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PLoS Comput Biol. 2012;8(4):e1002457. doi: 10.1371/journal.pcbi.1002457. Epub 2012 Apr 5.

Automatic filtering and substantiation of drug safety signals.

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1
Research Programme on Biomedical Informatics-GRIB, IMIM-Hospital del Mar Research Institute, DCEX, Universitat Pompeu Fabra, Barcelona, Spain.

Erratum in

  • PLoS Comput Biol. 2012 May;8(5): doi/10.1371/annotation/695450aa-95a0-491d-804d-470cbfa861e8.

Abstract

Drug safety issues pose serious health threats to the population and constitute a major cause of mortality worldwide. Due to the prominent implications to both public health and the pharmaceutical industry, it is of great importance to unravel the molecular mechanisms by which an adverse drug reaction can be potentially elicited. These mechanisms can be investigated by placing the pharmaco-epidemiologically detected adverse drug reaction in an information-rich context and by exploiting all currently available biomedical knowledge to substantiate it. We present a computational framework for the biological annotation of potential adverse drug reactions. First, the proposed framework investigates previous evidences on the drug-event association in the context of biomedical literature (signal filtering). Then, it seeks to provide a biological explanation (signal substantiation) by exploring mechanistic connections that might explain why a drug produces a specific adverse reaction. The mechanistic connections include the activity of the drug, related compounds and drug metabolites on protein targets, the association of protein targets to clinical events, and the annotation of proteins (both protein targets and proteins associated with clinical events) to biological pathways. Hence, the workflows for signal filtering and substantiation integrate modules for literature and database mining, in silico drug-target profiling, and analyses based on gene-disease networks and biological pathways. Application examples of these workflows carried out on selected cases of drug safety signals are discussed. The methodology and workflows presented offer a novel approach to explore the molecular mechanisms underlying adverse drug reactions.

PMID:
22496632
PMCID:
PMC3320573
DOI:
10.1371/journal.pcbi.1002457
[Indexed for MEDLINE]
Free PMC Article
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