A Similarity Regression Fusion Model for Integrating Multi-Omics Data to Identify Cancer Subtypes.
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ABSTRACT:
SUBMITTER: Guo Y
PROVIDER: S-EPMC6070922 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Stroke ranks the second leading cause of death among people over the age of 60 in the world. Stroke is widely regarded as a complex disease that is affected by genetic and environmental factors. Evidence from twin and family studies suggests that genetic factors may play an important role in its pathogenesis. Therefore, research on the genetic association of susceptibility genes can help understand the mechanism of stroke. Genome-wide association study (GWAS) has found a large number of stroke-related loci, but their mechanism is unknown. In order to explore the function of single-nucleotide polymorphisms (SNPs) at the molecular level, in this paper, we integrated 8 GWAS datasets with brain expression quantitative trait loci (eQTL) dataset to identify SNPs and genes which are related to four types of stroke (ischemic stroke, large artery stroke, cardioembolic stroke, small vessel stroke). Thirty-eight SNPs which can affect 14 genes expression are found to be associated with stroke. Among these 14 genes, 10 genes expression are associated with ischemic stroke, one gene for large artery stroke, six genes for cardioembolic stroke and eight genes for small vessel stroke. To explore the effects of environmental factors on stroke, we identified methylation susceptibility loci associated with stroke using methylation quantitative trait loci (MQTL). Thirty-one of these 38 SNPs are at greater risk of methylation and can significantly change gene expression level. Overall, the genetic pathogenesis of stroke is explored from locus to gene, gene to gene expression and gene expression to phenotype.
| S-EPMC6993083 | biostudies-literature
Project description:BackgroundThe problem of assessing associations between multiple omics data including genomics and metabolomics data to identify biomarkers potentially predictive of complex diseases has garnered considerable research interest nowadays. A popular epidemiology approach is to consider an association of each of the predictors with each of the response using a univariate linear regression model, and to select predictors that meet a priori specified significance level. Although this approach is simple and intuitive, it tends to require larger sample size which is costly. It also assumes variables for each data type are independent, and thus ignores correlations that exist between variables both within each data type and across the data types.ResultsWe consider a multivariate linear regression model that relates multiple predictors with multiple responses, and to identify multiple relevant predictors that are simultaneously associated with the responses. We assume the coefficient matrix of the responses on the predictors is both row-sparse and of low-rank, and propose a group Dantzig type formulation to estimate the coefficient matrix.ConclusionExtensive simulations demonstrate the competitive performance of our proposed method when compared to existing methods in terms of estimation, prediction, and variable selection. We use the proposed method to integrate genomics and metabolomics data to identify genetic variants that are potentially predictive of atherosclerosis cardiovascular disease (ASCVD) beyond well-established risk factors. Our analysis shows some genetic variants that increase prediction of ASCVD beyond some well-established factors of ASCVD, and also suggest a potential utility of the identified genetic variants in explaining possible association between certain metabolites and ASCVD.
| S-EPMC7333421 | biostudies-literature
Project description:With recent advances in technologies to profile multi-omics data at the single-cell level, integrative multi-omics data analysis has been increasingly popular. It is increasingly common that information such as methylation changes, chromatin accessibility, and gene expression are jointly collected in a single-cell experiment. In biomedical studies, it is often of interest to study the associations between various data types and to examine how these associations might change according to other factors such as cell types and gene regulatory components. However, since each data type usually has a distinct marginal distribution, joint analysis of these changes of associations using multi-omics data is statistically challenging. In this paper, we propose a flexible copula-based framework to model covariate-dependent correlation structures independent of their marginals. In addition, the proposed approach could jointly combine a wide variety of univariate marginal distributions, either discrete or continuous, including the class of zero-inflated distributions. The performance of the proposed framework is demonstrated through a series of simulation studies. Finally, it is applied to a set of experimental data to investigate the dynamic relationship between single-cell RNA sequencing, chromatin accessibility, and DNA methylation at different germ layers during mouse gastrulation.
