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Information theory is valuable in multiple-variable analysis for being model-free and nonparametric, and for the modest sensitivity to undersampling. We previously introduced a general approach to finding multiple dependencies that provides accurate measures of levels of dependency for subsets of variables in a data set, which is significantly nonzero only if the subset of variables is collectively dependent. This is useful, however, only if we can avoid a combinatorial explosion of calculations for increasing numbers of variables. The proposed dependence measure for a subset of variables, τ , differential interaction information, Δ( τ ), has the property that for subsets of τ some of the factors of Δ( τ ) are significantly nonzero, when the full dependence includes more variables. We use this property to suppress the combinatorial explosion by following the 'shadows' of multivariable dependency on smaller subsets. Rather than calculating the marginal entropies of all subsets at each degree level, we need to consider only calculations for subsets of variables with appropriate 'shadows.' The number of calculations for n variables at a degree level of d grows therefore, at a much smaller rate than the binomial coefficient ( n, d), but depends on the parameters of the 'shadows' calculation. This approach, avoiding a combinatorial explosion, enables the use of our multivariable measures on very large data sets. We demonstrate this method on simulated data sets, and characterize the effects of noise and sample numbers. In addition, we analyze a data set of a few thousand mutant yeast strains interacting with a few thousand chemical compounds. [ABSTRACT FROM AUTHOR]

For the computational analysis of biological problems-analyzing data, inferring networks and complex models, and estimating model parameters-it is common to use a range of methods based on probabilistic logic constructions, sometimes collectively called machine learning methods. Probabilistic modeling methods such as Bayesian Networks (BN) fall into this class, as do Hierarchical Bayesian Networks (HBN), Probabilistic Boolean Networks (PBN), Hidden Markov Models (HMM), and Markov Logic Networks (MLN). In this review, we describe the most general of these (MLN), and show how the above-mentioned methods are related to MLN and one another by the imposition of constraints and restrictions. This approach allows us to illustrate a broad landscape of constructions and methods, and describe some of the attendant strengths, weaknesses, and constraints of many of these methods. We then provide some examples of their applications to problems in biology and medicine, with an emphasis on genetics. The key concepts needed to picture this landscape of methods are the ideas of probabilistic graphical models, the structures of the graphs, and the scope of the logical language repertoire used (from First-Order Logic [FOL] to Boolean logic.) These concepts are interlinked and together define the nature of each of the probabilistic logic methods. Finally, we discuss the initial applications of MLN to genetics, show the relationship to less general methods like BN, and then mention several examples where such methods could be effective in new applications to specific biological and medical problems. [ABSTRACT FROM AUTHOR]

Phenotypic variation, including that which underlies health and disease in humans, results in part from multiple interactions among both genetic variation and environmental factors. While diseases or phenotypes caused by single gene variants can be identified by established association methods and family-based approaches, complex phenotypic traits resulting from multi-gene interactions remain very difficult to characterize. Here we describe a new method based on information theory, and demonstrate how it improves on previous approaches to identifying genetic interactions, including both synthetic and modifier kinds of interactions. We apply our measure, called interaction distance, to previously analyzed data sets of yeast sporulation efficiency, lipid related mouse data and several human disease models to characterize the method. We show how the interaction distance can reveal novel gene interaction candidates in experimental and simulated data sets, and outperforms other measures in several circumstances. The method also allows us to optimize case/control sample composition for clinical studies. [ABSTRACT FROM AUTHOR]