Identifying the critical states of complex diseases by the dynamic change of multivariate distribution

The dynamics of complex diseases are not always smooth; they are occasionally abrupt, i.e. there is a critical state transition or tipping point at which the disease undergoes a sudden qualitative shift. There are generally a few significant differences in the critical state in terms of gene expressions or other static measurements, which may lead to the failure of traditional differential expression-based biomarkers to identify such a tipping point. In this study, we propose a computational method, the direct interaction network-based divergence, to detect the critical state of complex diseases by exploiting the dynamic changes in multivariable distributions inferred from observable samples and local biomolecular direct interaction networks. Such a method is model-free and applicable to both bulk and single-cell expression data. Our approach was validated by successfully identifying the tipping point just before the occurrence of a critical transition for both a simulated data set and seven real data sets, including those from The Cancer Genome Atlas and two single-cell RNA-sequencing data sets of cell differentiation. Functional and pathway enrichment analyses also validated the computational results from the perspectives of both molecules and networks.