Université Paris Cité, Inserm, IAME, F-75018, Paris, France.
Department of Biostatistics, Roche Innovation Center Basel, Basel, Switzerland.
AAPS J. 2024 Apr 23;26(3):53. doi: 10.1208/s12248-024-00905-x.
The standard errors (SE) of the maximum likelihood estimates (MLE) of the population parameter vector in nonlinear mixed effect models (NLMEM) are usually estimated using the inverse of the Fisher information matrix (FIM). However, at a finite distance, i.e. far from the asymptotic, the FIM can underestimate the SE of NLMEM parameters. Alternatively, the standard deviation of the posterior distribution, obtained in Stan via the Hamiltonian Monte Carlo algorithm, has been shown to be a proxy for the SE, since, under some regularity conditions on the prior, the limiting distributions of the MLE and of the maximum a posterior estimator in a Bayesian framework are equivalent. In this work, we develop a similar method using the Metropolis-Hastings (MH) algorithm in parallel to the stochastic approximation expectation maximisation (SAEM) algorithm, implemented in the saemix R package. We assess this method on different simulation scenarios and data from a real case study, comparing it to other SE computation methods. The simulation study shows that our method improves the results obtained with frequentist methods at finite distance. However, it performed poorly in a scenario with the high variability and correlations observed in the real case study, stressing the need for calibration.
非线性混合效应模型(NLMEM)中群体参数向量的最大似然估计(MLE)的标准误差(SE)通常使用 Fisher 信息矩阵(FIM)的逆来估计。然而,在有限的距离内,即在远离渐近的情况下,FIM 可能会低估 NLMEM 参数的 SE。或者,通过 Hamiltonian 蒙特卡罗算法在 Stan 中获得的后验分布的标准差已被证明是 SE 的代理,因为在一些正则条件下,贝叶斯框架中的 MLE 和最大后验估计的极限分布是等效的。在这项工作中,我们使用 Metropolis-Hastings(MH)算法开发了一种类似的方法,该算法与在 saemix R 包中实现的随机逼近期望最大化(SAEM)算法并行运行。我们在不同的模拟场景和真实案例研究的数据上评估了这种方法,并将其与其他 SE 计算方法进行了比较。模拟研究表明,我们的方法在有限的距离内改善了与频率主义方法相比的结果。然而,在真实案例研究中观察到的高变异性和相关性的情况下,它的表现不佳,强调了需要校准。