Search

Phylodynamic modelling, which studies the joint dynamics of epidemiological and evolutionary processes, has made significant progress in recent years due to increasingly available genomic data and advances in statistical modelling. These advances have greatly improved our understanding of transmission dynamics of many important pathogens. Nevertheless, there remains a lack of effective, targetted diagnostic tools for systematically detecting model mis-specification. Development of such tools is essential for model criticism, refinement, and calibration. The idea of utilising latent residuals for model assessment has already been exploited in general spatio-temporal epidemiological settings. Specifically, by proposing appropriately designed non-centered, re-parameterizations of a given epidemiological process, one can construct latent residuals with known sampling distributions which can be used to quantify evidence of model mis-specification. In this paper, we extend this idea to formulate a novel model-diagnostic framework for phylodynamic models. Using simulated examples, we show that our framework may effectively detect a particular form of mis-specification in a phylodynamic model, particularly in the event of superspreading. We also exemplify our approach by applying the framework to a dataset describing a local foot-and-mouth (FMD) outbreak in the UK, eliciting strong evidence against the assumption of no within-host-diversity in the outbreak. We further demonstrate that our framework can facilitate model calibration in real-life scenarios, by proposing a within-host-diversity model which appears to offer a better fit to data than one that assumes no within-host-diversity of FMD virus. [ABSTRACT FROM AUTHOR]

In recent years there has been growing availability of individual-level spatio-temporal disease data, particularly due to the use of modern communicating devices with GPS tracking functionality. These detailed data have been proven useful for inferring disease transmission to a more refined level than previously. However, there remains a lack of statistically sound frameworks to model the underlying transmission dynamic in a mechanistic manner. Such a development is particularly crucial for enabling a general epidemic predictive framework at the individual level. In this paper we propose a new statistical framework for mechanistically modelling individual-to-individual disease transmission in a landscape with heterogeneous population density. Our methodology is first tested using simulated datasets, validating our inferential machinery. The methodology is subsequently applied to data that describes a regional Ebola outbreak in Western Africa (2014-2015). Our results show that the methods are able to obtain estimates of key epidemiological parameters that are broadly consistent with the literature, while revealing a significantly shorter distance of transmission. More importantly, in contrast to existing approaches, we are able to perform a more general model prediction that takes into account the susceptible population. Finally, our results show that, given reasonable scenarios, the framework can be an effective surrogate for susceptible-explicit individual models which are often computationally challenging. [ABSTRACT FROM AUTHOR]

To eliminate and eradicate gambiense human African trypanosomiasis (HAT), maximizing the effectiveness of active case finding is of key importance. The progression of the epidemic is largely influenced by the planning of these operations. This paper introduces and analyzes five models for predicting HAT prevalence in a given village based on past observed prevalence levels and past screening activities in that village. Based on the quality of prevalence level predictions in 143 villages in Kwamouth (DRC), and based on the theoretical foundation underlying the models, we consider variants of the Logistic Model—a model inspired by the SIS epidemic model—to be most suitable for predicting HAT prevalence levels. Furthermore, we demonstrate the applicability of this model to predict the effects of planning policies for screening operations. Our analysis yields an analytical expression for the screening frequency required to reach eradication (zero prevalence) and a simple approach for determining the frequency required to reach elimination within a given time frame (one case per 10000). Furthermore, the model predictions suggest that annual screening is only expected to lead to eradication if at least half of the cases are detected during the screening rounds. This paper extends knowledge on control strategies for HAT and serves as a basis for further modeling and optimization studies. [ABSTRACT FROM AUTHOR]

Hosts diverge widely in how, and how well, they defend themselves against infection and immunopathology. Why are hosts so heterogeneous? Both epidemiology and life history are commonly hypothesized to influence host immune strategy, but the relationship between immune strategy and each factor has commonly been investigated in isolation. Here, we show that interactions between life history and epidemiology are crucial for determining optimal immune specificity and sensitivity. We propose a demographically-structured population dynamics model, in which we explore sensitivity and specificity of immune responses when epidemiological risks vary with age. We find that variation in life history traits associated with both reproduction and longevity alters optimal immune strategies–but the magnitude and sometimes even direction of these effects depends on how epidemiological risks vary across life. An especially compelling example that explains previously-puzzling empirical observations is that depending on whether infection risk declines or rises at reproductive maturity, later reproductive maturity can select for either greater or lower immune specificity, potentially illustrating why studies of lifespan and immune variation across taxa have been inconclusive. Thus, the sign of selection on the life history-immune specificity relationship can be reversed in different epidemiological contexts. Drawing on published life history data from a variety of chordate taxa, we generate testable predictions for this facet of the optimal immune strategy. Our results shed light on the causes of the heterogeneity found in immune defenses both within and among species and the ultimate variability of the relationship between life history and immune specificity. Author summary: Organisms must use their immune defenses to counter infections, and their particular immune needs and optimal strategy for defense are likely to depend on the infection threats they face and their reproductive and survival schedules. Yet little is known about how these factors might interact together to influence immune strategy. We used a population dynamics model to examine how optimal immune specificity in host recognition of parasites depends simultaneously upon reproduction, survival, and parasite threats across life. We find that the strength and direction of the association between immune specificity and reproduction or survival depends on parasite threats and how they vary with age. For example, a highly specific immune response is favored for long-lived, slow-reproducing organisms when infection risk declines with age but is also favored for short-lived, fast-reproducing organisms when infection risk rises with age. Thus organisms with very different schedules may have identical specificities depending on their particular circumstances. Our research highlights how the immune strategies needed to "live fast and die young" or "live long and prosper" are not fixed but rather will depend on the interplay of different pathogen risks at different stages of life with when, during their lives, organisms reproduce. [ABSTRACT FROM AUTHOR]

Measuring the overlap between two populations is, in principle, straightforward. Upon fully sampling both populations, the number of shared objects—species, taxonomical units, or gene variants, depending on the context—can be directly counted. In practice, however, only a fraction of each population’s objects are likely to be sampled due to stochastic data collection or sequencing techniques. Although methods exists for quantifying population overlap under subsampled conditions, their bias is well documented and the uncertainty of their estimates cannot be quantified. Here we derive and validate a method to rigorously estimate the population overlap from incomplete samples when the total number of objects, species, or genes in each population is known, a special case of the more general β-diversity problem that is particularly relevant in the ecology and genomic epidemiology of malaria. By solving a Bayesian inference problem, this method takes into account the rates of subsampling and produces unbiased and Bayes-optimal estimates of overlap. In addition, it provides a natural framework for computing the uncertainty of its estimates, and can be used prospectively in study planning by quantifying the tradeoff between sampling effort and uncertainty. [ABSTRACT FROM AUTHOR]

We develop a flexible, two-locus model for the spread of insecticide resistance applicable to mosquito species that transmit human diseases such as malaria. The model allows differential exposure of males and females, allows them to encounter high or low concentrations of insecticide, and allows selection pressures and dominance values to differ depending on the concentration of insecticide encountered. We demonstrate its application by investigating the relative merits of sequential use of insecticides versus their deployment as a mixture to minimise the spread of resistance. We recover previously published results as subsets of this model and conduct a sensitivity analysis over an extensive parameter space to identify what circumstances favour mixtures over sequences. Both strategies lasted more than 500 mosquito generations (or about 40 years) in 24% of runs, while in those runs where resistance had spread to high levels by 500 generations, 56% favoured sequential use and 44% favoured mixtures. Mixtures are favoured when insecticide effectiveness (their ability to kill homozygous susceptible mosquitoes) is high and exposure (the proportion of mosquitoes that encounter the insecticide) is low. If insecticides do not reliably kill homozygous sensitive genotypes, it is likely that sequential deployment will be a more robust strategy. Resistance to an insecticide always spreads slower if that insecticide is used in a mixture although this may be insufficient to outperform sequential use: for example, a mixture may last 5 years while the two insecticides deployed individually may last 3 and 4 years giving an overall ‘lifespan’ of 7 years for sequential use. We emphasise that this paper is primarily about designing and implementing a flexible modelling strategy to investigate the spread of insecticide resistance in vector populations and demonstrate how our model can identify vector control strategies most likely to minimise the spread of insecticide resistance. [ABSTRACT FROM AUTHOR]

