## Workshop 4: Evolution and Spread of Disease

### Organizers

Linda Allen
Mathematics, Texas Tech University
Sally Blower
Semel Institute, University of California, Los Angeles
Sylvie Meleard
Applied Mathematics,
Helen Wearing
Biology, Mathematics & Statistics, University of New Mexico

The study of epidemiology, evolutionary biology and immunology are well-developed fields in their own right. However, current problems in disease dynamics have arisen that cross these disciplinary boundaries and where stochastic modeling and methods are essential to progress in these fields. Stochasticity plays an important role in the study of emergence of new diseases, pathogen evolution in response to control strategies or therapies, chance interactions of multiple species or multiple pathogens, variability in the host immune response, and disease propagation locally and globally. Tools from branching processes, percolation theory and network theory have demonstrated the importance of connectivity and cluster size in disease spread. The study of stochastic epidemic models has provided information about the duration and final size distributions, the probability of pathogen extinction or persistence and the quasistationary distribution. The availability of increasing amounts of data on within-host pathogens and on recent epidemics and the increase in computational power allow more accurate predictions of future trends and enable model predictions to be statistically tested and the uncertainty quantified. New mathematical, statistical and computational approaches for discrete- and continuous-time processes are needed to realistically model, analyze, compute and test the within-host and the between-host variability in response to a pathogen invasion and to connect the large-scale stochastic spatial epidemic or pandemic models to the small-scale within-host pathogen dynamics. Through collaboration among mathematicians, statisticians and applied scientists, important interdisciplinary problems in epidemiology, immunology and evolutionary biology can be addressed which will involve challenges in model development, statistical analysis, and computational methodology.

### Accepted Speakers

Frank Ball
School of Mathematical Sciences, University of Nottingham
Tom Britton
Mathematics, Stockholm University
Gerardo Chowell-Puente
School of Human Evolution and Social Change, Arizona State University
Troy Day
Mathematics and Statistics, Queen's University
Mathematics, University of Bristol
Valerie Isham
Statistical Science, University College London
Jan Medlock
Biomedical Sciences, Oregon State University
J. A. J. Metz
Plant Ecology and Phytochemistry, Analysis and Dynamical Systems, Institute of Biology, Mathematical Institute
Nicole Mideo
Center for Infectious Disease Dynamics, Pennsylvania State University
Philip O'Neill
School of Mathematical Sciences, University of Nottingham
José Miguel Ponciano Castellanos
Biology, University of Florida
Chi Viet Tran
Alex Vespignani
School of Informatics and Computing, Indiana University
Center for Biomedical Modeling, David Geffen School of Medicine, University of California, Los Angeles
Monday, March 19, 2012
Time Session
09:00 AM
10:00 AM
Alex Vespignani - Real Time Numerical Forecast of Global Epidemic Spreading
Mathematical and computational models are increasingly used in support decisions in public health, however the perception of their reliability and the criteria for their uses is contrasted among domain experts. We consider the Global Epidemic and Mobility model that generates stochastic realizations of epidemic evolution worldwide from which we can gather information such as prevalence, morbidity, number of secondary cases and number and date of imported cases for 3,360 subpopulation in 220 countries with a time resolution of 1 day. GLEaM has been used to anticipate the geographical spreading for the 2009 H1N1 pandemic by estimating the transmission potential and the relevant model parameters with a Monte Carlo likelihood analysis of the arrival time distribution generated by 1 million computationally simulated epidemics. We present an extensive validation analysis of the obtained results from surveillance and virological sources collected in 46 countries of the Northern Hemisphere during the course of the pandemic. We focus on discussing the challenges posed by the real-time estimation of parameters, the different levels of data-integration and the validation through high quality data sets. In particular, data gathered during and after the 2009 H1N1 influenza crisis represent an unprecedented opportunity to i) test the robustness of the prediction intervals with respect to additional parameters unknown concurrently or before the end of the pandemic; ii) test the sensitivity of prediction intervals to the different levels of data integration by considering progressively increasing knowledge of socio-demographic and human mobility data.
10:30 AM
11:00 AM
Frank Ball - R0 and other reproduction numbers for epidemic models with households and other social structures
The basic reproduction number R0 is one of the most important quantities in epidemiology. However, for epidemic models with explicit social structure involving small mixing units such as households, its definition is not straightforward and a wealth of other threshold parameters has appeared in the literature. In this talk I use branching processes to define R0, apply this definition to models with households or other more complex social structures, provide a method for calculating R0 and show inequalities comparing R0 with previous threshold parameters. The comparisons imply that, if R0 > 1, vaccinating a fraction 1 - 1/R0 of the population, chosen uniformly at random, with a perfect vaccine is insufficient to be sure of preventing a large outbreak, and they lead to sharper, easily-computed bounds for the critical vaccination coverage than were previously available.

