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Geeleher P, Cox NJ, Huang RS. Cancer biomarker discovery is improved by accounting for variability in general levels of drug sensitivity in pre-clinical models. Genome Biol. 2016;17(1):190doi: 10.1186/s13059-016-1050-9.
Geeleher, P., Cox, N. J., & Huang, R. S. (2016). Cancer biomarker discovery is improved by accounting for variability in general levels of drug sensitivity in pre-clinical models. Genome biology, 17(1), 190. https://doi.org/10.1186/s13059-016-1050-9
Geeleher, Paul, et al. "Cancer biomarker discovery is improved by accounting for variability in general levels of drug sensitivity in pre-clinical models." Genome biology vol. 17,1 (2016): 190. doi: https://doi.org/10.1186/s13059-016-1050-9
Geeleher P, Cox NJ, Huang RS. Cancer biomarker discovery is improved by accounting for variability in general levels of drug sensitivity in pre-clinical models. Genome Biol. 2016 Sep 21;17(1):190. doi: 10.1186/s13059-016-1050-9. PMID: 27654937; PMCID: PMC5031330.
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Genome Biol. 2016 Sep 21;17(1):190. doi: 10.1186/s13059-016-1050-9.

Cancer biomarker discovery is improved by accounting for variability in general levels of drug sensitivity in pre-clinical models.

Genome biology

Paul Geeleher, Nancy J Cox, R Stephanie Huang

Affiliations

  1. Section of Hematology/Oncology, The University of Chicago, 900 E 57th Street, KCBD room 7148, Chicago, IL, 60637, USA.
  2. Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, 60637, USA.
  3. Division of Genetic Medicine, Vanderbilt University, Nashville, TN, USA.
  4. Section of Hematology/Oncology, The University of Chicago, 900 E 57th Street, KCBD room 7148, Chicago, IL, 60637, USA. [email protected].

PMID: 27654937 PMCID: PMC5031330 DOI: 10.1186/s13059-016-1050-9

Abstract

We show that variability in general levels of drug sensitivity in pre-clinical cancer models confounds biomarker discovery. However, using a very large panel of cell lines, each treated with many drugs, we could estimate a general level of sensitivity to all drugs in each cell line. By conditioning on this variable, biomarkers were identified that were more likely to be effective in clinical trials than those identified using a conventional uncorrected approach. We find that differences in general levels of drug sensitivity are driven by biologically relevant processes. We developed a gene expression based method that can be used to correct for this confounder in future studies.

References

  1. PLoS One. 2013 Apr 30;8(4):e61318 - PubMed
  2. Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50 - PubMed
  3. BMC Cancer. 2014 Nov 05;14:813 - PubMed
  4. Cancer Res. 2012 Apr 1;72 (7):1608-13 - PubMed
  5. Nat Chem Biol. 2016 Feb;12(2):109-16 - PubMed
  6. Nat Rev Drug Discov. 2013 May;12(5):358-69 - PubMed
  7. Hum Mol Genet. 2015 Jan 1;24(1):142-53 - PubMed
  8. J Clin Oncol. 2008 Dec 1;26(34):5544-52 - PubMed
  9. Nat Biotechnol. 2014 Sep;32(9):896-902 - PubMed
  10. Annu Rev Med. 2002;53:615-27 - PubMed
  11. Nat Rev Mol Cell Biol. 2000 Dec;1(3):233-6 - PubMed
  12. Biostatistics. 2012 Jul;13(3):539-52 - PubMed
  13. Future Oncol. 2015 ;11(1):17-26 - PubMed
  14. Leuk Res. 2010 Oct;34(10):1255-68 - PubMed
  15. Nature. 2013 Dec 19;504(7480):389-93 - PubMed
  16. Clin Cancer Res. 2015 Mar 1;21(5):995-1001 - PubMed
  17. Cancer Discov. 2015 Nov;5(11):1210-23 - PubMed
  18. Nat Rev Cancer. 2013 Oct;13(10):714-26 - PubMed
  19. Adv Drug Deliv Rev. 2013 Nov;65(13-14):1686-98 - PubMed
  20. Nat Rev Drug Discov. 2012 Nov;11(11):873-86 - PubMed
  21. Mol Cancer Ther. 2008 Sep;7(9):2575-88 - PubMed
  22. Expert Opin Pharmacother. 2014 Feb;15(3):407-20 - PubMed
  23. Nat Genet. 2008 May;40(5):600-8 - PubMed
  24. Nature. 2012 Mar 28;483(7391):570-5 - PubMed
  25. J Natl Cancer Inst. 2007 Oct 3;99(19):1441-54 - PubMed
  26. Nat Methods. 2016 Jun;13(6):521-7 - PubMed
  27. Invest New Drugs. 2014 Aug;32(4):626-35 - PubMed
  28. Nat Clin Pract Oncol. 2009 Jan;6(1):43-52 - PubMed
  29. Nature. 2015 Dec 3;528(7580):84-7 - PubMed
  30. Mol Biol Cell. 2012 Jan;23(1):1-6 - PubMed
  31. Nature. 2012 Mar 28;483(7391):603-7 - PubMed
  32. PLoS Genet. 2013;9(9):e1003806 - PubMed
  33. Br J Cancer. 2008 Dec 16;99(12 ):2020-8 - PubMed
  34. Nat Rev Drug Discov. 2011 Aug 31;10(9):712 - PubMed
  35. N Engl J Med. 2006 Dec 7;355(23):2408-17 - PubMed
  36. Bioinformatics. 2001 Jun;17(6):520-5 - PubMed
  37. Nucleic Acids Res. 2005 Nov 10;33(20):e175 - PubMed
  38. Biostatistics. 2003 Apr;4(2):249-64 - PubMed

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