Estimation Methods for Nonlinear ODE Models in AIDS Research Abstract In this project we propose identifiability methods and statistical estimation methods for ordinary differential equation (ODE) models to support HIV/AIDS research. Although many mathematical models and statistical methods have been developed for epidemiological and clinical studies in AIDS research, very few identifiability and estimation methods are developed for nonlinear ODE models which are widely used in AIDS research. It is challenging to estimate the parameters in the ODE models when no closed-form solution is available for nonlinear ODEs. Very few formal statistical estimation methods are available for ODE models. To fill this gap, in this project we propose novel statistical estimation methods for nonlinear ODE models derived from HIV/AIDS research. In particular, we propose four specific aims: 1) Integrate parameter identifiability techniques from different research disciplines to address the identifiability issues for ordinary differential equation (ODE) models;2) Develop novel statistical estimation methods for ODE models and study the asymptotic and finite-sample properties of the estimators;3) Evaluate the new methods by comparing them to the existing methods based on theoretical perspective, finite sample properties and computational efficiency, and test and validate the proposed methods using the examples and data from studies of immune response to viral infections;4) Develop efficient computational algorithms and user-friendly software packages to implement the proposed methods. We propose several novel estimation methods including sieve-based methods for estimating both constant and time-varying parameters, penalized kernel estimation methods and numerical algorithm-based regression approaches for ODE models. The model identifiability analysis for ODE models is also relatively innovative from statistical perspective. To achieve our aims, we have formed a strong interdisciplinary research team consisting of statisticians, computational scientists and software developers with necessary expertise for this project. The differential equation models are often developed based on mechanisms of biomedical systems. The model parameters usually have meaningful biological interpretations and are important in their own rights. It is very important to reliably estimate these model parameters from experimental data. The estimation results may help HIV/AIDS investigators better understand the biological mechanisms and pathogenesis of HIV infection, which may lead to novel scientific findings and provide guidance to develop treatment strategies.

Public Health Relevance

The developed statistical methods for ODE models of HIV dynamics and AIDS epidemics allow to reliably estimate the unknown kinetic or epidemic parameters of HIV dynamics and AIDS epidemics. These parameters and the ODE models can be used to help HIV/AIDS investigators better understand the biological mechanisms and pathogenesis of HIV infection, which may lead to novel scientific findings and provide guidance to develop treatment strategies.

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 Rochester
Biostatistics & Other Math Sci
Schools of Dentistry
United States
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Wu, Hulin; Miao, Hongyu; Xue, Hongqi et al. (2015) Quantifying Immune Response to Influenza Virus Infection via Multivariate Nonlinear ODE Models with Partially Observed State Variables and Time-Varying Parameters. Stat Biosci 7:147-166
Qiu, Xing; Wu, Shuang; Hilchey, Shannon P et al. (2015) Diversity in Compartmental Dynamics of Gene Regulatory Networks: The Immune Response in Primary Influenza A Infection in Mice. PLoS One 10:e0138110
Zand, Martin S; Wang, Jiong; Hilchey, Shannon (2015) Graphical Representation of Proximity Measures for Multidimensional Data: Classical and Metric Multidimensional Scaling. Math J 17:
Luque, Amneris E; Orlando, Mark S; Leong, U-Cheng et al. (2014) Hearing function in patients living with HIV/AIDS. Ear Hear 35:e282-90
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
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
Linel, Patrice; Wu, Shuang; Deng, Nan et al. (2014) Dynamic transcriptional signatures and network responses for clinical symptoms in influenza-infected human subjects using systems biology approaches. J Pharmacokinet Pharmacodyn 41:509-21
Wu, Shuang; Xue, Hongqi; Wu, Yichao et al. (2014) Variable Selection for Sparse High-Dimensional Nonlinear Regression Models by Combining Nonnegative Garrote and Sure Independence Screening. Stat Sin 24:1365-1387
Ding, A Adam; Wu, Hulin (2014) Estimation of Ordinary Differential Equation Parameters Using Constrained Local Polynomial Regression. Stat Sin 24:1613-1631
Miao, Hongyu; Wu, Hulin; Xue, Hongqi (2014) Generalized Ordinary Differential Equation Models. J Am Stat Assoc 109:1672-1682

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