Based on work done jointly with Lorenzo Pellis (Imperial College London) and Pieter Trapman (Stockholm University).
11:00 AM
11:30 AM
Tom Britton - Weighted networks with applications to epidemics
In the talk we present a simple extension of the configuration model to weighted networks, and state some asymptotic properties of the network model. The weights may be used for some stochastic process taking place on the network; for example an epidemic where the probability of transmission between two individuals depends on the weight of the connected edge (the weight for example reflecting social distance). We also consider the case where individuals (nodes) are heterogeneous in he sense that the transmission probability depends on the infectivity of the infector and the susceptibility of the victim. We end with analysis of some empirical networks: movement of patients in hospitals in Stockholm (for mrsa), workplaces and households of the Swedish population (for influenza), and census of sex-contacts (for STDs).
02:00 PM
02:30 PM
Jean-Stephane Dhersin - Large graph limit for a SIR process in a random network with heterogeneous connectivity
We consider a SIR epidemic model propagating on a random network generated by a configuration model, where the degree distribution of the vertices is given and where the edges are randomly matched. The evolution of the epidemics is summed up into three measure-valued equations that describe the degrees of the susceptible individuals and the number of edges from an infectious or removed individual to the set of susceptibles. These three degree distributions are sufficient to describe the course of the disease. The limit in large population is investigated. As a corollary, this provides a rigorous proof of equations obtained by Volz.

This is a joint work with Laurent Decreusefond, Pascal Moyal and Viet Chi Tran
02:30 PM
03:00 PM
Chi Viet Tran - Modelling of the Cuban HIV Epidemics
HIV has been introduced in Cuban in 1986. From the beginning of the epidemics, contact-tracing is used, in the purpose of detecting more HIV-positive individuals and of controlling the spread of the disease. The data generated from this contact-tracing program provide some partial information on the social networks underlying the propagation of HIV. In this talk, we present this big network (5389 nodes, with a giant component of 2386 nodes) together with some possible modelling of the phenomenon.
03:30 PM
05:00 PM
Pieter Trapman - Afternoon discussion leader: Pieter Trapman (Moderator: Linda Allen)
N/A
Tuesday, March 20, 2012
Time Session
09:00 AM
10:00 AM
Valerie Isham - An introduction to stochastic models for epidemics and the effects of population structure
The first part of my talk will be an introduction to epidemic modelling aimed at those coming from a non-mathematical background. In it I will briefly review the historical background and describe some of the topics that have preoccupied researchers in recent years. I will concentrate on model structure and general modelling issues rather than on models for specific infections. The second part of the talk will focus on the effects of population structure and I will concentrate particularly on population networks. I will discuss the effect of different network structures on the transmission dynamics of epidemics and on thresholds for widespread transmission.
10:30 AM
11:00 AM
Philip O'Neill - Modelling and inference for healthcare-associated infection
Multi-drug resistant pathogens such as MRSA and VRE give rise to substantial morbidity and mortality, and impose a huge economic burden on healthcare systems. In this talk we describe a framework for analysing patient-level data from hosptials on such pathogens, employing stochastic transmission models and using Markov chain Monte Carlo methods witin a Bayesian statistical framework. The methods are illustrated with various data sets and used to address various clinically-relevant questions.
11:00 AM
11:30 AM
Gerardo Chowell-Puente - Disentangling the spatio-temporal dynamics of the 2009 A/H1N1 influenza pandemic in Mexico and Peru
Detailed surveillance data on the 2009 A/H1N1 influenza pandemic are crucial to quantify the spatial and temporal characteristics of pandemic influenza. We provide a quantitative description of the age-specific and regional 2009 A/H1N1 pandemic incidence patterns using data from Mexico and Peru. We used daily cases of influenza-like-illness, tests for A/H1N1 influenza virus infections, and laboratory-confirmed A/H1N1 influenza cases to analyze the geographic spread of the pandemic waves and their association with the winter school closing periods, demographic factors, and absolute humidity. We also estimated the reproduction number and quantified the association between school closing periods and the age distribution of cases. Our results indicate substantial regional variation in pandemic pattern, highlight the importance of school cycles on the transmission dynamics of this pandemic influenza strain, and suggests that school closure and other mitigation measures could be useful to mitigate future influenza pandemics.
02:00 PM
02:30 PM
José Miguel Ponciano Castellanos - Modeling the diversity and stability of human vaginal microbial communities
Our understanding of the ecological and evolutionary conditions that permit the establishment and persistence of different bacterial species in host-associated microbial communities is incomplete. Recent work done to characterize human vaginal bacterial communities by experimental and analytical approaches has shown that idiosyncratic changes in species composition and wide fluctuations in the relative abundances of the different species are undeniably associated with specific environmental drivers. An understanding of the mechanisms, ecological processes and evolutionary routes behind the genesis of such associations and fluctuations remain an important knowledge gap. If the structure and composition of a given ecological community often alternates between distinct, widely different states, then better predictions about the chances of a dramatic community shift can be achieved using mechanistic, stochastic population dynamics models. In human bacterial communities research, there is a strong need to confront problems of risk assessment and prediction using such modeling approach. In this work, we develop a modeling framework based on the multivariate Ornstein-Uhlenbeck stochastic process to predict the unfolding of complex microbial community dynamics. We derive a suite of stochastic models derived from first biological principles will be used to evaluate time-series data on the relative abundances of bacterial species in vaginal communities. The statistical inferences done with these models have broad implications to the understanding of the processes governing the composition, structure and function of bacterial communities associated to humans. Finally, our research opens the door to a better assessment of the risk to diseases associated with responses to disturbances of human-associated microbial ecosystems.
02:30 PM
03:00 PM
Shweta Bansal - Contact Networks for Modeling Immunizing Infectious Disease Dynamics
In models of disease transmission on contact networks, the probability of exposure is determined by the connectivity (degree) of the individual (node). Thus, the most highly connected individuals in a contact network have both a higher probability of spreading infection through the population and a higher rate of exposure (susceptibility) through social contacts. As an epidemic sweeps through a population, this heterogeneity leads to systematic structural changes in the active portion of the network, removing immunized individuals who no longer participate in the chains of transmission. While the impact of network structure on the progression of an epidemic has been well studied, there has been relatively little work on network evolution during the course of an epidemic. We analytically investigate the impact of epidemic dynamics on the underlying host population structure and find that the structural evolution of the network varies with the original topology of the network and the contagiousness of the disease. We identify the mechanisms acting on the network topology to make them sparser, consider questions about the patterns of immunity that arise during disease outbreaks, and explore their impact on future epidemics and key public health policies.
03:30 PM
05:00 PM
Aaron King, Helen Wearing - Afternoon discussion leader: Aaron King (Moderator: Helen Wearing)
N/A
Wednesday, March 21, 2012
Time Session
09:00 AM
10:00 AM
J. A. J. Metz - The interplay of infectivity that decreases with virulence and limited cross-immunity: (toy) models for respiratory disease evolution
Models for the evolution of virulence traditionally assume a trade-off between inverse disease-induced mortality rate and infectivity, resulting in intermediate virulence. The underlying intuition is that faster growing agent populations do both more damage and produce more infective particles. This intuition implicitly assumes a well-mixed host body. In reality both damage and infectivity depend mainly on the location in the body where the agents lodge. This is related i.a. to the surface proteins that allow agents to dock on and penetrate into different cell types. The typical example is respiratory diseases where more deeply seated ones are both less infective and more harmful. With the other standard assumption, full cross-immunity between disease strains, this would lead to evolution towards the tip of the nose. In reality cross-immunity depends on surface antigens and hence is at least in part connected to depth. In this talk I discuss a simple adaptive dynamics style model taking on board the aforementioned considerations. The inference is that disease diversity should decrease with depth.

