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1.  Pathway-based joint effects analysis of rare genetic variants using Genetic Analysis Workshop 17 exon sequence data 
BMC Proceedings  2011;5(Suppl 9):S45.
Pathway-based analysis has been recently used in joint tests of association between disease and a group of common genetic variants. Here we explore this idea for the joint effects analysis of rare genetic variants and their association with quantitative traits and disease. We accumulate multiple rare minor alleles in a genetic risk score for each individual in a given pathway; this score is then used to assess association with quantitative phenotypes and disease. We demonstrate that this approach may be better than studying single rare variants or a gene risk score for identifying individuals with significantly greater risk.
PMCID: PMC3287882  PMID: 22373371
2.  A pathway-based association analysis model using common and rare variants 
BMC Proceedings  2011;5(Suppl 9):S85.
How various genetic effects in combination affect susceptibility to certain disease states continues to be a major area of methodological research. Various rare variant models have been proposed, in response to a common failure to either identify or validate biologically driven causal genetic variants in genome-wide association studies. Adopting the idea that multiple rare variants may effectively produce a combined effect equal to a single common variant effect through common linkage with this variant, we construct a pathway-based genetic association analysis model using both common and rare variants. This genetic model is applied to the disease status of unrelated individuals in replication 1 from Genetic Analysis Workshop 17. In this simulated example, we were able to identify several pathways that were potentially associated with the disease status and found that common variants showed stronger genetic effect than rare variants.
PMCID: PMC3287926  PMID: 22373433
3.  Using a higher criticism statistic to detect modest effects in a genome-wide study of rheumatoid arthritis 
BMC Proceedings  2009;3(Suppl 7):S40.
In high-dimensional studies such as genome-wide association studies, the correction for multiple testing in order to control total type I error results in decreased power to detect modest effects. We present a new analytical approach based on the higher criticism statistic that allows identification of the presence of modest effects. We apply our method to the genome-wide study of rheumatoid arthritis provided in the Genetic Analysis Workshop 16 Problem 1 data set. There is evidence for unknown bias in this study that could be explained by the presence of undetected modest effects. We compared the asymptotic and empirical thresholds for the higher criticism statistic. Using the asymptotic threshold we detected the presence of modest effects genome-wide. We also detected modest effects using 90th percentile of the empirical null distribution as a threshold; however, there is no such evidence when the 95th and 99th percentiles were used. While the higher criticism method suggests that there is some evidence for modest effects, interpreting individual single-nucleotide polymorphisms with significant higher criticism statistics is of undermined value. The goal of higher criticism is to alert the researcher that genetic effects remain to be discovered and to promote the use of more targeted and powerful studies to detect the remaining effects.
PMCID: PMC2795939  PMID: 20018032
4.  Pathway-based analysis of a genome-wide case-control association study of rheumatoid arthritis 
BMC Proceedings  2009;3(Suppl 7):S128.
Evaluation of the association between single-nucleotide polymorphisms (SNPs) and disease outcomes is widely used to identify genetic risk factors for complex diseases. Although this analysis paradigm has made significant progress in many genetic studies, many challenges remain, such as the requirement of a large sample size to achieve adequate power. Here we use rheumatoid arthritis (RA) as an example and explore a new analysis strategy: pathway-based analysis to search for related genes and SNPs contributing to the disease.
We first propose the application of measure of explained variation to quantify the predictive ability of a given SNP. We then use gene set enrichment analysis to evaluate enrichment of specific pathways, where pathways, are considered enriched if they consist of genes that are associated with the phenotype of interest above and beyond is expected by chance. The results are also compared with score tests for association analysis by adjusting for population stratification.
Our study identified some significantly enriched pathways, such as "cell adhesion molecules," which are known to play a key role in RA. Our results showed that pathway-based analysis may identify other biologically interesting loci (e.g., rs1018361) related to RA: the gene (CTLA4) closest to this marker has previously been shown to be associated with RA and the gene is in the significant pathways we identified, even though the marker has not reached genome-wide significance in univariate single-marker analysis.
PMCID: PMC2795901  PMID: 20017994
5.  Impact of normalization and filtering on linkage analysis of gene expression data 
BMC Proceedings  2007;1(Suppl 1):S150.
