title: Integrative top-down system metabolic modeling in experimental disease states via data-driven Bayesian methods.
abstract: Multivariate metabolic profiles from biofluids such as urine and plasma are highly indicative of the biological fitness of complex organisms and can be captured analytically in order to derive top-down systems biology models. The application of currently available modeling approaches to human and animal metabolic pathway modeling is problematic because of multicompartmental cellular and tissue exchange of metabolites operating on many time scales. Hence, novel approaches are needed to analyze metabolic data obtained using minimally invasive sampling methods in order to reconstruct the patho-physiological modulations of metabolic interactions that are representative of whole system dynamics. Here, we show that spectroscopically derived metabolic data in experimental liver injury studies (induced by hydrazine and alpha-napthylisothiocyanate treatment) can be used to derive insightful probabilistic graphical models of metabolite dependencies, which we refer to as metabolic interactome maps. Using these, system level mechanistic information on homeostasis can be inferred, and the degree of reversibility of induced lesions can be related to variations in the metabolic network patterns. This approach has wider application in assessment of system level dysfunction in animal or human studies from noninvasive measurements.
authors.affiliation: Department of Biomolecular Medicine, Division of Surgery, Oncology, Reproductive Biology & Anaesthetics, Sir Alexander Fleming Building, Imperial College, London SW7 2AZ, UK.
authors.forename: Jung-Wook
authors.initials: JW
authors.lastname: Bang
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Crockford
authors.forename: Elaine
authors.initials: E
authors.lastname: Holmes
authors.forename: Florencio
authors.initials: F
authors.lastname: Pazos
authors.forename: Michael J E
authors.initials: MJ
authors.lastname: Sternberg
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Muggleton
authors.forename: Jeremy K
authors.initials: JK
authors.lastname: Nicholson
mesh_terms: D000818:Animals; D001499:Bayes Theorem; D019295:Computational Biology; D004195:Disease Models, Animal; D008107:Liver Diseases / Q000097:blood / Q000378:metabolism* / Q000652:urine; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D049490:Systems Biology