In January 2020, a COVID-19 outbreak was detected in Sichuan Province of China. Six weeks later, the outbreak was successfully contained. The aim of this work is to characterize the epidemiology of the Sichuan outbreak and estimate the impact of interventions in limiting SARS-CoV-2 transmission. We analyzed patient records for all laboratory-confirmed cases reported in the province for the period of January 21 to March 16, 2020. To estimate the basic and daily reproduction numbers, we used a Bayesian framework. In addition, we estimate the number of cases averted by the implemented control strategies. The outbreak resulted in 539 confirmed cases, lasted less than two months, and no further local transmission was detected after February 27. The median age of local cases was 8 years older than that of imported cases. We estimated R0 at 2.4 (95% CI: 1.6–3.7). The epidemic was self-sustained for about 3 weeks before going below the epidemic threshold 3 days after the declaration of a public health emergency by Sichuan authorities. Our findings indicate that, were the control measures be adopted four weeks later, the epidemic could have lasted 49 days longer (95% CI: 31–68 days), causing 9,216 more cases (95% CI: 1,317–25,545). Author summary: Since its emergence in Wuhan, SARS-CoV-2 rapidly started its spread across China. On January 21, 2020 the first COVID-19 case was detected in the Sichuan Province of China and led to an outbreak of local transmission. Less than two months later, the outbreak was over with the last reported case on March 4, 2020. In this study, we analyzed patient records for all laboratory-confirmed cases reported in the Sichuan to provide an epidemiological characterization of the outbreak, to estimate SARS-CoV-2 transmission potential, and to assess the impact of the adopted interventions. We estimated that, during the initial exponential growth phase of the outbreak, each COVID-19 case has generated a mean of 2.4 secondary cases (95% CI: 1.6–3.7). Moreover, we estimated that, were the Sichuan strict containment measures implemented four weeks later, the outbreak would have caused 9,216 more cases (95% CI: 1,317–25,545). Our findings suggest the key role of a quick response to COVID-19 outbreaks and the importance of an adequate surveillance and monitoring system. [ABSTRACT FROM AUTHOR]

Simple spatial interaction models of human mobility based on physical laws have been used extensively in the social, biological, and physical sciences, and in the study of the human dynamics underlying the spread of disease. Recent analyses of commuting patterns and travel behavior in high-income countries have led to the suggestion that these models are highly generalizable, and as a result, gravity and radiation models have become standard tools for describing population mobility dynamics for infectious disease epidemiology. Communities in Sub-Saharan Africa may not conform to these models, however; physical accessibility, availability of transport, and cost of travel between locations may be variable and severely constrained compared to high-income settings, informal labor movements rather than regular commuting patterns are often the norm, and the rise of mega-cities across the continent has important implications for travel between rural and urban areas. Here, we first review how infectious disease frameworks incorporate human mobility on different spatial scales and use anonymous mobile phone data from nearly 15 million individuals to analyze the spatiotemporal dynamics of the Kenyan population. We find that gravity and radiation models fail in systematic ways to capture human mobility measured by mobile phones; both severely overestimate the spatial spread of travel and perform poorly in rural areas, but each exhibits different characteristic patterns of failure with respect to routes and volumes of travel. Thus, infectious disease frameworks that rely on spatial interaction models are likely to misrepresent population dynamics important for the spread of disease in many African populations. [ABSTRACT FROM AUTHOR]

Identifying important nodes for disease spreading is a central topic in network epidemiology. We investigate how well the position of a node, characterized by standard network measures, can predict its epidemiological importance in any graph of a given number of nodes. This is in contrast to other studies that deal with the easier prediction problem of ranking nodes by their epidemic importance in given graphs. As a benchmark for epidemic importance, we calculate the exact expected outbreak size given a node as the source. We study exhaustively all graphs of a given size, so do not restrict ourselves to certain generative models for graphs, nor to graph data sets. Due to the large number of possible nonisomorphic graphs of a fixed size, we are limited to ten-node graphs. We find that combinations of two or more centralities are predictive (R2 scores of 0.91 or higher) even for the most difficult parameter values of the epidemic simulation. Typically, these successful combinations include one normalized spectral centrality (such as PageRank or Katz centrality) and one measure that is sensitive to the number of edges in the graph. Author summary: A central challenge in network epidemiology is to find nodes that are important for disease spreading. Usually, one starts from a certain graph, and tries to rank the nodes in a way that correlates as strongly as possible with measures of importance estimated using simulations of outbreaks. A more challenging prediction task, and the one we take, is to ask if one can guess, from measures of the network structure alone, the values of quantities describing the outbreak. Having this predictive power is important: one can then target nodes that are more important than a certain threshold, rather than just a top fraction of nodes. By exhaustively studying all small graphs, we show that such prediction is possible to achieve with high accuracy by combining standard network measures. [ABSTRACT FROM AUTHOR]

Despite advances in the modeling and understanding of colorectal cancer development, the dynamics of the progression from benign adenomatous polyp to colorectal carcinoma are still not fully resolved. To take advantage of adenoma size and prevalence data in the National Endoscopic Database of the Clinical Outcomes Research Initiative (CORI) as well as colorectal cancer incidence and size data from the Surveillance Epidemiology and End Results (SEER) database, we construct a two-type branching process model with compartments representing adenoma and carcinoma cells. To perform parameter inference we present a new large-size approximation to the size distribution of the cancer compartment and validate our approach on simulated data. By fitting the model to the CORI and SEER data, we learn biologically relevant parameters, including the transition rate from adenoma to cancer. The inferred parameters allow us to predict the individualized risk of the presence of cancer cells for each screened patient. We provide a web application which allows the user to calculate these individual probabilities at https://ccrc-eth.shinyapps.io/CCRC/. For example, we find a 1 in 100 chance of cancer given the presence of an adenoma between 10 and 20mm size in an average risk patient at age 50. We show that our two-type branching process model recapitulates the early growth dynamics of colon adenomas and cancers and can recover epidemiological trends such as adenoma prevalence and cancer incidence while remaining mathematically and computationally tractable. Author summary: Colorectal cancer is a major public health burden. The development of colorectal cancer starts with the mutational initiation of non-cancerous growths in the form of benign adenomatous polyps. These adenomas grow over time with the potential to develop into carcinomas. Many mathematical and simulation-based models have been used to gain insight into this process. We aimed to understand rates of adenoma growth and transition into carcinomas, to enable better planning of colorectal cancer screening strategies. To this end, we expand the two-type branching process model, and fit it on data describing the frequency of sizes of adenomas and carcinomas. The results provide new, data-based, estimates of the rates of development for colorectal cancer. [ABSTRACT FROM AUTHOR]

Seasonal influenza is a sometimes surprisingly impactful disease, causing thousands of deaths per year along with much additional morbidity. Timely knowledge of the outbreak state is valuable for managing an effective response. The current state of the art is to gather this knowledge using in-person patient contact. While accurate, this is time-consuming and expensive. This has motivated inquiry into new approaches using internet activity traces, based on the theory that lay observations of health status lead to informative features in internet data. These approaches risk being deceived by activity traces having a coincidental, rather than informative, relationship to disease incidence; to our knowledge, this risk has not yet been quantitatively explored. We evaluated both simulated and real activity traces of varying deceptiveness for influenza incidence estimation using linear regression. We found that deceptiveness knowledge does reduce error in such estimates, that it may help automatically-selected features perform as well or better than features that require human curation, and that a semantic distance measure derived from the Wikipedia article category tree serves as a useful proxy for deceptiveness. This suggests that disease incidence estimation models should incorporate not only data about how internet features map to incidence but also additional data to estimate feature deceptiveness. By doing so, we may gain one more step along the path to accurate, reliable disease incidence estimation using internet data. This capability would improve public health by decreasing the cost and increasing the timeliness of such estimates. [ABSTRACT FROM AUTHOR]

One of network epidemiology's central assumptions is that the contact structure over which infectious diseases propagate can be represented as a static network. However, contacts are highly dynamic, changing at many time scales. In this paper, we investigate conceptually simple methods to construct static graphs for network epidemiology from temporal contact data. We evaluate these methods on empirical and synthetic model data. For almost all our cases, the network representation that captures most relevant information is a so-called exponential-threshold network. In these, each contact contributes with a weight decreasing exponentially with time, and there is an edge between a pair of vertices if the weight between them exceeds a threshold. Networks of aggregated contacts over an optimally chosen time window perform almost as good as the exponential-threshold networks. On the other hand, networks of accumulated contacts over the entire sampling time, and networks of concurrent partnerships, perform worse. We discuss these observations in the context of the temporal and topological structure of the data sets. [ABSTRACT FROM AUTHOR]

