A framework for long-lasting, slowly varying transient dynamics.

Much of the focus of applied dynamical systems is on asymptotic dynamics such as equilibria and periodic solutions. However, in many systems there are transient phenomena, such as temporary population collapses and the honeymoon period after the start of mass vaccination, that can last for a very long time and play an important role in ecological and epidemiological applications. In previous work we defined transient centers which are points in state space that give rise to arbitrarily long and arbitrarily slow transient dynamics. Here we present the mathematical properties of transient centers and provide further insight into these special points. We show that under certain conditions, the entire forward and backward trajectory of a transient center, as well as all its limit points must also be transient centers. We also derive conditions that can be used to verify which points are transient centers and whether those are reachable transient centers. Finally we present examples to demonstrate the utility of the theory, including applications to predatory-prey systems and disease transmission models, and show that the long transience noted in these models are generated by transient centers.

The impact of threshold decision mechanisms of collective behavior on disease spread.

Humans are a hyper-social species, which greatly impacts the spread of infectious diseases. How do social dynamics impact epidemiology and what are the implications for public health policy? Here, we develop a model of disease transmission that incorporates social dynamics and a behavior that reduces the spread of disease, a voluntary nonpharmaceutical intervention (NPI). We use a "tipping-point" dynamic, previously used in the sociological literature, where individuals adopt a behavior given a sufficient prevalence of the behavior in the population. The thresholds at which individuals adopt the NPI behavior are modulated by the perceived risk of infection, i.e., the disease prevalence and transmission rate, costs to adopt the NPI behavior, and the behavior of others. Social conformity creates a type of "stickiness" whereby individuals are resistant to changing their behavior due to the population's inertia. In this model, we observe a nonmonotonicity in the attack rate as a function of various biological and social parameters such as the transmission rate, efficacy of the NPI, costs of the NPI, weight of social consequences of shirking the social norm, and the degree of heterogeneity in the population. We also observe that the attack rate can be highly sensitive to these parameters due to abrupt shifts in the collective behavior of the population. These results highlight the complex interplay between the dynamics of epidemics and norm-driven collective behaviors.

The impact of infection-derived immunity on disease dynamics.

When modeling infectious diseases, it is common to assume that infection-derived immunity is either (1) non-existent or (2) perfect and lifelong. However there are many diseases in which infection-derived immunity is known to be present but imperfect. There are various ways in which infection-derived immunity can fail, which can ultimately impact the probability that an individual be reinfected by the same pathogen, as well as the long-run population-level prevalence of the pathogen. Here we discuss seven different models of imperfect infection-derived immunity, including waning, leaky and all-or-nothing immunity. For each model we derive the probability that an infected individual becomes reinfected during their lifetime, given that the system is at endemic equilibrium. This can be thought of as the impact that each of these infection-derived immunity failures have on reinfection. This measure is useful because it provides us with a way to compare different modes of failure of infection-derived immunity.

Optimal Control of Mitigation Strategies for Dengue Virus Transmission.

Dengue virus is transmitted by Aedes mosquitoes, posing threat to people's health and leading to great economic cost in many tropical and subtropical regions. We develop an ordinary differential equation model taking into account multiple strains of dengue virus. Using the model, we assess the effectiveness of human vaccination considering its waning and failure. We derive the lower bound and upper bound for the final size of the epidemic. Sensitivity analysis quantifies the impact of parameters on the basic reproduction number. Different scenarios of vaccinating humans show that it is better to vaccinate humans at early stages. We find that the cumulative number of infected humans is small when the vaccination rate is high or the waning rate is low for previously infected humans. We analyze the necessary conditions for implementing optimal control and derive the corresponding optimal solutions for mitigation dengue virus transmission by applying Pontryagin's Maximum Principle. Our findings may provide guidance for the public health authorities to implement human vaccination and other mitigation strategies.

Assessing systemic and non-systemic transmission risk of tick-borne encephalitis virus in Hungary.

Estimating the tick-borne encephalitis (TBE) infection risk under substantial uncertainties of the vector abundance, environmental condition and human-tick interaction is important for evidence-informed public health intervention strategies. Estimating this risk is computationally challenging since the data we observe, i.e., the human incidence of TBE, is only the final outcome of the tick-host transmission and tick-human contact processes. The challenge also increases since the complex TBE virus (TBEV) transmission cycle involves the non-systemic route of transmission between co-feeding ticks. Here, we describe the hidden Markov transition process, using a novel TBEV transmission-human case reporting cascade model that couples the susceptible-infected compartmental model describing the TBEV transmission dynamics among ticks, animal hosts and humans, with the stochastic observation process of human TBE reporting given infection. By fitting human incidence data in Hungary to the transmission model, we estimate key parameters relevant to the tick-host interaction and tick-human transmission. We then use the parametrized cascade model to assess the transmission potential of TBEV in the enzootic cycle with respect to the climate change, and to evaluate the contribution of non-systemic transmission. We show that the TBEV transmission potential in the enzootic cycle has been increasing along with the increased temperature though the TBE human incidence has dropped since 1990s, emphasizing the importance of persistent public health interventions. By demonstrating that non-systemic transmission pathway is a significant factor in the transmission of TBEV in Hungary, we conclude that the risk of TBE infection will be highly underestimated if the non-systemic transmission route is neglected in the risk assessment.

The impact of past vaccination coverage and immunity on pertussis resurgence.

