One of the major challenges arising from single-cell transcriptomics experiments is the question of how to annotate the associated single-cell transcriptomic profiles. Because of the large size and the high dimensionality of the data, automated methods for annotation are needed. We focus here on datasets obtained in the context of developmental biology, where the differentiation process leads to a hierarchical structure. We consider a frequent setting where both labeled and unlabeled data are available at training time, but the sets of the labels of labeled data on one side and of the unlabeled data on the other side, are disjoint. It is an instance of the Novel Class Discovery problem. The goal is to achieve two objectives, clustering the data and mapping the clusters with labels. We propose extensions of k-Means and GMM clustering methods for solving the problem and report comparative results on artificial and experimental transcriptomic datasets. Our approaches take advantage of the hierarchical nature of the data.

In this work we present a deep learning approach to conduct hypothesis-free, transcriptomics-based matching of drugs for diseases. Our proposed neural network architecture is trained on approved drug-disease indications, taking as input the relevant disease and drug differential gene expression profiles, and learns to identify novel indications. We assemble an evaluation dataset of disease-drug indications spanning 68 diseases and evaluate in silico our approach against the most widely used transcriptomics-based matching baselines, CMap and the Characteristic Direction. Our results show a more than 200% improvement over both baselines in terms of standard retrieval metrics. We further showcase our model's ability to capture different genes' expressions interactions among drugs and diseases. We provide our trained models, data and code to predict with them at https://github.com/healx/dgem-nn-public.

Gene regulation is a dynamic process that connects genotype and phenotype. Given the difficulty of physically mapping mammalian gene circuitry, we require new computational methods to learn regulatory rules. Natural language is a valuable analogy to the communication of regulatory control. Machine learning systems model natural language by explicitly learning context dependencies between words. We propose a similar system applied to single-cell RNA expression profiles to learn context dependencies between genes. Our model, Exceiver, is trained across a diversity of cell types using a self-supervised task formulated for discrete count data, accounting for feature sparsity. We found agreement between the similarity profiles of latent sample representations and learned gene embeddings with respect to biological annotations. We evaluated Exceiver on a new dataset and a downstream prediction task and found that pretraining supports transfer learning. Our work provides a framework to model gene regulation on a single-cell level and transfer knowledge to downstream tasks.