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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.01384

Additive Dose Response Models: Defining Synergy

  • 1Radboud University Nijmegen, Netherlands
  • 2Institute for Computing and Information Sciences, Radboud University Nijmegen, Netherlands
  • 3Max Planck Institute for Developmental Biology, Germany

In synergy studies, one focuses on compound combinations that promise a synergistic or antagonistic effect. With the help of high-throughput techniques, a huge amount of compound combinations can be screened and filtered for suitable candidates for a more detailed analysis. Those promising candidates are chosen based on the deviance between a measured response and an expected non-interactive response. A non-interactive response is based on a principle of no interaction, such as Loewe Additivity (Loewe, 1928) or Bliss Independence (Bliss, 1939). In Lederer et al. (2018b), an explicit formulation of the hitherto implicitly defined Loewe Additivity has been introduced, the so-called Explicit Mean Equation. In the current study we show that this Explicit Mean Equation outperforms the original implicit formulation of Loewe Additivity and Bliss Independence when measuring synergy in terms of the deviance between measured and expected response, called the lack-of-fit. Further, we show that computing synergy as lack-of-fit outperforms a parametric approach. We show this on two datasets of compound combinations that are categorized into synergistic, non-interactive and antagonistic (Yadav et al., 2015; Cokol et al., 2011).

Keywords: General Isobole Equation, null reference model, response surface, Lack-of-fit, Explicit Mean Equaiton, Dose equivalence, Synergy, Bliss independence, Loewe Addittivity

Received: 29 Jul 2019; Accepted: 30 Oct 2019.

Copyright: © 2019 Lederer, Dijkstra and Heskes. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Mx. Simone Lederer, Radboud University Nijmegen, Nijmegen, Netherlands,
Dr. Tjeerd M. Dijkstra, Max Planck Institute for Developmental Biology, Tübingen, 72076, Baden-Württemberg, Germany,