Systems modeling of molecular mechanisms controlling cytokine-driven CD4+ T cell differentiation and phenotype plasticity.

Differentiation of CD4+ T cells into effector or regulatory phenotypes is tightly controlled by the cytokine milieu, complex intracellular signaling networks and numerous transcriptional regulators. We combined experimental approaches and computational modeling to investigate the mechanisms controlling differentiation and plasticity of CD4+ T cells in the gut of mice. Our computational model encompasses the major intracellular pathways involved in CD4+ T cell differentiation into T helper 1 (Th1), Th2, Th17 and induced regulatory T cells (iTreg). Our modeling efforts predicted a critical role for peroxisome proliferator-activated receptor gamma (PPARγ) in modulating plasticity between Th17 and iTreg cells. PPARγ regulates differentiation, activation and cytokine production, thereby controlling the induction of effector and regulatory responses, and is a promising therapeutic target for dysregulated immune responses and inflammation. Our modeling efforts predict that following PPARγ activation, Th17 cells undergo phenotype switch and become iTreg cells. This prediction was validated by results of adoptive transfer studies showing an increase of colonic iTreg and a decrease of Th17 cells in the gut mucosa of mice with colitis following pharmacological activation of PPARγ. Deletion of PPARγ in CD4+ T cells impaired mucosal iTreg and enhanced colitogenic Th17 responses in mice with CD4+ T cell-induced colitis. Thus, for the first time we provide novel molecular evidence in vivo demonstrating that PPARγ in addition to regulating CD4+ T cell differentiation also plays a major role controlling Th17 and iTreg plasticity in the gut mucosa.

A simulation environment for the dynamic evaluation of disaster preparedness policies and interventions.

Disasters affect a society at many levels. Simulation-based studies often evaluate the effectiveness of 1 or 2 response policies in isolation and are unable to represent impact of the policies to coevolve with others. Similarly, most in-depth analyses are based on a static assessment of the "aftermath" rather than capturing dynamics. We have developed a data-centric simulation environment for applying a systems approach to a dynamic analysis of complex combinations of disaster responses. We analyze an improvised nuclear detonation in Washington, District of Columbia, with this environment. The simulated blast affects the transportation system, communications infrastructure, electrical power system, behaviors and motivations of population, and health status of survivors. The effectiveness of partially restoring wireless communications capacity is analyzed in concert with a range of other disaster response policies. Despite providing a limited increase in cell phone communication, overall health was improved.

High-performance biocomputing for simulating the spread of contagion over large contact networks.

BACKGROUND: Many important biological problems can be modeled as contagion diffusion processes over interaction networks. This article shows how the EpiSimdemics interaction-based simulation system can be applied to the general contagion diffusion problem. Two specific problems, computational epidemiology and human immune system modeling, are given as examples. We then show how the graphics processing unit (GPU) within each compute node of a cluster can effectively be used to speed-up the execution of these types of problems. RESULTS: We show that a single GPU can accelerate the EpiSimdemics computation kernel by a factor of 6 and the entire application by a factor of 3.3, compared to the execution time on a single core. When 8 CPU cores and 2 GPU devices are utilized, the speed-up of the computational kernel increases to 9.5. When combined with effective techniques for inter-node communication, excellent scalability can be achieved without significant loss of accuracy in the results. CONCLUSIONS: We show that interaction-based simulation systems can be used to model disparate and highly relevant problems in biology. We also show that offloading some of the work to GPUs in distributed interaction-based simulations can be an effective way to achieve increased intra-node efficiency.

EpiK: A Knowledge Base for Epidemiological Modeling and Analytics of Infectious Diseases.

