Journal
IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING
Volume 67, Issue 5, Pages 1418-1428Publisher
IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC
DOI: 10.1109/TBME.2019.2937228
Keywords
Matrix decomposition; Entropy; Optimization; Sparse matrices; Correlation; Data models; Stability analysis; Single cell; transition states; cell clustering; optimization model
Categories
Funding
- National Natural Science Foundation of China [11831015, 61672388]
- National Key Research and Development Program of China [2018YFC1314600]
- NIH [U01AR073159]
- NSF [DMS1763272, DMS1562176]
- Simons Foundation [594598]
- Koskinas TedGiovanis Foundation for Health and Policy
- Breast Cancer Research Foundation
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Single cell technologies provide an unprecedented opportunity to explore the heterogeneity in a biological process at the level of single cells. One major challenge in analyzing single cell data is to identify cell subpopulations, stable cell states, and cells in transition between states. To elucidate the transition mechanisms in cell fate dynamics, it is highly desirable to quantitatively characterize cellular states and intermediate states. Here, we present scRCMF, an unsupervised method that identifies stable cell states and transition cells by adopting a nonlinear optimization model that infers the latent substructures from a gene-cell matrix. We incorporate a random coefficient matrix-based regularization into the standard nonnegative matrix decomposition model to improve the reliability and stability of estimating latent substructures. To quantify the transition capability of each cell, we propose two new measures: single-cell transition entropy (scEntropy) and transition probability (scTP). When applied to two simulated and three published scRNA-seq datasets, scRCMF not only successfully captures multiple subpopulations and transition processes in large-scale data, but also identifies transition states and some known marker genes associated with cell state transitions and subpopulations. Furthermore, the quantity scEntropy is found to be significantly higher for transition cells than other cellular states during the global differentiation, and the scTP predicts the fate decisions of transition cells within the transition. The present study provides new insights into transition events during differentiation and development.
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