A Deep Dive into Single-Cell RNA Sequencing Foundation Models

Abstract Large-scale foundation models, which are pre-trained on massive, unlabeled datasets and subsequently fine-tuned on specific tasks, have recently achieved unparalleled success on a wide array of applications, including in healthcare and biology. In this paper, we explore two foundation models recently developed for single-cell RNA sequencing data, scBERT and scGPT. Focusing on the fine-tuning task of cell type annotation, we explore the relative performance of pre-trained models compared to a simple baseline, L1-regularized logistic regression, including in the few-shot setting. We perform ablation studies to understand whether pretraining improves model performance and to better understand the difficulty of the pre-training task in scBERT. Finally, using scBERT as an example, we demonstrate the potential sensitivity of fine-tuning to hyperparameter settings and parameter initializations. Taken together, our results highlight the importance of rigorously testing foundation models against well established baselines, establishing challenging fine-tuning tasks on which to benchmark foundation models, and performing deep introspection into the embeddings learned by the model in order to more effectively harness these models to transform single-cell data analysis. Code is available at https://github.com/clinicalml/sc-foundation-eval .