Professor GARY MIRAMS's Outputs (124)

Empirical Quantification of Predictive Uncertainty Due to Model Discrepancy by Training with an Ensemble of Experimental Designs: An Application to Ion Channel Kinetics (2023)
Journal Article
Shuttleworth, J. G., Lei, C. L., Whittaker, D. G., Windley, M. J., Hill, A. P., Preston, S. P., & Mirams, G. R. (2024). Empirical Quantification of Predictive Uncertainty Due to Model Discrepancy by Training with an Ensemble of Experimental Designs: An Application to Ion Channel Kinetics. Bulletin of Mathematical Biology, 86(1), Article 2. https://doi.org/10.1007/s11538-023-01224-6

When using mathematical models to make quantitative predictions for clinical or industrial use, it is important that predictions come with a reliable estimate of their accuracy (uncertainty quantification). Because models of complex biological system... Read More about Empirical Quantification of Predictive Uncertainty Due to Model Discrepancy by Training with an Ensemble of Experimental Designs: An Application to Ion Channel Kinetics.

The impact of uncertainty in hERG binding mechanism on in silico predictions of drug-induced proarrhythmic risk (2023)
Journal Article
Lei, C. L., Whittaker, D. G., & Mirams, G. R. (2024). The impact of uncertainty in hERG binding mechanism on in silico predictions of drug-induced proarrhythmic risk. British Journal of Pharmacology, 181(7), 987-1004. https://doi.org/10.1111/bph.16250

Background and Purpose
Drug-induced reduction of the rapid delayed rectifier potassium current carried by the human Ether-à-go-go-Related Gene (hERG) channel is associated with increased risk of arrhythmias. Recent updates to drug safety regulatory... Read More about The impact of uncertainty in hERG binding mechanism on in silico predictions of drug-induced proarrhythmic risk.

Leak current, even with gigaohm seals, can cause misinterpretation of stem cell-derived cardiomyocyte action potential recordings (2023)
Journal Article
Clark, A. P., Clerx, M., Wei, S., Lei, C. L., de Boer, T. P., Mirams, G. R., Christini, D. J., & Krogh-Madsen, T. (2023). Leak current, even with gigaohm seals, can cause misinterpretation of stem cell-derived cardiomyocyte action potential recordings. EP-Europace, 25(9), Article euad243. https://doi.org/10.1093/europace/euad243

Aims
Human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have become an essential tool to study arrhythmia mechanisms. Much of the foundational work on these cells, as well as the computational models built from the resultant data,... Read More about Leak current, even with gigaohm seals, can cause misinterpretation of stem cell-derived cardiomyocyte action potential recordings.

Model-driven optimal experimental design for calibrating cardiac electrophysiology models (2023)
Journal Article
Lei, C. L., Clerx, M., Gavaghan, D. J., & Mirams, G. R. (2023). Model-driven optimal experimental design for calibrating cardiac electrophysiology models. Computer Methods and Programs in Biomedicine, 240, Article 107690. https://doi.org/10.1016/j.cmpb.2023.107690

Background and Objective: Models of the cardiomyocyte action potential have contributed immensely to the understanding of heart function, pathophysiology, and the origin of heart rhythm disturbances. However, action potential models are highly nonlin... Read More about Model-driven optimal experimental design for calibrating cardiac electrophysiology models.

Model-driven optimal experimental design for calibrating cardiac electrophysiology models (2023)
Journal Article
Lei, C. L., Clerx, M., Gavaghan, D. J., & Mirams, G. R. (2023). Model-driven optimal experimental design for calibrating cardiac electrophysiology models. Computer Methods and Programs in Biomedicine, 240, Article 107690. https://doi.org/10.1016/j.cmpb.2023.107690

Background and Objective: Models of the cardiomyocyte action potential have contributed immensely to the understanding of heart function, pathophysiology, and the origin of heart rhythm disturbances. However, action potential models are highly nonlin... Read More about Model-driven optimal experimental design for calibrating cardiac electrophysiology models.