(The reported work was done in collaboration with Kevin Kleine and Juan E. Keymer Vergara of Delft University of Technology.)
10:30 AM
11:00 AM
Viggo Andreasen - The final outcome of an epidemic with two strains
The competition between two pathogen strains during the course of a single epidemic represents a fundamental step in the early evolution of emerging diseases as well as in antigenic drift processes. The outcome however, depends not only on the epidemic properties of the two strains but also on the timing and size of the introduction, characteristics that are poorly captured by deterministic mean-field epidemic models.

I will present a framework that allows us to describe those aspects of the competition that can be determined from the mean-field models giving the range of possible outcomes that could be observed in an epidemic with two fully or partially cross-reacting strains.
11:00 AM
11:30 AM
Jan Medlock - The impact of vaccination on dengue virulence
Virulence evolution has a long history, including the now-classic paper of Gandon et al. 2001 on the impact of malaria vaccination on the virulence of the parasite. Gandon et al. found that a vaccine with the action of reducing the pathogen growth rate in the host selects for more virulent pathogens, while an infection-blocking vaccine selects for less virulent pathogens. We found that, in the context of mosquito transgenesis, that relaxing one assumption of Gandon et al. leads to an inability to predict the direction of selection on pathogen virulence. I will discuss these issues in the context of dengue vaccine.
02:00 PM
02:30 PM
Ayalvadi Ganesh - Tuberculosis drug resistance and the Luria-Delbruck distribution
Tuberculosis is one of the major global diseases in terms of both prevalance and mortality. In recent decades, strains of the disease have evolved that are resistant to several, or all, of the drugs used to treat the disease. Drug resistance is conferred by rare mutations, raising the question of how multiple mutations might have arisen in a single strain. Motivated by this question, we study models of branching processes with mutations which generalize the pioneering work of Luria and Delbruck. We look at the sizes of mutant populations in the limit of mutation rates decreasing to zero, and characterize their limiting distribution. The results show a transition between two regimes depending on the relative growth rate of the mutants: in the slow growth regime, the limiting distribution is Gaussian, while if the mutants reproduce quickly enough, it is heavy-tailed.
02:30 PM
03:00 PM
Bradley Wagner - HIV strains with drug-resistant mutations: the effect of fitness costs and genetic bottlenecks in limiting transmission
Transmission of HIV strains with drug-resistant mutations (DRMs) is a public health concern in resource rich countries. Fitness costs and genetic bottlenecks limit transmission of these DRMs. In this talk I will discuss how to assess this effect, using invitro data from viral competition experiments and stochastic HIV transmission models. I will also discuss, in light of the assay sensitivity for currently employed resistance tests, the potential for existence of hidden epidemics of transmitted resistance.

This work was done in collaboration with J. Gerardo Garcia-Lerma at the Centers for Disease Control and Prevention and Sally Blower at the David Geffen School of Medicine, UCLA.
03:30 PM
05:00 PM
Helen Wearing, Andrew Park - Afternoon discussion leader: Aaron King (Moderator: Helen Wearing)
N/A
Thursday, March 22, 2012
Time Session
09:00 AM
10:00 AM
Troy Day - Branching Process Models in Evolutionary Epidemiology
I will provide a brief overview of multitype branching processes, with particular emphasis on their application in evolutionary epidemiology. I will then discuss some recent work on how such analyses can be used to understand the evolutionary emergence of diseases like pandemic influenza in humans and to evaluate the utility of different interventions. Time permitting I will also discuss how branching processes are being used to understand and control the emergence of drug resistance.
10:30 AM
11:00 AM
Nicolas Champagnat - An individual-based approach to adaptive dynamics: a study of evolution and diversification through concentration scalings
We consider an stochastic, individual-based model of an evolving population with logistic density-dependence, where individuals are characterized by a quantitative phenotypic trait. Under appropriate parameters scalings of rare mutations and large populations, we obtain a stochastic jump process on the mutation time-scale, where evolution proceeds through successive invasions of mutants, followed by competition phases on shorter time scales, where disadvantaged traits are eliminated. Under an additional scaling of small mutations and on an appropriate time scales, the evolution can be described as ordinary differential equations on the trait space, known as "canonical equations of adaptive dynamics", followed by diversification phases where the number of traits present in the population may increase, a phenomenon known as "evolutionary branching".

This is joint work with Sylvie M�l�ard (Ecole Polytechnique).
11:00 AM
11:30 AM
Malwina Luczak - Central limit approximations for Markov population processes with countably many types
When modelling metapopulation dynamics, the influence of a single patch on the metapopulation depends on the number of individuals in the patch. Since there is usually no obvious natural upper limit on the number of individuals in a patch, this leads to systems in which there are countably infinitely many possible types of entity. Analogous considerations apply in the transmission of parasitic diseases. We prove central limit theorems for quite general systems of this kind, together with bounds on the rate of convergence in an appropriately chosen weighted $ell_1$ norm.

This is joint work with Andrew Barbour.
02:00 PM
02:30 PM
Julien Arino - A model for the propagation of resistance to a parasite in vectors
One tool envisioned as part of the array of measures used in the fight against malaria takes advantage of a naturally occurring "resistance" of vectors to the parasite. This mechanism results in the disruption of the parasite's life cycle in vectors, rendering the bite of an infected vector harmless because the parasites have not reached the stage where they are infectious to hosts. However, this resistance is not transmitted through regular evolutionary mechanisms and requires the use of so-called transposons. I will present a naive model for the spread of this resistance in a population of vectors.
02:30 PM
03:00 PM
Nicole Mideo - Life in cells, hosts, and vectors: parasite evolution across scales
Parasite evolution is increasingly being recognized as one of the most important challenges in applied evolutionary biology. Understanding how parasites maximize fitness whilst facing the diverse challenges of living in cells, hosts, and vectors, is central to disease control and offers a novel testing ground for evolutionary theory. Along with Sam Brown, I recently hosted a symposium to address the question "How do parasites maximise fitness across a range of biological scales?". The symposium brought together researchers whose work looks across scales and environments to understand why and how parasites 'do what they do', tying together mechanism, evolutionary explanations, and public health implications. I will report on some of the fascinating research that suggests that understanding the evolution of parasite traits � and the diseases they cause � often requires an appreciation that parasite lives are complex and forces outwith focal host-parasite interactions can shape their traits. I will also highlight an existing theoretical framework for studying parasite evolution, which should provide a useful starting point for embracing this complexity.
03:30 PM
05:00 PM
Linda Allen, Sally Blower - Afternoon discussion leader: Sally Blower (Moderator: Linda Allen)
N/A
Friday, March 23, 2012
Time Session
Name Email Affiliation
Aggarwal, Nitish aggarwal.nitish@gmail.com Mathematics, The Ohio State University
Akudibillah, Gordon gakudib@clemson.edu Mathematical Sciences, Clemson University
Allen, Linda linda.j.allen@ttu.edu Mathematics, Texas Tech University
Andreasen, Viggo viggo@ruc.dk Dept of Science,
Angel, Jordan zjba15@goldmail.etsu.edu Mathematics and Statistics, East Tennessee State University
Arino, Julien arinoj@cc.umanitoba.ca Mathematics, University of Manitoba
Bagheri, Homayoun homayoun.bagheri@ieu.uzh.ch Institute of Evolutionary Biology and environmental Studies,
Ball, Frank frank.ball@nottingham.ac.uk. School of Mathematical Sciences, University of Nottingham
Bansal, Shweta shweta@sbansal.com CIDD, Penn State University
Blower, Sally sally.blower@gmail.com Semel Institute, University of California, Los Angeles
Bokil, Vrushali bokilv@math.oregonstate.edu Mathematics, Oregon State University
Brewer, Chris brewercc@goldmail.etsu.edu Mathematics, East Tennessee State University
Britton, Tom tomb@math.su.se Mathematics, Stockholm University
Cazelles, Bernard bernard.cazelles@upmc.fr UMR 7625,
Champagnat, Nicolas Nicolas.Champagnat@sophia.inria.fr IECN, Team TOSCA, INRIA Nancy - Grand Est
Cherif, Alhaji cherif@maths.ox.ac.uk Mathematical Institute, University of Oxford
Chowell-Puente, Gerardo gchowell@asu.edu School of Human Evolution and Social Change, Arizona State University
Cintron-Arias, Ariel ariel@cam.cornell.edu Mathematics and Statistics, East Tennessee State University
Cortez, Michael mhc37@cornell.edu School of Biology and School of Mathematics, Georgia Institute of Technology
Day, Troy tday@mast.queensu.ca Mathematics and Statistics, Queen's University
Dhersin, Jean-Stephane dhersin@math.univ-paris13.fr Mathematics,
Ganesh, Ayalvadi a.ganesh@bristol.ac.uk Mathematics, University of Bristol
Goncalves, Bruno bgoncalves@gmail.com Laboratory for the Modeling of Biological and Socio-technical Systems, Northeastern University
Handel, Andreas ahandel@uga.edu Epidemiology & Biostatistics, University of Georgia
Howk, Cory cory-howk@uiowa.edu Obstetrics & Gynecology, University of Iowa
Isham, Valerie valerie@stats.ucl.ac.uk Statistical Science, University College London
Joo, Jaewook jjoo1@utk.edu Physics, University of Tennessee
King, Aaron kingaa@umich.edu Ecology and Evolutionary Biology/Mathematics, University of Michigan
Kratz, Peter kratz@math.hu-berlin.de Mathematics, Universite de Provence
Lloyd, Alun alun_lloyd@ncsu.edu Biomathematics Graduate Program, Department of Mathematics, North Carolina State University
Luczak, Malwina m.luczak@sheffield.ac.uk Department of Mathematics,
Lunsford, Jessica jessicalunsford1234@yahoo.com Mathematics, East Tennessee State University
Luo, Shishi szl@math.duke.edu Mathematics, Duke University
Medlock, Jan medlock@clemson.edu Biomedical Sciences, Oregon State University
Meleard, Sylvie sylvie.meleard@polytechnique.edu Applied Mathematics,
Metz, Johan (=Hans) j.a.j.metz@biology.leidenuniv.nl Plant Ecology and Phytochemistry, Analysis and Dynamical Systems, Institute of Biology, Mathematical Institute
Mideo, Nicole N.Mideo@ed.ac.uk Center for Infectious Disease Dynamics, Pennsylvania State University
O'Neill, Philip Philip.ONeill@nottingham.ac.uk School of Mathematical Sciences, University of Nottingham
Park, Andrew awpark@uga.edu Ecology, University of Georgia
Pasteur, R. Drew rpasteur@wooster.edu Mathematics and Computer Science, The College of Wooster
Peters, Samuel peterssf@goldmail.etsu.edu Mathematics and Statistics, East Tennessee State University
Pomeroy, Laura pomeroy.26@osu.edu Veterinary Preventive Medicine, Ohio State University
Ponciano Castellanos, Jose josemi@ufl.edu Biology, University of Florida
Powell, Megan megan.powell@lyon.edu Division of Science and Mathematics, Lyon College
Shuai, Zhisheng zshuai@uvic.ca Mathematics and Statistics, University of Victoria
Singh, Sarabjeet ss2365@cornell.edu Theoretical and Applied Mechanics, Cornell University
Towers, Sherry stowers@purdue.edu Mathematics, Purdue University
Tran, Viet Chi chi.tran@math.univ-lille1.fr Laboratoire Paul PainlevÃ©, UniversitÃ© des Sciences et Technologies Lille 1
Trapman, Pieter ptrapman@math.su.se Department of Mathematics,
Vespignani, Alessandro alexv@indiana.edu School of Informatics and Computing, Indiana University
Wagner, Bradley bradwgnr@gmail.com Center for Biomedical Modeling, David Geffen School of Medicine, University of California, Los Angeles
Wang, Jin j3wang@odu.edu Mathematics, Old Dominion University
Wearing, Helen hwearing@math.unm.edu Biology, Mathematics & Statistics, University of New Mexico
Yakubu, Abdul-Aziz ayakubu@Howard.edu Mathematics Department, Howard University
Yi, Fengqi fengqi.yi@gmail.com Department of Mathematics, Harbin Engineering University
You, Yuncheng you@mail.usf.edu Mathematics and Statistics, University of South Florida
Afternoon discussion leader: Sally Blower (Moderator: Linda Allen)
N/A
The final outcome of an epidemic with two strains
The competition between two pathogen strains during the course of a single epidemic represents a fundamental step in the early evolution of emerging diseases as well as in antigenic drift processes. The outcome however, depends not only on the epidemic properties of the two strains but also on the timing and size of the introduction, characteristics that are poorly captured by deterministic mean-field epidemic models.

I will present a framework that allows us to describe those aspects of the competition that can be determined from the mean-field models giving the range of possible outcomes that could be observed in an epidemic with two fully or partially cross-reacting strains.
A model for the propagation of resistance to a parasite in vectors
One tool envisioned as part of the array of measures used in the fight against malaria takes advantage of a naturally occurring "resistance" of vectors to the parasite. This mechanism results in the disruption of the parasite's life cycle in vectors, rendering the bite of an infected vector harmless because the parasites have not reached the stage where they are infectious to hosts. However, this resistance is not transmitted through regular evolutionary mechanisms and requires the use of so-called transposons. I will present a naive model for the spread of this resistance in a population of vectors.
R0 and other reproduction numbers for epidemic models with households and other social structures
The basic reproduction number R0 is one of the most important quantities in epidemiology. However, for epidemic models with explicit social structure involving small mixing units such as households, its definition is not straightforward and a wealth of other threshold parameters has appeared in the literature. In this talk I use branching processes to define R0, apply this definition to models with households or other more complex social structures, provide a method for calculating R0 and show inequalities comparing R0 with previous threshold parameters. The comparisons imply that, if R0 > 1, vaccinating a fraction 1 - 1/R0 of the population, chosen uniformly at random, with a perfect vaccine is insufficient to be sure of preventing a large outbreak, and they lead to sharper, easily-computed bounds for the critical vaccination coverage than were previously available.

