Optimal Objective-Based Experimental Design for Uncertain Dynamical Gene Networks with Experimental Error

In systems biology, network models are often used to study interactions among cellular components, a salient aim being to develop drugs and therapeutic mechanisms to change the dynamical behavior of the network to avoid undesirable phenotypes. Owing to limited knowledge, model uncertainty is commonplace and network dynamics can be updated in different ways, thereby giving multiple dynamic trajectories, that is, dynamics uncertainty. In this manuscript, we propose an experimental design method that can effectively reduce the dynamics uncertainty and improve performance in an interaction-based network. Both dynamics uncertainty and experimental error are quantified with respect to the modeling objective, herein, therapeutic intervention. The aim of experimental design is to select among a set of candidate experiments the experiment whose outcome, when applied to the network model, maximally reduces the dynamics uncertainty pertinent to the intervention objective.

[1]  A. Citri,et al.  EGF–ERBB signalling: towards the systems level , 2006, Nature Reviews Molecular Cell Biology.

[2]  G. A. Whitmore,et al.  Importance of replication in microarray gene expression studies: statistical methods and evidence from repetitive cDNA hybridizations. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Aniruddha Datta,et al.  Bayesian Robustness in the Control of Gene Regulatory Networks , 2007, IEEE Transactions on Signal Processing.

[4]  Edward R. Dougherty,et al.  Effect of Function Perturbation on the Steady-State Distribution of Genetic Regulatory Networks: Optimal Structural Intervention , 2008, IEEE Transactions on Signal Processing.

[5]  D. Riethmacher,et al.  The ErbB2 and ErbB3 receptors and their ligand, neuregulin-1, are essential for development of the sympathetic nervous system. , 1998, Genes & development.

[6]  H. Lane,et al.  ERBB receptors and cancer: the complexity of targeted inhibitors , 2005, Nature Reviews Cancer.

[7]  A. Hopkins Network pharmacology: the next paradigm in drug discovery. , 2008, Nature chemical biology.

[8]  M. Leake,et al.  Experimental approaches for addressing fundamental biological questions in living, functioning cells with single molecule precision , 2012, Open Biology.

[9]  Aniruddha Datta,et al.  Optimal infinite horizon control for probabilistic Boolean networks , 2006, 2006 American Control Conference.

[10]  Peter A. J. Hilbers,et al.  Optimal experiment design for model selection in biochemical networks , 2014, BMC Systems Biology.

[11]  Aniruddha Datta,et al.  Robust Intervention in Probabilistic Boolean Networks , 2007, 2007 American Control Conference.

[12]  E. Wagner,et al.  Liver Tumor Development c-Jun Antagonizes the Proapoptotic Activity of p53 , 2003, Cell.

[13]  Byung-Jun Yoon,et al.  Efficient experimental design for uncertainty reduction in gene regulatory networks , 2015, BMC Bioinformatics.

[14]  Jinde Cao,et al.  Stabilization of genetic regulatory networks with mixed time-delays: an adaptive control approach , 2015, IMA Journal of Mathematical Control and Information.

[15]  N. Sampas,et al.  Molecular classification of cutaneous malignant melanoma by gene expression profiling , 2000, Nature.

[16]  S. Klewer,et al.  Heart-valve mesenchyme formation is dependent on hyaluronan-augmented activation of ErbB2–ErbB3 receptors , 2002, Nature Medicine.

[17]  Edward R. Dougherty,et al.  Intrinsically Optimal Bayesian Robust Filtering , 2014, IEEE Transactions on Signal Processing.

[18]  Jinde Cao,et al.  Global robust power-rate stability of delayed genetic regulatory networks with noise perturbations , 2010, Cognitive Neurodynamics.

[19]  M. Volm,et al.  Prognostic significance of the expression of c-fos, c-jun and c-erbB-1 oncogene products in human squamous cell lung carcinomas , 2005, Journal of Cancer Research and Clinical Oncology.

[20]  Ilya Shmulevich,et al.  Send Orders of Reprints at Reprints@benthamscience.org on the Limitations of Biological Knowledge , 2022 .