| S-EPMC9701244 | biostudies-literature
Project description:Heart failure with preserved ejection fraction (HFpEF) is associated with multiple etiologic and pathophysiologic factors. HFpEF leads to significant cardiovascular morbidity and mortality. There are various reasons that fail to identify effective therapeutic interventions for HFpEF, primarily due to its clinical heterogeneity causing significant difficulties in determining physiologic and prognostic implications for this syndrome. Thus, identifying clinical subtypes using multi-omics data has great implications for efficient treatment and prognosis of HFpEF patients. Here we proposed to integrate mRNA, DNA methylation and microRNA (miRNA) expression data of HFpEF with a similarity network fusion (SNF) method following a network enhancement (ne-SNF) denoising technique to form a fused network. A spectral clustering method was then used to obtain clusters of patient subtypes. Experiments on HFpEF datasets demonstrated that ne-SNF significantly outperforms single data subtype analysis and other integrated methods. The identified subgroups were shown to have statistically significant differences in survival. Two HFpEF subtypes were defined: a high-risk group (16.8%) and a low-risk group (83.2%). The 5-year mortality rates were 63.3% and 33.0% for the high- and low-risk group, respectively. After adjusting for the effects of clinical covariates, HFpEF patients in the high-risk group were 2.43 times more likely to die than the low-risk group. A total of 157 differentially expressed (DE) mRNAs, 2199 abnormal methylations and 121 DE miRNAs were identified between two subtypes. They were also enriched in many HFpEF-related biological processes or pathways. The ne-SNF method provides a novel pipeline for subtype identification in integrated analysis of multi-omics data.
| S-EPMC8039555 | biostudies-literature
Project description:Optimizing feed efficiency through the feed conversion ratio (FCR) is paramount for economic viability and sustainability. In this study, we integrated RNA-seq, ATAC-seq, and genome-wide association study (GWAS) data to investigate key functional variants associated with feed efficiency in pigs. Identification of differentially expressed genes in the duodenal and muscle tissues of low- and high-FCR pigs revealed that pathways related to digestion of dietary carbohydrate are responsible for differences in feed efficiency between individuals. Differential open chromatin regions identified by ATAC-seq were linked to genes involved in glycolytic and fatty acid processes. GWAS identified 211 significant single nucleotide polymorphisms associated with feed efficiency traits, with candidate genes PPP1R14C, TH, and CTSD. Integration of duodenal ATAC-seq data and GWAS data identified six key functional variants, particularly in the 1500985–1509676 region on chromosome 2. In those regions, CTSD was found to be highly expressed in the duodenal tissues of pigs with a high feed conversion ratio, suggesting its role as a potential target gene. Overall, the integration of multi-omics data provided insights into the genetic basis of feed efficiency, offering valuable information for breeding more efficient pig breeds.
2024-09-30 | GSE270124 | GEO
Project description:Abstract Molecular subtyping of brain tissue provides insights into the heterogeneity of common neurodegenerative conditions, such as Alzheimer’s disease. However, existing subtyping studies have mostly focused on single data modalities and only those individuals with severe cognitive impairment. To address these gaps, we applied similarity network fusion, a method capable of integrating multiple high-dimensional multi-omic data modalities simultaneously, to an elderly sample spanning the full spectrum of cognitive ageing trajectories. We analyzed human frontal cortex brain samples characterized by five omic modalities: bulk RNA sequencing (18 629 genes), DNA methylation (53 932 CpG sites), histone acetylation (26 384 peaks), proteomics (7737 proteins) and metabolomics (654 metabolites). Similarity network fusion followed by spectral clustering was used for subtype detection, and subtype numbers were determined by Eigen-gap and rotation cost statistics. Normalized mutual information determined the relative contribution of each modality to the fused network. Subtypes were characterized by associations with 13 age-related neuropathologies and cognitive decline. Fusion of all five data modalities (n = 111) yielded two subtypes (nS1 = 53, nS2 = 58), which were nominally associated with diffuse amyloid plaques; however, this effect was not significant after correction for multiple testing. Histone acetylation (normalized mutual information = 0.38), DNA methylation (normalized mutual information = 0.18) and RNA abundance (normalized mutual information = 0.15) contributed most strongly to this network. Secondary analysis integrating only these three modalities in a larger subsample (n = 513) indicated support for both three- and five-subtype solutions, which had significant overlap, but showed varying degrees of internal stability and external validity. One subtype showed marked cognitive decline, which remained significant even after correcting for tests across both three- and five-subtype solutions (pBonf = 5.9 × 10−3). Comparison to single-modality subtypes demonstrated that the three-modal subtypes were able to uniquely capture cognitive variability. Comprehensive sensitivity analyses explored influences of sample size and cluster number parameters. We identified highly integrative molecular subtypes of ageing derived from multiple high dimensional, multi-omic data modalities simultaneously. Fusing RNA abundance, DNA methylation, and histone acetylation measures generated subtypes that were associated with cognitive decline. This work highlights the potential value and challenges of multi-omic integration in unsupervised subtyping of post-mortem brain. Detecting multi-omic molecular subtypes of ageing will enable Yang et al. to understand the complexity and heterogeneity of the human ageing process. By applying similarity network fusion, Yang et al. were able to integrate five data modalities simultaneously and identify molecular subtypes associated with longitudinal cognitive decline. Graphical Abstract Graphical Abstract
