TiMEG: an integrative statistical method for partially missing multi-omics data.
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ABSTRACT:
SUBMITTER: Das S
PROVIDER: S-EPMC8674330 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Abstract Unravelling the regulatory programs from single-cell multi-omics data has long been one of the major challenges in genomics, especially in the current emerging single-cell field. Currently there is a huge gap between fast-growing single-cell multi-omics data and effective methods for the integrative analysis of these inherent sparse and heterogeneous data. In this study, we have developed a novel method, Single-cell Multi-omics Gene co-Regulatory algorithm (SMGR), to detect coherent functional regulatory signals and target genes from the joint single-cell RNA-sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) data obtained from different samples. Given that scRNA-seq and scATAC-seq data can be captured by zero-inflated Negative Binomial distribution, we utilize a generalized linear regression model to identify the latent representation of consistently expressed genes and peaks, thus enables the identification of co-regulatory programs and the elucidation of regulating mechanisms. Results from both simulation and experimental data demonstrate that SMGR outperforms the existing methods with considerably improved accuracy. To illustrate the biological insights of SMGR, we apply SMGR to mixed-phenotype acute leukemia (MPAL) and identify the MPAL-specific regulatory program with significant peak-gene links, which greatly enhance our understanding of the regulatory mechanisms and potential targets of this complex tumor.
| S-EPMC9326599 | biostudies-literature
Project description:MotivationIt is more and more common to perform multi-omics analyses to explore the genome at diverse levels and not only at a single level. Through integrative statistical methods, multi-omics data have the power to reveal new biological processes, potential biomarkers and subgroups in a cohort. Matrix factorization (MF) is an unsupervised statistical method that allows a clustering of individuals, but also reveals relevant omics variables from the various blocks.ResultsHere, we present PIntMF (Penalized Integrative Matrix Factorization), an MF model with sparsity, positivity and equality constraints. To induce sparsity in the model, we used a classical Lasso penalization on variable and individual matrices. For the matrix of samples, sparsity helps in the clustering, while normalization (matching an equality constraint) of inferred coefficients is added to improve interpretation. Moreover, we added an automatic tuning of the sparsity parameters using the famous glmnet package. We also proposed three criteria to help the user to choose the number of latent variables. PIntMF was compared with other state-of-the-art integrative methods including feature selection techniques in both synthetic and real data. PIntMF succeeds in finding relevant clusters as well as variables in two types of simulated data (correlated and uncorrelated). Next, PIntMF was applied to two real datasets (Diet and cancer), and it revealed interpretable clusters linked to available clinical data. Our method outperforms the existing ones on two criteria (clustering and variable selection). We show that PIntMF is an easy, fast and powerful tool to extract patterns and cluster samples from multi-omics data.Availability and implementationAn R package is available at https://github.com/mpierrejean/pintmf.Supplementary informationSupplementary data are available at Bioinformatics online.
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Project description:BackgroundData errors, including sample swapping and mis-labeling, are inevitable in the process of large-scale omics data generation. Data errors need to be identified and corrected before integrative data analyses where different types of data are merged on the basis of the annotated labels. Data with labeling errors dampen true biological signals. More importantly, data analysis with sample errors could lead to wrong scientific conclusions. We developed a robust probabilistic multi-omics data matching procedure, proMODMatcher, to curate data and identify and correct data annotation and errors in large databases.ResultsApplication to simulated datasets suggests that proMODMatcher achieved robust statistical power even when the number of cis-associations was small and/or the number of samples was large. Application of our proMODMatcher to multi-omics datasets in The Cancer Genome Atlas and International Cancer Genome Consortium identified sample errors in multiple cancer datasets. Our procedure was not only able to identify sample-labeling errors but also to unambiguously identify the source of the errors. Our results demonstrate that these errors should be identified and corrected before integrative analysis.ConclusionsOur results indicate that sample-labeling errors were common in large multi-omics datasets. These errors should be corrected before integrative analysis.
