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1.  Comparative analysis of different approaches for dealing with candidate regions in the context of a genome-wide association study 
BMC Proceedings  2009;3(Suppl 7):S93.
Genome-wide association studies (GWAS) test hundreds of thousands of single-nucleotide polymorphisms (SNPs) for association to a trait, treating each marker equally and ignoring prior evidence of association to specific regions. Typically, promising regions are selected for further investigation based on p-values obtained from simple tests of association. However, loci that exert only a weak, low-penetrant role on the trait, producing modest evidence of association, are not detectable in the context of a GWAS. Implementing prior knowledge of association in GWAS could increase power, help distinguish between false and true positives, and identify better sets of SNPs for follow-up studies.
Here we performed a GWAS on rheumatoid arthritis (RA) patients and controls (Problem 1, Genetic Analysis Workshop 16). In order to include prior information in the analysis, we applied four methods that distinctively deal with markers in candidate genes in the context of GWAS. SNPs were divided into a random and a candidate subset, then we applied empirical correction by permutation, false-discovery rate, false-positive report probability, and posterior odds of association using different prior probabilities. We repeated the same analyses on two different sets of candidate markers defined on the basis of previously reported association to RA following two different approaches. The four methods showed similar relative behavior when applied to the two sets, with the proportion of candidate SNPs ranked among the top 2,000 varying from 0 to 100%. The use of different prior probabilities changed the stringency of the methods, but not their relative performance.
PMCID: PMC2795997  PMID: 20018090
2.  Genome-wide analysis of haplotype interaction for the data from the North American Rheumatoid Arthritis Consortium 
BMC Proceedings  2009;3(Suppl 7):S34.
Recent genome-wide association studies on several complex diseases have focused on individual single-nucleotide polymorphism (SNP) analysis; however, not many studies have reported interactions among genes perhaps because the gene-gene and gene-environment interaction analysis could be infeasible due to heavy computing requirements. In this study we propose a new strategy for exploring the interactions among haplotypes. The proposed method consists of two steps. Step 1 tests the single-SNP association of whole genome with multiple testing corrections and finds the haplotype blocks of the significant SNPs. Step 2 performs interaction analysis of haplotypes within blocks. Our proposed method is applied to the rheumatoid arthritis data for Genetic Analysis Workshop 16.
PMCID: PMC2795932  PMID: 20018025
3.  Elastic-net regularization approaches for genome-wide association studies of rheumatoid arthritis 
BMC Proceedings  2009;3(Suppl 7):S25.
The current trend in genome-wide association studies is to identify regions where the true disease-causing genes may lie by evaluating thousands of single-nucleotide polymorphisms (SNPs) across the whole genome. However, many challenges exist in detecting disease-causing genes among the thousands of SNPs. Examples include multicollinearity and multiple testing issues, especially when a large number of correlated SNPs are simultaneously tested. Multicollinearity can often occur when predictor variables in a multiple regression model are highly correlated, and can cause imprecise estimation of association. In this study, we propose a simple stepwise procedure that identifies disease-causing SNPs simultaneously by employing elastic-net regularization, a variable selection method that allows one to address multicollinearity. At Step 1, the single-marker association analysis was conducted to screen SNPs. At Step 2, the multiple-marker association was scanned based on the elastic-net regularization. The proposed approach was applied to the rheumatoid arthritis (RA) case-control data set of Genetic Analysis Workshop 16. While the selected SNPs at the screening step are located mostly on chromosome 6, the elastic-net approach identified putative RA-related SNPs on other chromosomes in an increased proportion. For some of those putative RA-related SNPs, we identified the interactions with sex, a well known factor affecting RA susceptibility.
PMCID: PMC2795922  PMID: 20018015
4.  Association tests based on the principal-component analysis 
BMC Proceedings  2007;1(Suppl 1):S130.
