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The Human Cell Atlas (HCA) is a large project that aims to identify all cell types in the human body. The dimension reduction and clustering for identification of cell types from single-cell RNA-sequencing (scRNA-seq) data have become foundational approaches to HCA. The major challenges of current computational analyses are of poor performance on large scale data and sensitive to initial data. We present a new ensemble framework called Adaptive Slice KNNs (scASK) to address the challenges for analyzing scRNA-seq data with high dimensionality. scASK consists of three innovational modules, called DAS (Data Adaptive Slicing), MCS (Meta Classifiers Selecting) and EMS (Ensemble Mode Switching), respectively, which facilitate scASK to approximate a bias-variance tradeoff beyond classification. Thirteen real scRNA-seq datasets are used to evaluate the performance of scASK. Compared with five popular classification algorithms, our experimental results indicate that scASK achieves the best accuracy and robustness among all competing methods. In conclusion, adaptive slicing is an effective structural reduction procedure, and meanwhile scASK provides novel and robust ensemble framework especially for classifying cell types based on scRNA-seq data. scASK is now publically available at https://github.com/liubo2358/scASKcmd.

Disease development and cell differentiation both involve dynamic changes; therefore, the reconstruction of dynamic gene regulatory networks (DGRNs) is an important but difficult problem in systems biology. With recent technical advances in single-cell RNA sequencing (scRNA-seq), large volumes of scRNA-seq data are being obtained for various processes. However, most current methods of inferring DGRNs from bulk samples may not be suitable for scRNA-seq data. In this work, we present scPADGRN, a novel DGRN inference method using "time-series" scRNA-seq data. scPADGRN combines the preconditioned alternating direction method of multipliers with cell clustering for DGRN reconstruction. It exhibits advantages in accuracy, robustness and fast convergence. Moreover, a quantitative index called Differentiation Genes' Interaction Enrichment (DGIE) is presented to quantify the interaction enrichment of genes related to differentiation. From the DGIE scores of relevant subnetworks, we infer that the functions of embryonic stem (ES) cells are most active initially and may gradually fade over time. The communication strength of known contributing genes that facilitate cell differentiation increases from ES cells to terminally differentiated cells. We also identify several genes responsible for the changes in the DGIE scores occurring during cell differentiation based on three real single-cell datasets. Our results demonstrate that single-cell analyses based on network inference coupled with quantitative computations can reveal key transcriptional regulators involved in cell differentiation and disease development., Competing Interests: The authors have declared that no competing interests exist.

In this paper, we focus on the study of evolutionary algorithms for solving multiobjective optimization problems with a large number of objectives. First, a comparative study of a newly developed dynamical multiobjective evolutionary algorithm (DMOEA) and some modern algorithms, such as the indicator-based evolutionary algorithm, multiple single objective Pareto sampling, and nondominated sorting genetic algorithm II, is presented by employing the convergence metric and relative hypervolume metric. For three scalable test problems (namely, DTLZ1, DTLZ2, and DTLZ6), which represent some of the most difficult problems studied in the literature, the DMOEA shows good performance in both converging to the true Pareto-optimal front and maintaining a widely distributed set of solutions. Second, a new definition of optimality (namely, L-optimality) is proposed in this paper, which not only takes into account the number of improved objective values but also considers the values of improved objective functions if all objectives have the same importance. We prove that L-optimal solutions are subsets of Pareto-optimal solutions. Finally, the new algorithm based on L-optimality (namely, MDMOEA) is developed, and simulation and comparative results indicate that well-distributed L-optimal solutions can be obtained by utilizing the MDMOEA but cannot be achieved by applying L-optimality to make a posteriori selection within the huge Pareto nondominated solutions. We can conclude that our new algorithm is suitable to tackle many-objective problems.

Robustness, the ability to maintain performance in the face of perturbations and uncertainty, is believed to be a necessary property of biological systems. In this paper, we address the issue of robustness in an important signal transduction network--epidermal growth factor receptor (EGFR) network. First, we analyze the robustness in the EGFR signaling network using all rate constants against the Gauss variation which was described as "the reference parameter set" in the previous study [Kholodenko, B.N., Demin, O.V., Moehren, G., Hoek, J.B., 1999. Quantification of short term signaling by the epidermal growth factor receptor. J. Biol. Chem. 274, 30169-30181]. The simulation results show that signal time, signal duration and signal amplitude of the EGRR signaling network are relatively not robust against the simultaneous variation of the reference parameter set. Second, robustness is quantified using some statistical quantities. Finally, a multi-objective evolutionary algorithm (MOEA) is presented to search reaction rate constants which optimize the robustness of network and compared with the NSGA-II, which is a representation of a class of modern multi-objective evolutionary algorithms. Our simulation results demonstrate that signal time, signal duration and signal amplitude of the four key components--the most downstream variable in each of the pathways: R-Sh-G-S, R-PLP, R-G-S and the phosphorylated receptor RP in EGRR signaling network for the optimized parameter sets have better robustness than those for the reference parameter set and the NSGA-II. These results can provide valuable insight into experimental designs and the dynamics of the signal-response relationship between the dimerized and activated EGFR and the activation of downstream proteins.

Differential evolution (DE) has been used to solve real-parameter optimization problems with nonlinear and multimodal functions for more than a decade of years. However, it is pointed out that this classical DE harbors restricted efficiency and limited local search ability. Inspired by that gradient-based algorithms have powerful local search ability, we propose a new algorithm, which is diversity-maintained DE based on gradient local search (namely, DMGBDE), by incorporating approximate gradient-based algorithms into the DE search while maintaining the diversity of the population. The primary novelties of the proposed DMGBDE are the following: (1) the gradient-based algorithm is embedded into DE in a different manner and (2) a diversity-maintained mutation is introduced to slow down the learning procedure from the searched best individual. We conduct numerical experiments with a number of benchmark problems to measure the performance of the proposed DMGBDE. Simulation results show that the proposed DMGBDE outperforms classical DE and variant without gradient local search or diversity-based mutation. Moreover, comparison with some other recently reported approaches indicates that our proposed DMGBDE is rather competitive. [ABSTRACT FROM AUTHOR]

For the global optimization problems with continuous variables, evolutionary algorithms (EAs) are often used to find the approximate solutions. The number of generations for an EA to find the approximate solutions, called the first hitting time, is an important index to measure the performance of the EA. However, calculating the first hitting time is still difficult in theory. This paper proposes some new drift conditions that are used to estimate the upper bound of the first hitting times of EAs for finding the approximate solutions. Two case studies are given to show how to apply these conditions to estimate the first hitting times. [ABSTRACT FROM AUTHOR]

In this article, we propose a fast annealing genetic algorithm (FAGA), based on the principle of the minimal free energy in statistical physics, for solving multi-objective optimization problems. The novelties of FAGA are: (1) providing a new fitness assignment strategy by combining Pareto-dominance relation and Gibbs entropy, (2) introducing a new criterion for selection of new individuals to maintain the diversity of the population. We make many experiments to measure the performance of the proposed FAGA, and estimate its convergence rate for a number of test problems. Simulation results show that the FAGA is a very fast and effective algorithm. [ABSTRACT FROM AUTHOR]

In this paper, we introduce a new dynamical evolutionary algorithm (DEA) that aims to find the global optimum and give the theoretical explanation from statistical mechanics. The algorithm has been evaluated numerically using a wide set of test functions which are nonlinear, multimodal and multidimensional. The numerical results show that it is possible to obtain global optimum or more accurate solutions than other methods for the investigated hard problems. [ABSTRACT FROM AUTHOR]