Identifying the dynamic gene regulatory network during latent HIV-1 reactivation using high-dimensional ordinary differential equations.
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ABSTRACT:
SUBMITTER: Song J
PROVIDER: S-EPMC8442249 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We consider the task of learning a dynamical system from high-dimensional time-course data. For instance, we might wish to estimate a gene regulatory network from gene expression data measured at discrete time points. We model the dynamical system nonparametrically as a system of additive ordinary differential equations. Most existing methods for parameter estimation in ordinary differential equations estimate the derivatives from noisy observations. This is known to be challenging and inefficient. We propose a novel approach that does not involve derivative estimation. We show that the proposed method can consistently recover the true network structure even in high dimensions, and we demonstrate empirical improvement over competing approaches. Supplementary materials for this article are available online.
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Project description:Single-cell transcriptomics technologies can uncover changes in the molecular states that underlie cellular phenotypes. However, understanding the dynamic cellular processes requires extending from inferring trajectories from snapshots of cellular states to estimating temporal changes in cellular gene expression. To address this challenge, we have developed a neural ordinary differential-equation-based method, RNAForecaster, for predicting gene expression states in single cells for multiple future time steps in an embedding-independent manner. We demonstrate that RNAForecaster can accurately predict future expression states in simulated single-cell transcriptomic data with cellular tracking over time. We then show that by using metabolic labeling single-cell RNA sequencing (scRNA-seq) data from constitutively dividing cells, RNAForecaster accurately recapitulates many of the expected changes in gene expression during progression through the cell cycle over a 3-day period. Thus, RNAForecaster enables short-term estimation of future expression states in biological systems from high-throughput datasets with temporal information.
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Project description:Ordinary differential equations (ODEs) are widely used in modeling dynamic systems and have ample applications in the fields of physics, engineering, economics and biological sciences. The ODE parameters often possess physiological meanings and can help scientists gain better understanding of the system. One key interest is thus to well estimate these parameters. Ideally, constant parameters are preferred due to their easy interpretation. In reality, however, constant parameters can be too restrictive such that even after incorporating error terms, there could still be unknown sources of disturbance that lead to poor agreement between observed data and the estimated ODE system. In this paper, we address this issue and accommodate short-term interferences by allowing parameters to vary with time. We propose a new regularized estimation procedure on the time-varying parameters of an ODE system so that these parameters could change with time during transitions but remain constants within stable stages. We found, through simulation studies, that the proposed method performs well and tends to have less variation in comparison to the non-regularized approach. On the theoretical front, we derive finite-sample estimation error bounds for the proposed method. Applications of the proposed method to modeling the hare-lynx relationship and the measles incidence dynamic in Ontario, Canada lead to satisfactory and meaningful results.
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Project description:To combine a feedforward neural network (FNN) and Lie group (symmetry) theory of differential equations (DEs), an alternative artificial NN approach is proposed to solve the initial value problems (IVPs) of ordinary DEs (ODEs). Introducing the Lie group expressions of the solution, the trial solution of ODEs is split into two parts. The first part is a solution of other ODEs with initial values of original IVP. This is easily solved using the Lie group and known symbolic or numerical methods without any network parameters (weights and biases). The second part consists of an FNN with adjustable parameters. This is trained using the error back propagation method by minimizing an error (loss) function and updating the parameters. The method significantly reduces the number of the trainable parameters and can more quickly and accurately learn the real solution, compared to the existing similar methods. The numerical method is applied to several cases, including physical oscillation problems. The results have been graphically represented, and some conclusions have been made.
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Project description:BackgroundOrdinary differential equations are widely-used in the field of systems biology and chemical engineering to model chemical reaction networks. Numerous techniques have been developed to estimate parameters like rate constants, initial conditions or steady state concentrations from time-resolved data. In contrast to this countable set of parameters, the estimation of entire courses of network components corresponds to an innumerable set of parameters.ResultsThe approach presented in this work is able to deal with course estimation for extrinsic system inputs or intrinsic reactants, both not being constrained by the reaction network itself. Our method is based on variational calculus which is carried out analytically to derive an augmented system of differential equations including the unconstrained components as ordinary state variables. Finally, conventional parameter estimation is applied to the augmented system resulting in a combined estimation of courses and parameters.ConclusionsThe combined estimation approach takes the uncertainty in input courses correctly into account. This leads to precise parameter estimates and correct confidence intervals. In particular this implies that small motifs of large reaction networks can be analysed independently of the rest. By the use of variational methods, elements from control theory and statistics are combined allowing for future transfer of methods between the two fields.
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