COMPLEX SYSTEMS AND COMPUTATIONAL BIOLOGY APPROACHES TO ACUTE INFLAMMATION

Preface
Contents
About the Editors
Part I: Overview
	Chapter 1: An Overview of the Translational Dilemma and the Need for Model-Based Precision Medicine
		Introduction
		Progress in Translational Systems Biology of Inflammation
		Challenges and Future Perspectives
		References
Part II: Computational Modeling Methods and Biomedical Applications
	Chapter 2: Translational Equation-Based Modeling
		Equation-Based Models of Biological Systems
			Historical Perspective
			Types of Equation-Based Models
			Advantages of Equation-Based Models
			Disadvantages of Equation-Based Models
			Models Big and Small
		Validating Equation-Based Models
		Using Equation-Based Models as a Prediction Tool
			Parameter Estimation and the Inverse Problem
			Approaches to Solving the Ill-Posed Inverse Problem
			Hybrid Models
		Translational Applications
			The Interdisciplinary Perspective
			Enhancing Current Trial Design
			In Silico Clinical Trials
			Parameter Ensembles vs. Data: Different Worldviews
			Novel Approaches to Personalized Therapies for the Critically Ill
		Conclusion
		References
	Chapter 3: Agent-Based Modeling in Translational Systems Biology
		The Translational Dilemma and the Need for Dynamic Knowledge Representation
		Dynamic Knowledge Representation with Agent-Based Modeling
			Related Modeling Methods
			Agent-Based Models Versus Multiagent Systems
			Properties of Agent-Based Models
				Representation of Spatial Relationships
				Representation of Parallelism and Concurrency
				Incorporation of Stochasticity and Randomness
				Modular Architecture
				Generation of Nonintuitive System-Level Phenomenon
				Readily Facilitates Useful and Detailed Abstraction
			Tools for Agent-Based Modeling
			Agent-Based Modeling of Inflammation
				ABMs of Inflammation-Related Intracellular Processes
				Cell-Level ABMs of Systemic Inflammation and Simulated Trials for Sepsis
				ABMs of Multiorgan Inflammation and Failure
			Moving Forward: Scaling Dynamic Knowledge Representation, the Agent-Based Modeling Format (ABMF)
		Challenges to the Use of Agent-Based Modeling
		Conclusion
		References
	Chapter 4: Integrating Data-Driven and Mechanistic Models of the Inflammatory Response in Sepsis and Trauma
		Introduction
		A Systems Approach to Inflammation
			Data-Driven (Correlative) Approaches to Dynamic Inflammation Data
			Dynamic, Mechanistic Modeling of Inflammation
			Combining Data-Driven and Mechanistic Modeling of Inflammation
		Conclusions and Future Prospects
		References
	Chapter 5: Therapeutics as Control: Model-Based Control Discovery for Sepsis
		Introduction
		Model-Based Control Discovery: Overcoming Limitations of Current Biomedical Research
		Sepsis as a Control Problem
		Insights from Model Predictive Control of Sepsis
		Model-Based Control Discovery Using Agent-Based Models
		Discussion
		References
Part III: Translational Modeling of Sepsis and Trauma
	Chapter 6: Disorder of Systemic Inflammation in Sepsis and Trauma: A Systems Perspective
		Introduction
		Sensing Mechanisms
			Infection
			Tissue Damage
			Hypoxia/Ischemia
		Cellular Factors of the Inflammatory Response
		Effectors of the Inflammatory Response
			ROS & RNS
			Coagulation Cascade
			Neuroendocrine
			Cytokines and Chemokines
			Complement
		Consequences of the Inflammatory Response
		Derangements of Systemic Inflammation
			Excessive Inflammation from Severe Injury
			Immunosuppression
			Apoptosis
			Th1 to Th2 Conversion
			Immune Response with Age
		Treatment Considerations
			Mitigating the Hyperinflammatory Response
			Reversing Immunosuppression
		Conclusion
		References
	Chapter 7: Multiscale Equation-Based Models: Insights for Inflammation and Physiological Variability
		Introduction
		Multiscale Modeling of Human Endotoxemia
			Immune Cells
		Identification of Key Transcriptional Responses
		Indirect Response Modeling
			Central Control of Immunomodulatory Hormones
		Circadian Rhythms
		Ultradian Rhythms
			Heart Rate and Heart Rate Variability
		Autonomic Origins of Heart Rate Variability
		Discrete-Continuous Modeling
