Dataset Information

Automated refinement and inference of analytical models for metabolic networks.

ABSTRACT: The reverse engineering of metabolic networks from experimental data is traditionally a labor-intensive task requiring a priori systems knowledge. Using a proven model as a test system, we demonstrate an automated method to simplify this process by modifying an existing or related model--suggesting nonlinear terms and structural modifications--or even constructing a new model that agrees with the system's time series observations. In certain cases, this method can identify the full dynamical model from scratch without prior knowledge or structural assumptions. The algorithm selects between multiple candidate models by designing experiments to make their predictions disagree. We performed computational experiments to analyze a nonlinear seven-dimensional model of yeast glycolytic oscillations. This approach corrected mistakes reliably in both approximated and overspecified models. The method performed well to high levels of noise for most states, could identify the correct model de novo, and make better predictions than ordinary parametric regression and neural network models. We identified an invariant quantity in the model, which accurately derived kinetics and the numerical sensitivity coefficients of the system. Finally, we compared the system to dynamic flux estimation and discussed the scaling and application of this methodology to automated experiment design and control in biological systems in real time.

SUBMITTER: Schmidt MD

PROVIDER: S-EPMC4109817 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Automated refinement and inference of analytical models for metabolic networks.

Schmidt Michael D MD Vallabhajosyula Ravishankar R RR Jenkins Jerry W JW Hood Jonathan E JE Soni Abhishek S AS Wikswo John P JP Lipson Hod H

Physical biology 20110810 5

The reverse engineering of metabolic networks from experimental data is traditionally a labor-intensive task requiring a priori systems knowledge. Using a proven model as a test system, we demonstrate an automated method to simplify this process by modifying an existing or related model--suggesting nonlinear terms and structural modifications--or even constructing a new model that agrees with the system's time series observations. In certain cases, this method can identify the full dynamical mod ...[more]

PMID: 21832805

Similar Datasets

Project description:There is a strong need for computational frameworks that integrate different biological processes and data-types to unravel cellular regulation. Current efforts to reconstruct transcriptional regulatory networks (TRNs) focus primarily on proximal data such as gene co-expression and transcription factor (TF) binding. While such approaches enable rapid reconstruction of TRNs, the overwhelming combinatorics of possible networks limits identification of mechanistic regulatory interactions. Utilizing growth phenotypes and systems-level constraints to inform regulatory network reconstruction is an unmet challenge. We present our approach Gene Expression and Metabolism Integrated for Network Inference (GEMINI) that links a compendium of candidate regulatory interactions with the metabolic network to predict their systems-level effect on growth phenotypes. We then compare predictions with experimental phenotype data to select phenotype-consistent regulatory interactions. GEMINI makes use of the observation that only a small fraction of regulatory network states are compatible with a viable metabolic network, and outputs a regulatory network that is simultaneously consistent with the input genome-scale metabolic network model, gene expression data, and TF knockout phenotypes. GEMINI preferentially recalls gold-standard interactions (p-value = 10(-172)), significantly better than using gene expression alone. We applied GEMINI to create an integrated metabolic-regulatory network model for Saccharomyces cerevisiae involving 25,000 regulatory interactions controlling 1597 metabolic reactions. The model quantitatively predicts TF knockout phenotypes in new conditions (p-value = 10(-14)) and revealed potential condition-specific regulatory mechanisms. Our results suggest that a metabolic constraint-based approach can be successfully used to help reconstruct TRNs from high-throughput data, and highlights the potential of using a biochemically-detailed mechanistic framework to integrate and reconcile inconsistencies across different data-types. The algorithm and associated data are available at https://sourceforge.net/projects/gemini-data/

Project description:Functional networks play an important role in the analysis of biological processes and systems. The inference of these networks from high-throughput (-omics) data is an area of intense research. So far, the similarity-based inference paradigm (e.g. gene co-expression) has been the most popular approach. It assumes a functional relationship between genes which are expressed at similar levels across different samples. An alternative to this paradigm is the inference of relationships from the structure of machine learning models. These models are able to capture complex relationships between variables, that often are different/complementary to the similarity-based methods.We propose a protocol to infer functional networks from machine learning models, called FuNeL. It assumes, that genes used together within a rule-based machine learning model to classify the samples, might also be functionally related at a biological level. The protocol is first tested on synthetic datasets and then evaluated on a test suite of 8 real-world datasets related to human cancer. The networks inferred from the real-world data are compared against gene co-expression networks of equal size, generated with 3 different methods. The comparison is performed from two different points of view. We analyse the enriched biological terms in the set of network nodes and the relationships between known disease-associated genes in a context of the network topology. The comparison confirms both the biological relevance and the complementary character of the knowledge captured by the FuNeL networks in relation to similarity-based methods and demonstrates its potential to identify known disease associations as core elements of the network. Finally, using a prostate cancer dataset as a case study, we confirm that the biological knowledge captured by our method is relevant to the disease and consistent with the specialised literature and with an independent dataset not used in the inference process.The implementation of our network inference protocol is available at: http://ico2s.org/software/funel.html.

Dataset Information

Automated refinement and inference of analytical models for metabolic networks.

Publications

Automated refinement and inference of analytical models for metabolic networks.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets