Implementing neural network mixed-effects models in Template Model Builder (TMB)

Hierarchical data is ubiquitous in the empirical sciences and is most commonly analyzed with generalized linear mixed-effects models (GLMMs). Bayesian inference for GLMMs yields calibrated uncertainty but requires MCMC; the No-U-Turn Sampler (NUTS) is the gold standard but is slow and must restart from scratch for every new dataset, model and prior. We introduce metabeta, a pretrained neural network for prior-amortized in-context Bayesian inference over GLMMs. Unlike previous neural posterior estimators that fix the prior at training time, metabeta accepts prior families and hyperparameters as inputs at test time, enabling zero-shot generalization. Two set transformers and conditional normalizing flows mirror the posterior's two-level structure (global parameters shared across groups, local parameters per group). The model is trained on millions of realistic simulated datasets spanning continuous, binary, and count outcomes. By default, the flow posterior is refined by Independence Metropolis-Hastings against the unnormalized posterior, so its correctness rests on the sampler rather than the network; this yields tuning-free inference two to three orders of magnitude faster than NUTS. Alternatively, the flow can warm-start NUTS, giving nearly identical inference with substantially increased speed and stability. On controlled benchmarks with ground-truth parameters, metabeta matches NUTS in parameter recovery, calibration and out-of-sample prediction. On out-of-distribution real datasets, its posteriors closely match those of NUTS across all parameter types, and they remain faithful under misspecified likelihoods and priors, out-of-distribution predictors, collinear designs, and data-poor regimes. The model is open-source and open-weights and thus immediately deployable.

Nonlinear Mixed Effects models (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) a 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 was fitted for a limited number of iterations to measure the time per iteration and demonstrate VEM's scalability.

The experience sampling method (ESM) is a longitudinal research design where participants report their thoughts, emotional states and behaviours multiple times a day. Our work is motivated by such data collected by the GrowIt! app, which was released to investigate daily emotions among adolescents during the COVID-19 pandemic. Current procedures to analyse ESM data face various challenges. While standard statistical techniques may not scale well to a high-dimensional setting, machine learning procedures can give biased results due to selection bias introduced by missingness. In our motivating dataset, adolescents dropped out due to previous strong feelings of negative emotions. Hence, the implied missing data are of the missing-at-random type that standard machine learning procedures cannot accommodate. We develop a novel neural network architecture that generalises mixed effects models to deep learning to overcome these challenges. It allows semi-parametric and flexible modelling of data's mean and correlation structure through fixed and random effects. For estimation, we use an adaptation of variational auto-encoders and a Bayesian data augmentation algorithm. Through this approach, the model can accommodate longitudinal outcomes following generic distributions, scale well to high-dimensional settings and provide valid inference when data are missing-at-random. We applied the Deep Generalised Mixed Model to the GrowIt! study and various simulations. The results show potential for the Deep Generalised Mixed Model, yet suboptimal performance due to model instability.