Computational epidemiology seeks to develop computational methods to study the distribution and determinants of health-related states or events (including disease), and the application of this study to the control of diseases and other health problems. Recent advances in computing and data sciences have led to the development of innovative modeling environments to support this important goal. The datasets used to drive the dynamic models as well as the data produced by these models presents unique challenges owing to their size, heterogeneity and diversity. These datasets form the basis of effective and easy to use decision support and analytical environments. As a result, it is important to develop scalable data management systems to store, manage and integrate these datasets. In this paper, we develop EpiK-a knowledge base that facilitates the development of decision support and analytical environments to support epidemic science. An important goal is to develop a framework that links the input as well as output datasets to facilitate effective spatio-temporal and social reasoning that is critical in planning and intervention analysis before and during an epidemic. The data management framework links modeling workflow data and its metadata using a controlled vocabulary. The metadata captures information about storage, the mapping between the linked model and the physical layout, and relationships to support services. EpiK is designed to support agent-based modeling and analytics frameworks-aggregate models can be seen as special cases and are thus supported. We use semantic web technologies to create a representation of the datasets that encapsulates both the location and the schema heterogeneity. The choice of RDF as a representation language is motivated by the diversity and growth of the datasets that need to be integrated. A query bank is developed-the queries capture a broad range of questions that can be posed and answered during a typical case study pertaining to disease outbreaks. The queries are constructed using SPARQL Protocol and RDF Query Language (SPARQL) over the EpiK. EpiK can hide schema and location heterogeneity while efficiently supporting queries that span the computational epidemiology modeling pipeline: from model construction to simulation output. We show that the performance of benchmark queries varies significantly with respect to the choice of hardware underlying the database and resource description framework (RDF) engine.

EpiCaster: An Integrated Web Application For Situation Assessment and Forecasting of Global Epidemics.

Public health decision makers need access to high resolution situation assessment tools for understanding the extent of various epidemics in different regions of the world. In addition, they need insights into the future course of epidemics by way of forecasts. Such forecasts are essential for planning the allocation of limited resources and for implementing several policy-level and behavioral intervention strategies. The need for such forecasting systems became evident in the wake of the recent Ebola outbreak in West Africa. We have developed EpiCaster, an integrated Web application for situation assessment and forecasting of various epidemics, such as Flu and Ebola, that are prevalent in different regions of the world. Using EpiCaster, users can assess the magnitude and severity of different epidemics at highly resolved spatio-temporal levels. EpiCaster provides time-varying heat maps and graphical plots to view trends in the disease dynamics. EpiCaster also allows users to visualize data gathered through surveillance mechanisms, such as Google Flu Trends (GFT) and the World Health Organization (WHO). The forecasts provided by EpiCaster are generated using different epidemiological models, and the users can select the models through the interface to filter the corresponding forecasts. EpiCaster also allows the users to study epidemic propagation in the presence of a number of intervention strategies specific to certain diseases. Here we describe the modeling techniques, methodologies and computational infrastructure that EpiCaster relies on to support large-scale predictive analytics for situation assessment and forecasting of global epidemics.

Sensitivity Analysis of an ENteric Immunity SImulator (ENISI)-Based Model of Immune Responses to Helicobacter pylori Infection.

Agent-based models (ABM) are widely used to study immune systems, providing a procedural and interactive view of the underlying system. The interaction of components and the behavior of individual objects is described procedurally as a function of the internal states and the local interactions, which are often stochastic in nature. Such models typically have complex structures and consist of a large number of modeling parameters. Determining the key modeling parameters which govern the outcomes of the system is very challenging. Sensitivity analysis plays a vital role in quantifying the impact of modeling parameters in massively interacting systems, including large complex ABM. The high computational cost of executing simulations impedes running experiments with exhaustive parameter settings. Existing techniques of analyzing such a complex system typically focus on local sensitivity analysis, i.e. one parameter at a time, or a close "neighborhood" of particular parameter settings. However, such methods are not adequate to measure the uncertainty and sensitivity of parameters accurately because they overlook the global impacts of parameters on the system. In this article, we develop novel experimental design and analysis techniques to perform both global and local sensitivity analysis of large-scale ABMs. The proposed method can efficiently identify the most significant parameters and quantify their contributions to outcomes of the system. We demonstrate the proposed methodology for ENteric Immune SImulator (ENISI), a large-scale ABM environment, using a computational model of immune responses to Helicobacter pylori colonization of the gastric mucosa.

