Integrating dynamic mixed-effect modelling and penalized regression to explore genetic association with pharmacokinetics.
Integrating dynamic mixed-effect modelling and penalized regression to explore genetic association with pharmacokinetics.
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DOI：
10.1097/fpc.0000000000000127
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发表时间：
2015-05
影响因子：
2.6
通讯作者：
Balding DJ
中科院分区：
文献类型：
--
作者：
Bertrand J;De Iorio M;Balding DJ
补充数字内容可在文本中找到。在以前的工作中，我们已经表明，惩罚回归方法可以允许许多遗传变异以计算和统计效率都很高的方式纳入复杂的药代动力学（PK）模型。表型是个体模型参数估计值，获得模型拟合的后验，已知对研究设计敏感。本研究的目的是提出一种综合方法，其中遗传效应大小与PK模型参数同时估计，这将提高估计精度并降低对研究设计的敏感性。在空值和以下三种替代方案中的每一种下模拟了总共200个数据集：（i）一项II期研究，N=300名受试者，n=6个采样时间，其中6个未观察到的因果变异影响药物消除清除率;（ii）增加临床常规中收集的残留浓度的受试者，（N=300，n=6加N=700，n=1）;和（iii）II期研究（N=300，n=6），其中四个未观察到的因果变量影响两个不同的模型参数。在所有情况下，综合方法检测到更少的误报。在情景（i）中，真阳性率较低，逐步程序优于综合方法。在设想情况（二）中，各种方法的效果相似，发生率较高。在设想（三）中，综合办法优于逐步程序。N=300的PK II期研究缺乏使用基因阵列检测对PK的遗传效应的能力。我们的方法可以同时分析II期和临床常规数据，并确定遗传变异何时影响多个PK参数。
Supplemental Digital Content is available in the text. In a previous work, we have shown that penalized regression approaches can allow many genetic variants to be incorporated into sophisticated pharmacokinetic (PK) models in a way that is both computationally and statistically efficient. The phenotypes were the individual model parameter estimates, obtained a posteriori of the model fit and known to be sensitive to the study design. The aim of this study was to propose an integrated approach in which genetic effect sizes are estimated simultaneously with the PK model parameters, which should improve the estimate precision and reduce sensitivity to study design. A total of 200 data sets were simulated under the null and each of the following three alternative scenarios: (i) a phase II study with N=300 participants and n=6 sampling times, wherein six unobserved causal variants affect the drug elimination clearance; (ii) the addition of participants with a residual concentration collected in clinical routine (N=300, n=6 plus N=700, n=1); and (iii) a phase II study (N=300, n=6) in which four unobserved causal variants affect two different model parameters. In all scenarios the integrated approach detected fewer false positives. In scenario (i), true-positive rates were low and the stepwise procedure outperformed the integrated approach. In scenario (ii), approaches performed similarly and rates were higher. In scenario (iii), the integrated approach outperformed the stepwise procedure. A PK phase II study with N=300 lacks the power to detect genetic effects on PK using genetic arrays. Our approach can simultaneously analyse phase II and clinical routine data and identify when genetic variants affect multiple PK parameters.