Computational Cardiac Safety Testing (2023)
Book Chapter
Mirams, G. R. (2023). Computational Cardiac Safety Testing. In F. J. Hock, M. R. Gralinski, & M. K. Pugsley (Eds.), Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays (1-33). Springer. https://doi.org/10.1007/978-3-030-73317-9_137-1

In recent years, computational cardiac electrophysiology simulations using mathematical models have begun to be used in industrial and regulatory assessment of the proarrhythmic risk of candidate drug compounds. The aim of this chapter is to equip th... Read More about Computational Cardiac Safety Testing.

Using many different voltage protocols to characterise discrepancy in mathematical ion channel models (2023)
Journal Article
Shuttleworth, J. G., Lok Lei, C., Windley, M., Hill, A. P., Perry, M. D., Preston, S., & Mirams, G. R. (2023). Using many different voltage protocols to characterise discrepancy in mathematical ion channel models. Biophysical Journal, 122(3, Suppl. 1), 242a. https://doi.org/10.1016/j.bpj.2022.11.1415

The Kv11.1 protein encoded by the hERG gene forms the primary subunit of a voltage-sensitive ion channel responsible for IKr in cardiomyocytes. Mathematical models of the macroscopic current are fitted to data from patch-clamp experiments - in which... Read More about Using many different voltage protocols to characterise discrepancy in mathematical ion channel models.

Derivative-based Inference for Cell and Channel Electrophysiology Models (2022)
Presentation / Conference Contribution
Clerx, M., Augustin, D., Dale-Evans, A. R., & Mirams, G. R. (2022, September). Derivative-based Inference for Cell and Channel Electrophysiology Models. Presented at 2022 Computing in Cardiology Conference, Tampere, Finland (online)

Models of ionic currents or of the cardiac action potential (AP) are frequently calibrated by defining an error function that quantifies the mismatch between simulations and data, and using numerical optimisation to find the parameter values that min... Read More about Derivative-based Inference for Cell and Channel Electrophysiology Models.

Modelling the Effect of Intracellular Calcium in the Rundown of L-Type Calcium Current (2022)
Presentation / Conference Contribution
Agrawal, A., Clerx, M., Wang, K., Polonchuk, L., Gavaghan, D. J., & Mirams, G. R. (2022, September). Modelling the Effect of Intracellular Calcium in the Rundown of L-Type Calcium Current. Presented at 2022 Computing in Cardiology Conference, Tampere, Finland

The L-type calcium current (ICaL) is a key current of the heart playing an important role in the contraction of the cardiomyocyte. Patch-clamp recordings of ionic currents can be associated with a reduction of the current magnitude with time (termed... Read More about Modelling the Effect of Intracellular Calcium in the Rundown of L-Type Calcium Current.

Normalisation of Action Potential Data Recorded with Sharp Electrodes Maximises Its Utility for Model Development (2022)
Presentation / Conference Contribution
Barral, Y. S. H., Polonchuk, L., R. Mirams, G., Clerx, M., Page, G., Sweat, K., Abi-Gerges, N., Wang, K., & Gavaghan, D. J. (2022, September). Normalisation of Action Potential Data Recorded with Sharp Electrodes Maximises Its Utility for Model Development. Presented at 2022 Computing in Cardiology Conference, Tampere, Finland

In silico models of cardiomyocyte electrophysiology describe the various ionic currents and fluxes that lead to the formation of action potentials (APs). Experimental data used to create such models can be recorded in adult human cardiac trabeculae u... Read More about Normalisation of Action Potential Data Recorded with Sharp Electrodes Maximises Its Utility for Model Development.

Uncertainty and error in SARS-CoV-2 epidemiological parameters inferred from population-level epidemic models (2022)
Journal Article
Whittaker, D. G., Herrera-Reyes, A. D., Hendrix, M., Owen, M. R., Band, L. R., Mirams, G. R., Bolton, K. J., & Preston, S. P. (2023). Uncertainty and error in SARS-CoV-2 epidemiological parameters inferred from population-level epidemic models. Journal of Theoretical Biology, 558, Article 111337. https://doi.org/10.1016/j.jtbi.2022.111337

During the SARS-CoV2 pandemic, epidemic models have been central to policy-making. Public health responses have been shaped by model-based projections and inferences, especially related to the impact of various non-pharmaceutical interventions. Accom... Read More about Uncertainty and error in SARS-CoV-2 epidemiological parameters inferred from population-level epidemic models.

