使用后验预测检验评估药代动力学/药效学模型。

Evaluating pharmacokinetic/pharmacodynamic models using the posterior predictive check.

作者信息

Yano Y, Beal S L, Sheiner L B

机构信息

Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco, San Francisco, California, USA.

出版信息

J Pharmacokinet Pharmacodyn. 2001 Apr;28(2):171-92. doi: 10.1023/a:1011555016423.

Abstract

The posterior predictive check (PPC) is a model evaluation tool. It assigns a value (pPPC) to the probability that the value of a given statistic computed from data arising under an analysis model is as or more extreme than the value computed from the real data themselves. If this probability is too small, the analysis model is regarded as invalid for the given statistic. Properties of the PPC for pharmacokinetic (PK) and pharmacodynamic (PD) model evaluation are examined herein for a particularly simple simulation setting: extensive sampling of a single individual's data arising from simple PK/PD and error models. To test the performance characteristics of the PPC, repeatedly, "real" data are simulated and for a variety of statistics, the PPC is applied to an analysis model, which may (null hypothesis) or may not (alternative hypothesis) be identical to the simulation model. Five models are used here: (PK1) mono-exponential with proportional error, (PK2) biexponential with proportional error, (PK2 epsilon) biexponential with additive error, (PD1) Emax model with additive error under the logit transform, and (PD2) sigmoid Emax model with additive error under the logit transform. Six simulation/analysis settings are studied. The first three, (PK1/PK1), (PK2/PK2), and (PD1/PD1) evaluate whether the PPC has appropriate type-I error level, whereas the second three (PK2/PK1), (PK2 epsilon/PK2), and (PD2/PD1) evaluate whether the PPC has adequate power. For a set of 100 data sets simulated/analyzed under each model pair according to a stipulated extensive sampling design, the pPPC is computed for a number of statistics in three different ways (each way uses a different approximation to the posterior distribution on the model parameters). We find that in general; (i) The PPC is conservative under the null in the sense that for many statistics, prob(pPPC < or = alpha) < alpha for small alpha. With respect to such statistics, this means that useful models will rarely be regarded incorrectly as invalid. A high correlation of a statistic with the parameter estimates obtained from the same data used to compute the statistic (a measure of statistical "sufficiency") tends to identify the most conservative statistics. (ii) Power is not very great, at least for the alternative models we tested, and it is especially poor with "statistics" that are in part a function of parameters as well as data. Although there is a tendency for nonsufficient statistics (as we have measured this) to have greater power, this is by no means an infallible diagnostic. (iii) No clear advantage for one or another method of approximating the posterior distribution on model parameters is found.

摘要

后验预测检验(PPC)是一种模型评估工具。它为这样一种概率赋予一个值(pPPC),即从分析模型下产生的数据计算得到的给定统计量的值与从实际数据本身计算得到的值一样极端或更极端的概率。如果这个概率太小,那么对于给定的统计量,分析模型被视为无效。本文针对一种特别简单的模拟设置,研究了PPC在药代动力学(PK)和药效动力学(PD)模型评估中的特性:对来自简单PK/PD和误差模型的单个个体的数据进行广泛采样。为了测试PPC的性能特征,反复模拟“真实”数据,并针对各种统计量,将PPC应用于一个分析模型,该分析模型可能(原假设)也可能不(备择假设)与模拟模型相同。这里使用了五个模型:(PK1)具有比例误差的单指数模型,(PK2)具有比例误差的双指数模型,(PK2 ε)具有加性误差的双指数模型,(PD1)在logit变换下具有加性误差的Emax模型,以及(PD2)在logit变换下具有加性误差的S形Emax模型。研究了六种模拟/分析设置。前三种,即(PK1/PK1)、(PK2/PK2)和(PD1/PD1),评估PPC是否具有适当的I型错误水平,而后三种,即(PK2/PK1)、(PK2 ε/PK2)和(PD2/PD1),评估PPC是否具有足够的检验功效。对于根据规定的广泛采样设计在每个模型对下模拟/分析的一组100个数据集,以三种不同方式为多个统计量计算pPPC(每种方式对模型参数的后验分布使用不同的近似)。我们发现,一般来说:(i)在原假设下,PPC是保守的,即对于许多统计量,当α较小时,prob(pPPC≤α)<α。对于这样的统计量,这意味着有用的模型很少会被错误地视为无效。一个统计量与从用于计算该统计量的相同数据获得的参数估计值的高相关性(一种统计“充分性”的度量)往往能识别出最保守的统计量。(ii)检验功效不是很大,至少对于我们测试的备择模型是这样,而且对于部分是参数以及数据的函数的“统计量”来说尤其差。尽管存在非充分统计量(如我们所测量的)具有更大检验功效的趋势,但这绝不是一个可靠的诊断方法。(iii)没有发现一种近似模型参数后验分布的方法相对于另一种方法有明显优势。

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