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      Optimization of neural network architecture using genetic programming improves detection and modeling of gene-gene interactions in studies of human diseases

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          Abstract

          Background

          Appropriate definition of neural network architecture prior to data analysis is crucial for successful data mining. This can be challenging when the underlying model of the data is unknown. The goal of this study was to determine whether optimizing neural network architecture using genetic programming as a machine learning strategy would improve the ability of neural networks to model and detect nonlinear interactions among genes in studies of common human diseases.

          Results

          Using simulated data, we show that a genetic programming optimized neural network approach is able to model gene-gene interactions as well as a traditional back propagation neural network. Furthermore, the genetic programming optimized neural network is better than the traditional back propagation neural network approach in terms of predictive ability and power to detect gene-gene interactions when non-functional polymorphisms are present.

          Conclusion

          This study suggests that a machine learning strategy for optimizing neural network architecture may be preferable to traditional trial-and-error approaches for the identification and characterization of gene-gene interactions in common, complex human diseases.

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          Most cited references29

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          A perspective on epistasis: limits of models displaying no main effect.

          The completion of a draft sequence of the human genome and the promise of rapid single-nucleotide-polymorphism-genotyping technologies have resulted in a call for the abandonment of linkage studies in favor of genome scans for association. However, there exists a large class of genetic models for which this approach will fail: purely epistatic models with no additive or dominance variation at any of the susceptibility loci. As a result, traditional association methods (such as case/control, measured genotype, and transmission/disequilibrium test [TDT]) will have no power if the loci are examined individually. In this article, we examine this class of models, delimiting the range of genetic determination and recurrence risks for two-, three-, and four-locus purely epistatic models. Our study reveals that these models, although giving rise to no additive or dominance variation, do give rise to increased allele sharing between affected sibs. Thus, a genome scan for linkage could detect genomic subregions harboring susceptibility loci. We also discuss some simple multilocus extensions of single-locus analysis methods, including a conditional form of the TDT.
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            Who's afraid of epistasis?

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              A complete enumeration and classification of two-locus disease models.

              W Li, J Reich (2000)
              There are 512 two-locus, two-allele, two-phenotype, fully penetrant disease models. Using the permutation between two alleles, between two loci, and between being affected and unaffected, one model can be considered to be equivalent to another model under the corresponding permutation. These permutations greatly reduce the number of two-locus models in the analysis of complex diseases. This paper determines the number of nonredundant two-locus models (which can be 102, 100, 96, 51, 50, or 58, depending on which permutations are used, and depending on whether zero-locus and single-locus models are excluded). Whenever possible, these nonredundant two-locus models are classified by their property. Besides the familiar features of multiplicative models (logical AND), heterogeneity models (logical OR), and threshold models, new classifications are added or expanded: modifying-effect models, logical XOR models, interference and negative interference models (neither dominant nor recessive), conditionally dominant/recessive models, missing lethal genotype models, and highly symmetric models. The following aspects of two-locus models are studied: the marginal penetrance tables at both loci, the expected joint identity-by-descent (IBD) probabilities, and the correlation between marginal IBD probabilities at the two loci. These studies are useful for linkage analyses using single-locus models while the underlying disease model is two-locus, and for correlation analyses using the linkage signals at different locations obtained by a single-locus model. Copyright 2000 S. Karger AG, Basel
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                Author and article information

                Journal
                BMC Bioinformatics
                BMC Bioinformatics
                BioMed Central (London )
                1471-2105
                2003
                7 July 2003
                : 4
                : 28
                Affiliations
                [1 ]Program in Human Genetics and Department of Molecular Physiology and Biophysics, Vanderbilt University Medical School, Nashville, TN, 37232-0700, USA
                Article
                1471-2105-4-28
                10.1186/1471-2105-4-28
                183838
                12846935
                46d2d982-9803-401d-8115-df616848ad5c
                Copyright © 2003 Ritchie et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.
                History
                : 12 March 2003
                : 7 July 2003
                Categories
                Methodology Article

                Bioinformatics & Computational biology
                Bioinformatics & Computational biology

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