Biological networks and epistasis in genome-wide association studies

Over the last few years, technological improvements have made possible the genotyping of hundreds of thousands of SNPs, enabling whole-genome association studies. The first genome-wide association studies have recently been completed to detect causal variant for complex traits. Although increasing evidence suggests that interaction between loci, such as epistasis between two loci, should be considered, most of these studies proceed by considering each SNP independently. One reason for this choice is that looking at all pairs of SNPs increases dramatically the number of tests (approximatively 50 billions of tests for a 300,000 SNPs data set) that faces with computational limitation and strong multiple testing correction.
We proposed to reduce the number of tests by focusing on pairs of SNPs that belong to genes known to interact in some metabolic network. Although some interactions might be missed, these pairs of genes are good candidates for epistasis. Furthermore the use of protein interaction databases (such as the STRING database) may reduce the number of tests by a factor of 5,000.
Results using this approach will be presented on simulated data sets and on public data sets.
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SMILE: A novel dissimilarity-based procedure for detecting sparse-specific profiles in sparse contingency tables

International audienceA novel statistical procedure for clustering individuals characterized by sparse-specific profiles is introduced in the context of data summarized in sparse contingency tables. The proposed procedure relies on a single-linkage clustering based on a new dissimilarity measure designed to give equal influence to sparsity and specificity of profiles. Theoretical properties of the new dissimilarity are derived by characterizing single-linkage clustering using Minimum Spanning Trees. Such characterization allows the description of situations for which the proposed dissimilarity outperforms competing dissimilarities. Simulation examples are performed to demonstrate the strength of the new dissimilarity compared to 11 other methods. The analysis of a genomic data set dedicated to the study of molecular signatures of selection is used to illustrate the efficiency of the proposed method in a real situatio

Protein engineering to increase the potential of a therapeutic antibody Fab for long-acting delivery to the eye

To date, ocular antibody therapies for the treatment of retinal diseases rely on injection of the drug into the vitreous chamber of the eye. Given the burden for patients undergoing this procedure, less frequent dosing through the use of long-acting delivery (LAD) technologies is highly desirable. These technologies usually require a highly concentrated formulation and the antibody must be stable against extended exposure to physiological conditions. Here we have increased the potential of a therapeutic antibody antigen-binding fragment (Fab) for LAD by using protein engineering to enhance the chemical and physical stability of the molecule. Structure-guided amino acid substitutions in a negatively charged complementarity determining region (CDR-L1) of an anti-factor D (AFD) Fab resulted in increased chemical stability and solubility. A variant of AFD (AFD.v8), which combines light chain substitutions (VL-D28S:D30E:D31S) with a substitution (VH-D61E) to stabilize a heavy chain isomerization site, retained complement factor D binding and inhibition potency and has properties suitable for LAD. This variant was amenable to high protein concentration (>250 mg/mL), low ionic strength formulation suitable for intravitreal injection. AFD.v8 had acceptable pharmacokinetic (PK) properties upon intravitreal injection in rabbits, and improved stability under both formulation and physiological conditions. Simulations of expected human PK behavior indicated greater exposure with a 25-mg dose enabled by the increased solubility of AFD.v8

Gene-Based Methods to Detect Gene-Gene Interaction in R: The GeneGeneInteR Package

GeneGeneInteR is an R package dedicated to the detection of an association between a case-control phenotype and the interaction between two sets of biallelic markers (single nucleotide polymorphisms or SNPs) in case-control genome-wide associations studies. The development of statistical procedures for searching gene-gene interaction at the SNP-set level has indeed recently grown in popularity as these methods confer advantage in both statistical power and biological interpretation. However, all these methods have been implemented in home made softwares that are for most of them available only on request to the authors and at best have a web interface. Since the implementation of these methods is not straightforward, there is a need for a user-friendly tool to perform gene-based genegene interaction. The purpose of GeneGeneInteR is to propose a collection of tools for all the steps involved in gene-based gene-gene interaction testing in case-control association studies. Illustrated by an example of a dataset related to rheumatoid arthritis, this paper details the implementation of the functions available in GeneGeneInteR to perform an analysis of a collection of SNP sets. Such an analysis aims at addressing the complete statistical pipeline going from data importation to the visualization of the results through data manipulation and statistical analysis

Taking into account sensory knowledge: the case of geo-techologies for children with visual impairments

This paper argues for designing geo-technologies supporting non-visual sensory knowledge. Sensory knowledge refers to the implicit and explicit knowledge guiding our uses of our senses to understand the world. To support our argument, we build on an 18 months field-study on geography classes for primary school children with visual impairments. Our findings show (1) a paradox in the use of non-visual sensory knowledge: described as fundamental to the geography curriculum, it is mostly kept out of school; (2) that accessible geo-technologies in the literature mainly focus on substituting vision with another modality, rather than enabling teachers to build on children's experiences; (3) the importance of the hearing sense in learning about space. We then introduce a probe, a wrist-worn device enabling children to record audio cues during field-trips. By giving importance to children's hearing skills, it modified existing practices and actors' opinions on non-visual sensory knowledge. We conclude by reflecting on design implications, and the role of technologies in valuing diverse ways of understanding the world