		Challenges in Translational Modeling of Heart Rate Variability in Endotoxemia
		Conclusions
		References
	Chapter 8: In Silico Trials and Personalized Therapy for Sepsis and Trauma
		Inflammatory Diseases: A Pox on All Our Houses
		Insufficiencies in the Current Process of Drug/Device Design and Executing Clinical Trials
		Inflammation in Critical Illness: Rational Systems Approaches for a Complex Therapeutic Target
		Dynamic Knowledge Representation in the Context of In Silico Clinical Trials
		Dynamic Knowledge Representation at the Individual Level: Optimization of Diagnosis and Therapy
		Conclusions and Perspectives
		References
	Chapter 9: Computational Modeling of the Coagulation Response During Trauma
		Introduction
		Multiscale Modeling of Bleeding During Trauma
		Coagulation Modeling
		Coagulation During Bleeding
		Data-Driven Development of Subject-Specific Platelet Function Profiles
		Conclusion
		References
Part IV: Translational Modeling of Organ/Tissue Specific Inflammatory Disease Processes
	Chapter 10: Disorders of Localized Inflammation in Wound Healing
		Introduction
		Hemostasis
		Inflammation
		Epithelialization
		Angiogenesis
		Provisional Matrix Formation
		Remodeling
		Conclusion
		References
	Chapter 11: Equation-Based Models of Wound Healing and Collective Cell Migration
		Introduction
		Modeling
		ODE Models
		PDE Models
		Agent-Based Models of Cell Migration
		Applications of Wound Healing Models
		Conclusion
		References
	Chapter 12: Agent-Based Modeling of Wound Healing: Examples for Basic and Translational Research
		Introduction
		Wound Healing and Inflammation
		Agent-Based Modeling
			Agent-Based Modeling of Wound Healing
			Agent-Based Modeling for Basic Science Knowledge Integration: An ABM of Epithelial Restitution
			Model Construction and Overall Architecture
			Model Calibration: System-Level Dynamics
			Simulation Experiments
			Agent-Based Modeling as a Clinical–Translational Aid: An ABM of Pressure Ulcer Formation in Spinal Cord Injury Patients
			Model Architecture
			I/R Mechanism: Implementation and Validation
			Inflammation Mechanism: Implementation and Validation
			Sensitivity Analysis and In Silico Trials
		Discussion and Conclusions
		References
	Chapter 13: Multiscale and Tissue Realistic Translational Modeling of Gut Inflammation
		Introduction
		The Spatially Explicit General-Purpose Model of Enteric Tissue (SEGMEnT)
			General Description
			Behaviors: Calibration and Validation
			Anatomic Scale: Whole Organ Simulation with SEGMEnT_HPC
			Challenges in Anatomic Scale Modeling: Buffering
			Challenges in Anatomic Scale Modeling: Load Balancing
		Conclusion
		References
	Chapter 14: Data-Driven Modeling of Liver Injury, Inflammation, and Fibrosis
		Introduction
			Data-Driven Modeling: Clinical Insights into Pediatric Acute Liver Failure
			Data-Driven Modeling: Tissue-Scale Insights in Liver Tissue Preservation
			Data-Driven Modeling: Cellular-Scale Insights into Hypoxia, Ischemia, and Hemorrhagic Shock
			Traversing In Vitro and Clinical Data Using Computational Modeling
		Conclusions and Future Prospects
		References
	Chapter 15: Temporal and Spatial Analyses of TB Granulomas to Predict Long-Term Outcomes
		Introduction
		Methods
		GranSim: A Hybrid Agent-Based Model
		Generating a Repository of Simulated Granulomas
		Immunohistochemical Staining of NHP Tissue Samples
		Using GIS to Identify Locations of T Cells and Macrophages in an IHC Image of a Granuloma
		Methods for Classification and Analysis of Granulomas
			Temporal Classification
			Spatial Analysis
		Prediction of Future Temporal Behavior from Spatial Structure Analysis
		Results
			Temporal Classification of Simulated Granulomas Based on CFU and Lesion Size
			Spatial Analysis of Simulated and Experimental Granulomas
			Spatial Structure Predicts Future Temporal Granuloma Stability
			Identifying Spatial Characteristics that Correlate with Granuloma Severity
		Discussion
		References
Part V: Future Perspectives: Translation to Implementation
	Chapter 16: The Rationale and Implementation of Model-Based Precision Medicine for Inflammatory Diseases
		References
Index