Nuanced Interactions between AKAP79 and STIM1 with Orai1 Ca 2+ Channels at Endoplasmic Reticulum-Plasma Membrane Junctions Sustain NFAT Activation (2022)
Journal Article
Lin, Y.-P., Scappini, E., Landaverde, C., Parekh-Glitsch, F., Tucker, C. J., Mirams, G. R., & Parekh, A. B. (2022). Nuanced Interactions between AKAP79 and STIM1 with Orai1 Ca 2+ Channels at Endoplasmic Reticulum-Plasma Membrane Junctions Sustain NFAT Activation. Molecular and Cellular Biology, 42(11), Article e00175-22. https://doi.org/10.1128/mcb.00175-22

A-kinase anchoring protein 79 (AKAP79) is a human scaffolding protein that organizes Ca2+/calmodulin-dependent protein phosphatase calcineurin, calmodulin, cAMP-dependent protein kinase, protein kinase C, and the transcription factor nuclear factor o... Read More about Nuanced Interactions between AKAP79 and STIM1 with Orai1 Ca 2+ Channels at Endoplasmic Reticulum-Plasma Membrane Junctions Sustain NFAT Activation.

Models of the cardiac L-type calcium current: A quantitative review (2022)
Journal Article
Agrawal, A., Wang, K., Polonchuk, L., Cooper, J., Hendrix, M., Gavaghan, D. J., Gavaghan, D. J., Mirams, G. R., & Clerx, M. (2022). Models of the cardiac L-type calcium current: A quantitative review. Wiley Interdisciplinary Reviews: Mechanisms of Disease, 15(1), Article e1581. https://doi.org/10.1002/wsbm.1581

The L-type calcium current ((Formula presented.)) plays a critical role in cardiac electrophysiology, and models of (Formula presented.) are vital tools to predict arrhythmogenicity of drugs and mutations. Five decades of measuring and modeling (Form... Read More about Models of the cardiac L-type calcium current: A quantitative review.

Ion channel model reduction using manifold boundaries (2022)
Journal Article
Whittaker, D. G., Wang, J., Shuttleworth, J., Venkateshappa, R., Kemp, J. M., Claydon, T. W., & Mirams, G. R. (2022). Ion channel model reduction using manifold boundaries. Journal of the Royal Society, Interface, 19(193), Article 20220193. https://doi.org/10.1098/rsif.2022.0193

Mathematical models of voltage-gated ion channels are used in basic research, industrial and clinical settings. These models range in complexity, but typically contain numerous variables representing the proportion of channels in a given state, and p... Read More about Ion channel model reduction using manifold boundaries.

cellmlmanip and chaste_codegen: automatic CellML to C++ code generation with fixes for singularities and automatically generated Jacobians (2022)
Journal Article
Hendrix, M., Clerx, M., Tamuri, A. U., Keating, S. M., Johnstone, R. H., Cooper, J., & Mirams, G. R. (2022). cellmlmanip and chaste_codegen: automatic CellML to C++ code generation with fixes for singularities and automatically generated Jacobians. Wellcome Open Research, 6, Article 261. https://doi.org/10.12688/wellcomeopenres.17206.2

Hundreds of different mathematical models have been proposed for describing electrophysiology of various cell types. These models are quite complex (nonlinear systems of typically tens of ODEs and sometimes hundreds of parameters) and software packag... Read More about cellmlmanip and chaste_codegen: automatic CellML to C++ code generation with fixes for singularities and automatically generated Jacobians.

