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    Keywords: CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; CELL ; COMBINATION ; Germany ; human ; MODEL ; MODELS ; PATHWAY ; NETWORKS ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; RNA ; DNA ; SIMULATION ; BIOLOGY ; BREAST ; breast cancer ; BREAST-CANCER ; score ; gene expression ; MICROARRAY DATA ; DNA microarray ; microarrays ; CANCER-CELLS ; bioinformatics ; RECONSTRUCTION ; signaling ; FEATURES ; RE ; INTERFERENCE ; RNA INTERFERENCE ; EXTENSION ; methods ; microbiology ; ENGLAND ; NOV ; UPSTREAM ; PROFILE ; biotechnology ; SIGNALING NETWORK ; BREAST-CANCER-CELLS ; INTERVENTIONS ; PROBABILITY ; differential gene expression
    Abstract: 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-alpha 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
    Type of Publication: Journal article published
    PubMed ID: 18227117
    Signatur Availability
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