BACKGROUND: Gene set analysis aims to identify gene sets containing differentially expressed genes between two different experimental conditions. A representative example of gene sets is a gene regulatory network where multiple genes are linked with each other for regulation of gene expression. Most of statistical methods for gene set analysis were designed to capture group-based association signals, ignoring a genetic network structure. Consequently, they often fail to identify gene sets where the number of differentially expressed genes are only a few and they have sparse association signals. RESULTS: We propose a new computational method to utilize prior network knowledge for gene set analysis. The proposed method is essentially combines the coefficient estimates of network-based regularization into overlapping group lasso. Network-based regularization can boost association signals among linked genes while overlapping group lasso performs selection of gene sets including differentially expressed genes. In our extensive simulation study, the performance of the proposed method has been evaluated, compared with the existing methods. We also applied it to gene expression data of The Cancer Genome Atlas Breast Invasive Carcinoma Collection (TCGA-BRCA). We were able to identify cancer-related pathways that were missed by the existing methods. CONCLUSION: Overlapping group lasso is a regularization method for group selection allowing overlapping variables. Network-based regularization is a variable selection method utilizing graph information among variables. The proposed weighted overlapping group lasso (wOGL) adopts the coefficient estimates of network-based regularization for the weight of overlapping group lasso. Consequently, it can identify gene sets containing differentially expressed genes, utilizing prior network knowledge.

BACKGROUND: Identification of pleiotropic variants associated with multiple phenotypic traits has received increasing attention in genetic association studies. Overlapping genetic associations from multiple traits help to detect weak genetic associations missed by single-trait analyses. Many statistical methods were developed to identify pleiotropic variants with most of them being limited to quantitative traits when pleiotropic effects on both quantitative and qualitative traits have been observed. This is a statistically challenging problem because there does not exist an appropriate multivariate distribution to model both quantitative and qualitative data together. Alternatively, meta-analysis methods can be applied, which basically integrate summary statistics of individual variants associated with either a quantitative or a qualitative trait without accounting for correlations among genetic variants. RESULTS: We propose a new statistical selection method based on a unified selection score quantifying how a genetic variant, i.e., a pleiotropic variant associates with both quantitative and qualitative traits. In our extensive simulation studies where various types of pleiotropic effects on both quantitative and qualitative traits were considered, we demonstrated that the proposed method outperforms the existing meta-analysis methods in terms of true positive selection. We also applied the proposed method to a peanut dataset with 6 quantitative and 2 qualitative traits, and a cowpea dataset with 2 quantitative and 6 qualitative traits. We were able to detect some potentially pleiotropic variants missed by the existing methods in both analyses. CONCLUSIONS: The proposed method is able to locate pleiotropic variants associated with both quantitative and qualitative traits. It has been implemented into an R package 'UNISS', which can be downloaded from http://github.com/statpng/uniss.

BACKGROUND: In human genetic association studies with high-dimensional gene expression data, it has been well known that statistical selection methods utilizing prior biological network knowledge such as genetic pathways and signaling pathways can outperform other methods that ignore genetic network structures in terms of true positive selection. In recent epigenetic research on case-control association studies, relatively many statistical methods have been proposed to identify cancer-related CpG sites and their corresponding genes from high-dimensional DNA methylation array data. However, most of existing methods are not designed to utilize genetic network information although methylation levels between linked genes in the genetic networks tend to be highly correlated with each other. RESULTS: We propose new approach that combines data dimension reduction techniques with network-based regularization to identify outcome-related genes for analysis of high-dimensional DNA methylation data. In simulation studies, we demonstrated that the proposed approach overwhelms other statistical methods that do not utilize genetic network information in terms of true positive selection. We also applied it to the 450K DNA methylation array data of the four breast invasive carcinoma cancer subtypes from The Cancer Genome Atlas (TCGA) project. CONCLUSIONS: The proposed variable selection approach can utilize prior biological network information for analysis of high-dimensional DNA methylation array data. It first captures gene level signals from multiple CpG sites using data a dimension reduction technique and then performs network-based regularization based on biological network graph information. It can select potentially cancer-related genes and genetic pathways that were missed by the existing methods.