Gravity models have a long history of use in describing and forecasting the movements of people as well as goods and services, making them a natural basis for disease transmission rates over distance. In agent-based micro-simulations, gravity models can be directly used to represent movement of individuals and hence disease. In this paper, we consider a range of gravity models as fits to movement data from the UK and the US. We examine the ability of synthetic networks generated from fitted models to match those from the data in terms of epidemic behaviour; in particular, times to first infection. For both datasets, best fits are obtained with a two-piece 'matched' power law distance distribution. Epidemics on synthetic UK networks match well those on data networks across all but the smallest nodes for a range of aggregation levels. We derive an expression for time to infection between nodes in terms of epidemiological and network parameters which illuminates the influence of network clustering in spread across networks and suggests an approximate relationship between the log-likelihood deviance of model fit and the match times to infection between synthetic and data networks. On synthetic US networks, the match in epidemic behaviour is initially poor and sensitive to the initially infected node. Analysis of times to infection indicates a failure of models to capture infrequent long-range contact between large nodes. An assortative model based on node population size captures this heterogeneity, considerably improving the epidemiological match between synthetic and data networks. [ABSTRACT FROM AUTHOR]

In this paper we used a general stochastic processes framework to derive from first principles the incidence rate function that characterizes epidemic models. We investigate a particular case, the Liu-Hethcote-van den Driessche's (LHD) incidence rate function, which results from modeling the number of successful transmission encounters as a pure birth process. This derivation also takes into account heterogeneity in the population with regard to the per individual transmission probability. We adjusted a deterministic SIRS model with both the classical and the LHD incidence rate functions to time series of the number of children infected with syncytial respiratory virus in Banjul, Gambia and Turku, Finland. We also adjusted a deterministic SEIR model with both incidence rate functions to the famous measles data sets from the UK cities of London and Birmingham. Two lines of evidence supported our conclusion that the model with the LHD incidence rate may very well be a better description of the seasonal epidemic processes studied here. First, our model was repeatedly selected as best according to two different information criteria and two different likelihood formulations. The second line of evidence is qualitative in nature: contrary to what the SIRS model with classical incidence rate predicts, the solution of the deterministic SIRS model with LHD incidence rate will reach either the disease free equilibrium or the endemic equilibrium depending on the initial conditions. These findings along with computer intensive simulations of the models' Poincaré map with environmental stochasticity contributed to attain a clear separation of the roles of the environmental forcing and the mechanics of the disease transmission in shaping seasonal epidemics dynamics. [ABSTRACT FROM AUTHOR]

Yellow fever is a vector-borne disease endemic in tropical regions of Africa, where 90% of the global burden occurs, and Latin America. It is notoriously under-reported with uncertainty arising from a complex transmission cycle including a sylvatic reservoir and non-specific symptom set. Resulting estimates of burden, particularly in Africa, are highly uncertain. We examine two established models of yellow fever transmission within a Bayesian model averaging framework in order to assess the relative evidence for each model’s assumptions and to highlight possible data gaps. Our models assume contrasting scenarios of the yellow fever transmission cycle in Africa. The first takes the force of infection in each province to be static across the observation period; this is synonymous with a constant infection pressure from the sylvatic reservoir. The second model assumes the majority of transmission results from the urban cycle; in this case, the force of infection is dynamic and defined through a fixed value of R0 in each province. Both models are coupled to a generalised linear model of yellow fever occurrence which uses environmental covariates to allow us to estimate transmission intensity in areas where data is sparse. We compare these contrasting descriptions of transmission through a Bayesian framework and trans-dimensional Markov chain Monte Carlo sampling in order to assess each model’s evidence given the range of uncertainty in parameter values. The resulting estimates allow us to produce Bayesian model averaged predictions of yellow fever burden across the African endemic region. We find strong support for the static force of infection model which suggests a higher proportion of yellow fever transmission occurs as a result of infection from an external source such as the sylvatic reservoir. However, the model comparison highlights key data gaps in serological surveys across the African endemic region. As such, conclusions concerning the most prevalent transmission routes for yellow fever will be limited by the sparsity of data which is particularly evident in the areas with highest predicted transmission intensity. Our model and estimation approach provides a robust framework for model comparison and predicting yellow fever burden in Africa. However, key data gaps increase uncertainty surrounding estimates of model parameters and evidence. As more mathematical models are developed to address new research questions, it is increasingly important to compare them with established modelling approaches to highlight uncertainty in structures and data. [ABSTRACT FROM AUTHOR]

According to the Centers for Disease Control and Prevention (CDC), one in twenty five hospital patients are infected with at least one healthcare acquired infection (HAI) on any given day. Early detection of possible HAI outbreaks help practitioners implement countermeasures before the infection spreads extensively. Here, we develop an efficient data and model driven method to detect outbreaks with high accuracy. We leverage mechanistic modeling of C. difficile infection, a major HAI disease, to simulate its spread in a hospital wing and design efficient near-optimal algorithms to select people and locations to monitor using an optimization formulation. Results show that our strategy detects up to 95% of “future” C. difficile outbreaks. We design our method by incorporating specific hospital practices (like swabbing for infections) as well. As a result, our method outperforms state-of-the-art algorithms for outbreak detection. Finally, a qualitative study of our result shows that the people and locations we select to monitor as sensors are intuitive and meaningful. [ABSTRACT FROM AUTHOR]

Stochastic mechanistic epidemiological models largely contribute to better understand pathogen emergence and spread, and assess control strategies at various scales (from within-host to transnational scale). However, developing realistic models which involve multi-disciplinary knowledge integration faces three major challenges in predictive epidemiology: lack of readability once translated into simulation code, low reproducibility and reusability, and long development time compared to outbreak time scale. We introduce here EMULSION, an artificial intelligence-based software intended to address those issues and help modellers focus on model design rather than programming. EMULSION defines a domain-specific language to make all components of an epidemiological model (structure, processes, parameters…) explicit as a structured text file. This file is readable by scientists from other fields (epidemiologists, biologists, economists), who can contribute to validate or revise assumptions at any stage of model development. It is then automatically processed by EMULSION generic simulation engine, preventing any discrepancy between model description and implementation. The modelling language and simulation architecture both rely on the combination of advanced artificial intelligence methods (knowledge representation and multi-level agent-based simulation), allowing several modelling paradigms (from compartment- to individual-based models) at several scales (up to metapopulation). The flexibility of EMULSION and its capability to support iterative modelling are illustrated here through examples of progressive complexity, including late revisions of core model assumptions. EMULSION is also currently used to model the spread of several diseases in real pathosystems. EMULSION provides a command-line tool for checking models, producing model diagrams, running simulations, and plotting outputs. Written in Python 3, EMULSION runs on Linux, MacOS, and Windows. It is released under Apache-2.0 license. A comprehensive documentation with installation instructions, a tutorial and many examples are available from: . [ABSTRACT FROM AUTHOR]

Estimation of influenza-like illness (ILI) using search trends activity was intended to supplement traditional surveillance systems, and was a motivation behind the development of Google Flu Trends (GFT). However, several studies have previously reported large errors in GFT estimates of ILI in the US. Following recent release of time-stamped surveillance data, which better reflects real-time operational scenarios, we reanalyzed GFT errors. Using three data sources—GFT: an archive of weekly ILI estimates from Google Flu Trends; ILIf: fully-observed ILI rates from ILINet; and, ILIp: ILI rates available in real-time based on partial reporting—five influenza seasons were analyzed and mean square errors (MSE) of GFT and ILIp as estimates of ILIf were computed. To correct GFT errors, a random forest regression model was built with ILI and GFT rates from the previous three weeks as predictors. An overall reduction in error of 44% was observed and the errors of the corrected GFT are lower than those of ILIp. An 80% reduction in error during 2012/13, when GFT had large errors, shows that extreme failures of GFT could have been avoided. Using autoregressive integrated moving average (ARIMA) models, one- to four-week ahead forecasts were generated with two separate data streams: ILIp alone, and with both ILIp and corrected GFT. At all forecast targets and seasons, and for all but two regions, inclusion of GFT lowered MSE. Results from two alternative error measures, mean absolute error and mean absolute proportional error, were largely consistent with results from MSE. Taken together these findings provide an error profile of GFT in the US, establish strong evidence for the adoption of search trends based 'nowcasts' in influenza forecast systems, and encourage reevaluation of the utility of this data source in diverse domains. [ABSTRACT FROM AUTHOR]

