Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/19088
Title: Identification of in vitro and in vivo disconnects using transcriptomic data
Authors: OTAVA, Martin 
SHKEDY, Ziv 
TALLOEN, Willem 
Verheyen, Geert R.
KASIM, Adetayo 
Issue Date: 2015
Source: BMC GENOMICS, 16
Abstract: Background: Integrating transcriptomic experiments within drug development is increasingly advocated for the early detection of toxicity. This is partly to reduce costs related to drug failures in the late, and expensive phases of clinical trials. Such an approach has proven useful both in the study of toxicology and carcinogenicity. However, general lack of translation of in vitro findings to in vivo systems remains one of the bottle necks in drug development. This paper proposes a method for identifying disconnected genes between in vitro and in vivo toxicogenomic rat experiments. The analytical framework is based on the joint modeling of dose-dependent in vitro and in vivo data using a fractional polynomial framework and biclustering algorithm. Results: Most disconnected genes identified belonged to known pathways, such as drug metabolism and oxidative stress due to reactive metabolites, bilirubin increase, glutathion depletion and phospholipidosis. We also identified compounds that were likely to induce disconnect in gene expression between in vitro and in vivo toxicogenomic rat experiments. These compounds include: sulindac and diclofenac (both linked to liver damage), naphtyl isothiocyanate (linked to hepatoxocity), indomethacin and naproxen (linked to gastrointestinal problem and damage of intestines). Conclusion: The results confirmed that there are important discrepancies between in vitro and in vivo toxicogenomic experiments. However, the contribution of this paper is to provide a tool to identify genes that are disconnected between the two systems. Pathway analysis of disconnected genes may improve our understanding of uncertainties in the mechanism of actions of drug candidates in humans, especially concerning the early detection of toxicity.
Notes: Correspondence: a.s.kasim@durham.ac.uk
Keywords: in vitro; in vivo; toxicogenomics; gene expression; dose-response relationship; liver toxicity
Document URI: http://hdl.handle.net/1942/19088
ISSN: 1471-2164
e-ISSN: 1471-2164
DOI: 10.1186/s12864-015-1726-7
ISI #: 000359526500003
Rights: © 2015 Otava et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated
Category: A1
Type: Journal Contribution
Validations: ecoom 2016
Appears in Collections:Research publications

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