IntLIM: integration using linear models of metabolomics and gene expression data

Abstract

BackgroundIntegration of transcriptomic and metabolomic data improves functional interpretation of disease-related metabolomic phenotypes, and facilitates discovery of putative metabolite biomarkers and gene targets. For this reason, these data are increasingly collected in large (> 100 participants) cohorts, thereby driving a need for the development of user-friendly and open-source methods/tools for their integration. Of note, clinical/translational studies typically provide snapshot (e.g. one time point) gene and metabolite profiles and, oftentimes, most metabolites measured are not identified. Thus, in these types of studies, pathway/network approaches that take into account the complexity of transcript-metabolite relationships may neither be applicable nor readily uncover novel relationships. With this in mind, we propose a simple linear modeling approach to capture disease-(or other phenotype) specific gene-metabolite associations, with the assumption that co-regulation patterns reflect functionally related genes and metabolites.ResultsThe proposed linear model, metabolite ~ gene + phenotype + gene:phenotype, specifically evaluates whether gene-metabolite relationships differ by phenotype, by testing whether the relationship in one phenotype is significantly different from the relationship in another phenotype (via a statistical interaction gene:phenotype p-value). Statistical interaction p-values for all possible gene-metabolite pairs are computed and significant pairs are then clustered by the directionality of associations (e.g. strong positive association in one phenotype, strong negative association in another phenotype). We implemented our approach as an R package, IntLIM, which includes a user-friendly R Shiny web interface, thereby making the integrative analyses accessible to non-computational experts. We applied IntLIM to two previously published datasets, collected in the NCI-60 cancer cell lines and in human breast tumor and non-tumor tissue, for which transcriptomic and metabolomic data are available. We demonstrate that IntLIM captures relevant tumor-specific gene-metabolite associations involved in known cancer-related pathways, including glutamine metabolism. Using IntLIM, we also uncover biologically relevant novel relationships that could be further tested experimentally.ConclusionsIntLIM provides a user-friendly, reproducible framework to integrate transcriptomic and metabolomic data and help interpret metabolomic data and uncover novel gene-metabolite relationships. The IntLIM R package is publicly available in GitHub (https://github.com/mathelab/IntLIM) and includes a user-friendly web application, vignettes, sample data and data/code to reproduce results.Electronic supplementary materialThe online version of this article (10.1186/s12859-018-2085-6) contains supplementary material, which is available to authorized users.

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“…In the current study, we integrated untargeted metabolomic and transcriptomic data. We used a numerical data integration approach that employed the integration of a linear model (IntLIM package) to predict metabolite levels from gene-expression in a phenotype dependent manner [ 23 ].…”

“…To uncover the complex relationship between metabolites and genes, we adopted a linear model framework using the IntLIM (Integration of Linear model) R-package (version 0.1.0) ( ) [ 23 ]. The IntLIM approach allows us to integrate the metabolomic-transcriptomic data considering a case-control design.…”

Metabonomic-Transcriptome Integration Analysis on Osteoarthritis and Rheumatoid Arthritis

“…Based on Linear Models. Based on the results of PCA analysis on gene expression data and metabonomic data, the P values of DEG-metabolite relevance between OA samples and RA samples were obtained using the IntLim (version: 0.1.0, https://github.com/mathelab/IntLIM) linear model algorithm [21]. The computation formula is as follows:…”

Tools and resources for metabolomics research community: A 2017–2018 update

“…IntLIM is an R package for integrative analyses accessible to noncomputational experts, that is, metabolomics and transcriptomics, using a simple linear modeling approach to capture disease (or other phenotype)‐specific gene–metabolite associations, with the assumption that coregulation patterns reflect functionally related genes and metabolites .…”