdependentfromindependentregulation.Ourmodelsalso performedwellonnewexperimentalconditionssuchasdoubleknockoutmutationsthatwerenotincludedintheprovided datasets. Conclusions:Theinferenceofbiologicalnetworkssubstantiallybenefitsfrommethodsthatareexpressiveenoughtodeal with diverse datasets in a unified way. At the same time, overly complex approaches could generate multiple different modelsthatexplainthedataequallywell.PNFLappearstostrikethebalancebetweenexpressivepowerandcomplexity. This also applies to the intuitive representation of PNFL models combining a straightforward graphical notation with colloquialfuzzyparameters. Citation:Ku¨ffnerR,PetriT,WindhagerL,ZimmerR(2010)PetriNetswithFuzzyLogic(PNFL):ReverseEngineeringandParametrization.PLoSONE5(9):e12807. doi:10.1371/journal.pone.0012807 Editor:MarkIsalan,CenterforGenomicRegulation,Spain ReceivedMarch31,2010;AcceptedJune18,2010;PublishedSeptember20,2010 Copyright: