Abstract
There is growing interest in applying detailed mathematical models of the heart for ion-channel related cardiac toxicity prediction. However, a debate as to whether such complex models are required exists. Here an assessment in the predictive performance between two established large-scale biophysical cardiac models and a simple linear model Bnet was conducted. Three ion-channel data-sets were extracted from literature. Each compound was designated a cardiac risk category using two different classification schemes based on information within CredibleMeds. The predictive performance of each model within each data-set for each classification scheme was assessed via a leave-one-out cross validation. Overall the Bnet model performed equally as well as the leading cardiac models in two of the data-sets and outperformed both cardiac models on the latest. These results highlight the importance of benchmarking complex versus simple models but also encourage the development of simple models.
Highlights
There is a growing belief within the pharmaceutical industry that in order to improve predictions of future experiments more detailed mathematical models of biology are required (Peterson & Riggs, 2015; Knight-Schrijver et al, 2016)
The objective of this study is to look at this issue within the field of drug induced ion-channel cardiac toxicity
This prolongation is due to delayed repolarisation of cardiac cells within the ventricular wall, which is due to the drugs effect on the hERG ion-channel
Summary
There is a growing belief within the pharmaceutical industry that in order to improve predictions of future experiments more detailed mathematical models of biology are required (Peterson & Riggs, 2015; Knight-Schrijver et al, 2016). The objective of this study is to look at this issue within the field of drug induced ion-channel cardiac toxicity. This area has a well-defined question relating to prediction where a debate about the complexity of the model needed is ongoing. Prior to observing drug induced TdeP, prolongation of the QT interval is commonly seen within a patient. This prolongation is due to delayed repolarisation of cardiac cells within the ventricular wall, which is due to the drugs effect on the hERG ion-channel.
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