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1.  Testing gene-environment interactions in gene-based association studies 
BMC Proceedings  2011;5(Suppl 9):S26.
Gene-based and single-nucleotide polymorphism (SNP) set association studies provide an important complement to SNP analysis. Kernel-based nonparametric regression has recently emerged as a powerful and flexible tool for this purpose. Our goal is to explore whether this approach can be extended to incorporate and test for interaction effects, especially for genes containing rare variant SNPs. Here, we construct nonparametric regression models that can be used to include a gene-environment interaction effect under the framework of the least-squares kernel machine and examine the performance of the proposed method on the Genetic Analysis Workshop 17 unrelated individuals data set. Two hundred simulated replicates were used to explore the power for detecting interaction. We demonstrate through a genome scan of the quantitative phenotype Q1 that the simulated gene-environment interaction effect in the data can be detected with reasonable power by using the least-squares kernel machine method.
doi:10.1186/1753-6561-5-S9-S26
PMCID: PMC3287861  PMID: 22373316
2.  Comparison of univariate and multivariate linkage analysis of traits related to hypertension 
BMC Proceedings  2009;3(Suppl 7):S99.
Complex traits are often manifested by multiple correlated traits. One example of this is hypertension (HTN), which is measured on a continuous scale by systolic blood pressure (SBP). Predisposition to HTN is predicted by hyperlipidemia, characterized by elevated triglycerides (TG), low-density lipids (LDL), and high-density lipids (HDL). We hypothesized that the multivariate analysis of TG, LDL, and HDL would be more powerful for detecting HTN genes via linkage analysis compared with univariate analysis of SBP. We conducted linkage analysis of four chromosomal regions known to contain genes associated with HTN using SBP as a measure of HTN in univariate Haseman-Elston regression and using the correlated traits TG, LDL, and HDL in multivariate Haseman-Elston regression. All analyses were conducted using the Framingham Heart Study data. We found that multivariate linkage analysis was better able to detect chromosomal regions in which the angiotensinogen, angiotensin receptor, guanine nucleotide-binding protein 3, and prostaglandin I2 synthase genes reside. Univariate linkage analysis only detected the AGT gene. We conclude that multivariate analysis is appropriate for the analysis of multiple correlated phenotypes, and our findings suggest that it may yield new linkage signals undetected by univariate analysis.
PMCID: PMC2796003  PMID: 20018096
3.  Mendelian randomization in family data 
BMC Proceedings  2009;3(Suppl 7):S45.
The phrase "mendelian randomization" has become associated with the use of genetic polymorphisms to uncover causal relationships between phenotypic variables. The statistical methods useful in mendelian randomization are known as instrumental variable techniques. We present an approach to instrumental variable estimation that is useful in family data and is robust to the use of weak instruments. We illustrate our method to measure the causal influence of low-density lipoprotein on high-density lipoprotein, body mass index, triglycerides, and systolic blood pressure. We use the Framingham Heart Study data as distributed to participants in the Genetics Analysis Workshop 16.
PMCID: PMC2795944  PMID: 20018037
4.  Comparison of affected sibling-pair linkage methods to identify gene × gene interaction in GAW15 simulated data 
BMC Proceedings  2007;1(Suppl 1):S66.
Non-parametric linkage methods have had limited success in detecting gene by gene interactions. Using affected sibling-pair (ASP) data from all replicates of the simulated data from Problem 3, we assessed the statistical power of three approaches to identify the gene × gene interaction between two loci on different chromosomes. The first method conditioned on linkage at the primary disease susceptibility locus (DR), to find linkage to a simulated effect modifier at Locus A with a mean allele sharing test. The second approach used a regression-based mean test to identify either the presence of interaction between the two loci or linkage to the A locus in the presence of linkage to DR. The third method applied a conditional logistic model designed to test for the presence of interacting loci. The first approach had decreased power over an unconditional linkage analysis, supporting the idea that gene × gene interaction cannot be detected with ASP data. The regression-based mean test and the conditional logistic model had the lowest power to detect gene × gene interaction, possibly because of the complex recoding of the tri-allelic DR locus for use as a covariate. We conclude that the ASP approaches tested have low power to successfully identify the interaction between the DR and A loci despite the large sample size, which may be due to the low prevalence of the high-risk DR genotypes. Additionally, the lack of data on discordant sibships may have decreased the power to identify gene × gene interactions.
PMCID: PMC2367530  PMID: 18466567
5.  Modeling the complex gene × environment interplay in the simulated rheumatoid arthritis GAW15 data using latent variable structural equation modeling 
BMC Proceedings  2007;1(Suppl 1):S118.
Rheumatoid arthritis is a complex disease that appears to involve multiple genetic and environmental factors. Using the Genetic Analysis Workshop 15 simulated rheumatoid arthritis data and the structural equation modeling framework, we tested hypothesized "causal" rheumatoid arthritis model(s) by employing a novel latent gene construct approach that models individual genes as latent variables defined by multiple dense and non-dense single-nucleotide polymorphisms (SNPs). Our approach produced valid latent gene constructs, particularly with dense SNPs, which when coupled with other factors involved in rheumatoid arthritis, were able to generate good fitting models by certain goodness of fit indices. We observed that Gene F, C, DR, sex and smoking were significant predictors of rheumatoid arthritis but Genes A and E were not, which was generally, but not entirely, consistent with how the data were simulated. Our approach holds promise in unravelling complex diseases and improves upon current "one SNP (haplotype)-at-a-time" regression approaches by decreasing the number of statistical tests while minimizing problems with multicolinearity and haplotype estimation algorithm error. Furthermore, when genes are modeled as latent constructs simultaneously with other key cofactors, the approach provides enhanced control of confounding that should lead to less biased effect estimates among genes as well as between gene(s) and the complex disease. However, further study is needed to quantify bias, evaluate fit index disparity, and resolve multiplicative latent gene interactions. Moreover, because some a priori biological information is needed to form an initial substantive model, our approach may be most appropriate for candidate gene SNP panel applications.
PMCID: PMC2367478  PMID: 18466459

Results 1-5 (5)