Aberrant DNA methylation disrupts normal gene expression in cancer and broadly contributes to oncogenesis. We previously developed MethylMix, a model-based algorithmic approach to identify epigenetically regulated driver genes. MethylMix identifies genes where methylation likely executes a functional role by using transcriptomic data to select only methylation events that can be linked to changes in gene expression. However, given that proteins more closely link genotype to phenotype recent high-throughput proteomic data provides an opportunity to more accurately identify functionally relevant abnormal methylation events. Here we present a MethylMix analysis that refines nominations for epigenetic driver genes by leveraging quantitative high-throughput proteomic data to select only genes where DNA methylation is predictive of protein abundance. Applying our algorithm across three cancer cohorts we find that using protein abundance data narrows candidate nominations, where the effect of DNA methylation is often buffered at the protein level. Next, we find that MethylMix genes predictive of protein abundance are enriched for biological processes involved in cancer including functions involved in epithelial and mesenchymal transition. Moreover, our results are also enriched for tumor markers which are predictive of clinical features like tumor stage and we find clustering using MethylMix genes predictive of protein abundance captures cancer subtypes. [ABSTRACT FROM AUTHOR]

Cancer is mainly caused by somatic genome alterations (SGAs). Precision oncology involves identifying and targeting tumor-specific aberrations resulting from causative SGAs. We developed a novel tumor-specific computational framework that finds the likely causative SGAs in an individual tumor and estimates their impact on oncogenic processes, which suggests the disease mechanisms that are acting in that tumor. This information can be used to guide precision oncology. We report a tumor-specific causal inference (TCI) framework, which estimates causative SGAs by modeling causal relationships between SGAs and molecular phenotypes (e.g., transcriptomic, proteomic, or metabolomic changes) within an individual tumor. We applied the TCI algorithm to tumors from The Cancer Genome Atlas (TCGA) and estimated for each tumor the SGAs that causally regulate the differentially expressed genes (DEGs) in that tumor. Overall, TCI identified 634 SGAs that are predicted to cause cancer-related DEGs in a significant number of tumors, including most of the previously known drivers and many novel candidate cancer drivers. The inferred causal relationships are statistically robust and biologically sensible, and multiple lines of experimental evidence support the predicted functional impact of both the well-known and the novel candidate drivers that are predicted by TCI. TCI provides a unified framework that integrates multiple types of SGAs and molecular phenotypes to estimate which genome perturbations are causally influencing one or more molecular/cellular phenotypes in an individual tumor. By identifying major candidate drivers and revealing their functional impact in an individual tumor, TCI sheds light on the disease mechanisms of that tumor, which can serve to advance our basic knowledge of cancer biology and to support precision oncology that provides tailored treatment of individual tumors. [ABSTRACT FROM AUTHOR]

The effectiveness of a mass vaccination program can engender its own undoing if individuals choose to not get vaccinated believing that they are already protected by herd immunity. This would appear to be the optimal decision for an individual, based on a strategic appraisal of her costs and benefits, even though she would be vulnerable during subsequent outbreaks if the majority of the population argues in this manner. We investigate how voluntary vaccination can nevertheless emerge in a social network of rational agents, who make informed decisions whether to be vaccinated, integrated with a model of epidemic dynamics. The information available to each agent includes the prevalence of the disease in their local network neighborhood and/or globally in the population, as well as the fraction of their neighbors that are protected against the disease. Crucially, the payoffs governing the decision of agents vary with disease prevalence, resulting in the vaccine uptake behavior changing in response to contagion spreading. The collective behavior of the agents responding to local prevalence can lead to a significant reduction in the final epidemic size, particularly for less contagious diseases having low basic reproduction number . Near the epidemic threshold () the use of local prevalence information can result in divergent responses in the final vaccine coverage. Our results suggest that heterogeneity in the risk perception resulting from the spatio-temporal evolution of an epidemic differentially affects agents’ payoffs, which is a critical determinant of the success of voluntary vaccination schemes. [ABSTRACT FROM AUTHOR]

Emerging and re-emerging pathogens exhibit very complex dynamics, are hard to model and difficult to predict. Their dynamics might appear intractable. However, new statistical approaches—rooted in dynamical systems and the theory of stochastic processes—have yielded insight into the dynamics of emerging and re-emerging pathogens. We argue that these approaches may lead to new methods for predicting epidemics. This perspective views pathogen emergence and re-emergence as a “critical transition,” and uses the concept of noisy dynamic bifurcation to understand the relationship between the system observables and the distance to this transition. Because the system dynamics exhibit characteristic fluctuations in response to perturbations for a system in the vicinity of a critical point, we propose this information may be harnessed to develop early warning signals. Specifically, the motion of perturbations slows as the system approaches the transition. [ABSTRACT FROM AUTHOR]

The inherent capacity of somatic cells to switch their phenotypic status in response to damage stimuli in vivo might have a pivotal role in ageing and cancer. However, how the entry-exit mechanisms of phenotype reprogramming are established remains poorly understood. In an attempt to elucidate such mechanisms, we herein introduce a stochastic model of combined epigenetic regulation (ER)-gene regulatory network (GRN) to study the plastic phenotypic behaviours driven by ER heterogeneity. To deal with such complex system, we additionally formulate a multiscale asymptotic method for stochastic model reduction, from which we derive an efficient hybrid simulation scheme. Our analysis of the coupled system reveals a regime of tristability in which pluripotent stem-like and differentiated steady-states coexist with a third indecisive state, with ER driving transitions between these states. Crucially, ER heterogeneity of differentiation genes is for the most part responsible for conferring abnormal robustness to pluripotent stem-like states. We formulate epigenetic heterogeneity-based strategies capable of unlocking and facilitating the transit from differentiation-refractory (stem-like) to differentiation-primed epistates. The application of the hybrid numerical method validates the likelihood of such switching involving solely kinetic changes in epigenetic factors. Our results suggest that epigenetic heterogeneity regulates the mechanisms and kinetics of phenotypic robustness of cell fate reprogramming. The occurrence of tunable switches capable of modifying the nature of cell fate reprogramming might pave the way for new therapeutic strategies to regulate reparative reprogramming in ageing and cancer. [ABSTRACT FROM AUTHOR]

Seasonal influenza surveillance is usually carried out by sentinel general practitioners (GPs) who compile weekly reports based on the number of influenza-like illness (ILI) clinical cases observed among visited patients. This traditional practice for surveillance generally presents several issues, such as a delay of one week or more in releasing reports, population biases in the health-seeking behaviour, and the lack of a common definition of ILI case. On the other hand, the availability of novel data streams has recently led to the emergence of non-traditional approaches for disease surveillance that can alleviate these issues. In Europe, a participatory web-based surveillance system called Influenzanet represents a powerful tool for monitoring seasonal influenza epidemics thanks to aid of self-selected volunteers from the general population who monitor and report their health status through Internet-based surveys, thus allowing a real-time estimate of the level of influenza circulating in the population. In this work, we propose an unsupervised probabilistic framework that combines time series analysis of self-reported symptoms collected by the Influenzanet platforms and performs an algorithmic detection of groups of symptoms, called syndromes. The aim of this study is to show that participatory web-based surveillance systems are capable of detecting the temporal trends of influenza-like illness even without relying on a specific case definition. The methodology was applied to data collected by Influenzanet platforms over the course of six influenza seasons, from 2011-2012 to 2016-2017, with an average of 34,000 participants per season. Results show that our framework is capable of selecting temporal trends of syndromes that closely follow the ILI incidence rates reported by the traditional surveillance systems in the various countries (Pearson correlations ranging from 0.69 for Italy to 0.88 for the Netherlands, with the sole exception of Ireland with a correlation of 0.38). The proposed framework was able to forecast quite accurately the ILI trend of the forthcoming influenza season (2016-2017) based only on the available information of the previous years (2011-2016). Furthermore, to broaden the scope of our approach, we applied it both in a forecasting fashion to predict the ILI trend of the 2016-2017 influenza season (Pearson correlations ranging from 0.60 for Ireland and UK, and 0.85 for the Netherlands) and also to detect gastrointestinal syndrome in France (Pearson correlation of 0.66). The final result is a near-real-time flexible surveillance framework not constrained by any specific case definition and capable of capturing the heterogeneity in symptoms circulation during influenza epidemics in the various European countries. [ABSTRACT FROM AUTHOR]