A Parameter Representing Missing Charge Should Be Considered when Calibrating Action Potential Models (2022)
Journal Article
Barral, Y.-S. H. M., Shuttleworth, J., Clerx, M., Whittaker, D. G., Wang, K., Polonchuk, L., Gavaghan, D. J., & Mirams, G. R. (2022). A Parameter Representing Missing Charge Should Be Considered when Calibrating Action Potential Models. Frontiers in Physiology, 13, Article 879035. https://doi.org/10.3389/fphys.2022.879035

Computational models of the electrical potential across a cell membrane are longstanding and vital tools in electrophysiology research and applications. These models describe how ionic currents, internal fluxes, and buffering interact to determine me... Read More about A Parameter Representing Missing Charge Should Be Considered when Calibrating Action Potential Models.

chaste codegen: automatic CellML to C++ code generation with fixes for singularities and automatically generated Jacobians (2022)
Journal Article
Hendrix, M., Clerx, M., Tamuri, A. U., Keating, S. M., Johnstone, R. H., Cooper, J., & Mirams, G. R. (2022). chaste codegen: automatic CellML to C++ code generation with fixes for singularities and automatically generated Jacobians. Wellcome Open Research, 6, Article 261. https://doi.org/10.12688/wellcomeopenres.17206.1

Hundreds of different mathematical models have been proposed for describing electrophysiology of various cell types. These models are quite complex (nonlinear systems of typically tens of ODEs and sometimes hundreds of parameters) and software packag... Read More about chaste codegen: automatic CellML to C++ code generation with fixes for singularities and automatically generated Jacobians.

A Quantitative Systems Pharmacology Perspective on the Importance of Parameter Identifiability (2022)
Journal Article
Sher, A., Niederer, S. A., Mirams, G. R., Kirpichnikova, A., Allen, R., Pathmanathan, P., Gavaghan, D. J., van der Graaf, P. H., & Noble, D. (2022). A Quantitative Systems Pharmacology Perspective on the Importance of Parameter Identifiability. Bulletin of Mathematical Biology, 84(3), Article 39. https://doi.org/10.1007/s11538-021-00982-5

There is an inherent tension in Quantitative Systems Pharmacology (QSP) between the need to incorporate mathematical descriptions of complex physiology and drug targets with the necessity of developing robust, predictive and well-constrained models.... Read More about A Quantitative Systems Pharmacology Perspective on the Importance of Parameter Identifiability.

A nonlinear and time-dependent leak current in the presence of calcium fluoride patch-clamp seal enhancer (2021)
Journal Article
Lei, C. L., Fabbri, A., Whittaker, D. G., Clerx, M., Windley, M. J., Hill, A. P., Mirams, G. R., & de Boer, T. P. (2021). A nonlinear and time-dependent leak current in the presence of calcium fluoride patch-clamp seal enhancer. Wellcome Open Research, 5, 1-34. https://doi.org/10.12688/wellcomeopenres.15968.2

Automated patch-clamp platforms are widely used and vital tools in both academia and industry to enable high-throughput studies such as drug screening. A leak current to ground occurs whenever the seal between a pipette and cell (or internal solution... Read More about A nonlinear and time-dependent leak current in the presence of calcium fluoride patch-clamp seal enhancer.

Electrophysiological characterization of the hERG R56Q LQTS variant and targeted rescue by the activator RPR260243 (2021)
Journal Article
Kemp, J. M., Whittaker, D. G., Venkateshappa, R., Pang, Z. K., Johal, R., Sergeev, V., Tibbits, G. F., Mirams, G. R., & Claydon, T. W. (2021). Electrophysiological characterization of the hERG R56Q LQTS variant and targeted rescue by the activator RPR260243. Journal of General Physiology, 153(10), Article e202112923. https://doi.org/10.1085/jgp.202112923

Human Ether-à-go-go (hERG) channels contribute to cardiac repolarization, and inherited variants or drug block are associated with long QT syndrome type 2 (LQTS2) and arrhythmia. Therefore, hERG activator compounds present a therapeutic opportunity f... Read More about Electrophysiological characterization of the hERG R56Q LQTS variant and targeted rescue by the activator RPR260243.