[21]  J. Newsom-Davis,et al.  Human muscle acetylcholine receptor alpha-subunit gene (CHRNA1) association with autoimmune myasthenia gravis in black, mixed-ancestry and Caucasian subjects. , 1996, Journal of autoimmunity.

[22]  Yasser M Kadah,et al.  Construction of gene regulatory networks using biclustering and bayesian networks , 2011, Theoretical Biology and Medical Modelling.

[23]  Jianping Hua,et al.  Dynamical modeling of uncertain interaction-based genomic networks , 2015, BMC Bioinformatics.

[24]  Edward R. Dougherty,et al.  Quantifying the Objective Cost of Uncertainty in Complex Dynamical Systems , 2013, IEEE Transactions on Signal Processing.

[25]  Jinde Cao,et al.  Stability analysis for genetic regulatory networks with delays: The continuous-time case and the discrete-time case , 2013, Appl. Math. Comput..

[26]  M. Ringnér,et al.  Classification and diagnostic prediction of cancers using gene expression profiling and artificial neural networks , 2001, Nature Medicine.

[27]  Anthony C. Atkinson,et al.  Optimum Experimental Designs , 1992 .

[28]  W. Talbot,et al.  erbb3 and erbb2 Are Essential for Schwann Cell Migration and Myelination in Zebrafish , 2005, Current Biology.

[29]  Michael P. H. Stumpf,et al.  Maximizing the Information Content of Experiments in Systems Biology , 2013, PLoS Comput. Biol..

[30]  Edward R. Dougherty,et al.  Optimal Experimental Design for Gene Regulatory Networks in the Presence of Uncertainty , 2015, IEEE/ACM Transactions on Computational Biology and Bioinformatics.

[31]  Y. Tu,et al.  Quantitative noise analysis for gene expression microarray experiments , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[32]  D. Sawyer,et al.  The Role of Neuregulin 1 β /ErbB signaling in the heart , 2009 .

[33]  T. Hudson,et al.  Characterization of variability in large-scale gene expression data: implications for study design. , 2002, Genomics.

[34]  H. Kitano Systems Biology: A Brief Overview , 2002, Science.

[35]  D. Stern,et al.  ErbB2 is required for ductal morphogenesis of the mammary gland. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Daoud Sie,et al.  The T7-Primer Is a Source of Experimental Bias and Introduces Variability between Microarray Platforms , 2008, PloS one.

[37]  J. Chan,et al.  ErbB2 directly activates the exchange factor Dock7 to promote Schwann cell migration , 2008, The Journal of cell biology.

[38]  Edward R. Dougherty,et al.  A comparison study of optimal and suboptimal intervention policies for gene regulatory networks in the presence of uncertainty , 2014, EURASIP J. Bioinform. Syst. Biol..

[39]  A. Barabasi,et al.  Network biology: understanding the cell's functional organization , 2004, Nature Reviews Genetics.

[40]  Edward R. Dougherty,et al.  Probabilistic Boolean Networks - The Modeling and Control of Gene Regulatory Networks , 2010 .

[41]  H. Kitano,et al.  Computational systems biology , 2002, Nature.

[42]  H. Lochmüller,et al.  Congenital myasthenic syndromes: Achievements and limitations of phenotype‐guided gene‐after‐gene sequencing in diagnostic practice: A study of 680 patients , 2012, Human mutation.

[43]  Béla Bollobás,et al.  Graph Theory: An Introductory Course , 1980, The Mathematical Gazette.

[44]  Ruth Nussinov,et al.  Structure and dynamics of molecular networks: A novel paradigm of drug discovery. A comprehensive review , 2012, Pharmacology & therapeutics.

[45]  J. Banga,et al.  Computational procedures for optimal experimental design in biological systems. , 2008, IET systems biology.

[46]  Jason B. Lee,et al.  Melanoma adapts to RAF/MEK inhibitors through FOXD3-mediated upregulation of ERBB3. , 2013, The Journal of clinical investigation.

[47]  F. Maurer,et al.  The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[48]  C. Arteaga,et al.  ErbB3 ablation impairs PI3K/Akt-dependent mammary tumorigenesis. , 2011, Cancer research.