Human networks of sexual contacts are dynamic by nature, with partnerships forming and breaking continuously over time. Sexual behaviours are also highly heterogeneous, so that the number of partners reported by individuals over a given period of time is typically distributed as a power-law. Both the dynamism and heterogeneity of sexual partnerships are likely to have an effect in the patterns of spread of sexually transmitted diseases. To represent these two fundamental properties of sexual networks, we developed a stochastic process of dynamic partnership formation and dissolution, which results in power-law numbers of partners over time. Model parameters can be set to produce realistic conditions in terms of the exponent of the power-law distribution, of the number of individuals without relationships and of the average duration of relationships. Using an outbreak of antibiotic resistant gonorrhoea amongst men have sex with men as a case study, we show that our realistic dynamic network exhibits different properties compared to the frequently used static networks or homogeneous mixing models. We also consider an approximation to our dynamic network model in terms of a much simpler branching process. We estimate the parameters of the generation time distribution and offspring distribution which can be used for example in the context of outbreak reconstruction based on genomic data. Finally, we investigate the impact of a range of interventions against gonorrhoea, including increased condom use, more frequent screening and immunisation, concluding that the latter shows great promise to reduce the burden of gonorrhoea, even if the vaccine was only partially effective or applied to only a random subset of the population. [ABSTRACT FROM AUTHOR]

The advent of Next-Generation Sequencing (NGS) technologies has opened new perspectives in deciphering the genetic mechanisms underlying complex diseases. Nowadays, the amount of genomic data is massive and substantial efforts and new tools are required to unveil the information hidden in the data. The Genomic Data Commons (GDC) Data Portal is a platform that contains different genomic studies including the ones from The Cancer Genome Atlas (TCGA) and the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiatives, accounting for more than 40 tumor types originating from nearly 30000 patients. Such platforms, although very attractive, must make sure the stored data are easily accessible and adequately harmonized. Moreover, they have the primary focus on the data storage in a unique place, and they do not provide a comprehensive toolkit for analyses and interpretation of the data. To fulfill this urgent need, comprehensive but easily accessible computational methods for integrative analyses of genomic data that do not renounce a robust statistical and theoretical framework are required. In this context, the R/Bioconductor package TCGAbiolinks was developed, offering a variety of bioinformatics functionalities. Here we introduce new features and enhancements of TCGAbiolinks in terms of i) more accurate and flexible pipelines for differential expression analyses, ii) different methods for tumor purity estimation and filtering, iii) integration of normal samples from other platforms iv) support for other genomics datasets, exemplified here by the TARGET data. Evidence has shown that accounting for tumor purity is essential in the study of tumorigenesis, as these factors promote confounding behavior regarding differential expression analysis. With this in mind, we implemented these filtering procedures in TCGAbiolinks. Moreover, a limitation of some of the TCGA datasets is the unavailability or paucity of corresponding normal samples. We thus integrated into TCGAbiolinks the possibility to use normal samples from the Genotype-Tissue Expression (GTEx) project, which is another large-scale repository cataloging gene expression from healthy individuals. The new functionalities are available in the TCGAbiolinks version 2.8 and higher released in Bioconductor version 3.7. [ABSTRACT FROM AUTHOR]

The world is continuously urbanising, resulting in clusters of densely populated urban areas and more sparsely populated rural areas. We propose a method for generating spatial fields with controllable levels of clustering of the population. We build a synthetic country, and use this method to generate versions of the country with different clustering levels. Combined with a metapopulation model for infectious disease spread, this allows us to in silico explore how urbanisation affects infectious disease spread. In a baseline scenario with no interventions, the underlying population clustering seems to have little effect on the final size and timing of the epidemic. Under within-country restrictions on non-commuting travel, the final size decreases with increased population clustering. The effect of travel restrictions on reducing the final size is larger with higher clustering. The reduction is larger in the more rural areas. Within-country travel restrictions delay the epidemic, and the delay is largest for lower clustering levels. We implemented three different vaccination strategies—uniform vaccination (in space), preferentially vaccinating urban locations and preferentially vaccinating rural locations. The urban and uniform vaccination strategies were most effective in reducing the final size, while the rural vaccination strategy was clearly inferior. Visual inspection of some European countries shows that many countries already have high population clustering. In the future, they will likely become even more clustered. Hence, according to our model, within-country travel restrictions are likely to be less and less effective in delaying epidemics, while they will be more effective in decreasing final sizes. In addition, to minimise final sizes, it is important not to neglect urban locations when distributing vaccines. To our knowledge, this is the first study to systematically investigate the effect of urbanisation on infectious disease spread and in particular, to examine effectiveness of prevention measures as a function of urbanisation. [ABSTRACT FROM AUTHOR]

The relationship between the underlying contact network over which a pathogen spreads and the pathogen phylogenetic trees that are obtained presents an opportunity to use sequence data to learn about contact networks that are difficult to study empirically. However, this relationship is not explicitly known and is usually studied in simulations, often with the simplifying assumption that the contact network is static in time, though human contact networks are dynamic. We simulate pathogen phylogenetic trees on dynamic Erdős-Renyi random networks and on two dynamic networks with skewed degree distribution, of which one is additionally clustered. We use tree shape features to explore how adding dynamics changes the relationships between the overall network structure and phylogenies. Our tree features include the number of small substructures (cherries, pitchforks) in the trees, measures of tree imbalance (Sackin index, Colless index), features derived from network science (diameter, closeness), as well as features using the internal branch lengths from the tip to the root. Using principal component analysis we find that the network dynamics influence the shapes of phylogenies, as does the network type. We also compare dynamic and time-integrated static networks. We find, in particular, that static network models like the widely used Barabasi-Albert model can be poor approximations for dynamic networks. We explore the effects of mis-specifying the network on the performance of classifiers trained identify the transmission rate (using supervised learning methods). We find that both mis-specification of the underlying network and its parameters (mean degree, turnover rate) have a strong adverse effect on the ability to estimate the transmission parameter. We illustrate these results by classifying HIV trees with a classifier that we trained on simulated trees from different networks, infection rates and turnover rates. Our results point to the importance of correctly estimating and modelling contact networks with dynamics when using phylodynamic tools to estimate epidemiological parameters. [ABSTRACT FROM AUTHOR]

Mutation signatures in cancer genomes reflect endogenous and exogenous mutational processes, offering insights into tumour etiology, features for prognostic and biologic stratification and vulnerabilities to be exploited therapeutically. We present a novel machine learning formalism for improved signature inference, based on multi-modal correlated topic models (MMCTM) which can at once infer signatures from both single nucleotide and structural variation counts derived from cancer genome sequencing data. We exemplify the utility of our approach on two hormone driven, DNA repair deficient cancers: breast and ovary (n = 755 samples total). We show how introducing correlated structure both within and between modes of mutation can increase accuracy of signature discovery, particularly in the context of sparse data. Our study emphasizes the importance of integrating multiple mutation modes for signature discovery and patient stratification, and provides a statistical modeling framework to incorporate additional features of interest for future studies. [ABSTRACT FROM AUTHOR]

Real-time forecasts based on mathematical models can inform critical decision-making during infectious disease outbreaks. Yet, epidemic forecasts are rarely evaluated during or after the event, and there is little guidance on the best metrics for assessment. Here, we propose an evaluation approach that disentangles different components of forecasting ability using metrics that separately assess the calibration, sharpness and bias of forecasts. This makes it possible to assess not just how close a forecast was to reality but also how well uncertainty has been quantified. We used this approach to analyse the performance of weekly forecasts we generated in real time for Western Area, Sierra Leone, during the 2013–16 Ebola epidemic in West Africa. We investigated a range of forecast model variants based on the model fits generated at the time with a semi-mechanistic model, and found that good probabilistic calibration was achievable at short time horizons of one or two weeks ahead but model predictions were increasingly unreliable at longer forecasting horizons. This suggests that forecasts may have been of good enough quality to inform decision making based on predictions a few weeks ahead of time but not longer, reflecting the high level of uncertainty in the processes driving the trajectory of the epidemic. Comparing forecasts based on the semi-mechanistic model to simpler null models showed that the best semi-mechanistic model variant performed better than the null models with respect to probabilistic calibration, and that this would have been identified from the earliest stages of the outbreak. As forecasts become a routine part of the toolkit in public health, standards for evaluation of performance will be important for assessing quality and improving credibility of mathematical models, and for elucidating difficulties and trade-offs when aiming to make the most useful and reliable forecasts. [ABSTRACT FROM AUTHOR]

