Retout Sylvie, Comets Emmanuelle, Samson Adeline, Mentré France
Inserm, U738, Paris, France.
Stat Med. 2007 Dec 10;26(28):5162-79. doi: 10.1002/sim.2910.
We extend the methodology for designs evaluation and optimization in nonlinear mixed effects models with an illustration of the decrease of human immunodeficiency virus viral load after antiretroviral treatment initiation described by a bi-exponential model. We first show the relevance of the predicted standard errors (SEs) given by the computation of the population Fisher information matrix using the R function PFIM, in comparison to those computed with the stochastic approximation expectation-maximization algorithm, implemented in the Monolix software. We then highlight the usefulness of the Fedorov-Wynn (FW) algorithm for designs optimization compared to the Simplex algorithm. From the predicted SE of PFIM, we compute the predicted power of the Wald test to detect a treatment effect as well as the number of subjects needed to achieve a given power. Using the FW algorithm, we investigate the influence of the design on the power and show that, for optimized designs with the same total number of samples, the power increases when the number of subjects increases and the number of samples per subject decreases. A simulation study is also performed with the nlme function of R to confirm this result and show the relevance of the predicted powers compared to those observed by simulation.
我们扩展了非线性混合效应模型中设计评估和优化的方法，并通过双指数模型描述的抗逆转录病毒治疗开始后人类免疫缺陷病毒病毒载量的下降进行了说明。我们首先展示了使用R函数PFIM计算总体费舍尔信息矩阵得到的预测标准误差（SEs）与在Monolix软件中实现的随机近似期望最大化算法计算的标准误差相比的相关性。然后，我们强调了与单纯形算法相比，费多罗夫 - 韦恩（FW）算法在设计优化方面的有用性。根据PFIM的预测SE，我们计算了检测治疗效果的Wald检验的预测功效以及达到给定功效所需的受试者数量。使用FW算法，我们研究了设计对功效的影响，并表明，对于具有相同样本总数的优化设计，当受试者数量增加且每个受试者的样本数量减少时，功效会增加。还使用R的nlme函数进行了模拟研究，以证实这一结果，并展示预测功效与模拟观察到的功效相比的相关性。
