title: A model-driven methodology for exploring complex disease comorbidities applied to autism spectrum disorder and inflammatory bowel disease.
abstract: We propose a model-driven methodology aimed to shed light on complex disorders. Our approach enables exploring shared etiologies of comorbid diseases at the molecular pathway level. The method, Comparative Comorbidities Simulation (CCS), uses stochastic Petri net simulation for examining the phenotypic effects of perturbation of a network known to be involved in comorbidities to predict new roles for mutations in comorbid conditions. To demonstrate the utility of our novel methodology, we investigated the molecular convergence of autism spectrum disorder (ASD) and inflammatory bowel disease (IBD) on the autophagy pathway. In addition to validation by domain experts, we used formal analyses to demonstrate the model's self-consistency. We then used CCS to compare the effects of loss of function (LoF) mutations previously implicated in either ASD or IBD on the autophagy pathway. CCS identified similar dynamic consequences of these mutations in the autophagy pathway. Our method suggests that two LoF mutations previously implicated in IBD may contribute to ASD, and one ASD-implicated LoF mutation may play a role in IBD. Future targeted genomic or functional studies could be designed to directly test these predictions.
authors: Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA; Department of Information Systems, University of Haifa, Haifa, Israel. Electronic address: judith_somekh@hms.harvard.edu.
authors: Judith
authors: J
authors: Somekh
authors: Department of Information Systems, University of Haifa, Haifa, Israel.
authors: Mor
authors: M
authors: Peleg
authors: Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA; Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA; Department of Life Sciences, Ben Gurion University of the Negev, Beer-Sheva, Israel.
authors: Alal
authors: A
authors: Eran
authors: Department of Genetics, Harvard Medical School, Boston, MA, USA; Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA; Howard Hughes Medical Institute, Boston, MA, USA.
authors: Itay
authors: I
authors: Koren
authors: Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
authors: Ariel
authors: A
authors: Feiglin
authors: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors: Alik
authors: A
authors: Demishtein
authors: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors: Ruth
authors: R
authors: Shiloh
authors: Computer Science Institute, Brandenburg University of Technology, Cottbus, Germany.
authors: Monika
authors: M
authors: Heiner
authors: Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA.
authors: Sek Won
authors: SW
authors: Kong
authors: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors: Zvulun
authors: Z
authors: Elazar
authors: Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
authors: Isaac
authors: I
authors: Kohane
mesh_terms: D000067877:Autism Spectrum Disorder / Q000150:complications* / Q000235:genetics; D001343:Autophagy / Q000235:genetics; D015897:Comorbidity; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000150:complications* / Q000235:genetics; D009154:Mutation; D010641:Phenotype
keywords: ASD; Autism; Autophagy; IBD; Modeling; Petri nets