| S-EPMC10110975 | biostudies-literature
Project description:BackgroundMulti-omics data can provide a stereoscopic view to explore potential causal variations and genes, as well as underlying genetic mechanisms of complex traits. However, for many non-mammalian species, including chickens, these resources are poorly integrated and reused, greatly limiting genetic research and breeding processes of the species.ResultsHere, we constructed Galbase, an easily accessible repository that integrates public chicken multi-omics data from 928 re-sequenced genomes, 429 transcriptomes, 379 epigenomes, 15,275 QTL entries, and 7,526 associations. A total of 21.67 million SNPs, 2.71 million InDels, and 488,583 cis-regulatory elements were included. Galbase allows users to retrieve genomic variations in geographical maps, gene expression profiling in heatmaps, and epigenomic signals in peak patterns. It also provides modules for batch annotation of genes, regions, and loci based on multi-layered omics data. Additionally, a series of convenient tools, including the UCSC Genome Browser, WashU Epigenome Browser, BLAT, BLAST, and LiftOver, were also integrated to facilitate search, visualization, and analysis of sequence features.ConclusionGalbase grants new opportunities to research communities to undertake in-depth functional genomic studies on chicken. All features of Galbase make it a useful resource to identify genetic variations responsible for chicken complex traits. Galbase is publicly available at http://animal.nwsuaf.edu.cn/ChickenVar .
| S-EPMC9097087 | biostudies-literature
Project description:Genome-wide association studies reveal many non-coding variants associated with complex traits. However, model organism studies largely remain as an untapped resource for unveiling the effector genes of non-coding variants. We develop INFIMA, Integrative Fine-Mapping, to pinpoint causal SNPs for diversity outbred (DO) mice eQTL by integrating founder mice multi-omics data including ATAC-seq, RNA-seq, footprinting, and in silico mutation analysis. We demonstrate INFIMA's superior performance compared to alternatives with human and mouse chromatin conformation capture datasets. We apply INFIMA to identify novel effector genes for GWAS variants associated with diabetes. The results of the application are available at http://www.statlab.wisc.edu/shiny/INFIMA/ .
| S-EPMC8381555 | biostudies-literature
Project description:MotivationEpidemiologic, clinical and translational studies are increasingly generating multiplatform omics data. Methods that can integrate across multiple high-dimensional data types while accounting for differential patterns are critical for uncovering novel associations and underlying relevant subgroups.ResultsWe propose an integrative model to estimate latent unknown clusters (LUCID) aiming to both distinguish unique genomic, exposure and informative biomarkers/omic effects while jointly estimating subgroups relevant to the outcome of interest. Simulation studies indicate that we can obtain consistent estimates reflective of the true simulated values, accurately estimate subgroups and recapitulate subgroup-specific effects. We also demonstrate the use of the integrated model for future prediction of risk subgroups and phenotypes. We apply this approach to two real data applications to highlight the integration of genomic, exposure and metabolomic data.Availability and implementationThe LUCID method is implemented through the LUCIDus R package available on CRAN (https://CRAN.R-project.org/package=LUCIDus).Supplementary informationSupplementary materials are available at Bioinformatics online.
| S-EPMC7986585 | biostudies-literature
Project description:Deubiquitinating enzymes (DUBs), ~100 of which are found in human cells, are proteases that remove ubiquitin conjugates from proteins, thereby regulating protein turnover. They are involved in a wide range of cellular activities and are emerging therapeutic targets for cancer and other diseases. Drugs targeting USP1 and USP30 are in clinical development for cancer and kidney disease respectively. However, the majority of substrates and pathways regulated by DUBs remain unknown, impeding efforts to prioritize specific enzymes for research and drug development. To assemble a knowledgebase of DUB activities, co-dependent genes, and substrates, we combined targeted experiments using CRISPR libraries and inhibitors with systematic mining of functional genomic databases. Analysis of the Dependency Map, Connectivity Map, Cancer Cell Line Encyclopedia, and multiple protein-protein interaction databases yielded specific hypotheses about DUB function, a subset of which were confirmed in follow-on experiments. The data in this paper are browsable online in a newly developed DUB Portal and promise to improve understanding of DUBs as a family as well as the activities of incompletely characterized DUBs (e.g. USPL1 and USP32) and those already targeted with investigational cancer therapeutics (e.g. USP14, UCHL5, and USP7).
| S-EPMC9225015 | biostudies-literature