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Experimental Design for In Vitro Drug Combination Studies

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Topics in Applied Statistics

Part of the book series: Springer Proceedings in Mathematics & Statistics ((PROMS,volume 55))

Abstract

In vitro drug combination studies typically involve a large number of wells with various concentrations of two drugs added together. To gain the most information from an experiment, what should the drug concentrations be? Here, we consider the case where the single drug response curves are known beforehand, but no previous data is available from the combination. We consider several designs, including C- and D-optimal designs and a factorial design. We evaluate these designs based on the expected variance of the synergy score for a large set of in vitro experiments performed at Takeda Pharmaceuticals. Based on the results, we were able to identify which design was the most efficient and robust.

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References

  1. Chou, T.C., Talalay, P.: Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme. Reg. 22, 27-55 (1984)

    Article  Google Scholar 

  2. Berenbaum, M.C.: The expected effect of a combination of agents: The general solution. J. Theor. Biol. 114, 413-431 (1985)

    Article  Google Scholar 

  3. Peterson, J.J., Novik, S.J.: Nonlinear Blending: A Useful General Concept for the Assessment of Combination Drug Synergy. J. Recept. Signal. Transduct. Res. 27, 125-146 (2007)

    Article  Google Scholar 

  4. Bliss, C.I.: The toxicity of poisons combined jointly. Ann. Appl. Biol. 26, 585-615 (1939)

    Article  Google Scholar 

  5. Minto, C.F., Schnider, T.W., Short, T.G., Gregg, K.M., Gentilini, A., Shafer, S.L.: Response Surface Model for Anesthetic Drug Interactions. Anesthesiology 92, 1603-1616 (2000).

    Article  Google Scholar 

  6. Greco, W.R., Park, H.S., Rustum, Y.M.: Application of a New Approach for the Quantitation of Drug Synergism to the Combination of cis-Diamminedichloroplatinum and 1-b-d-Arabinofuranosylcytosine. Cancer Res 50, 5318-5327 (1990)

    Google Scholar 

  7. Pukelsheim, F.: Optimal design of experiments. New York: J. Wiley. (1993).

    MATH  Google Scholar 

  8. Chaloner, K., and Verdinelli, I.: Bayesian Experimental Design: A Review. Statistical Science 10, 273-304 (1995)

    Article  MathSciNet  MATH  Google Scholar 

  9. Tallarida, R.J., Stone, D.J. Jr., Raffa. R.B.: Efficient designs for studying synergistic drug combinations. Life Sciences 61, PL417-425 (1997)

    Article  Google Scholar 

  10. Chou, T.C.: Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies. Pharmacol. Rev. 58, 621-681 (2006)

    Article  Google Scholar 

  11. Hill, A.V.: The possible effects of the aggregation of the molecules of hæmoglobin on its dissociation curves. J. Physiol. 40, iv-vii (1910)

    Google Scholar 

  12. R Development Core Team: R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0, URL http://www.R-project.org. (2008)

  13. Cramer, H.: Mathematical Methods of Statistics. Princeton, NJ: Princeton Univ. Press. (1946)

    MATH  Google Scholar 

  14. Rao, C.R. Information and the accuracy attainable in the estimation of statistical parameters. Bulletin of the Calcutta Mathematical Society 37, 81-89 (1945)

    MathSciNet  MATH  Google Scholar 

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Acknowledgments

We would like to thank the Double Agent team at Takeda Pharmaceuticals for their support.

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Correspondence to Gregory Hather .

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Hather, G., Chen, H., Liu, R. (2013). Experimental Design for In Vitro Drug Combination Studies. In: Hu, M., Liu, Y., Lin, J. (eds) Topics in Applied Statistics. Springer Proceedings in Mathematics & Statistics, vol 55. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7846-1_27

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