Based on work done jointly with Lorenzo Pellis (Imperial College London) and Pieter Trapman (Stockholm University).
Contact Networks for Modeling Immunizing Infectious Disease Dynamics
In models of disease transmission on contact networks, the probability of exposure is determined by the connectivity (degree) of the individual (node). Thus, the most highly connected individuals in a contact network have both a higher probability of spreading infection through the population and a higher rate of exposure (susceptibility) through social contacts. As an epidemic sweeps through a population, this heterogeneity leads to systematic structural changes in the active portion of the network, removing immunized individuals who no longer participate in the chains of transmission. While the impact of network structure on the progression of an epidemic has been well studied, there has been relatively little work on network evolution during the course of an epidemic. We analytically investigate the impact of epidemic dynamics on the underlying host population structure and find that the structural evolution of the network varies with the original topology of the network and the contagiousness of the disease. We identify the mechanisms acting on the network topology to make them sparser, consider questions about the patterns of immunity that arise during disease outbreaks, and explore their impact on future epidemics and key public health policies.
Afternoon discussion leader: Sally Blower (Moderator: Linda Allen)
N/A
Weighted networks with applications to epidemics
In the talk we present a simple extension of the configuration model to weighted networks, and state some asymptotic properties of the network model. The weights may be used for some stochastic process taking place on the network; for example an epidemic where the probability of transmission between two individuals depends on the weight of the connected edge (the weight for example reflecting social distance). We also consider the case where individuals (nodes) are heterogeneous in he sense that the transmission probability depends on the infectivity of the infector and the susceptibility of the victim. We end with analysis of some empirical networks: movement of patients in hospitals in Stockholm (for mrsa), workplaces and households of the Swedish population (for influenza), and census of sex-contacts (for STDs).
An individual-based approach to adaptive dynamics: a study of evolution and diversification through concentration scalings
We consider an stochastic, individual-based model of an evolving population with logistic density-dependence, where individuals are characterized by a quantitative phenotypic trait. Under appropriate parameters scalings of rare mutations and large populations, we obtain a stochastic jump process on the mutation time-scale, where evolution proceeds through successive invasions of mutants, followed by competition phases on shorter time scales, where disadvantaged traits are eliminated. Under an additional scaling of small mutations and on an appropriate time scales, the evolution can be described as ordinary differential equations on the trait space, known as "canonical equations of adaptive dynamics", followed by diversification phases where the number of traits present in the population may increase, a phenomenon known as "evolutionary branching".

This is joint work with Sylvie Mï¿½lï¿½ard (Ecole Polytechnique).
Disentangling the spatio-temporal dynamics of the 2009 A/H1N1 influenza pandemic in Mexico and Peru
Detailed surveillance data on the 2009 A/H1N1 influenza pandemic are crucial to quantify the spatial and temporal characteristics of pandemic influenza. We provide a quantitative description of the age-specific and regional 2009 A/H1N1 pandemic incidence patterns using data from Mexico and Peru. We used daily cases of influenza-like-illness, tests for A/H1N1 influenza virus infections, and laboratory-confirmed A/H1N1 influenza cases to analyze the geographic spread of the pandemic waves and their association with the winter school closing periods, demographic factors, and absolute humidity. We also estimated the reproduction number and quantified the association between school closing periods and the age distribution of cases. Our results indicate substantial regional variation in pandemic pattern, highlight the importance of school cycles on the transmission dynamics of this pandemic influenza strain, and suggests that school closure and other mitigation measures could be useful to mitigate future influenza pandemics.
Branching Process Models in Evolutionary Epidemiology
I will provide a brief overview of multitype branching processes, with particular emphasis on their application in evolutionary epidemiology. I will then discuss some recent work on how such analyses can be used to understand the evolutionary emergence of diseases like pandemic influenza in humans and to evaluate the utility of different interventions. Time permitting I will also discuss how branching processes are being used to understand and control the emergence of drug resistance.
Large graph limit for a SIR process in a random network with heterogeneous connectivity
We consider a SIR epidemic model propagating on a random network generated by a configuration model, where the degree distribution of the vertices is given and where the edges are randomly matched. The evolution of the epidemics is summed up into three measure-valued equations that describe the degrees of the susceptible individuals and the number of edges from an infectious or removed individual to the set of susceptibles. These three degree distributions are sufficient to describe the course of the disease. The limit in large population is investigated. As a corollary, this provides a rigorous proof of equations obtained by Volz.

This is a joint work with Laurent Decreusefond, Pascal Moyal and Viet Chi Tran
Tuberculosis drug resistance and the Luria-Delbruck distribution
Tuberculosis is one of the major global diseases in terms of both prevalance and mortality. In recent decades, strains of the disease have evolved that are resistant to several, or all, of the drugs used to treat the disease. Drug resistance is conferred by rare mutations, raising the question of how multiple mutations might have arisen in a single strain. Motivated by this question, we study models of branching processes with mutations which generalize the pioneering work of Luria and Delbruck. We look at the sizes of mutant populations in the limit of mutation rates decreasing to zero, and characterize their limiting distribution. The results show a transition between two regimes depending on the relative growth rate of the mutants: in the slow growth regime, the limiting distribution is Gaussian, while if the mutants reproduce quickly enough, it is heavy-tailed.
An introduction to stochastic models for epidemics and the effects of population structure
The first part of my talk will be an introduction to epidemic modelling aimed at those coming from a non-mathematical background. In it I will briefly review the historical background and describe some of the topics that have preoccupied researchers in recent years. I will concentrate on model structure and general modelling issues rather than on models for specific infections. The second part of the talk will focus on the effects of population structure and I will concentrate particularly on population networks. I will discuss the effect of different network structures on the transmission dynamics of epidemics and on thresholds for widespread transmission.
Afternoon discussion leader: Aaron King (Moderator: Helen Wearing)
N/A
Central limit approximations for Markov population processes with countably many types
When modelling metapopulation dynamics, the influence of a single patch on the metapopulation depends on the number of individuals in the patch. Since there is usually no obvious natural upper limit on the number of individuals in a patch, this leads to systems in which there are countably infinitely many possible types of entity. Analogous considerations apply in the transmission of parasitic diseases. We prove central limit theorems for quite general systems of this kind, together with bounds on the rate of convergence in an appropriately chosen weighted $ell_1$ norm.

