Additive Dose Response Models: Explicit Formulation and the Loewe Additivity Consistency Condition
نویسندگان
چکیده
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.
منابع مشابه
Additive Dose Response Models: Explicit Formulations 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 based on the assumption that no compound interacts with itself and that doses of both compounds for ...
متن کاملParallel dose-response curves in combination experiments.
A possible experimental design for combination experiments is to compare the dose-response curve of a single agent with the corresponding curve of the same agent using either a fixed amount of a second one or a fixed dose ratio. No interaction is then often defined by a parallel shift of these curves. We have performed a systematic study for various types of dose-response relations both for the...
متن کاملDefining an additivity framework for mixture research in inducible whole-cell biosensors
A novel additivity framework for mixture effect modelling in the context of whole cell inducible biosensors has been mathematically developed and implemented in R. The proposed method is a multivariate extension of the effective dose (EDp) concept. Specifically, the extension accounts for differential maximal effects among analytes and response inhibition beyond the maximum permissive concentra...
متن کاملAn Approach to Characterizing the Type of Combined Environmental Toxicity Based on Epidemiologically Assessed Exposure-Response Relationships
Using a dataset obtained in an earlier published epidemiological study that revealed the dependence of the probability of subclinical kidney damage in 260 children on the concentration of lead and cadmium in their urine, we have tested some methodological approaches to assessing the type of combined nephrotoxicity produced by these two metals. We have found that the environmentally caused damag...
متن کاملCombiTool - A New Computer Program for Analyzing Combination Experiments with Biologically Active Agents
CombiTool is a new computer program for the analysis of combination effects of biologically active agents. It performs model calculations and an analysis of experimental combination effects for two or three agents according to both the Bliss independence and the Loewe additivity criteria. Zero interaction response surfaces are calculated from single-agent dose-response relations and compared to...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
دوره 9 شماره
صفحات -
تاریخ انتشار 2018