Infectious disease transmission in animals is an inherently spatial process in which a host’s home location and their social mixing patterns are important, with the mixing of infectious individuals often different to that of susceptible individuals. Although incidence data for humans have traditionally been aggregated into low-resolution data sets, modern representative surveillance systems such as electronic hospital records generate high volume case data with precise home locations. Here, we use a gridded spatial transmission model of arbitrary resolution to investigate the theoretical relationship between population density, differential population movement and local variability in incidence. We show analytically that a uniform local attack rate is only possible for individual pixels in the grid if susceptible and infectious individuals move in the same way. Using a population in Guangdong, China, for which a robust quantitative description of movement is available (a movement kernel), and a natural history consistent with pandemic influenza; we show that local cumulative incidence is positively correlated with population density when susceptible individuals are more connected in space than infectious individuals. Conversely, under the less intuitively likely scenario, when infectious individuals are more connected, local cumulative incidence is negatively correlated with population density. The strength and direction of correlation changes sign for other kernel parameter values. We show that simulation models in which it is assumed implicitly that only infectious individuals move are assuming a slightly unusual specific correlation between population density and attack rate. However, we also show that this potential structural bias can be corrected by using the appropriate non-isotropic kernel that maps infectious-only code onto the isotropic dual-mobility kernel. These results describe a precise relationship between the spatio-social mixing of infectious and susceptible individuals and local variability in attack rates. More generally, these results suggest a genuine risk that mechanistic models of high-resolution attack rate data may reach spurious conclusions if the precise implications of spatial force-of-infection assumptions are not first fully characterized, prior to models being fit to data. [ABSTRACT FROM AUTHOR]

Population genetic modeling can enhance Bayesian phylogenetic inference by providing a realistic prior on the distribution of branch lengths and times of common ancestry. The parameters of a population genetic model may also have intrinsic importance, and simultaneous estimation of a phylogeny and model parameters has enabled phylodynamic inference of population growth rates, reproduction numbers, and effective population size through time. Phylodynamic inference based on pathogen genetic sequence data has emerged as useful supplement to epidemic surveillance, however commonly-used mechanistic models that are typically fitted to non-genetic surveillance data are rarely fitted to pathogen genetic data due to a dearth of software tools, and the theory required to conduct such inference has been developed only recently. We present a framework for coalescent-based phylogenetic and phylodynamic inference which enables highly-flexible modeling of demographic and epidemiological processes. This approach builds upon previous structured coalescent approaches and includes enhancements for computational speed, accuracy, and stability. A flexible markup language is described for translating parametric demographic or epidemiological models into a structured coalescent model enabling simultaneous estimation of demographic or epidemiological parameters and time-scaled phylogenies. We demonstrate the utility of these approaches by fitting compartmental epidemiological models to Ebola virus and Influenza A virus sequence data, demonstrating how important features of these epidemics, such as the reproduction number and epidemic curves, can be gleaned from genetic data. These approaches are provided as an open-source package PhyDyn for the BEAST2 phylogenetics platform. [ABSTRACT FROM AUTHOR]

In Bangladesh, the poultry industry is an economically and socially important sector, but it is persistently threatened by the effects of H5N1 highly pathogenic avian influenza. Thus, identifying the optimal control policy in response to an emerging disease outbreak is a key challenge for policy-makers. To inform this aim, a common approach is to carry out simulation studies comparing plausible strategies, while accounting for known capacity restrictions. In this study we perform simulations of a previously developed H5N1 influenza transmission model framework, fitted to two separate historical outbreaks, to assess specific control objectives related to the burden or duration of H5N1 outbreaks among poultry farms in the Dhaka division of Bangladesh. In particular, we explore the optimal implementation of ring culling, ring vaccination and active surveillance measures when presuming disease transmission predominately occurs from premises-to-premises, versus a setting requiring the inclusion of external factors. Additionally, we determine the sensitivity of the management actions under consideration to differing levels of capacity constraints and outbreaks with disparate transmission dynamics. While we find that reactive culling and vaccination policies should pay close attention to these factors to ensure intervention targeting is optimised, across multiple settings the top performing control action amongst those under consideration were targeted proactive surveillance schemes. Our findings may advise the type of control measure, plus its intensity, that could potentially be applied in the event of a developing outbreak of H5N1 amongst originally H5N1 virus-free commercially-reared poultry in the Dhaka division of Bangladesh. [ABSTRACT FROM AUTHOR]

The spread of disease through human populations is complex. The characteristics of disease propagation evolve with time, as a result of a multitude of environmental and anthropic factors, this non-stationarity is a key factor in this huge complexity. In the absence of appropriate external data sources, to correctly describe the disease propagation, we explore a flexible approach, based on stochastic models for the disease dynamics, and on diffusion processes for the parameter dynamics. Using such a diffusion process has the advantage of not requiring a specific mathematical function for the parameter dynamics. Coupled with particle MCMC, this approach allows us to reconstruct the time evolution of some key parameters (average transmission rate for instance). Thus, by capturing the time-varying nature of the different mechanisms involved in disease propagation, the epidemic can be described. Firstly we demonstrate the efficiency of this methodology on a toy model, where the parameters and the observation process are known. Applied then to real datasets, our methodology is able, based solely on simple stochastic models, to reconstruct complex epidemics, such as flu or dengue, over long time periods. Hence we demonstrate that time-varying parameters can improve the accuracy of model performances, and we suggest that our methodology can be used as a first step towards a better understanding of a complex epidemic, in situation where data is limited and/or uncertain. [ABSTRACT FROM AUTHOR]

Annual incidence rates of varicella infection in the general population in France have been rather stable since 1991 when clinical surveillance started. Rates however show a statistically significant increase over time in children aged 0–3 years, and a decline in older individuals. A significant increase in day-care enrolment and structures’ capacity in France was also observed in the last decade. In this work we investigate the potential interplay between an increase of contacts of young children possibly caused by earlier socialization in the community and varicella transmission dynamics. To this aim, we develop an age-structured mathematical model, informed with historical demographic data and contact matrix estimates in the country, accounting for longitudinal linear increase of early childhood contacts. While the reported overall varicella incidence is well reproduced independently of mixing variations, age-specific empirical trends are better captured by accounting for an increase in contacts among pre-school children in the last decades. We found that the varicella data are consistent with a 30% increase in the number of contacts at day-care facilities, which would imply a 50% growth in the contribution of 0-3y old children to overall yearly infections in 1991–2015. Our findings suggest that an earlier exposure to pathogens due to changes in day-care contact patterns, represents a plausible explanation for the epidemiological patterns observed in France. Obtained results suggest that considering temporal changes in social factors in addition to demographic ones is critical to correctly interpret varicella transmission dynamics. [ABSTRACT FROM AUTHOR]

Accurate and reliable forecasts of seasonal epidemics of infectious disease can assist in the design of countermeasures and increase public awareness and preparedness. This article describes two main contributions we made recently toward this goal: a novel approach to probabilistic modeling of surveillance time series based on “delta densities”, and an optimization scheme for combining output from multiple forecasting methods into an adaptively weighted ensemble. Delta densities describe the probability distribution of the change between one observation and the next, conditioned on available data; chaining together nonparametric estimates of these distributions yields a model for an entire trajectory. Corresponding distributional forecasts cover more observed events than alternatives that treat the whole season as a unit, and improve upon multiple evaluation metrics when extracting key targets of interest to public health officials. Adaptively weighted ensembles integrate the results of multiple forecasting methods, such as delta density, using weights that can change from situation to situation. We treat selection of optimal weightings across forecasting methods as a separate estimation task, and describe an estimation procedure based on optimizing cross-validation performance. We consider some details of the data generation process, including data revisions and holiday effects, both in the construction of these forecasting methods and when performing retrospective evaluation. The delta density method and an adaptively weighted ensemble of other forecasting methods each improve significantly on the next best ensemble component when applied separately, and achieve even better cross-validated performance when used in conjunction. We submitted real-time forecasts based on these contributions as part of CDC’s 2015/2016 FluSight Collaborative Comparison. Among the fourteen submissions that season, this system was ranked by CDC as the most accurate. [ABSTRACT FROM AUTHOR]

