From local to global gene co-expression estimation using single-cell RNA-seq data.

In genomics studies, the investigation of gene relationships often brings important biological insights. Currently, the large heterogeneous datasets impose new challenges for statisticians because gene relationships are often local. They change from one sample point to another, may only exist in a subset of the sample, and can be nonlinear or even nonmonotone. Most previous dependence measures do not specifically target local dependence relationships, and the ones that do are computationally costly. In this paper, we explore a state-of-the-art network estimation technique that characterizes gene relationships at the single cell level, under the name of cell-specific gene networks. We first show that averaging the cell-specific gene relationship over a population gives a novel univariate dependence measure, the averaged Local Density Gap (aLDG), that accumulates local dependence and can detect any nonlinear, nonmonotone relationship. Together with a consistent nonparametric estimator, we establish its robustness on both the population and empirical levels. Then, we show that averaging the cell-specific gene relationship over mini-batches determined by some external structure information (eg, spatial or temporal factor) better highlights meaningful local structure change points. We explore the application of aLDG and its minibatch variant in many scenarios, including pairwise gene relationship estimation, bifurcating point detection in cell trajectory, and spatial transcriptomics structure visualization. Both simulations and real data analysis show that aLDG outperforms existing ones.