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Causal integration of multi-omics data with prior knowledge to generate mechanistic hypotheses.

Molecular systems biology (2021-01-28)
Aurelien Dugourd, Christoph Kuppe, Marco Sciacovelli, Enio Gjerga, Attila Gabor, Kristina B Emdal, Vitor Vieira, Dorte B Bekker-Jensen, Jennifer Kranz, Eric M J Bindels, Ana S H Costa, Abel Sousa, Pedro Beltrao, Miguel Rocha, Jesper V Olsen, Christian Frezza, Rafael Kramann, Julio Saez-Rodriguez
ABSTRACT

Multi-omics datasets can provide molecular insights beyond the sum of individual omics. Various tools have been recently developed to integrate such datasets, but there are limited strategies to systematically extract mechanistic hypotheses from them. Here, we present COSMOS (Causal Oriented Search of Multi-Omics Space), a method that integrates phosphoproteomics, transcriptomics, and metabolomics datasets. COSMOS combines extensive prior knowledge of signaling, metabolic, and gene regulatory networks with computational methods to estimate activities of transcription factors and kinases as well as network-level causal reasoning. COSMOS provides mechanistic hypotheses for experimental observations across multi-omics datasets. We applied COSMOS to a dataset comprising transcriptomics, phosphoproteomics, and metabolomics data from healthy and cancerous tissue from eleven clear cell renal cell carcinoma (ccRCC) patients. COSMOS was able to capture relevant crosstalks within and between multiple omics layers, such as known ccRCC drug targets. We expect that our freely available method will be broadly useful to extract mechanistic insights from multi-omics studies.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Trizma® base, Primary Standard and Buffer, ≥99.9% (titration), crystalline
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Tris(2-carboxyethyl)phosphine hydrochloride, powder
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Guanidine hydrochloride, for molecular biology, ≥99%
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Ammonium bicarbonate, BioUltra, ≥99.5% (T)
Roche
cOmplete, Mini Protease Inhibitor Cocktail, Tablets provided in EASYpacks
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Trypsin from porcine pancreas, BioReagent, Proteomics Grade, Dimethylated
Supelco
2,5-Dihydroxybenzoic acid, matrix substance for MALDI-MS, >99.0% (HPLC)
Millipore
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Supelco
Empore SPE Disks, matrix active group C8, diam. 47 mm, pk of 20