Epidemic transitions are an important feature of infectious disease systems. As the transmissibility of a pathogen increases, the dynamics of disease spread shifts from limited stuttering chains of transmission to potentially large scale outbreaks. One proposed method to anticipate this transition are early-warning signals (EWS), summary statistics which undergo characteristic changes as the transition is approached. Although theoretically predicted, their mathematical basis does not take into account the nature of epidemiological data, with are typically aggregated into periodic case reports and subject to reporting error. The viability of EWS for epidemic transitions therefore remains uncertain. Here we demonstrate that most EWS can predict emergence even when calculated from imperfect data. We quantify performance using the area under the curve (AUC) statistic, a measure of how well an EWS distinguishes between numerical simulations of an emerging disease and one which is stationary. Values of the AUC statistic are compared across a range of different reporting scenarios. We find that different EWS respond to imperfect data differently. The mean, variance and first differenced variance all perform well unless reporting error is highly overdispersed. The autocorrelation, autocovariance and decay time perform well provided that the aggregation period of the data is larger than the serial interval and reporting error is not highly overdispersed. The coefficient of variation, skewness and kurtosis are found to be unreliable indicators of emergence. Overall, we find that seven of ten EWS considered perform well for most realistic reporting scenarios. We conclude that imperfect epidemiological data is not a barrier to using EWS for many potentially emerging diseases. [ABSTRACT FROM AUTHOR]

Dynamic models in disease ecology have historically evaluated vaccination strategies under the assumption that they are implemented homogeneously in space and time. However, this approach fails to formally account for operational and logistical constraints inherent in the distribution of vaccination to the population at risk. Thus, feedback between the dynamic processes of vaccine distribution and transmission might be overlooked. Here, we present a spatially explicit, stochastic Susceptible-Infected-Recovered-Vaccinated model that highlights the density-dependence and spatial constraints of various diffusive strategies of vaccination during an outbreak. The model integrates an agent-based process of disease spread with a partial differential process of vaccination deployment. We characterize the vaccination response in terms of a diffusion rate that describes the distribution of vaccination to the population at risk from a central location. This generates an explicit trade-off between slow diffusion, which concentrates effort near the central location, and fast diffusion, which spreads a fixed vaccination effort thinly over a large area. We use stochastic simulation to identify the optimum vaccination diffusion rate as a function of population density, interaction scale, transmissibility, and vaccine intensity. Our results show that, conditional on a timely response, the optimal strategy for minimizing outbreak size is to distribute vaccination resource at an intermediate rate: fast enough to outpace the epidemic, but slow enough to achieve local herd immunity. If the response is delayed, however, the optimal strategy for minimizing outbreak size changes to a rapidly diffusive distribution of vaccination effort. The latter may also result in significantly larger outbreaks, thus suggesting a benefit of allocating resources to timely outbreak detection and response. [ABSTRACT FROM AUTHOR]

Disease tolerance is a defense strategy against infections that aims at maintaining host health even at high pathogen replication or load. Tolerance mechanisms are currently intensively studied with the long-term goal of exploiting them therapeutically. Because tolerance-based treatment imposes less selective pressure on the pathogen it has been hypothesised to be “evolution-proof”. However, the primary public health goal is to reduce the incidence and mortality associated with a disease. From this perspective, tolerance-based treatment bears the risk of increasing the prevalence of the disease, which may lead to increased mortality. We assessed the promise of tolerance-based treatment strategies using mathematical models. Conventional treatment was implemented as an increased recovery rate, while tolerance-based treatment was assumed to reduce the disease-related mortality of infected hosts without affecting recovery. We investigated the endemic phase of two types of infections: acute and chronic. Additionally, we considered the effect of pathogen resistance against conventional treatment. We show that, for low coverage of tolerance-based treatment, chronic infections can cause even more deaths than without treatment. Overall, we found that conventional treatment always outperforms tolerance-based treatment, even when we allow the emergence of pathogen resistance. Our results cast doubt on the potential benefit of tolerance-based over conventional treatment. Any clinical application of tolerance-based treatment of infectious diseases has to consider the associated detrimental epidemiological feedback. [ABSTRACT FROM AUTHOR]

Genetically-controlled plant resistance can reduce the damage caused by pathogens. However, pathogens have the ability to evolve and overcome such resistance. This often occurs quickly after resistance is deployed, resulting in significant crop losses and a continuing need to develop new resistant cultivars. To tackle this issue, several strategies have been proposed to constrain the evolution of pathogen populations and thus increase genetic resistance durability. These strategies mainly rely on varying different combinations of resistance sources across time (crop rotations) and space. The spatial scale of deployment can vary from multiple resistance sources occurring in a single cultivar (pyramiding), in different cultivars within the same field (cultivar mixtures) or in different fields (mosaics). However, experimental comparison of the efficiency (i.e. ability to reduce disease impact) and durability (i.e. ability to limit pathogen evolution and delay resistance breakdown) of landscape-scale deployment strategies presents major logistical challenges. Therefore, we developed a spatially explicit stochastic model able to assess the epidemiological and evolutionary outcomes of the four major deployment options described above, including both qualitative resistance (i.e. major genes) and quantitative resistance traits against several components of pathogen aggressiveness: infection rate, latent period duration, propagule production rate, and infectious period duration. This model, implemented in the R package landsepi, provides a new and useful tool to assess the performance of a wide range of deployment options, and helps investigate the effect of landscape, epidemiological and evolutionary parameters. This article describes the model and its parameterisation for rust diseases of cereal crops, caused by fungi of the genus Puccinia. To illustrate the model, we use it to assess the epidemiological and evolutionary potential of the combination of a major gene and different traits of quantitative resistance. The comparison of the four major deployment strategies described above will be the objective of future studies. [ABSTRACT FROM AUTHOR]

Numerical models for simulating outbreaks of infectious diseases are powerful tools for informing surveillance and control strategy decisions. However, large-scale spatially explicit models can be limited by the amount of computational resources they require, which poses a problem when multiple scenarios need to be explored to provide policy recommendations. We introduce an easily implemented method that can reduce computation time in a standard Susceptible-Exposed-Infectious-Removed (SEIR) model without introducing any further approximations or truncations. It is based on a hierarchical infection process that operates on entire groups of spatially related nodes (cells in a grid) in order to efficiently filter out large volumes of susceptible nodes that would otherwise have required expensive calculations. After the filtering of the cells, only a subset of the nodes that were originally at risk are then evaluated for actual infection. The increase in efficiency is sensitive to the exact configuration of the grid, and we describe a simple method to find an estimate of the optimal configuration of a given landscape as well as a method to partition the landscape into a grid configuration. To investigate its efficiency, we compare the introduced methods to other algorithms and evaluate computation time, focusing on simulated outbreaks of foot-and-mouth disease (FMD) on the farm population of the USA, the UK and Sweden, as well as on three randomly generated populations with varying degree of clustering. The introduced method provided up to 500 times faster calculations than pairwise computation, and consistently performed as well or better than other available methods. This enables large scale, spatially explicit simulations such as for the entire continental USA without sacrificing realism or predictive power. [ABSTRACT FROM AUTHOR]

