TY - JOUR
T1 - Evolutionary diagnosis of non-synonymous variants involved in differential drug response
AU - Gerek, Nevin Z.
AU - Liu, Li
AU - Gerold, Kristyn
AU - Biparva, Pegah
AU - Thomas, Eric D.
AU - Kumar, Sudhir
N1 - Funding Information:
The authors thank Sayaka Miura for insightful comments, Maxwell Sanderford for initial database cross-reference and Ms. Carol Williams for editorial support. This research was supported by research grants from the National Institutes of Health (LM011941-1) to N.G. and Mayo/ASU seed grant to S.K.
Funding Information:
Publication charges for this article have been funded from research grants from National Institutes of Health (NIH; LM011941-1) and HiCi-1434-117-2 from KAU. This article has been published as part of BMC Medical Genomics Volume 8 Supplement 1, 2015: Selected articles from the 2nd International Genomic Medical Conference (IGMC 2013): Medical Genomics. The full contents of the supplement are available online at http://www.biomedcentral.com/ bmcmedgenomics/supplements/8/S1 1Institute for Genomics and Evolutionary Medicine, Temple University, Philadelphia, PA 19122, USA. 2Department of Biology, Temple University, Philadelphia, PA 19122, USA. 3Center for Excellence in Genome Medicine and Research, King Abdulaziz University, Jeddah, Saudi Arabia. 4Center for Evolutionary Medicine and Informatics, Biodesign Institute, Arizona State University, Tempe, AZ 85287-5301, USA.
Publisher Copyright:
© 2015 Gerek et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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.
PY - 2015/1/15
Y1 - 2015/1/15
N2 - Background: Many pharmaceutical drugs are known to be ineffective or have negative side effects in a substantial proportion of patients. Genomic advances are revealing that some non-synonymous single nucleotide variants (nsSNVs) may cause differences in drug efficacy and side effects. Therefore, it is desirable to evaluate nsSNVs of interest in their ability to modulate the drug response. Results: We found that the available data on the link between drug response and nsSNV is rather modest. There were only 31 distinct drug response-altering (DR-altering) and 43 distinct drug response-neutral (DR-neutral) nsSNVs in the whole Pharmacogenomics Knowledge Base (PharmGKB). However, even with this modest dataset, it was clear that existing bioinformatics tools have difficulties in correctly predicting the known DR-altering and DR-neutral nsSNVs. They exhibited an overall accuracy of less than 50%, which was not better than random diagnosis. We found that the underlying problem is the markedly different evolutionary properties between positions harboring nsSNVs linked to drug responses and those observed for inherited diseases. To solve this problem, we developed a new diagnosis method, Drug-EvoD, which was trained on the evolutionary properties of nsSNVs associated with drug responses in a sparse learning framework. Drug-EvoD achieves a TPR of 84% and a TNR of 53%, with a balanced accuracy of 69%, which improves upon other methods significantly. Conclusions: The new tool will enable researchers to computationally identify nsSNVs that may affect drug responses. However, much larger training and testing datasets are needed to develop more reliable and accurate tools.
AB - Background: Many pharmaceutical drugs are known to be ineffective or have negative side effects in a substantial proportion of patients. Genomic advances are revealing that some non-synonymous single nucleotide variants (nsSNVs) may cause differences in drug efficacy and side effects. Therefore, it is desirable to evaluate nsSNVs of interest in their ability to modulate the drug response. Results: We found that the available data on the link between drug response and nsSNV is rather modest. There were only 31 distinct drug response-altering (DR-altering) and 43 distinct drug response-neutral (DR-neutral) nsSNVs in the whole Pharmacogenomics Knowledge Base (PharmGKB). However, even with this modest dataset, it was clear that existing bioinformatics tools have difficulties in correctly predicting the known DR-altering and DR-neutral nsSNVs. They exhibited an overall accuracy of less than 50%, which was not better than random diagnosis. We found that the underlying problem is the markedly different evolutionary properties between positions harboring nsSNVs linked to drug responses and those observed for inherited diseases. To solve this problem, we developed a new diagnosis method, Drug-EvoD, which was trained on the evolutionary properties of nsSNVs associated with drug responses in a sparse learning framework. Drug-EvoD achieves a TPR of 84% and a TNR of 53%, with a balanced accuracy of 69%, which improves upon other methods significantly. Conclusions: The new tool will enable researchers to computationally identify nsSNVs that may affect drug responses. However, much larger training and testing datasets are needed to develop more reliable and accurate tools.
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U2 - 10.1186/1755-8794-8-S1-S6
DO - 10.1186/1755-8794-8-S1-S6
M3 - Article
C2 - 25952014
AN - SCOPUS:85027917201
SN - 1755-8794
VL - 8
JO - BMC Medical Genomics
JF - BMC Medical Genomics
M1 - S6
ER -