用于诊断非线性混合效应模型的预测校正可视化预测检验。

Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models.

机构信息

Department of Pharmaceutical Biosciences, Uppsala University, Sweden.

出版信息

AAPS J. 2011 Jun;13(2):143-51. doi: 10.1208/s12248-011-9255-z. Epub 2011 Feb 8.

Abstract

Informative diagnostic tools are vital to the development of useful mixed-effects models. The Visual Predictive Check (VPC) is a popular tool for evaluating the performance of population PK and PKPD models. Ideally, a VPC will diagnose both the fixed and random effects in a mixed-effects model. In many cases, this can be done by comparing different percentiles of the observed data to percentiles of simulated data, generally grouped together within bins of an independent variable. However, the diagnostic value of a VPC can be hampered by binning across a large variability in dose and/or influential covariates. VPCs can also be misleading if applied to data following adaptive designs such as dose adjustments. The prediction-corrected VPC (pcVPC) offers a solution to these problems while retaining the visual interpretation of the traditional VPC. In a pcVPC, the variability coming from binning across independent variables is removed by normalizing the observed and simulated dependent variable based on the typical population prediction for the median independent variable in the bin. The principal benefit with the pcVPC has been explored by application to both simulated and real examples of PK and PKPD models. The investigated examples demonstrate that pcVPCs have an enhanced ability to diagnose model misspecification especially with respect to random effects models in a range of situations. The pcVPC was in contrast to traditional VPCs shown to be readily applicable to data from studies with a priori and/or a posteriori dose adaptations.

摘要

信息性诊断工具对于开发有用的混合效应模型至关重要。可视预测检查(VPC)是评估群体 PK 和 PKPD 模型性能的常用工具。理想情况下,VPC 将诊断混合效应模型中的固定效应和随机效应。在许多情况下,这可以通过将观察数据的不同分位数与模拟数据的分位数进行比较来实现,通常在自变量的箱内分组。然而,VPC 的诊断价值可能会受到剂量和/或有影响的协变量的大变异的箱分的阻碍。如果将 VPC 应用于自适应设计(例如剂量调整)后的数据,也可能会产生误导。预测校正 VPC(pcVPC)在保留传统 VPC 的视觉解释的同时,为这些问题提供了一种解决方案。在 pcVPC 中,通过根据箱中中位数自变量的典型人群预测,对观察到的和模拟的因变量进行归一化,消除了因自变量箱分引起的变异性。通过对 PK 和 PKPD 模型的模拟和真实示例的应用,已经探讨了 pcVPC 的主要优势。所研究的示例表明,pcVPC 具有增强的诊断模型指定错误的能力,尤其是在各种情况下的随机效应模型方面。与传统 VPC 相比,pcVPC 被证明易于应用于具有事先和/或事后剂量调整的研究的数据。

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