MOTIVATION: DNA methylation plays an important role in many biological processes and cancer progression. Recent studies have found that there are also differences in methylation variations in different groups other than differences in methylation means. Several methods have been developed that consider both mean and variance signals in order to improve statistical power of detecting differentially methylated loci. Moreover, as methylation levels of neighboring CpG sites are known to be strongly correlated, methods that incorporate correlations have also been developed. We previously developed a network-based penalized logistic regression for correlated methylation data, but only focusing on mean signals. We have also developed a generalized exponential tilt model that captures both mean and variance signals but only examining one CpG site at a time. RESULTS: In this article, we proposed a penalized Exponential Tilt Model (pETM) using network-based regularization that captures both mean and variance signals in DNA methylation data and takes into account the correlations among nearby CpG sites. By combining the strength of the two models we previously developed, we demonstrated the superior power and better performance of the pETM method through simulations and the applications to the 450K DNA methylation array data of the four breast invasive carcinoma cancer subtypes from The Cancer Genome Atlas (TCGA) project. The developed pETM method identifies many cancer-related methylation loci that were missed by our previously developed method that considers correlations among nearby methylation loci but not variance signals. AVAILABILITY AND IMPLEMENTATION: The R package 'pETM' is publicly available through CRAN: http://cran.r-project.org . CONTACT: [email protected]. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Existing association methods for rare variants from sequencing data have focused on aggregating variants in a gene or a genetic region because of the fact that analysing individual rare variants is underpowered. However, these existing rare variant detection methods are not able to identify which rare variants in a gene or a genetic region of all variants are associated with the complex diseases or traits. Once phenotypic associations of a gene or a genetic region are identified, the natural next step in the association study with sequencing data is to locate the susceptible rare variants within the gene or the genetic region. RESULTS: In this article, we propose a power set-based statistical selection procedure that is able to identify the locations of the potentially susceptible rare variants within a disease-related gene or a genetic region. The selection performance of the proposed selection procedure was evaluated through simulation studies, where we demonstrated the feasibility and superior power over several comparable existing methods. In particular, the proposed method is able to handle the mixed effects when both risk and protective variants are present in a gene or a genetic region. The proposed selection procedure was also applied to the sequence data on the ANGPTL gene family from the Dallas Heart Study to identify potentially susceptible rare variants within the trait-related genes. AVAILABILITY AND IMPLEMENTATION: An R package 'rvsel' can be downloaded from http://www.columbia.edu/∼sw2206/ and http://statsun.pusan.ac.kr.

MOTIVATION: DNA methylation is a molecular modification of DNA that plays crucial roles in regulation of gene expression. Particularly, CpG rich regions are frequently hypermethylated in cancer tissues, but not methylated in normal tissues. However, there are not many methodological literatures of case-control association studies for high-dimensional DNA methylation data, compared with those of microarray gene expression. One key feature of DNA methylation data is a grouped structure among CpG sites from a gene that are possibly highly correlated. In this article, we proposed a penalized logistic regression model for correlated DNA methylation CpG sites within genes from high-dimensional array data. Our regularization procedure is based on a combination of the l(1) penalty and squared l(2) penalty on degree-scaled differences of coefficients of CpG sites within one gene, so it induces both sparsity and smoothness with respect to the correlated regression coefficients. We combined the penalized procedure with a stability selection procedure such that a selection probability of each regression coefficient was provided which helps us make a stable and confident selection of methylation CpG sites that are possibly truly associated with the outcome. RESULTS: Using simulation studies we demonstrated that the proposed procedure outperforms existing main-stream regularization methods such as lasso and elastic-net when data is correlated within a group. We also applied our method to identify important CpG sites and corresponding genes for ovarian cancer from over 20 000 CpGs generated from Illumina Infinium HumanMethylation27K Beadchip. Some genes identified are potentially associated with cancers.