Using the Problem 1 data set made available for Genetic Analysis Workshop 15, we assessed sensitivity of linkage results to a correlation-based feature extraction method as well as to different normalization procedures applied to the raw Affymetrix gene expression microarray data. The impact of these procedures on heritability estimates and on expression quantitative trait loci are investigated. The filtering algorithm we propose in this paper ranks genes based on the total absolute correlation of each gene with all other genes on the array and has the potential to extract features that may play role in functional pathways and gene networks. Our results showed that the normalization and filtering algorithms can have a profound influence on genetic analysis of gene expression data.
PMCID: PMC2367572  PMID: 18466495
6.  Identifying cis- and trans-acting single-nucleotide polymorphisms controlling lymphocyte gene expression in humans 
BMC Proceedings  2007;1(Suppl 1):S7.
Assuming multiple loci play a role in regulating the expression level of a single phenotype, we propose a new approach to identify cis- and trans-acting loci that regulate gene expression. Using the Problem 1 data set made available for Genetic Analysis Workshop 15 (GAW15), we identified many expression phenotypes that have significant evidence of association and linkage to one or more chromosomal regions. In particular, six of ten phenotypes that we found to be regulated by cis- and trans-acting loci were also mapped by a previous analysis of these data in which a total of 27 phenotypes were identified with expression levels regulated by cis-acting determinants. However, in general, the p-values associated with these regulators identified in our study were larger than in their studies, since we had also identified other factors regulating expression. In fact, we found that most of the gene expression phenotypes are influenced by at least one trans-acting locus. Our study also shows that much of the observable heritability in the phenotypes could be explained by simple single-nucleotide polymorphism associations; residual heritability was reduced and the remaining heritability may represent complex regulation systems with interactions or noise.
PMCID: PMC2367558  PMID: 18466571
7.  Evidence of linkage to chromosome 1 for early age of onset of rheumatoid arthritis and HLA marker DRB1 genotype in NARAC data 
BMC Proceedings  2007;1(Suppl 1):S78.
Focusing on chromosome 1, a recursive partitioning linkage algorithm (RP) was applied to perform linkage analysis on the rheumatoid arthritis NARAC data, incorporating covariates such as HLA-DRB1 genotype, age at onset, severity, anti-cyclic citrullinated peptide (anti-CCP), and life time smoking. All 617 affected sib pairs from the ascertained families were used, and an RP linkage model was used to identify linkage possibly influenced by covariates. This algorithm includes a likelihood ratio (LR)-based splitting rule, a pruning algorithm to identify optimal tree size, and a bootstrap method for final tree selection.
The strength of the linkage signals was evaluated by empirical p-values, obtained by simulating marker data under null hypothesis of no linkage. Two suggestive linkage regions on chromosome 1 were detected by the RP linkage model, with identified associated covariates HLA-DRB1 genotype and age at onset. These results suggest possible gene × gene and gene × environment interactions at chromosome 1 loci and provide directions for further gene mapping.
PMCID: PMC2367509  PMID: 18466580
8.  Sex, age and generation effects on genome-wide linkage analysis of gene expression in transformed lymphoblasts 
BMC Proceedings  2007;1(Suppl 1):S92.
Many traits differ by age and sex in humans, but genetic analysis of gene expression has typically not included them in the analysis.
We used Genetic Analysis Workshop 15 Problem 1 data to determine whether gene expression in lymphoblasts showed differences by age and/or sex using generalized estimating equations (GEE). We performed quantitative trait linkage analysis of these genes including age and sex as covariates to determine whether the linkage results changed when they were included as covariates. Because the families included in the study all contain three generations, we also determined what effect inclusion of generation in the model had on the age effects.
When controlling the false-discovery rate at 1%, using GEE we identified 30 transcripts that showed significant differences in expression by sex, while 1950 transcripts showed differences in expression associated with age. When subjected to linkage analysis, there were 37 linkages that disappeared, while 17 appeared when sex was included as a covariate. All these genes were, as expected, on the sex chromosomes. In contrast, when age was included in the linkage analysis, 462 linkage signals were no longer significant, while 223 became significant. When generation was included in the model with age, all but 6 of the GEE age effects were no longer significant. However, there were minimal changes in the linkage results.
The effect of age on linkage analyses was apparent for the expression of many genes, which appear to be mostly due to differences between the generations.
PMCID: PMC2367486  PMID: 18466596

Results 1-8 (8)