Owing to the significant cost reduction of high-throughput technologies, frequent time course genome-wide gene expression data, in addition to time course cellular level and longitudinal phenotype response data, are often collected in recent HIV/AIDS studies and other biomedical projects. However, the effective use of the high-throughput time course data at transcriptomic and proteomics levels to study dynamic responses and network features is often hindered by lacking of statistical methods to reconstruct high-dimensional dynamic models. In this renewal project, we intend to fill this gap and propose the following specific aims: 1) Develop more efficient parameter estimation methods for high-dimensional ordinary differential equation (ODE) models.
Aim 1 intends to develop more efficient statistical methods to estimate high-dimensional ODE model parameters to provide a foundation for reconstructing biological networks at gene, protein and molecular levels. 2) Develop novel statistical methods and implementation procedures for high-dimensional ODE variable selection to reconstruct the dynamic networks. We combine new statistical estimation methods for ODE models and regularization-based variable selection techniques to identify ODE network edges. Statistical methodologies and theoretical justifications will be established for the proposed ODE-based network models. 3) Evaluate and validate the methodologies developed in Aims 1-2 using computer simulations and real data analysis from HIV/AIDS studies. It is important to carefully evaluate the high-dimensional ODE variable selection and parameter estimation methods developed in Aims 1-2, and perform comparisons with existing methods for practical use. In particular, it is necessary to apply the proposed methods to experimental data from HIV/AIDS studies in order to demonstrate the usefulness of the proposed methodologies to address scientific questions. 4) Develop and disseminate efficient computational algorithms and user-friendly software tools for the proposed methods to the broader research community. It is very important to develop efficient computing algorithms and share/disseminate the computational source codes to the general research community.

Public Health Relevance

This project intends to develop novel statistical methods and efficient implementation algorithms as well as theoretical justifications for ODE-based network construction, motivated by HIV/AIDS studies so that we can fill the gap and address the critical methodology barrier in systems biology research, which is one of the important research areas in HIV/AIDS and essential in ending AIDS epidemics.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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AIDS Clinical Studies and Epidemiology Study Section (ACE)
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Gezmu, Misrak
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University of Texas Health Science Center Houston
Biostatistics & Other Math Sci
Schools of Public Health
United States
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Chen, Iris; Kelkar, Yogeshwar D; Gu, Yu et al. (2017) High-dimensional linear state space models for dynamic microbial interaction networks. PLoS One 12:e0187822
Sun, Xiaodian; Hu, Fang; Wu, Shuang et al. (2016) Controllability and stability analysis of large transcriptomic dynamic systems for host response to influenza infection in human. Infect Dis Model 1:52-70
Carey, Michelle; Wu, Shuang; Gan, Guojun et al. (2016) Correlation-based iterative clustering methods for time course data: The identification of temporal gene response modules for influenza infection in humans. Infect Dis Model 1:28-39
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Miao, Hongyu; Wu, Hulin; Xue, Hongqi (2014) Generalized Ordinary Differential Equation Models. J Am Stat Assoc 109:1672-1682
Wu, Hulin; Lu, Tao; Xue, Hongqi et al. (2014) Sparse Additive Ordinary Differential Equations for Dynamic Gene Regulatory Network Modeling. J Am Stat Assoc 109:700-716
Wu, Shuang; Liu, Zhi-Ping; Qiu, Xing et al. (2014) Modeling genome-wide dynamic regulatory network in mouse lungs with influenza infection using high-dimensional ordinary differential equations. PLoS One 9:e95276

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