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Additive Dose Response Models: Explicit Formulation and the Loewe Additivity Consistency Condition

High-throughput techniques allow for massive screening of drug combinations. To find combinations that exhibit an interaction effect, one filters for promising compound combinations by comparing to a response without interaction. A common principle for no interaction is Loewe Additivity which is bas...

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Autores principales: Lederer, Simone, Dijkstra, Tjeerd M. H., Heskes, Tom
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808155/
https://www.ncbi.nlm.nih.gov/pubmed/29467650
http://dx.doi.org/10.3389/fphar.2018.00031
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author Lederer, Simone
Dijkstra, Tjeerd M. H.
Heskes, Tom
author_facet Lederer, Simone
Dijkstra, Tjeerd M. H.
Heskes, Tom
author_sort Lederer, Simone
collection PubMed
description High-throughput techniques allow for massive screening of drug combinations. To find combinations that exhibit an interaction effect, one filters for promising compound combinations by comparing to a response without interaction. A common principle for no interaction is Loewe Additivity which is based on the assumption that no compound interacts with itself and that two doses from different compounds having the same effect are equivalent. It then should not matter whether a component is replaced by the other or vice versa. We call this assumption the Loewe Additivity Consistency Condition (LACC). We derive explicit and implicit null reference models from the Loewe Additivity principle that are equivalent when the LACC holds. Of these two formulations, the implicit formulation is the known General Isobole Equation (Loewe, 1928), whereas the explicit one is the novel contribution. The LACC is violated in a significant number of cases. In this scenario the models make different predictions. We analyze two data sets of drug screening that are non-interactive (Cokol et al., 2011; Yadav et al., 2015) and show that the LACC is mostly violated and Loewe Additivity not defined. Further, we compare the measurements of the non-interactive cases of both data sets to the theoretical null reference models in terms of bias and mean squared error. We demonstrate that the explicit formulation of the null reference model leads to smaller mean squared errors than the implicit one and is much faster to compute.
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spelling pubmed-58081552018-02-21 Additive Dose Response Models: Explicit Formulation and the Loewe Additivity Consistency Condition Lederer, Simone Dijkstra, Tjeerd M. H. Heskes, Tom Front Pharmacol Pharmacology High-throughput techniques allow for massive screening of drug combinations. To find combinations that exhibit an interaction effect, one filters for promising compound combinations by comparing to a response without interaction. A common principle for no interaction is Loewe Additivity which is based on the assumption that no compound interacts with itself and that two doses from different compounds having the same effect are equivalent. It then should not matter whether a component is replaced by the other or vice versa. We call this assumption the Loewe Additivity Consistency Condition (LACC). We derive explicit and implicit null reference models from the Loewe Additivity principle that are equivalent when the LACC holds. Of these two formulations, the implicit formulation is the known General Isobole Equation (Loewe, 1928), whereas the explicit one is the novel contribution. The LACC is violated in a significant number of cases. In this scenario the models make different predictions. We analyze two data sets of drug screening that are non-interactive (Cokol et al., 2011; Yadav et al., 2015) and show that the LACC is mostly violated and Loewe Additivity not defined. Further, we compare the measurements of the non-interactive cases of both data sets to the theoretical null reference models in terms of bias and mean squared error. We demonstrate that the explicit formulation of the null reference model leads to smaller mean squared errors than the implicit one and is much faster to compute. Frontiers Media S.A. 2018-02-06 /pmc/articles/PMC5808155/ /pubmed/29467650 http://dx.doi.org/10.3389/fphar.2018.00031 Text en Copyright © 2018 Lederer, Dijkstra and Heskes. http://creativecommons.org/licenses/by/4.0/ 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 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.
spellingShingle Pharmacology
Lederer, Simone
Dijkstra, Tjeerd M. H.
Heskes, Tom
Additive Dose Response Models: Explicit Formulation and the Loewe Additivity Consistency Condition
title Additive Dose Response Models: Explicit Formulation and the Loewe Additivity Consistency Condition
title_full Additive Dose Response Models: Explicit Formulation and the Loewe Additivity Consistency Condition
title_fullStr Additive Dose Response Models: Explicit Formulation and the Loewe Additivity Consistency Condition
title_full_unstemmed Additive Dose Response Models: Explicit Formulation and the Loewe Additivity Consistency Condition
title_short Additive Dose Response Models: Explicit Formulation and the Loewe Additivity Consistency Condition
title_sort additive dose response models: explicit formulation and the loewe additivity consistency condition
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808155/
https://www.ncbi.nlm.nih.gov/pubmed/29467650
http://dx.doi.org/10.3389/fphar.2018.00031
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