The resurgence of pertussis over the past decades has resulted in incidence levels not witnessed in the United States since the 1950s. The underlying causes have been the subject of much speculation, with particular attention paid to the shortcomings of the latest generation of vaccines. We formulated transmission models comprising competing hypotheses regarding vaccine failure and challenged them to explain 16 years of highly resolved incidence data from Massachusetts, United States. Our results suggest that the resurgence of pertussis is a predictable consequence of incomplete historical coverage with an imperfect vaccine that confers slowly waning immunity. We found evidence that the vaccine itself is effective at reducing overall transmission, yet that routine vaccination alone would be insufficient for elimination of the disease. Our results indicated that the core transmission group is schoolchildren. Therefore, efforts aimed at curtailing transmission in the population at large, and especially in vulnerable infants, are more likely to succeed if targeted at schoolchildren, rather than adults.

The pertussis enigma: reconciling epidemiology, immunology and evolution.

Pertussis, a highly contagious respiratory infection, remains a public health priority despite the availability of vaccines for 70 years. Still a leading cause of mortality in developing countries, pertussis has re-emerged in several developed countries with high vaccination coverage. Resurgence of pertussis in these countries has routinely been attributed to increased awareness of the disease, imperfect vaccinal protection or high infection rates in adults. In this review, we first present 1980-2012 incidence data from 63 countries and show that pertussis resurgence is not universal. We further argue that the large geographical variation in trends probably precludes a simple explanation, such as the transition from whole-cell to acellular pertussis vaccines. Reviewing available evidence, we then propose that prevailing views on pertussis epidemiology are inconsistent with both historical and contemporary data. Indeed, we summarize epidemiological evidence showing that natural infection and vaccination both appear to provide long-term protection against transmission and disease, so that previously infected or vaccinated adults contribute little to overall transmission at a population level. Finally, we identify several promising avenues that may lead to a consistent explanation of global pertussis epidemiology and to more effective control strategies.

Integrated Model of Chemical Perturbations of a Biological Pathway Using 18 In Vitro High-Throughput Screening Assays for the Estrogen Receptor.

We demonstrate a computational network model that integrates 18 in vitro, high-throughput screening assays measuring estrogen receptor (ER) binding, dimerization, chromatin binding, transcriptional activation, and ER-dependent cell proliferation. The network model uses activity patterns across the in vitro assays to predict whether a chemical is an ER agonist or antagonist, or is otherwise influencing the assays through a manner dependent on the physics and chemistry of the technology platform ("assay interference"). The method is applied to a library of 1812 commercial and environmental chemicals, including 45 ER positive and negative reference chemicals. Among the reference chemicals, the network model correctly identified the agonists and antagonists with the exception of very weak compounds whose activity was outside the concentration range tested. The model agonist score also correlated with the expected potency class of the active reference chemicals. Of the 1812 chemicals evaluated, 111 (6.1%) were predicted to be strongly ER active in agonist or antagonist mode. This dataset and model were also used to begin a systematic investigation of assay interference. The most prominent cause of false-positive activity (activity in an assay that is likely not due to interaction of the chemical with ER) is cytotoxicity. The model provides the ability to prioritize a large set of important environmental chemicals with human exposure potential for additional in vivo endocrine testing. Finally, this model is generalizable to any molecular pathway for which there are multiple upstream and downstream assays available.

A mathematical model for pathogen cross-contamination dynamics during produce wash.

One of the main challenges for the fresh-food produce industry is to ensure that the produce is free from harmful pathogens. A potential area of risk is due to cross-contamination in a sanitizing chlorine wash-cycle, where the same water is used to wash contaminated as well as non-contaminated produce. However, this is also an area where effective intervention strategies are possible, provided we have a good understanding of the mechanism of cross-contamination. Based on recent experimental work by Luo, Y. et al. A pilot plant scale evaluation of a new process aid for enhancing chlorine efficacy against pathogen survival and cross-contamination during produce wash, International Journal of Food Microbiology, 158 (2012), 133-139, we have built mathematical models that allow us to quantify the amount of cross-contamination of Escherichia coli O157:H7 from spinach to lettuce, and assessed the efficacy of the associated wash-cycle protocols.

Avoidable errors in the modelling of outbreaks of emerging pathogens, with special reference to Ebola.

As an emergent infectious disease outbreak unfolds, public health response is reliant on information on key epidemiological quantities, such as transmission potential and serial interval. Increasingly, transmission models fit to incidence data are used to estimate these parameters and guide policy. Some widely used modelling practices lead to potentially large errors in parameter estimates and, consequently, errors in model-based forecasts. Even more worryingly, in such situations, confidence in parameter estimates and forecasts can itself be far overestimated, leading to the potential for large errors that mask their own presence. Fortunately, straightforward and computationally inexpensive alternatives exist that avoid these problems. Here, we first use a simulation study to demonstrate potential pitfalls of the standard practice of fitting deterministic models to cumulative incidence data. Next, we demonstrate an alternative based on stochastic models fit to raw data from an early phase of 2014 West Africa Ebola virus disease outbreak. We show not only that bias is thereby reduced, but that uncertainty in estimates and forecasts is better quantified and that, critically, lack of model fit is more readily diagnosed. We conclude with a short list of principles to guide the modelling response to future infectious disease outbreaks.

Wave fronts in neuronal fields with nonlocal post-synaptic axonal connections and delayed nonlocal feedback connections.

We consider a neuronal network model with both axonal connections (in the form of synaptic coupling) and delayed non-local feedback connections. The kernel in the feedback channel is assumed to be a standard non-local one, while for the kernel in the synaptic coupling, four types are considered. The main concern is the existence of travelling wave front. By employing the speed index function, we are able to obtain the existence of a travelling wave front for each of these four types within certain range of model parameters. We are also able to describe how the feedback coupling strength and the magnitude of the delay affect the wave speed. Some particular kernel functions for these four cases are chosen to numerically demonstrate the theoretical results.