Indemics: An Interactive High-Performance Computing Framework for Data Intensive Epidemic Modeling.

We describe the design and prototype implementation of Indemics (Interactive EpidemicSimulation)-a modeling environment utilizing high-performance computing technologies for supporting complex epidemic simulations. Indemics can support policy analysts and epidemiologists interested in planning and control of pandemics. Indemics goes beyond traditional epidemic simulations by providing a simple and powerful way to represent and analyze policy-based as well as individual-based adaptive interventions. Users can also stop the simulation at any point, assess the state of the simulated system, and add additional interventions. Indemics is available to end-users via a web-based interface. Detailed performance analysis shows that Indemics greatly enhances the capability and productivity of simulating complex intervention strategies with a marginal decrease in performance. We also demonstrate how Indemics was applied in some real case studies where complex interventions were implemented.

An Interactive, Web-based High Performance Modeling Environment for Computational Epidemiology.

We present an integrated interactive modeling environment to support public health epidemiology. The environment combines a high resolution individual-based model with a user-friendly web-based interface that allows analysts to access the models and the analytics back-end remotely from a desktop or a mobile device. The environment is based on a loosely-coupled service-oriented-architecture that allows analysts to explore various counter factual scenarios. As the modeling tools for public health epidemiology are getting more sophisticated, it is becoming increasingly hard for non-computational scientists to effectively use the systems that incorporate such models. Thus an important design consideration for an integrated modeling environment is to improve ease of use such that experimental simulations can be driven by the users. This is achieved by designing intuitive and user-friendly interfaces that allow users to design and analyze a computational experiment and steer the experiment based on the state of the system. A key feature of a system that supports this design goal is the ability to start, stop, pause and roll-back the disease propagation and intervention application process interactively. An analyst can access the state of the system at any point in time and formulate dynamic interventions based on additional information obtained through state assessment. In addition, the environment provides automated services for experiment set-up and management, thus reducing the overall time for conducting end-to-end experimental studies. We illustrate the applicability of the system by describing computational experiments based on realistic pandemic planning scenarios. The experiments are designed to demonstrate the system's capability and enhanced user productivity.

Predictive computational modeling of the mucosal immune responses during Helicobacter pylori infection.

T helper (Th) cells play a major role in the immune response and pathology at the gastric mucosa during Helicobacter pylori infection. There is a limited mechanistic understanding regarding the contributions of CD4+ T cell subsets to gastritis development during H. pylori colonization. We used two computational approaches: ordinary differential equation (ODE)-based and agent-based modeling (ABM) to study the mechanisms underlying cellular immune responses to H. pylori and how CD4+ T cell subsets influenced initiation, progression and outcome of disease. To calibrate the model, in vivo experimentation was performed by infecting C57BL/6 mice intragastrically with H. pylori and assaying immune cell subsets in the stomach and gastric lymph nodes (GLN) on days 0, 7, 14, 30 and 60 post-infection. Our computational model reproduced the dynamics of effector and regulatory pathways in the gastric lamina propria (LP) in silico. Simulation results show the induction of a Th17 response and a dominant Th1 response, together with a regulatory response characterized by high levels of mucosal Treg) cells. We also investigated the potential role of peroxisome proliferator-activated receptor γ (PPARγ) activation on the modulation of host responses to H. pylori by using loss-of-function approaches. Specifically, in silico results showed a predominance of Th1 and Th17 cells in the stomach of the cell-specific PPARγ knockout system when compared to the wild-type simulation. Spatio-temporal, object-oriented ABM approaches suggested similar dynamics in induction of host responses showing analogous T cell distributions to ODE modeling and facilitated tracking lesion formation. In addition, sensitivity analysis predicted a crucial contribution of Th1 and Th17 effector responses as mediators of histopathological changes in the gastric mucosa during chronic stages of infection, which were experimentally validated in mice. These integrated immunoinformatics approaches characterized the induction of mucosal effector and regulatory pathways controlled by PPARγ during H. pylori infection affecting disease outcomes.