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Project description:Pathways are composed of proteins forming a network to represent specific biological mechanisms and are often used to measure enrichment scores based on a list of genes in means to measure their biological activity. The pathway analysis is a de facto standard downstream analysis procedure in most genomic and transcriptomic studies. Here, we present MOPA (Multi-Omics Pathway Analysis), which is a multi-omics integrative method that scores individual pathways in a sample wise manner in terms of enriched multi-omics regulatory activity, which we refer to mES (multi-omics Enrichment Score). The mES score reflects the strength of regulatory relations between multi-omics in units of pathways. In addition, MOPA is able to measure how much each omics contribute to mES that may be used to observe what kind of omics are active in a pathway within a sample group (e.g., subtype, gender), which we refer to OCR (Omics Contribution Rate). Using nine different cancer types, 93 clinical features and three types of omics (i.e., gene expression, miRNA and methylation), MOPA was used to search for clinical features that were explainable in context of multi-omics. By evaluating the performance of MOPA, we showed that it yielded higher or at least equal performance compared to previous single and multi-omics pathway analysis tools. We find that the advantage of MOPA is the ability to explain pathways in terms of omics relation using mES and OCR. As one of the results, the TGF-beta signaling pathway was captured as an important pathway that showed distinct mES and OCR values specific to the CMS4 subtype in colon adenocarcinoma. The mES and OCR metrics suggested that the mRNA and miRNA expressions were significantly different from the other subtypes, which was concordant with previous studies. The MOPA software is available at https://github.com/jaeminjj/MOPA.
| S-EPMC10019735 | biostudies-literature
Project description:MotivationIntegrative analysis of multi-omics data from different high-throughput experimental platforms provides valuable insight into regulatory mechanisms associated with complex diseases, and gains statistical power to detect markers that are otherwise overlooked by single-platform omics analysis. In practice, a significant portion of samples may not be measured completely due to insufficient tissues or restricted budget (e.g. gene expression profile are measured but not methylation). Current multi-omics integrative methods require complete data. A common practice is to ignore samples with any missing platform and perform complete case analysis, which leads to substantial loss of statistical power.MethodsIn this article, inspired by the popular Integrative Bayesian Analysis of Genomics data (iBAG), we propose a full Bayesian model that allows incorporation of samples with missing omics data.ResultsSimulation results show improvement of the new full Bayesian approach in terms of outcome prediction accuracy and feature selection performance when sample size is limited and proportion of missingness is large. When sample size is large or the proportion of missingness is low, incorporating samples with missingness may introduce extra inference uncertainty and generate worse prediction and feature selection performance. To determine whether and how to incorporate samples with missingness, we propose a self-learning cross-validation (CV) decision scheme. Simulations and a real application on child asthma dataset demonstrate superior performance of the CV decision scheme when various types of missing mechanisms are evaluated.Availability and implementationFreely available on the GitHub at https://github.com/CHPGenetics/FBM.Supplementary informationSupplementary data are available at Bioinformatics online.
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Project description:Errors in sample annotation or labeling often occur in large-scale genetic or genomic studies and are difficult to avoid completely during data generation and management. For integrative genomic studies, it is critical to identify and correct these errors. Different types of genetic and genomic data are inter-connected by cis-regulations. On that basis, we developed a computational approach, Multi-Omics Data Matcher (MODMatcher), to identify and correct sample labeling errors in multiple types of molecular data, which can be used in further integrative analysis. Our results indicate that inspection of sample annotation and labeling error is an indispensable data quality assurance step. Applied to a large lung genomic study, MODMatcher increased statistically significant genetic associations and genomic correlations by more than two-fold. In a simulation study, MODMatcher provided more robust results by using three types of omics data than two types of omics data. We further demonstrate that MODMatcher can be broadly applied to large genomic data sets containing multiple types of omics data, such as The Cancer Genome Atlas (TCGA) data sets.