Haplotypes are composed of specific combinations of alleles at the several loci on the same chromosome. Because haplotypes incorporate linkage disequilibrium (LD) information from multiple loci, haplotype-based association analyses can provide greater powers than the single-marker analysis in the association studies. However, when we construct haplotypes using many markers simultaneously, we may be confronted with a sparseness problem due to a large number of haplotypes. In this paper, we propose the principal-component (PC) association test as an alternative to the haplotype-based association test. We define the PC scores from the LD blocks and perform the association test using logistic regression. The proposed PC test was applied to the analysis of the Genetic Analysis Workshop 15 simulated data set. By knowing the answers of Problem 3, we evaluated the performance of the PC test and the haplotype-based association test using Akaike Information Criterion (AIC), power, and type I error. The PC test performed better than the haplotype-based association test in the sense that the former tends to have smaller AIC values and slightly greater power than the latter.
PMCID: PMC2367557  PMID: 18466473
5.  Identification of expression quantitative trait loci by the interaction analysis using genetic algorithm 
BMC Proceedings  2007;1(Suppl 1):S69.
Many genes with major effects on quantitative traits have been reported to interact with other genes. However, finding a group of interacting genes from thousands of SNPs is challenging. Hence, an efficient and robust algorithm is needed. The genetic algorithm (GA) is useful in searching for the optimal solution from a very large searchable space. In this study, we show that genome-wide interaction analysis using GA and a statistical interaction model can provide a practical method to detect biologically interacting loci. We focus our search on transcriptional regulators by analyzing gene × gene interactions for cancer-related genes. The expression values of three cancer-related genes were selected from the expression data of the Genetic Analysis Workshop 15 Problem 1 data set. We implemented a GA to identify the expression quantitative trait loci that are significantly associated with expression levels of the cancer-related genes. The time complexity of the GA was compared with that of an exhaustive search algorithm. As a result, our GA, which included heuristic methods, such as archive, elitism, and local search, has greatly reduced computational time in a genome-wide search for gene × gene interactions. In general, the GA took one-fifth the computation time of an exhaustive search for the most significant pair of single-nucleotide polymorphisms.
PMCID: PMC2367540  PMID: 18466570
6.  Finding pathway regulators: gene set approach using peak identification algorithms 
BMC Proceedings  2007;1(Suppl 1):S90.
Recently, a number of different approaches have been used to examine variation in gene expression and to identify genes whose level of transcript differed greatly among unrelated individuals. Previous studies have commonly focused on identifying determinants that regulate gene expressions by targeting individual genes. However, it is difficult to detect true differences in the level of gene expression among genotypes from noise due to issues such as multiple testing and limited sample size. To increase the statistical power for detecting this difference, we consider a 'gene set' approach by focusing on subtle but coordinated changes in gene expression across multiple genes rather than individual genes. We defined a 'gene set' as a set of genes in the same biological pathway and focused on identifying common regulators based on an assumption that the genes within the same pathway are controlled by common regulators. We applied the gene set approach to the expression data of mRNA in Centre d'Etude du Polymorphisme Humain lymphoblast cells to identify regulators controlling the genes in a biological pathway. Our gene set approach successfully identified potent regulators controlling gene expression in an inflammatory response pathway.
PMCID: PMC2367538  PMID: 18466594
7.  Application of structural equation models to construct genetic networks using differentially expressed genes and single-nucleotide polymorphisms 
BMC Proceedings  2007;1(Suppl 1):S76.
Understanding the genetic basis of human variation is an important goal of biomedical research. In this study, we used structural equation models (SEMs) to construct genetic networks to model how specific single-nucleotide polymorphisms (SNPs) from two genes known to cause acute myeloid leukemia (AML) by somatic mutation, runt-related transcription factor 1 (RUNX1) and ets variant gene 6 (ETV6), affect expression levels of other genes and how RUNX1 and ETV6 are related to each other. The SEM approach allows us to compare several candidate models from which an explanatory genetic network can be constructed.
PMCID: PMC2367521  PMID: 18466578

Results 1-7 (7)