Scalable Krylov Subspace Methods for Generalized Mixed-Effects Models with Crossed Random Effects

We introduce Gradient Boosted Mixed Models (GBMixed), a framework which extends boosting to clustered data by jointly modeling the mean and variance components in a linear mixed model via likelihood-based gradients. GBMixed estimates a nonparametric fixed effects function characterizing the overall mean of the response, while also allowing the random effects covariance matrix along with the residual variance to depend on covariates in a flexible manner. We demonstrate how GBMixed facilitates covariate-dependent random effect predictions, and subsequently point predictions and prediction intervals for individual treatment effects, that can adapt between population-level and cluster-level information. Simulations and applications to two real-world datasets demonstrate that GBMixed can accurately recover complex nonlinear fixed effect functions and covariate-dependent covariances in a linear mixed model, while also improving point and probabilistic predictive performance compared with several existing approaches such as parametric linear mixed models, Natural Gradient Boosting, and Gaussian Process Boosting.

Nonlinear Mixed Effects (NLME) models are widely used in pharmacometrics and related fields to analyze hierarchical and longitudinal data. However, as the number of parameters and random effects increases, traditional methods for maximizing the marginal likelihood become computationally expensive. This paper explores the Variational Expectation Maximization (VEM) algorithm, a scalable alternative for fitting NLME models. Originally introduced in the context of probabilistic graphical models and later popularized through variational autoencoders, VEM has not been extensively applied to NLME modeling. By leveraging flexible variational families and reverse-mode automatic differentiation, VEM can efficiently maximize the marginal likelihood, scaling to NLME models with over 15,000 population parameters. This work provides a detailed description of VEM, compares it to other NLME fitting algorithms, and highlights its scalability through computational experiments. Using the Pumas statistical software, we fit two test models: 1) a standard warfarin model, and 2) an unnecessarily over-parameterized DeepNLME Friberg model with 15,410 population parameters and 16 random effects. The warfarin model was fitted to completion to demonstrate the correctness of VEM, while the DeepNLME Friberg model instead demonstrates VEM's scalability on a toy but large model. VEM improves the log likelihood steadily over hundreds of iterations at a practical per-iteration cost, while FOCE fails to complete even one iteration within a day. The model is deliberately over-parameterized for its small dataset and over-fits it, so what this experiment establishes is that VEM optimizes the objective of a model of this size at a practical cost. Applying VEM to large models that are genuinely useful is left to future work.

Across many scientific disciplines, multiple observations are collected from the same experimental units, and in modern datasets these observations often arise as non-Euclidean random objects. In such settings, the incorporation of random effects is a critical modeling step for efficient estimation and personalized prediction. Although mixed-effects models are well established for scalar outcomes and, more recently, for functional data in Hilbert spaces, general random-effects frameworks for objects in metric spaces remain underdeveloped. In this paper, we propose a nonlinear Fréchet-based algorithm for random-effects modeling of arbitrary random objects defined on a metric space. Using M-estimation theory, we establish conditions under which the proposed metric-space prediction target is consistently estimated under a working random-effects formulation. We then evaluate the empirical performance of the proposed method using both synthetic data and digital health datasets that require practical tools for analyzing random objects in metric spaces, such as multivariate probability distributions and random graphs. We show that, although our method is developed beyond Hilbert spaces, it can outperform existing Hilbert space-based methods.