During the past decade, findings of genome-wide association studies (GWAS) improved our knowledge and understanding of disease genetics. To date, thousands of SNPs have been associated with diseases and other complex traits. Statistical analysis typically looks for association between a phenotype and a SNP taken individually via single-locus tests. However, geneticists admit this is an oversimplified approach to tackle the complexity of underlying biological mechanisms. Interaction between SNPs, namely epistasis, must be considered. Unfortunately, epistasis detection gives rise to analytic challenges since analyzing every SNP combination is at present impractical at a genome-wide scale. In this review, we will present the main strategies recently proposed to detect epistatic interactions, along with their operating principle. Some of these methods are exhaustive, such as multifactor dimensionality reduction, likelihood ratio-based tests or receiver operating characteristic curve analysis; some are non-exhaustive, such as machine learning techniques (random forests, Bayesian networks) or combinatorial optimization approaches (ant colony optimization, computational evolution system).
In data analysis, latent variables play a central role because they help provide powerful insights into a wide variety of phenomena, ranging from biological to human sciences. The latent tree model, a particular type of probabilistic graphical models, deserves attention. Its simple structure - a tree - allows simple and efficient inference, while its latent variables capture complex relationships. In the past decade, the latent tree model has been subject to significant theoretical and methodological developments. In this review, we propose a comprehensive study of this model. First we summarize key ideas underlying the model. Second we explain how it can be efficiently learned from data. Third we illustrate its use within three types of applications: latent structure discovery, multidimensional clustering, and probabilistic inference. Finally, we conclude and give promising directions for future researches in this field
BackgroundDiscovering the genetic basis of common genetic diseases in the human genome represents a public health issue. However, the dimensionality of the genetic data (up to 1 million genetic markers) and its complexity make the statistical analysis a challenging task.ResultsWe present an accurate modeling of dependences between genetic markers, based on a forest of hierarchical latent class models which is a particular class of probabilistic graphical models. This model offers an adapted framework to deal with the fuzzy nature of linkage disequilibrium blocks. In addition, the data dimensionality can be reduced through the latent variables of the model which synthesize the information borne by genetic markers. In order to tackle the learning of both forest structure and probability distributions, a generic algorithm has been proposed. A first implementation of our algorithm has been shown to be tractable on benchmarks describing 105 variables for 2000 individuals.ConclusionsThe forest of hierarchical latent class models offers several advantages for genome-wide association studies: accurate modeling of linkage disequilibrium, flexible data dimensionality reduction and biological meaning borne by latent variables.
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