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Estimating large-scale signaling networks through nested effect models with intervention effects from microarray data

Motivation: Targeted interventions using RNA interference in combination with the measurement of secondary effects with DNA microarrays can be used to computationally reverse engineer features of upstream non-transcriptional signaling cascades based on the nested structure of effects. Results: We ex...

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Autores principales: Fröhlich, Holger, Fellmann, Mark, Sültmann, Holger, Poustka, Annemarie, Beissbarth, Tim
Formato: Texto
Lenguaje:English
Publicado: Oxford University Press 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2579711/
https://www.ncbi.nlm.nih.gov/pubmed/18227117
http://dx.doi.org/10.1093/bioinformatics/btm634
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author Fröhlich, Holger
Fellmann, Mark
Sültmann, Holger
Poustka, Annemarie
Beissbarth, Tim
author_facet Fröhlich, Holger
Fellmann, Mark
Sültmann, Holger
Poustka, Annemarie
Beissbarth, Tim
author_sort Fröhlich, Holger
collection PubMed
description Motivation: Targeted interventions using RNA interference in combination with the measurement of secondary effects with DNA microarrays can be used to computationally reverse engineer features of upstream non-transcriptional signaling cascades based on the nested structure of effects. Results: We extend previous work by Markowetz et al., who proposed a statistical framework to score different network hypotheses. Our extensions go in several directions: we show how prior assumptions on the network structure can be incorporated into the scoring scheme by defining appropriate prior distributions on the network structure as well as on hyperparameters. An approach called module networks is introduced to scale up the original approach, which is limited to around 5 genes, to infer large-scale networks of more than 30 genes. Instead of the data discretization step needed in the original framework, we propose the usage of a beta-uniform mixture distribution on the P-value profile, resulting from differential gene expression calculation, to quantify effects. Extensive simulations on artificial data and application of our module network approach to infer the signaling network between 13 genes in the ER-α pathway in human MCF-7 breast cancer cells show that our approach gives sensible results. Using a bootstrapping and a jackknife approach, this reconstruction is found to be statistically stable. Availability: The proposed method is available within the Bioconductor R-package nem. Contact: h.froehlich@dkfz-heidelberg.de
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spelling pubmed-25797112009-02-25 Estimating large-scale signaling networks through nested effect models with intervention effects from microarray data Fröhlich, Holger Fellmann, Mark Sültmann, Holger Poustka, Annemarie Beissbarth, Tim Bioinformatics German Conference on Bioinformatics Motivation: Targeted interventions using RNA interference in combination with the measurement of secondary effects with DNA microarrays can be used to computationally reverse engineer features of upstream non-transcriptional signaling cascades based on the nested structure of effects. Results: We extend previous work by Markowetz et al., who proposed a statistical framework to score different network hypotheses. Our extensions go in several directions: we show how prior assumptions on the network structure can be incorporated into the scoring scheme by defining appropriate prior distributions on the network structure as well as on hyperparameters. An approach called module networks is introduced to scale up the original approach, which is limited to around 5 genes, to infer large-scale networks of more than 30 genes. Instead of the data discretization step needed in the original framework, we propose the usage of a beta-uniform mixture distribution on the P-value profile, resulting from differential gene expression calculation, to quantify effects. Extensive simulations on artificial data and application of our module network approach to infer the signaling network between 13 genes in the ER-α pathway in human MCF-7 breast cancer cells show that our approach gives sensible results. Using a bootstrapping and a jackknife approach, this reconstruction is found to be statistically stable. Availability: The proposed method is available within the Bioconductor R-package nem. Contact: h.froehlich@dkfz-heidelberg.de Oxford University Press 2008-11-15 2008-01-28 /pmc/articles/PMC2579711/ /pubmed/18227117 http://dx.doi.org/10.1093/bioinformatics/btm634 Text en © 2008 The Author(s) http://creativecommons.org/licenses/by-nc/2.0/uk/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle German Conference on Bioinformatics
Fröhlich, Holger
Fellmann, Mark
Sültmann, Holger
Poustka, Annemarie
Beissbarth, Tim
Estimating large-scale signaling networks through nested effect models with intervention effects from microarray data
title Estimating large-scale signaling networks through nested effect models with intervention effects from microarray data
title_full Estimating large-scale signaling networks through nested effect models with intervention effects from microarray data
title_fullStr Estimating large-scale signaling networks through nested effect models with intervention effects from microarray data
title_full_unstemmed Estimating large-scale signaling networks through nested effect models with intervention effects from microarray data
title_short Estimating large-scale signaling networks through nested effect models with intervention effects from microarray data
title_sort estimating large-scale signaling networks through nested effect models with intervention effects from microarray data
topic German Conference on Bioinformatics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2579711/
https://www.ncbi.nlm.nih.gov/pubmed/18227117
http://dx.doi.org/10.1093/bioinformatics/btm634
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