This is joint work with Andrew Barbour.
The impact of vaccination on dengue virulence
Virulence evolution has a long history, including the now-classic paper of Gandon et al. 2001 on the impact of malaria vaccination on the virulence of the parasite. Gandon et al. found that a vaccine with the action of reducing the pathogen growth rate in the host selects for more virulent pathogens, while an infection-blocking vaccine selects for less virulent pathogens. We found that, in the context of mosquito transgenesis, that relaxing one assumption of Gandon et al. leads to an inability to predict the direction of selection on pathogen virulence. I will discuss these issues in the context of dengue vaccine.
The interplay of infectivity that decreases with virulence and limited cross-immunity: (toy) models for respiratory disease evolution
Models for the evolution of virulence traditionally assume a trade-off between inverse disease-induced mortality rate and infectivity, resulting in intermediate virulence. The underlying intuition is that faster growing agent populations do both more damage and produce more infective particles. This intuition implicitly assumes a well-mixed host body. In reality both damage and infectivity depend mainly on the location in the body where the agents lodge. This is related i.a. to the surface proteins that allow agents to dock on and penetrate into different cell types. The typical example is respiratory diseases where more deeply seated ones are both less infective and more harmful. With the other standard assumption, full cross-immunity between disease strains, this would lead to evolution towards the tip of the nose. In reality cross-immunity depends on surface antigens and hence is at least in part connected to depth. In this talk I discuss a simple adaptive dynamics style model taking on board the aforementioned considerations. The inference is that disease diversity should decrease with depth.

(The reported work was done in collaboration with Kevin Kleine and Juan E. Keymer Vergara of Delft University of Technology.)
Life in cells, hosts, and vectors: parasite evolution across scales
Parasite evolution is increasingly being recognized as one of the most important challenges in applied evolutionary biology. Understanding how parasites maximize fitness whilst facing the diverse challenges of living in cells, hosts, and vectors, is central to disease control and offers a novel testing ground for evolutionary theory. Along with Sam Brown, I recently hosted a symposium to address the question "How do parasites maximise fitness across a range of biological scales?". The symposium brought together researchers whose work looks across scales and environments to understand why and how parasites 'do what they do', tying together mechanism, evolutionary explanations, and public health implications. I will report on some of the fascinating research that suggests that understanding the evolution of parasite traits ï¿½ and the diseases they cause ï¿½ often requires an appreciation that parasite lives are complex and forces outwith focal host-parasite interactions can shape their traits. I will also highlight an existing theoretical framework for studying parasite evolution, which should provide a useful starting point for embracing this complexity.
Modelling and inference for healthcare-associated infection
Multi-drug resistant pathogens such as MRSA and VRE give rise to substantial morbidity and mortality, and impose a huge economic burden on healthcare systems. In this talk we describe a framework for analysing patient-level data from hosptials on such pathogens, employing stochastic transmission models and using Markov chain Monte Carlo methods witin a Bayesian statistical framework. The methods are illustrated with various data sets and used to address various clinically-relevant questions.
Afternoon discussion leader: Andrew Park (Moderator: Helen Wearing)
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Modeling the diversity and stability of human vaginal microbial communities
Our understanding of the ecological and evolutionary conditions that permit the establishment and persistence of different bacterial species in host-associated microbial communities is incomplete. Recent work done to characterize human vaginal bacterial communities by experimental and analytical approaches has shown that idiosyncratic changes in species composition and wide fluctuations in the relative abundances of the different species are undeniably associated with specific environmental drivers. An understanding of the mechanisms, ecological processes and evolutionary routes behind the genesis of such associations and fluctuations remain an important knowledge gap. If the structure and composition of a given ecological community often alternates between distinct, widely different states, then better predictions about the chances of a dramatic community shift can be achieved using mechanistic, stochastic population dynamics models. In human bacterial communities research, there is a strong need to confront problems of risk assessment and prediction using such modeling approach. In this work, we develop a modeling framework based on the multivariate Ornstein-Uhlenbeck stochastic process to predict the unfolding of complex microbial community dynamics. We derive a suite of stochastic models derived from first biological principles will be used to evaluate time-series data on the relative abundances of bacterial species in vaginal communities. The statistical inferences done with these models have broad implications to the understanding of the processes governing the composition, structure and function of bacterial communities associated to humans. Finally, our research opens the door to a better assessment of the risk to diseases associated with responses to disturbances of human-associated microbial ecosystems.
Modelling of the Cuban HIV Epidemics
HIV has been introduced in Cuban in 1986. From the beginning of the epidemics, contact-tracing is used, in the purpose of detecting more HIV-positive individuals and of controlling the spread of the disease. The data generated from this contact-tracing program provide some partial information on the social networks underlying the propagation of HIV. In this talk, we present this big network (5389 nodes, with a giant component of 2386 nodes) together with some possible modelling of the phenomenon.
Afternoon discussion leader: Pieter Trapman (Moderator: Linda Allen)
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Real Time Numerical Forecast of Global Epidemic Spreading
Mathematical and computational models are increasingly used in support decisions in public health, however the perception of their reliability and the criteria for their uses is contrasted among domain experts. We consider the Global Epidemic and Mobility model that generates stochastic realizations of epidemic evolution worldwide from which we can gather information such as prevalence, morbidity, number of secondary cases and number and date of imported cases for 3,360 subpopulation in 220 countries with a time resolution of 1 day. GLEaM has been used to anticipate the geographical spreading for the 2009 H1N1 pandemic by estimating the transmission potential and the relevant model parameters with a Monte Carlo likelihood analysis of the arrival time distribution generated by 1 million computationally simulated epidemics. We present an extensive validation analysis of the obtained results from surveillance and virological sources collected in 46 countries of the Northern Hemisphere during the course of the pandemic. We focus on discussing the challenges posed by the real-time estimation of parameters, the different levels of data-integration and the validation through high quality data sets. In particular, data gathered during and after the 2009 H1N1 influenza crisis represent an unprecedented opportunity to i) test the robustness of the prediction intervals with respect to additional parameters unknown concurrently or before the end of the pandemic; ii) test the sensitivity of prediction intervals to the different levels of data integration by considering progressively increasing knowledge of socio-demographic and human mobility data.
HIV strains with drug-resistant mutations: the effect of fitness costs and genetic bottlenecks in limiting transmission
Transmission of HIV strains with drug-resistant mutations (DRMs) is a public health concern in resource rich countries. Fitness costs and genetic bottlenecks limit transmission of these DRMs. In this talk I will discuss how to assess this effect, using invitro data from viral competition experiments and stochastic HIV transmission models. I will also discuss, in light of the assay sensitivity for currently employed resistance tests, the potential for existence of hidden epidemics of transmitted resistance.

