Four ways to fit an ion channel model
Four ways to fit an ion channel model
复制标题
拟合离子通道模型的四种方法
DOI：
10.1101/609875
复制
发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Clerx M
中科院分区：
文献类型：
--
作者：
Clerx M
离子电流的数学模型用于研究心脏、大脑、肠道和其他几个器官的电生理学。这些模型越来越多地用于临床预测，例如，预测基因突变、药物治疗或外科手术的风险和结果。这些安全关键应用依赖于对潜在离子电流的准确表征。在文献中可以找到四种不同的方法来将电压敏感离子通道模型拟合到全细胞电流测量：方法1，将模型方程直接拟合到时间常数、稳态和I-V汇总曲线;方法2，通过将这些汇总曲线的模拟版本与它们的实验对应物进行比较来拟合;方法3，拟合到来自一系列协议的电流迹线本身;方法4，将模型方程直接拟合到时间常数、稳态和I-V汇总曲线。以及方法4，拟合来自短且快速波动的电压钳协议的单个电流迹线。我们使用一组实验比较这些方法，其中在9个中国仓鼠卵巢细胞中测量hERG 1a电流。在每个单元中，应用相同的拟合方案序列以及独立的验证方案。我们发现，方法3和4提供了最好的预测的独立验证集和短，快速波动的协议，如方法4中使用的可以取代更长的传统协议，而不会损失的预测能力。虽然方法2的数据是最容易从文献中获得的，我们发现它执行差的方法3和4相比，无论是在预测的准确性和计算效率。我们的研究结果表明，新的实验和计算方法可以提高安全关键应用中的模型预测质量。
Mathematical models of ionic currents are used to study the electrophysiology of the heart, brain, gut, and several other organs. Increasingly, these models are being used predictively in the clinic, for example, to predict the risks and results of genetic mutations, pharmacological treatments, or surgical procedures. These safety-critical applications depend on accurate characterization of the underlying ionic currents. Four different methods can be found in the literature to fit voltage-sensitive ion channel models to whole-cell current measurements: method 1, fitting model equations directly to time-constant, steady-state, and I-V summary curves; method 2, fitting by comparing simulated versions of these summary curves to their experimental counterparts; method 3, fitting to the current traces themselves from a range of protocols; and method 4, fitting to a single current trace from a short and rapidly fluctuating voltage-clamp protocol. We compare these methods using a set of experiments in which hERG1a current was measured in nine Chinese hamster ovary cells. In each cell, the same sequence of fitting protocols was applied, as well as an independent validation protocol. We show that methods 3 and 4 provide the best predictions on the independent validation set and that short, rapidly fluctuating protocols like that used in method 4 can replace much longer conventional protocols without loss of predictive ability. Although data for method 2 are most readily available from the literature, we find it performs poorly compared to methods 3 and 4 both in accuracy of predictions and computational efficiency. Our results demonstrate how novel experimental and computational approaches can improve the quality of model predictions in safety-critical applications.