PLANNING AND RESPONSE IN THE AFTERMATH OF A LARGE CRISIS: AN AGENT-BASED INFORMATICS FRAMEWORK*

We present a synthetic information and modeling environment that can allow policy makers to study various counter-factual experiments in the event of a large human-initiated crisis. The specific scenario we consider is a ground detonation caused by an improvised nuclear device in a large urban region. In contrast to earlier work in this area that focuses largely on the prompt effects on human health and injury, we focus on co-evolution of individual and collective behavior and its interaction with the differentially damaged infrastructure. This allows us to study short term secondary and tertiary effects. The present environment is suitable for studying the dynamical outcomes over a two week period after the initial blast. A novel computing and data processing architecture is described; the architecture allows us to represent multiple co-evolving infrastructures and social networks at a highly resolved temporal, spatial, and individual scale. The representation allows us to study the emergent behavior of individuals as well as specific strategies to reduce casualties and injuries that exploit the spatial and temporal nature of the secondary and tertiary effects. A number of important conclusions are obtained using the modeling environment. For example, the studies decisively show that deploying ad hoc communication networks to reach individuals in the affected area is likely to have a significant impact on the overall casualties and injuries.

ENteric Immunity SImulator: a tool for in silico study of gastroenteric infections.

Clinical symptoms of microbial infection of the gastrointestinal (GI) tract are often exacerbated by inflammation induced pathology. Identifying novel avenues for treating and preventing such pathologies is necessary and complicated by the complexity of interacting immune pathways in the gut, where effector and inflammatory immune cells are regulated by anti-inflammatory or regulatory cells. Here we present new advances in the development of the ENteric Immunity SImulator (ENISI), a simulator of GI immune mechanisms in response to resident commensal bacteria as well as invading pathogens and the effect on the development of intestinal lesions. ENISI is a tool for identifying potential treatment strategies that reduce inflammation-induced damage and, at the same time, ensure pathogen removal by allowing one to test plausibility of in vitro observed behavior as explanations for observations in vivo, propose behaviors not yet tested in vitro that could explain these tissue-level observations, and conduct low-cost, preliminary experiments of proposed interventions/treatments. An example of such application is shown in which we simulate dysentery resulting from Brachyispira hyodysenteriae infection and identify aspects of the host immune pathways that lead to continued inflammation-induced tissue damage even after pathogen elimination.

Economic and social impact of influenza mitigation strategies by demographic class.

BACKGROUND: We aim to determine the economic and social impact of typical interventions proposed by the public health officials and preventive behavioral changes adopted by the private citizens in the event of a "flu-like" epidemic. METHOD: We apply an individual-based simulation model to the New River Valley area of Virginia for addressing this critical problem. The economic costs include not only the loss in productivity due to sickness but also the indirect cost incurred through disease avoidance and caring for dependents. RESULTS: The results show that the most important factor responsible for preventing income loss is the modification of individual behavior; it drops the total income loss by 62% compared to the base case. The next most important factor is the closure of schools which reduces the total income loss by another 40%. CONCLUSIONS: The preventive behavior of the private citizens is the most important factor in controlling the epidemic.

Detail in network models of epidemiology: are we there yet?

Network models of infectious disease epidemiology can potentially provide insight into how to tailor control strategies for specific regions, but only if the network adequately reflects the structure of the region's contact network. Typically, the network is produced by models that incorporate details about human interactions. Each detail added renders the models more complicated and more difficult to calibrate, but also more faithful to the actual contact network structure. We propose a statistical test to determine when sufficient detail has been added to the models and demonstrate its application to the models used to create a synthetic population and contact network for the USA.