This work was done in collaboration with J. Gerardo Garcia-Lerma at the Centers for Disease Control and Prevention and Sally Blower at the David Geffen School of Medicine, UCLA.
Afternoon discussion leader: Aaron King (Moderator: Helen Wearing)
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Afternoon discussion leader: Andrew Park (Moderator: Helen Wearing)
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The interplay of infectivity that decreases with virulence and limited cross-immunity: (toy) models for respiratory disease evolution
Johan (=Hans) Metz Models for the evolution of virulence traditionally assume a trade-off between inverse disease-induced mortality rate and infectivity, resulting in intermediate virulence. The underlying intuition is that faster growing agent populations do both more

Contact Networks for Modeling Immunizing Infectious Disease Dynamics
Shweta Bansal In models of disease transmission on contact networks, the probability of exposure is determined by the connectivity (degree) of the individual (node). Thus, the most highly connected individuals in a contact network have both a higher probability of

Real Time Numerical Forecast of Global Epidemic Spreading
Alessandro Vespignani Mathematical and computational models are increasingly used in support decisions in public health, however the perception of their reliability and the criteria for their uses is contrasted among domain experts. We consider the Global Epidemic and Mob

The impact of vaccination on dengue virulence
Jan Medlock Virulence evolution has a long history, including the now-classic paper of Gandon et al. 2001 on the impact of malaria vaccination on the virulence of the parasite. Gandon et al. found that a vaccine with the action of reducing the pathogen growth ra

Weighted networks with applications to epidemics
Tom Britton In the talk we present a simple extension of the configuration model to weighted networks, and state some asymptotic properties of the network model. The weights may be used for some stochastic process taking place on the network; for example an epid

Large graph limit for a SIR process in a random network with heterogeneous connectivity
Jean-Stephane Dhersin We consider a SIR epidemic model propagating on a random network generated by a configuration model, where the degree distribution of the vertices is given and where the edges are randomly matched. The evolution of the epidemics is summed up into thr

Life in cells, hosts, and vectors: parasite evolution across scales
Nicole Mideo Parasite evolution is increasingly being recognized as one of the most important challenges in applied evolutionary biology. Understanding how parasites maximize fitness whilst facing the diverse challenges of living in cells, hosts, and vectors, is

Tuberculosis drug resistance and the Luria-Delbruck distribution
Ayalvadi Ganesh Tuberculosis is one of the major global diseases in terms of both prevalance and mortality. In recent decades, strains of the disease have evolved that are resistant to several, or all, of the drugs used to treat the disease. Drug resistance is confe

R0 and other reproduction numbers for epidemic models with households and other social structures
Frank Ball The basic reproduction number R0 is one of the most important quantities in epidemiology. However, for epidemic models with explicit social structure involving small mixing units such as households, its definition is not straightforward and a wealth

Modelling and inference for healthcare-associated infection
Philip O'Neill Multi-drug resistant pathogens such as MRSA and VRE give rise to substantial morbidity and mortality, and impose a huge economic burden on healthcare systems. In this talk we describe a framework for analysing patient-level data from hosptials on suc

Modelling of the Cuban HIV Epidemics
Viet Chi Tran HIV has been introduced in Cuban in 1986. From the beginning of the epidemics, contact-tracing is used, in the purpose of detecting more HIV-positive individuals and of controlling the spread of the disease. The data generated from this contact-traci

An individual-based approach to adaptive dynamics: a study of evolution and diversification through concentration scalings
Nicolas Champagnat We consider an stochastic, individual-based model of an evolving population with logistic density-dependence, where individuals are characterized by a quantitative phenotypic trait. Under appropriate parameters scalings of rare mutations and large po

Modeling the diversity and stability of human vaginal microbial communities
Jose Ponciano Castellanos Our understanding of the ecological and evolutionary conditions that permit the establishment and persistence of different bacterial species in host-associated microbial communities is incomplete. Recent work done to characterize human vaginal bacter

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