Genetic differences contribute to variations in the immune response mounted by different individuals to a pathogen. Such differential response can influence the spread of infectious disease, indicating why such diseases impact some populations more than others. Here, we study the impact of population-level genetic heterogeneity on the epidemic spread of different strains of H1N1 influenza. For a population with known HLA class-I allele frequency and for a given H1N1 viral strain, we classify individuals into sub-populations according to their level of susceptibility to infection. Our core hypothesis is that the susceptibility of a given individual to a disease such as H1N1 influenza is inversely proportional to the number of high affinity viral epitopes the individual can present. This number can be extracted from the HLA genetic profile of the individual. We use ethnicity-specific HLA class-I allele frequency data, together with genome sequences of various H1N1 viral strains, to obtain susceptibility sub-populations for 61 ethnicities and 81 viral strains isolated in 2009, as well as 85 strains isolated in other years. We incorporate these data into a multi-compartment SIR model to analyse the epidemic dynamics for these (ethnicity, viral strain) epidemic pairs. Our results show that HLA allele profiles which lead to a large spread in individual susceptibility values can act as a protective barrier against the spread of influenza. We predict that populations skewed such that a small number of highly susceptible individuals coexist with a large number of less susceptible ones, should exhibit smaller outbreaks than populations with the same average susceptibility but distributed more uniformly across individuals. Our model tracks some well-known qualitative trends of influenza spread worldwide, suggesting that HLA genetic diversity plays a crucial role in determining the spreading potential of different influenza viral strains across populations. [ABSTRACT FROM AUTHOR]

Accurate and reliable predictions of infectious disease dynamics can be valuable to public health organizations that plan interventions to decrease or prevent disease transmission. A great variety of models have been developed for this task, using different model structures, covariates, and targets for prediction. Experience has shown that the performance of these models varies; some tend to do better or worse in different seasons or at different points within a season. Ensemble methods combine multiple models to obtain a single prediction that leverages the strengths of each model. We considered a range of ensemble methods that each form a predictive density for a target of interest as a weighted sum of the predictive densities from component models. In the simplest case, equal weight is assigned to each component model; in the most complex case, the weights vary with the region, prediction target, week of the season when the predictions are made, a measure of component model uncertainty, and recent observations of disease incidence. We applied these methods to predict measures of influenza season timing and severity in the United States, both at the national and regional levels, using three component models. We trained the models on retrospective predictions from 14 seasons (1997/1998–2010/2011) and evaluated each model’s prospective, out-of-sample performance in the five subsequent influenza seasons. In this test phase, the ensemble methods showed average performance that was similar to the best of the component models, but offered more consistent performance across seasons than the component models. Ensemble methods offer the potential to deliver more reliable predictions to public health decision makers. [ABSTRACT FROM AUTHOR]

Public health related decisions often have to balance the cost of intervention strategies with the benefit of the reduction in disease burden. While the cost can often be inferred, forward modelling of the effect of different intervention options is complicated and disease specific. Here we introduce a package that is aimed to simplify this process. The package allows one to infer parameters using a Bayesian approach, perform forward modelling of the likely results of the proposed intervention and finally perform cost effectiveness analysis of the results. The package is based on a method previously used in the UK to inform vaccination strategies for influenza, with extensions to make it easily adaptable to other diseases and data sources. [ABSTRACT FROM AUTHOR]

Laboratory and epidemiological evidence indicate that ambient humidity modulates the survival and transmission of influenza. Here we explore whether the inclusion of humidity forcing in mathematical models describing influenza transmission improves the accuracy of forecasts generated with those models. We generate retrospective forecasts for 95 cities over 10 seasons in the United States and assess both forecast accuracy and error. Overall, we find that humidity forcing improves forecast performance (at 1–4 lead weeks, 3.8% more peak week and 4.4% more peak intensity forecasts are accurate than with no forcing) and that forecasts generated using daily climatological humidity forcing generally outperform forecasts that utilize daily observed humidity forcing (4.4% and 2.6% respectively). These findings hold for predictions of outbreak peak intensity, peak timing, and incidence over 2- and 4-week horizons. The results indicate that use of climatological humidity forcing is warranted for current operational influenza forecast. [ABSTRACT FROM AUTHOR]

The article describes the R software package called Dynamical Systems Approaches to Infectious Disease Epidemiology (DSAIDE) that allows individuals to explore and study concepts of infectious disease epidemiology using a modern computational and modeling approach. It describes the DSAIDE software package and the ways for students to interact with the software through the graphical user interface, via simulation functions, and by contributing to the package and developing applications.

The availability of epidemiological data in the early stages of an outbreak of an infectious disease is vital for modelers to make accurate predictions regarding the likely spread of disease and preferred intervention strategies. However, in some countries, the necessary demographic data are only available at an aggregate scale. We investigated the ability of models of livestock infectious diseases to predict epidemic spread and obtain optimal control policies in the event of imperfect, aggregated data. Taking a geographic information approach, we used land cover data to predict UK farm locations and investigated the influence of using these synthetic location data sets upon epidemiological predictions in the event of an outbreak of foot-and-mouth disease. When broadly classified land cover data were used to create synthetic farm locations, model predictions deviated significantly from those simulated on true data. However, when more resolved subclass land use data were used, moderate to highly accurate predictions of epidemic size, duration and optimal vaccination and ring culling strategies were obtained. This suggests that a geographic information approach may be useful where individual farm-level data are not available, to allow predictive analyses to be carried out regarding the likely spread of disease. This method can also be used for contingency planning in collaboration with policy makers to determine preferred control strategies in the event of a future outbreak of infectious disease in livestock. [ABSTRACT FROM AUTHOR]

Heterogeneities in contact networks have a major effect in determining whether a pathogen can become epidemic or persist at endemic levels. Epidemic models that determine which interventions can successfully prevent an outbreak need to account for social structure and mixing patterns. Contact patterns vary across age and locations (e.g. home, work, and school), and including them as predictors in transmission dynamic models of pathogens that spread socially will improve the models’ realism. Data from population-based contact diaries in eight European countries from the POLYMOD study were projected to 144 other countries using a Bayesian hierarchical model that estimated the proclivity of age-and-location-specific contact patterns for the countries, using Markov chain Monte Carlo simulation. Household level data from the Demographic and Health Surveys for nine lower-income countries and socio-demographic factors from several on-line databases for 152 countries were used to quantify similarity of countries to estimate contact patterns in the home, work, school and other locations for countries for which no contact data are available, accounting for demographic structure, household structure where known, and a variety of metrics including workforce participation and school enrolment. Contacts are highly assortative with age across all countries considered, but pronounced regional differences in the age-specific contacts at home were noticeable, with more inter-generational contacts in Asian countries than in other settings. Moreover, there were variations in contact patterns by location, with work-place contacts being least assortative. These variations led to differences in the effect of social distancing measures in an age structured epidemic model. Contacts have an important role in transmission dynamic models that use contact rates to characterize the spread of contact-transmissible diseases. This study provides estimates of mixing patterns for societies for which contact data such as POLYMOD are not yet available. [ABSTRACT FROM AUTHOR]

We investigate methods to vaccinate contact networks—i.e. removing nodes in such a way that disease spreading is hindered as much as possible—with respect to their cost-efficiency. Any real implementation of such protocols would come with costs related both to the vaccination itself, and gathering of information about the network. Disregarding this, we argue, would lead to erroneous evaluation of vaccination protocols. We use the susceptible-infected-recovered model—the generic model for diseases making patients immune upon recovery—as our disease-spreading scenario, and analyze outbreaks on both empirical and model networks. For different relative costs, different protocols dominate. For high vaccination costs and low costs of gathering information, the so-called acquaintance vaccination is the most cost efficient. For other parameter values, protocols designed for query-efficient identification of the network’s largest degrees are most efficient. [ABSTRACT FROM AUTHOR]

The spread of pathogens into new environments poses a considerable threat to human, animal, and plant health, and by extension, human and animal wellbeing, ecosystem function, and agricultural productivity, worldwide. Early detection through effective surveillance is a key strategy to reduce the risk of their establishment. Whilst it is well established that statistical and economic considerations are of vital importance when planning surveillance efforts, it is also important to consider epidemiological characteristics of the pathogen in question—including heterogeneities within the epidemiological system itself. One of the most pronounced realisations of this heterogeneity is seen in the case of vector-borne pathogens, which spread between ‘hosts’ and ‘vectors’—with each group possessing distinct epidemiological characteristics. As a result, an important question when planning surveillance for emerging vector-borne pathogens is where to place sampling resources in order to detect the pathogen as early as possible. We answer this question by developing a statistical function which describes the probability distributions of the prevalences of infection at first detection in both hosts and vectors. We also show how this method can be adapted in order to maximise the probability of early detection of an emerging pathogen within imposed sample size and/or cost constraints, and demonstrate its application using two simple models of vector-borne citrus pathogens. Under the assumption of a linear cost function, we find that sampling costs are generally minimised when either hosts or vectors, but not both, are sampled. [ABSTRACT FROM AUTHOR]