title: Identification of genetic interaction networks via an evolutionary algorithm evolved Bayesian network.
abstract: BACKGROUND
  The future of medicine is moving towards the phase of precision medicine, with the goal to prevent and treat diseases by taking inter-individual variability into account. A large part of the variability lies in our genetic makeup. With the fast paced improvement of high-throughput methods for genome sequencing, a tremendous amount of genetics data have already been generated. The next hurdle for precision medicine is to have sufficient computational tools for analyzing large sets of data. Genome-Wide Association Studies (GWAS) have been the primary method to assess the relationship between single nucleotide polymorphisms (SNPs) and disease traits. While GWAS is sufficient in finding individual SNPs with strong main effects, it does not capture potential interactions among multiple SNPs. In many traits, a large proportion of variation remain unexplained by using main effects alone, leaving the door open for exploring the role of genetic interactions. However, identifying genetic interactions in large-scale genomics data poses a challenge even for modern computing.
  
  
  RESULTS
  For this study, we present a new algorithm, Grammatical Evolution Bayesian Network (GEBN) that utilizes Bayesian Networks to identify interactions in the data, and at the same time, uses an evolutionary algorithm to reduce the computational cost associated with network optimization. GEBN excelled in simulation studies where the data contained main effects and interaction effects. We also applied GEBN to a Type 2 diabetes (T2D) dataset obtained from the Marshfield Personalized Medicine Research Project (PMRP). We were able to identify genetic interactions for T2D cases and controls and use information from those interactions to classify T2D samples. We obtained an average testing area under the curve (AUC) of 86.8 %. We also identified several interacting genes such as INADL and LPP that are known to be associated with T2D.
  
  
  CONCLUSIONS
  Developing the computational tools to explore genetic associations beyond main effects remains a critically important challenge in human genetics. Methods, such as GEBN, demonstrate the utility of considering genetic interactions, as they likely explain some of the missing heritability.
authors.affiliation: Center for Systems Genomics, Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania, USA.
authors.forename: Ruowang
authors.initials: R
authors.lastname: Li
authors.affiliation: Center for Systems Genomics, Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Dudek
authors.affiliation: Center for Systems Genomics, Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania, USA.
authors.forename: Dokyoon
authors.initials: D
authors.lastname: Kim
authors.affiliation: Center for Systems Genomics, Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania, USA.
authors.forename: Molly A
authors.initials: MA
authors.lastname: Hall
authors.affiliation: Center for Systems Genomics, Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania, USA.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Bradford
authors.affiliation: Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, Marshfield, Wisconsin USA.
authors.forename: Peggy L
authors.initials: PL
authors.lastname: Peissig
authors.affiliation: Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, Marshfield, Wisconsin USA.
authors.forename: Murray H
authors.initials: MH
authors.lastname: Brilliant
authors.affiliation: Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, Marshfield, Wisconsin USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Linneman
authors.affiliation: Essentia Rural Health, Duluth, Minnesota USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: McCarty
authors.affiliation: Department of Statistics, Pennsylvania State University, University Park, Pennsylvania, USA.
authors.forename: Le
authors.initials: L
authors.lastname: Bao
authors.affiliation: Center for Systems Genomics, Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania, USA ; Biomedical & Translational Informatics, Geisinger Health System, Danville, Pennsylvania USA.
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
keywords: Bayesian Network; Discriminant analysis; Evolution algorithm; Genetic interactions; Type 2 diabetes