Dataset Information

Linear effects models of signaling pathways from combinatorial perturbation data.

ABSTRACT:

Motivation

Perturbations constitute the central means to study signaling pathways. Interrupting components of the pathway and analyzing observed effects of those interruptions can give insight into unknown connections within the signaling pathway itself, as well as the link from the pathway to the effects. Different pathway components may have different individual contributions to the measured perturbation effects, such as gene expression changes. Those effects will be observed in combination when the pathway components are perturbed. Extant approaches focus either on the reconstruction of pathway structure or on resolving how the pathway components control the downstream effects.

Results

Here, we propose a linear effects model, which can be applied to solve both these problems from combinatorial perturbation data. We use simulated data to demonstrate the accuracy of learning the pathway structure as well as estimation of the individual contributions of pathway components to the perturbation effects. The practical utility of our approach is illustrated by an application to perturbations of the mitogen-activated protein kinase pathway in Saccharomyces cerevisiaeAvailability and Implementation: lem is available as a R package at http://www.mimuw.edu.pl/?szczurek/lem

Contact

szczurek@mimuw.edu.pl; niko.beerenwinkel@bsse.ethz.ch

Supplementary information

Supplementary data are available at Bioinformatics online.

SUBMITTER: Szczurek E

PROVIDER: S-EPMC4908352 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Publications

Linear effects models of signaling pathways from combinatorial perturbation data.

Szczurek Ewa E Beerenwinkel Niko N

Bioinformatics (Oxford, England) 20160601 12

<h4>Motivation</h4>Perturbations constitute the central means to study signaling pathways. Interrupting components of the pathway and analyzing observed effects of those interruptions can give insight into unknown connections within the signaling pathway itself, as well as the link from the pathway to the effects. Different pathway components may have different individual contributions to the measured perturbation effects, such as gene expression changes. Those effects will be observed in combin ...[more]

PMID: 27307630

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Project description:Despite significant efforts and remarkable progress, the inference of signaling networks from experimental data remains very challenging. The problem is particularly difficult when the objective is to obtain a dynamic model capable of predicting the effect of novel perturbations not considered during model training. The problem is ill-posed due to the nonlinear nature of these systems, the fact that only a fraction of the involved proteins and their post-translational modifications can be measured, and limitations on the technologies used for growing cells in vitro, perturbing them, and measuring their variations. As a consequence, there is a pervasive lack of identifiability. To overcome these issues, we present a methodology called SELDOM (enSEmbLe of Dynamic lOgic-based Models), which builds an ensemble of logic-based dynamic models, trains them to experimental data, and combines their individual simulations into an ensemble prediction. It also includes a model reduction step to prune spurious interactions and mitigate overfitting. SELDOM is a data-driven method, in the sense that it does not require any prior knowledge of the system: the interaction networks that act as scaffolds for the dynamic models are inferred from data using mutual information. We have tested SELDOM on a number of experimental and in silico signal transduction case-studies, including the recent HPN-DREAM breast cancer challenge. We found that its performance is highly competitive compared to state-of-the-art methods for the purpose of recovering network topology. More importantly, the utility of SELDOM goes beyond basic network inference (i.e. uncovering static interaction networks): it builds dynamic (based on ordinary differential equation) models, which can be used for mechanistic interpretations and reliable dynamic predictions in new experimental conditions (i.e. not used in the training). For this task, SELDOM's ensemble prediction is not only consistently better than predictions from individual models, but also often outperforms the state of the art represented by the methods used in the HPN-DREAM challenge.

Project description:Perturbing a signaling system with a serial of single gene deletions and then observing corresponding expression changes in model organisms, such as yeast, is an important and widely used experimental technique for studying signaling pathways. People have developed different computational methods to analyze the perturbation data from gene deletion experiments for exploring the signaling pathways. The most popular methods/techniques include K-means clustering and hierarchical clustering techniques, or combining the expression data with knowledge, such as protein-protein interactions (PPIs) or gene ontology (GO), to search for new pathways. However, these methods neither consider nor fully utilize the intrinsic relation between the perturbation of a pathway and expression changes of genes regulated by the pathway, which served as the main motivation for developing a new computational method in this study. In our new model, we first find gene transcriptomic modules such that genes in each module are highly likely to be regulated by a common signal. We then use the expression status of those modules as readouts of pathway perturbations to search for up-stream pathways. Systematic evaluation, such as through gene ontology enrichment analysis, has provided evidence that genes in each transcriptomic module are highly likely to be regulated by a common signal. The PPI density analysis and literature search revealed that our new perturbation modules are functionally coherent. For example, the literature search revealed that 9 genes in one of our perturbation module are related to cell cycle and all 10 genes in another perturbation module are related by DNA damage, with much evidence from the literature coming from in vitro or/and in vivo verifications. Hence, utilizing the intrinsic relation between the perturbation of a pathway and the expression changes of genes regulated by the pathway is a useful method of searching for signaling pathways using genetic perturbation data. This model would also be suitable for analyzing drug experiment data, such as the CMap data, for finding drugs that perturb the same pathways.

Dataset Information

Linear effects models of signaling pathways from combinatorial perturbation data.

Motivation

Results

Contact

Supplementary information

Publications

Linear effects models of signaling pathways from combinatorial perturbation data.

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