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Project description:The integrative personal omics profile (iPOP) is a pioneering study that combines genomics, transcriptomics, proteomics, metabolomics and autoantibody profiles from a single individual over a 14-month period. The observation period includes two episodes of viral infection: a human rhinovirus and a respiratory syncytial virus. The profile studies give an informative snapshot into the biological functioning of an organism. We hypothesize that pathway expression levels are associated with disease status. To test this hypothesis, we use biological pathways to integrate metabolomics and proteomics iPOP data. The approach computes the pathways' differential expression levels at each time point, while taking into account the pathway structure and the longitudinal design. The resulting pathway levels show strong association with the disease status. Further, we identify temporal patterns in metabolite expression levels. The changes in metabolite expression levels also appear to be consistent with the disease status. The results of the integrative analysis suggest that changes in biological pathways may be used to predict and monitor the disease. The iPOP experimental design, data acquisition and analysis issues are discussed within the broader context of personal profiling.
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Project description:A key problem in systems biology is the discovery of regulatory mechanisms that drive phenotypic behaviour of complex biological systems in the form of multi-level networks. Modern multi-omics profiling techniques probe these fundamental regulatory networks but are often hampered by experimental restrictions leading to missing data or partially measured omics types for subsets of individuals due to cost restrictions. In such scenarios, in which missing data is present, classical computational approaches to infer regulatory networks are limited. In recent years, approaches have been proposed to infer sparse regression models in the presence of missing information. Nevertheless, these methods have not been adopted for regulatory network inference yet. In this study, we integrated regression-based methods that can handle missingness into KiMONo, a Knowledge guided Multi-Omics Network inference approach, and benchmarked their performance on commonly encountered missing data scenarios in single- and multi-omics studies. Overall, two-step approaches that explicitly handle missingness performed best for a wide range of random- and block-missingness scenarios on imbalanced omics-layers dimensions, while methods implicitly handling missingness performed best on balanced omics-layers dimensions. Our results show that robust multi-omics network inference in the presence of missing data with KiMONo is feasible and thus allows users to leverage available multi-omics data to its full extent.
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Project description:Private and public breeding programs, as well as companies and universities, have developed different genomics technologies that have resulted in the generation of unprecedented amounts of sequence data, which bring new challenges in terms of data management, query, and analysis. The magnitude and complexity of these datasets bring new challenges but also an opportunity to use the data available as a whole. Detailed phenotype data, combined with increasing amounts of genomic data, have an enormous potential to accelerate the identification of key traits to improve our understanding of quantitative genetics. Data harmonization enables cross-national and international comparative research, facilitating the extraction of new scientific knowledge. In this paper, we address the complex issue of combining high dimensional and unbalanced omics data. More specifically, we propose a covariance-based method for combining partial datasets in the genotype to phenotype spectrum. This method can be used to combine partially overlapping relationship/covariance matrices. Here, we show with applications that our approach might be advantageous to feature imputation based approaches; we demonstrate how this method can be used in genomic prediction using heterogeneous marker data and also how to combine the data from multiple phenotypic experiments to make inferences about previously unobserved trait relationships. Our results demonstrate that it is possible to harmonize datasets to improve available information across gene-banks, data repositories, or other data resources.
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Project description:Identifying personalized driver genes is essential for discovering critical biomarkers and developing effective personalized therapies of cancers. However, few methods consider weights for different types of mutations and efficiently distinguish driver genes over a larger number of passenger genes. We propose MinNetRank (Minimum used for Network-based Ranking), a new method for prioritizing cancer genes that sets weights for different types of mutations, considers the incoming and outgoing degree of interaction network simultaneously, and uses minimum strategy to integrate multi-omics data. MinNetRank prioritizes cancer genes among multi-omics data for each sample. The sample-specific rankings of genes are then integrated into a population-level ranking. When evaluating the accuracy and robustness of prioritizing driver genes, our method almost always significantly outperforms other methods in terms of precision, F1 score, and partial area under the curve (AUC) on six cancer datasets. Importantly, MinNetRank is efficient in discovering novel driver genes. SP1 is selected as a candidate driver gene only by our method (ranked top three), and SP1 RNA and protein differential expression between tumor and normal samples are statistically significant in liver hepatocellular carcinoma. The top seven genes stratify patients into two subtypes exhibiting statistically significant survival differences in five cancer types. These top seven genes are associated with overall survival, as illustrated by previous researchers. MinNetRank can be very useful for identifying cancer driver genes, and these biologically relevant marker genes are associated with clinical outcome. The R package of MinNetRank is available at https://github.com/weitinging/MinNetRank.
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