Mapping Subsets of Scholarly Information

We illustrate the use of machine learning techniques to analyze, structure, maintain, and evolve a large online corpus of academic literature. An emerging field of research can be identified as part of an existing corpus, permitting the implementation of a more coherent community structure for its practitioners.Comment: 10 pages, 4 figures, presented at Arthur M. Sackler Colloquium on "Mapping Knowledge Domains", 9--11 May 2003, Beckman Center, Irvine, CA, proceedings to appear in PNA

An Efficient Linear Mixed Model Framework for Meta-Analytic Association Studies Across Multiple Contexts

Linear mixed models (LMMs) can be applied in the meta-analyses of responses from individuals across multiple contexts, increasing power to detect associations while accounting for confounding effects arising from within-individual variation. However, traditional approaches to fitting these models can be computationally intractable. Here, we describe an efficient and exact method for fitting a multiple-context linear mixed model. Whereas existing exact methods may be cubic in their time complexity with respect to the number of individuals, our approach for multiple-context LMMs (mcLMM) is linear. These improvements allow for large-scale analyses requiring computing time and memory magnitudes of order less than existing methods. As examples, we apply our approach to identify expression quantitative trait loci from large-scale gene expression data measured across multiple tissues as well as joint analyses of multiple phenotypes in genome-wide association studies at biobank scale

Using genomic annotations increases statistical power to detect eGenes.

MotivationExpression quantitative trait loci (eQTLs) are genetic variants that affect gene expression. In eQTL studies, one important task is to find eGenes or genes whose expressions are associated with at least one eQTL. The standard statistical method to determine whether a gene is an eGene requires association testing at all nearby variants and the permutation test to correct for multiple testing. The standard method however does not consider genomic annotation of the variants. In practice, variants near gene transcription start sites (TSSs) or certain histone modifications are likely to regulate gene expression. In this article, we introduce a novel eGene detection method that considers this empirical evidence and thereby increases the statistical power.ResultsWe applied our method to the liver Genotype-Tissue Expression (GTEx) data using distance from TSSs, DNase hypersensitivity sites, and six histone modifications as the genomic annotations for the variants. Each of these annotations helped us detected more candidate eGenes. Distance from TSS appears to be the most important annotation; specifically, using this annotation, our method discovered 50% more candidate eGenes than the standard permutation [email protected] or [email protected]

Accounting for Population Structure in Gene-by-Environment Interactions in Genome-Wide Association Studies Using Mixed Models.

Although genome-wide association studies (GWASs) have discovered numerous novel genetic variants associated with many complex traits and diseases, those genetic variants typically explain only a small fraction of phenotypic variance. Factors that account for phenotypic variance include environmental factors and gene-by-environment interactions (GEIs). Recently, several studies have conducted genome-wide gene-by-environment association analyses and demonstrated important roles of GEIs in complex traits. One of the main challenges in these association studies is to control effects of population structure that may cause spurious associations. Many studies have analyzed how population structure influences statistics of genetic variants and developed several statistical approaches to correct for population structure. However, the impact of population structure on GEI statistics in GWASs has not been extensively studied and nor have there been methods designed to correct for population structure on GEI statistics. In this paper, we show both analytically and empirically that population structure may cause spurious GEIs and use both simulation and two GWAS datasets to support our finding. We propose a statistical approach based on mixed models to account for population structure on GEI statistics. We find that our approach effectively controls population structure on statistics for GEIs as well as for genetic variants

Effectively Identifying eQTLs from Multiple Tissues by Combining Mixed Model and Meta-analytic Approaches

Gene expression data, in conjunction with information on genetic variants, have enabled studies to identify expression quantitative trait loci (eQTLs) or polymorphic locations in the genome that are associated with expression levels. Moreover, recent technological developments and cost decreases have further enabled studies to collect expression data in multiple tissues. One advantage of multiple tissue datasets is that studies can combine results from different tissues to identify eQTLs more accurately than examining each tissue separately. The idea of aggregating results of multiple tissues is closely related to the idea of meta-analysis which aggregates results of multiple genome-wide association studies to improve the power to detect associations. In principle, meta-analysis methods can be used to combine results from multiple tissues. However, eQTLs may have effects in only a single tissue, in all tissues, or in a subset of tissues with possibly different effect sizes. This heterogeneity in terms of effects across multiple tissues presents a key challenge to detect eQTLs. In this paper, we develop a framework that leverages two popular meta-analysis methods that address effect size heterogeneity to detect eQTLs across multiple tissues. We show by using simulations and multiple tissue data from mouse that our approach detects many eQTLs undetected by traditional eQTL methods. Additionally, our method provides an interpretation framework that accurately predicts whether an eQTL has an effect in a particular tissue

Effectively identifying regulatory hotspots while capturing expression heterogeneity in gene expression studies

Expression quantitative trait loci (eQTL) mapping is a tool that can systematically identify genetic variation affecting gene expression. eQTL mapping studies have shown that certain genomic locations, referred to as regulatory hotspots, may affect the expression levels of many genes. Recently, studies have shown that various confounding factors may induce spurious regulatory hotspots. Here, we introduce a novel statistical method that effectively eliminates spurious hotspots while retaining genuine hotspots. Applied to simulated and real datasets, we validate that our method achieves greater sensitivity while retaining low false discovery rates compared to previous methods