{Phi}-Space: Continuous phenotyping of single-cell multi-omics data

Single-cell multi-omics technologies have empowered increasingly refined characterisation of the heterogeneity of cell populations. Automated cell type annotation methods have been developed to transfer cell type labels from well-annotated reference datasets to emerging query datasets. However, these methods suffer from some common caveats, including the failure to characterise transitional and novel cell states, sensitivity to batch effects and under-utilisation of phenotypic information other than cell types (e.g. sample source and disease conditions). We developed {Phi}-Space, a computational framework for the continuous phenotyping of single-cell multi-omics data. In {Phi}-Space we adopt a highly versatile modelling strategy to continuously characterise query cell identity in a low-dimensional phenotype space, defined by reference phenotypes. The phenotype space embedding enables various downstream analyses, including insightful visualisations, clustering and cell type labelling. We demonstrate through three case studies that {Phi}-Space (i) characterises developing and out-of-reference cell states; (ii) is robust against batch effects in both reference and query; (iii) adapts to annotation tasks involving multiple omics types; (iv) overcomes technical differences between reference and query. The versatility of {Phi}-Space makes it applicable to a wide range analytical tasks beyond cell type transfer, and its ability to model complex phenotypic variation will facilitate biological discoveries from different omics types.