Non linear mixed effect models are classical tools to analyze non linear longitudinal data in many fields such as population Pharmacokinetic. Groups of observations are usually compared by introducing the group affiliations as binary covariates with a reference group that is stated among the groups. This approach is relatively limited as it allows only the comparison of the reference group to the others. In this work, we propose to compare the groups using a penalized likelihood approach. Groups are described by the same structural model but with parameters that are group specific. The likelihood is penalized with a fused lasso penalty that induces sparsity on the differences between groups for both fixed effects and variances of random effects. A penalized Stochastic Approximation EM algorithm is proposed that is coupled to Alternating Direction Method Multipliers to solve the maximization step. An extensive simulation study illustrates the performance of this algorithm when comparing more than two groups. Then the approach is applied to real data from two pharmacokinetic drug-drug interaction trials.
Motivated by penalized likelihood maximization in complex models, we study optimization problems where neither the function to optimize nor its gradient have an explicit expression, but its gradient can be approximated by a Monte Carlo technique. We propose a new algorithm based on a stochastic approximation of the Proximal-Gradient (PG) algorithm. This new algorithm, named Stochastic Approximation PG (SAPG) is the combination of a stochastic gradient descent step which - roughly speaking - computes a smoothed approximation of the past gradient along the iterations, and a proximal step. The choice of the step size and the Monte Carlo batch size for the stochastic gradient descent step in SAPG are discussed. Our convergence results cover the cases of biased and unbiased Monte Carlo approximations. While the convergence analysis of the Monte Carlo-PG is already addressed in the literature (see Atchade et al. [2016]), the convergence analysis of SAPG is new. The two algorithms are compared on a linear mixed effect model as a toy example. A more challenging application is proposed on non-linear mixed effect models in high dimension with a pharmacokinetic data set including genomic covariates. To our best knowledge, our work provides the first convergence result of a numerical method designed to solve penalized Maximum Likelihood in a non-linear mixed effect model.
The estimation of high dimensional precision matrices has been a central topic in statistical learning. However, as the number of parameters scales quadratically with the dimension $p$, many state-of-the-art methods do not scale well to solve problems with a very large $p$. In this paper, we propose a very efficient algorithm for precision matrix estimation via penalized quadratic loss functions. Under the high dimension low sample size setting, the computation complexity of our algorithm is linear in both the sample size and the number of parameters. Such a computation complexity is in some sense optimal, as it is the same as the complexity needed for computing the sample covariance matrix. Numerical studies show that our algorithm is much more efficient than other state-of-the-art methods when the dimension $p$ is very large.
A current challenge for many Bayesian analyses is determining when to terminate high-dimensional Markov chain Monte Carlo simulations. To this end, we propose using an automated sequential stopping procedure that terminates the simulation when the computational uncertainty is small relative to the posterior uncertainty. Such a stopping rule has previously been shown to work well in settings with posteriors of moderate dimension. In this paper, we illustrate its utility in high-dimensional simulations while overcoming some current computational issues. Further, we investigate the relationship between the stopping rule and effective sample size. As examples, we consider two complex Bayesian analyses on spatially and temporally correlated datasets. The first involves a dynamic space-time model on weather station data and the second a spatial variable selection model on fMRI brain imaging data. Our results show the sequential stopping rule is easy to implement, provides uncertainty estimates, and performs well in high-dimensional settings.
The ability to generate samples of the random effects from their conditional distributions is fundamental for inference in mixed effects models. Random walk Metropolis is widely used to perform such sampling, but this method is known to converge slowly for medium dimensional problems, or when the joint structure of the distributions to sample is spatially heterogeneous. The main contribution consists of an independent Metropolis-Hastings (MH) algorithm based on a multidimensional Gaussian proposal that takes into account the joint conditional distribution of the random effects and does not require any tuning. Indeed, this distribution is automatically obtained thanks to a Laplace approximation of the incomplete data model. Such approximation is shown to be equivalent to linearizing the structural model in the case of continuous data. Numerical experiments based on simulated and real data illustrate the performance of the proposed methods. For fitting nonlinear mixed effects models, the suggested MH algorithm is efficiently combined with a stochastic approximation version of the EM algorithm for maximum likelihood estimation of the global parameters.
From an optimizers perspective, achieving the global optimum for a general nonconvex problem is often provably NP-hard using the classical worst-case analysis. In the case of Coxs proportional hazards model, by taking its statistical model structures into account, we identify local strong convexity near the global optimum, motivated by which we propose to use two convex programs to optimize the folded-concave penalized Coxs proportional hazards regression. Theoretically, we investigate the statistical and computational tradeoffs of the proposed algorithm and establish the strong oracle property of the resulting estimators. Numerical studies and real data analysis lend further support to our algorithm and theory.
Edouard Ollier
,Adeline Samson
,Xavier Delavenne
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(2015)
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"A SAEM Algorithm for Fused Lasso Penalized Non Linear Mixed Effect Models: Application to Group Comparison in Pharmacokinetic"
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Edouard Ollier
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