Dataset Information

Penalized logistic regression for high-dimensional DNA methylation data with case-control studies.

ABSTRACT:

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.

SUBMITTER: Sun H

PROVIDER: S-EPMC3348559 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Publications

Penalized logistic regression for high-dimensional DNA methylation data with case-control studies.

Sun Hokeun H Wang Shuang S

Bioinformatics (Oxford, England) 20120330 10

<h4>Motivation</h4>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 amon ...[more]

PMID: 22467913

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Project description:BackgroundThere is a growing awareness that interaction between multiple genes play an important role in the risk of common, complex multi-factorial diseases. Many common diseases are affected by certain genotype combinations (associated with some genes and their interactions). The identification and characterization of these susceptibility genes and gene-gene interaction have been limited by small sample size and large number of potential interactions between genes. Several methods have been proposed to detect gene-gene interaction in a case control study. The penalized logistic regression (PLR), a variant of logistic regression with L2 regularization, is a parametric approach to detect gene-gene interaction. On the other hand, the Multifactor Dimensionality Reduction (MDR) is a nonparametric and genetic model-free approach to detect genotype combinations associated with disease risk.MethodsWe compared the power of MDR and PLR for detecting two-way and three-way interactions in a case-control study through extensive simulations. We generated several interaction models with different magnitudes of interaction effect. For each model, we simulated 100 datasets, each with 200 cases and 200 controls and 20 SNPs. We considered a wide variety of models such as models with just main effects, models with only interaction effects or models with both main and interaction effects. We also compared the performance of MDR and PLR to detect gene-gene interaction associated with acute rejection(AR) in kidney transplant patients.ResultsIn this paper, we have studied the power of MDR and PLR for detecting gene-gene interaction in a case-control study through extensive simulation. We have compared their performances for different two-way and three-way interaction models. We have studied the effect of different allele frequencies on these methods. We have also implemented their performance on a real dataset. As expected, none of these methods were consistently better for all data scenarios, but, generally MDR outperformed PLR for more complex models. The ROC analysis on the real dataset suggests that MDR outperforms PLR in detecting gene-gene interaction on the real dataset.ConclusionAs one might expect, the relative success of each method is context dependent. This study demonstrates the strengths and weaknesses of the methods to detect gene-gene interaction.

Project description:BACKGROUND:Using high-dimensional penalized regression we studied genome-wide DNA-methylation in bone biopsies of 80 postmenopausal women in relation to their bone mineral density (BMD). The women showed BMD varying from severely osteoporotic to normal. Global gene expression data from the same individuals was available, and since DNA-methylation often affects gene expression, the overall aim of this paper was to include both of these omics data sets into an integrated analysis. METHODS:The classical penalized regression uses one penalty, but we incorporated individual penalties for each of the DNA-methylation sites. These individual penalties were guided by the strength of association between DNA-methylations and gene transcript levels. DNA-methylations that were highly associated to one or more transcripts got lower penalties and were therefore favored compared to DNA-methylations showing less association to expression. Because of the complex pathways and interactions among genes, we investigated both the association between DNA-methylations and their corresponding cis gene, as well as the association between DNA-methylations and trans-located genes. Two integrating penalized methods were used: first, an adaptive group-regularized ridge regression, and secondly, variable selection was performed through a modified version of the weighted lasso. RESULTS:When information from gene expressions was integrated, predictive performance was considerably improved, in terms of predictive mean square error, compared to classical penalized regression without data integration. We found a 14.7% improvement in the ridge regression case and a 17% improvement for the lasso case. Our version of the weighted lasso with data integration found a list of 22 interesting methylation sites. Several corresponded to genes that are known to be important in bone formation. Using BMD as response and these 22 methylation sites as covariates, least square regression analyses resulted in R2=0.726, comparable to an average R2=0.438 for 10000 randomly selected groups of DNA-methylations with group size 22. CONCLUSIONS:Two recent types of penalized regression methods were adapted to integrate DNA-methylation and their association to gene expression in the analysis of bone mineral density. In both cases predictions clearly benefit from including the additional information on gene expressions.

Dataset Information

Penalized logistic regression for high-dimensional DNA methylation data with case-control studies.

Motivation

Results

Publications

Penalized logistic regression for high-dimensional DNA methylation data with case-control studies.

Similar Datasets

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