Dataset Information

A Hybrid Ensemble Approach for Identifying Robust Differentially Methylated Loci in Pan-Cancers.

ABSTRACT: DNA methylation is a widely investigated epigenetic mark that plays a vital role in tumorigenesis. Advancements in high-throughput assays, such as the Infinium 450K platform, provide genome-scale DNA methylation landscapes in single-CpG locus resolution, and the identification of differentially methylated loci has become an insightful approach to deepen our understanding of cancers. However, the situation with extremely unbalanced numbers of samples and loci (approximately 1:1,000) makes it rather difficult to explore differential methylation between the sick and the normal. In this article, a hybrid approach based on ensemble feature selection for identifying differentially methylated loci (HyDML) was proposed by incorporating instance perturbation and multiple function models. Experiments on data from The Cancer Genome Atlas showed that HyDML not only achieved effective DML identification, but also outperformed the single-feature selection approach in terms of classification performance and the robustness of feature selection. The intensive analysis of the DML indicated that different types of cancers have mutual patterns, and the stable DML sharing in pan-cancers is of the great potential to be biomarkers, which may strengthen the confidence of domain experts to implement biological validations.

SUBMITTER: Tian Q

PROVIDER: S-EPMC6739624 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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A Hybrid Ensemble Approach for Identifying Robust Differentially Methylated Loci in Pan-Cancers.

Tian Qi Q Zou Jianxiao J Fang Yuan Y Yu Zhongli Z Tang Jianxiong J Song Ying Y Fan Shicai S

Frontiers in genetics 20190905

DNA methylation is a widely investigated epigenetic mark that plays a vital role in tumorigenesis. Advancements in high-throughput assays, such as the Infinium 450K platform, provide genome-scale DNA methylation landscapes in single-CpG locus resolution, and the identification of differentially methylated loci has become an insightful approach to deepen our understanding of cancers. However, the situation with extremely unbalanced numbers of samples and loci (approximately 1:1,000) makes it rath ...[more]

PMID: 31543899

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Project description:BACKGROUND:DNA methylation is an epigenetic modification that is studied at a single-base resolution with bisulfite treatment followed by high-throughput sequencing. After alignment of the sequence reads to a reference genome, methylation counts are analyzed to determine genomic regions that are differentially methylated between two or more biological conditions. Even though a variety of software packages is available for different aspects of the bioinformatics analysis, they often produce results that are biased or require excessive computational requirements. RESULTS:DMRfinder is a novel computational pipeline that identifies differentially methylated regions efficiently. Following alignment, DMRfinder extracts methylation counts and performs a modified single-linkage clustering of methylation sites into genomic regions. It then compares methylation levels using beta-binomial hierarchical modeling and Wald tests. Among its innovative attributes are the analyses of novel methylation sites and methylation linkage, as well as the simultaneous statistical analysis of multiple sample groups. To demonstrate its efficiency, DMRfinder is benchmarked against other computational approaches using a large published dataset. Contrasting two replicates of the same sample yielded minimal genomic regions with DMRfinder, whereas two alternative software packages reported a substantial number of false positives. Further analyses of biological samples revealed fundamental differences between DMRfinder and another software package, despite the fact that they utilize the same underlying statistical basis. For each step, DMRfinder completed the analysis in a fraction of the time required by other software. CONCLUSIONS:Among the computational approaches for identifying differentially methylated regions from high-throughput bisulfite sequencing datasets, DMRfinder is the first that integrates all the post-alignment steps in a single package. Compared to other software, DMRfinder is extremely efficient and unbiased in this process. DMRfinder is free and open-source software, available on GitHub ( github.com/jsh58/DMRfinder ); it is written in Python and R, and is supported on Linux.

Project description:MotivationDNA methylation is a key epigenetic modification that can modulate gene expression. Over the past decade, a lot of studies have focused on profiling DNA methylation and investigating its alterations in complex diseases such as cancer. While early studies were mostly restricted to CpG islands or promoter regions, recent findings indicate that many of important DNA methylation changes can occur in other regions and DNA methylation needs to be examined on a genome-wide scale. In this article, we apply the wavelet-based functional mixed model methodology to analyze the high-throughput methylation data for identifying differentially methylated loci across the genome. Contrary to many commonly-used methods that model probes independently, this framework accommodates spatial correlations across the genome through basis function modeling as well as correlations between samples through functional random effects, which allows it to be applied to many different settings and potentially leads to more power in detection of differential methylation.ResultsWe applied this framework to three different high-dimensional methylation data sets (CpG Shore data, THREE data and NIH Roadmap Epigenomics data), studied previously in other works. A simulation study based on CpG Shore data suggested that in terms of detection of differentially methylated loci, this modeling approach using wavelets outperforms analogous approaches modeling the loci as independent. For the THREE data, the method suggests newly detected regions of differential methylation, which were not reported in the original study.Availability and implementationAutomated software called WFMM is available at https://biostatistics.mdanderson.org/SoftwareDownload CpG Shore data is available at http://rafalab.dfci.harvard.edu NIH Roadmap Epigenomics data is available at http://compbio.mit.edu/roadmapSupplementary informationSupplementary data are available at Bioinformatics online.Contactjefmorris@mdanderson.org.

Project description:Hypermethylation of promoter CpG islands is strongly correlated to transcriptional gene silencing and epigenetic maintenance of the silenced state. As well as its role in tumor development, CpG island methylation contributes to the acquisition of resistance to chemotherapy. Differential Methylation Hybridisation (DMH) is one technique used for genome-wide DNA methylation analysis. The study of such microarray data sets should ideally account for the specific biological features of DNA methylation and the non-symmetrical distribution of the ratios of unmethylated and methylated sequences hybridised on the array. We have therefore developed a novel algorithm tailored to this type of data, Methylation Linear Discriminant Analysis (MLDA).MLDA was programmed in R (version 2.7.0) and the package is available at CRAN 1. This approach utilizes linear regression models of non-normalised hybridisation data to define methylation status. Log-transformed signal intensities of unmethylated controls on the microarray are used as a reference. The signal intensities of DNA samples digested with methylation sensitive restriction enzymes and mock digested are then transformed to the likelihood of a locus being methylated using this reference. We tested the ability of MLDA to identify loci differentially methylated as analysed by DMH between cisplatin sensitive and resistant ovarian cancer cell lines. MLDA identified 115 differentially methylated loci and 23 out of 26 of these loci have been independently validated by Methylation Specific PCR and/or bisulphite pyrosequencing.MLDA has advantages for analyzing methylation data from CpG island microarrays, since there is a clear rational for the definition of methylation status, it uses DMH data without between-group normalisation and is less influenced by cross-hybridisation of loci. The MLDA algorithm successfully identified differentially methylated loci between two classes of samples analysed by DMH using CpG island microarrays.

Dataset Information

A Hybrid Ensemble Approach for Identifying Robust Differentially Methylated Loci in Pan-Cancers.

Publications

A Hybrid Ensemble Approach for Identifying Robust Differentially Methylated Loci in Pan-Cancers.

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