Clustering of Omic Data Using Semi-Supervised Transfer Learning for Gaussian Mixture Models via Natural-Gradient Variational Inference: Method and Applications to Bulk and Single-Cell Transcriptomics.

Recent advances in high-throughput technologies have enabled observational studies to collect high-dimensional omic data. However, such data, often measured on small sample sizes, pose challenges to model-based clustering approaches such as Gaussian Mixture Models. Existing methods often fail to generalize due to model instability under complex mixture patterns. To overcome these limitations, we propose a natural-gradient variational inference framework for Gaussian mixture models named Praxis-BGM that incorporates informative priors-cluster-specific means, covariances, and structural connectivity-from large-scale reference data with known cluster or class labels to enable semi-supervised transfer learning. We derive natural-gradient updates that integrate prior knowledge, leveraging the Variational Online Newton algorithm. We also perform feature selection for clustering using Bayes Factors. Implemented using the JAX library for accelerator-oriented computation, Praxis-BGM is computationally efficient and scalable. We demonstrate the effectiveness of Praxis-BGM in extensive simulations and with two real-world applications: bulk transcriptomic datasets for breast cancer subtyping (the Cancer Genome Atlas Breast Invasive Carcinoma and the Molecular Taxonomy of Breast Cancer International Consortium), and transferring cell-type annotations between single-cell transcriptomic datasets produced by different single-cell RNA-seq technologies in a human pancreas study. Even when priors are partially mismatched with the target data, Praxis-BGM enhances semi-supervised clustering accuracy and biological interpretability.