Variability in high−throughput ion channel screening data and consequences for cardiac safety assessment
Introduction: unwanted drug interactions with ionic currents in the heart can lead to an increased pro-arrhythmic risk to patients in the clinic. It is therefore a priority for pharmaceutical safety pharmacology teams to detect block of cardiac ion channels, and new technologies have enabled the dev...
| Main Authors: | , , , , , , |
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| Format: | Journal article |
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2013
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| _version_ | 1826271434564960256 |
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| author | Elkins, R Davies, M Brough, S Gavaghan, D Cui, Y Abi−Gerges, N Mirams, G |
| author_facet | Elkins, R Davies, M Brough, S Gavaghan, D Cui, Y Abi−Gerges, N Mirams, G |
| author_sort | Elkins, R |
| collection | OXFORD |
| description | Introduction: unwanted drug interactions with ionic currents in the heart can lead to an increased pro-arrhythmic risk to patients in the clinic. It is therefore a priority for pharmaceutical safety pharmacology teams to detect block of cardiac ion channels, and new technologies have enabled the development of automated and high-throughput screening assays using cell lines. As a result of screening multiple ion-channels there is a need to integrate information, particularly for compounds affecting more than one current, and mathematical electrophysiology in-silico action potential models are beginning to be used for this. Methods: we quantified the variability associat11 ed with concentration-effect curves fitted to recordings from high-throughput Molecular Devices IonWorks® Quattro— screens when detecting block of IKr (hERG), INa (NaV1.5), ICaL (CaV1.2), IKs (KCNQ1/minK) and Ito Kv4.3/KChIP2.2), and the Molecular Devices FLIPR® Tetra fluorescence screen for ICaL (CaV1.2), for control compounds used at AstraZeneca and GlaxoSmithKline. We examined how screening variability propagates through in-silico action potential models for whole cell electrical behaviour, and how confidence intervals on model predictions can be estimated with repeated simulations. Results: there are significant levels of variability associated with high-throughput ion channel electrophysiology screens. This variability is of a similar magnitude for different cardiac ion currents and different compounds. Uncertainty in the Hill coefficients of reported concentration-effect curves is particularly high. Depending on a compound’s ion channel blocking profile, the uncertainty introduced into whole-cell predictions can become significant. Discussion: our technique allows confidence intervals to be placed on computational model predictions that are based on high-throughput ion channel screens. This allows us to suggest when repeated screens should be performed to reduce uncertainty in a compound’s action to acceptable levels, to allow a meaningful interpretation of the data. |
| first_indexed | 2024-03-06T21:56:36Z |
| format | Journal article |
| id | oxford-uuid:4d20d2fc-c0c6-4539-861b-565d35158422 |
| institution | University of Oxford |
| last_indexed | 2024-03-06T21:56:36Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | oxford-uuid:4d20d2fc-c0c6-4539-861b-565d351584222022-03-26T15:53:35ZVariability in high−throughput ion channel screening data and consequences for cardiac safety assessmentJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:4d20d2fc-c0c6-4539-861b-565d35158422Department of Computer Science2013Elkins, RDavies, MBrough, SGavaghan, DCui, YAbi−Gerges, NMirams, GIntroduction: unwanted drug interactions with ionic currents in the heart can lead to an increased pro-arrhythmic risk to patients in the clinic. It is therefore a priority for pharmaceutical safety pharmacology teams to detect block of cardiac ion channels, and new technologies have enabled the development of automated and high-throughput screening assays using cell lines. As a result of screening multiple ion-channels there is a need to integrate information, particularly for compounds affecting more than one current, and mathematical electrophysiology in-silico action potential models are beginning to be used for this. Methods: we quantified the variability associat11 ed with concentration-effect curves fitted to recordings from high-throughput Molecular Devices IonWorks® Quattro— screens when detecting block of IKr (hERG), INa (NaV1.5), ICaL (CaV1.2), IKs (KCNQ1/minK) and Ito Kv4.3/KChIP2.2), and the Molecular Devices FLIPR® Tetra fluorescence screen for ICaL (CaV1.2), for control compounds used at AstraZeneca and GlaxoSmithKline. We examined how screening variability propagates through in-silico action potential models for whole cell electrical behaviour, and how confidence intervals on model predictions can be estimated with repeated simulations. Results: there are significant levels of variability associated with high-throughput ion channel electrophysiology screens. This variability is of a similar magnitude for different cardiac ion currents and different compounds. Uncertainty in the Hill coefficients of reported concentration-effect curves is particularly high. Depending on a compound’s ion channel blocking profile, the uncertainty introduced into whole-cell predictions can become significant. Discussion: our technique allows confidence intervals to be placed on computational model predictions that are based on high-throughput ion channel screens. This allows us to suggest when repeated screens should be performed to reduce uncertainty in a compound’s action to acceptable levels, to allow a meaningful interpretation of the data. |
| spellingShingle | Elkins, R Davies, M Brough, S Gavaghan, D Cui, Y Abi−Gerges, N Mirams, G Variability in high−throughput ion channel screening data and consequences for cardiac safety assessment |
| title | Variability in high−throughput ion channel screening data and consequences for cardiac safety assessment |
| title_full | Variability in high−throughput ion channel screening data and consequences for cardiac safety assessment |
| title_fullStr | Variability in high−throughput ion channel screening data and consequences for cardiac safety assessment |
| title_full_unstemmed | Variability in high−throughput ion channel screening data and consequences for cardiac safety assessment |
| title_short | Variability in high−throughput ion channel screening data and consequences for cardiac safety assessment |
| title_sort | variability in high throughput ion channel screening data and consequences for cardiac safety assessment |
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