Multimodal Empirical Bayes Variational Autoencoders for Joint Longitudinal and Time-to-Event Modeling
For pharmacometric modeling, this provides a flexible framework to combine neural dynamics, mechanistic structure, and high-dimensional covariates, though the improvements are incremental over existing methods.
The paper extends the empirical Bayes variational autoencoder (EB-VAE) to jointly model longitudinal tumor measurements and time-to-event dropout, integrating genomic covariates. The hybrid decoder recovered treatment-effect parameters consistent with previous methods, and genetic conditioning improved individual-level predictions in melanoma and breast cancer experiments.
Longitudinal tumor measurements, dropout information, and genetic covariates provide complementary information about treatment response, but integrating these data sources within a single population modeling framework remains challenging. We extend the empirical Bayes variational autoencoder (EB-VAE) framework to joint longitudinal and time-to-event modeling and evaluate it on tumor growth data. The framework represents inter-individual variability using latent individual effects regularized by a covariate-conditioned empirical Bayes prior, while a decoder maps these latent effects to tumor-volume trajectories. To account for informative dropout, the decoder was augmented with a hazard model, yielding joint predictions of tumor growth and time to dropout. We further compared fully neural and hybrid semi-mechanistic decoder formulations and incorporated genomic covariates through a genetics-conditioned prior adaptation. The hybrid decoder recovered treatment-effect parameters broadly consistent with previously reported nonlinear mixed-effects estimates, while achieving prior predictive performance comparable to the neural decoder. The joint model reproduced both tumor-volume distributions and dropout patterns in held-out individuals, and genetic conditioning improved individual-level prior predictions in both cutaneous melanoma and breast cancer experiments. Stability selection identified several biologically plausible genetic indicators, including alterations in BRAF, NRAS, NF1, and MDM2. These results demonstrate that EB-VAE provides a flexible probabilistic framework for combining neural dynamics, mechanistic structure, time-to-event modeling, and high-dimensional covariates in pharmacometric applications.