A systems biology approach to integrating pathogen evolution and epidemiology

Lead Research Organisation: University of Glasgow
Department Name: School of Life Sciences

Abstract

Considering the obvious over-riding importance of transmission in epidemiology, we know remarkably little about it. Recent advances in epidemiological theory have underlined the importance of variation in the transmission of infection between individuals (or groups of individuals) for the design and implementation of disease control measures. It is often the case that the majority of transmission events over the course of an epidemic are due to a surprisingly small number of infected individuals. If these can be characterized and identified, control programs can be designed to be vastly more efficient and effective. However, transmission is a notoriously difficult process to observe directly, and identifying transmission patterns is often not possible. Where it is attempted, it is usually conducted through a statistically informal process of 'contact tracing' that supplements data on potential host contacts with epidemiological data relating to incubation periods, infectious periods, and the timing of infections. RNA viruses comprise a large and important set of agricultural pathogens of both animals and plants, together with the majority of emerging and re-emerging pathogens. The high mutation rate characteristic of RNA virus genomes results in a detectable micro-evolutionary process over the course of an epidemic, and provides an important opportunity to identify transmission patterns, through analysis of the distribution of shared virus mutations recovered from different host individuals. However, there exists no rigorous statistical framework with which sequence data and more traditional epidemiological data can be integrated together to make reliable and efficient inference about transmission patterns. The increasing rapidity and economy with which sequence data can be generated enables multi-gene or even whole viral genome data to be acquired / even in 'real-time' situations / and used to provide potentially high resolution information about transmission processes that facilitates the design and implementation of disease control programs. It is inevitable that pathogen sequence data will be used increasingly to study transmission processes in epidemiology. It is therefore essential that statistical methodologies keep pace with the changing nature of the data and the different questions that can be asked of them. Here, we bring together an unusual multi-disciplinary research team to develop a series of scale-nested models of population genetic processes characteristic of viral transmission systems, using Foot-and-mouth disease virus and Plum pox virus as example systems. We will model processes as they occur at three different scales: within individual hosts, within host groups (such as herds, crops, or orchards), and between host groups. Processes at these different scales are all too often studied in isolation. Our multi-scale approach will enable information available at each of these scales to be made self-supporting and complementary to each other. These models will be used to develop statistically efficient and powerful models that will be fitted to combined genetic data (such as gene or genome sequences) and epidemiological data (such as time of infection, incubation period, and time that individuals cease to be infectious). These methods can be used to estimate unknown parameters related to smaller-scale processes from data acquired at larger-scales, and to provide a rigorous statistical analysis of series of possible transmission events between individuals or groups of individuals that give rise to epidemics.

Technical Summary

Heterogeneities in disease transmission offer important opportunities to enhance the efficiency and effectiveness of control programs. However, transmission is a difficult process to observe directly, and identifying transmission links is often not possible. Where it is attempted, it is usually conducted through a statistically informal process of 'contact tracing' that is based on epidemiological data such as incubation periods, infectious periods, and the timing of infections. The high mutation rate characteristic of RNA virus genomes offer an important opportunity to identify transmission patterns, through analysis of the distribution of shared virus mutations between infected hosts. The increasing rapidity and economy with which sequence data can be generated makes it evermore likely that pathogen sequence data will be used increasingly to study transmission processes in epidemiology. It is essential that statistical methodologies keep pace with the changing nature of the data and the different questions asked of them. Here, we propose to develop a series of scale-nested models of population genetic processes characteristic of viral transmission systems, using Foot-and-mouth disease virus and Plum pox virus as example systems. We will model processes as they occur at three different scales: within individual hosts, within host groups (such as herds, crops, or orchards), and between host groups. These models will be used to develop statistically efficient and powerful Bayesian likelihood models that will be fitted to combined genetic data (such as gene or genome sequences) and epidemiological data (such as time of infection, incubation period, and time that individuals cease to be infectious) using Monte-Carlo Markov Chain methods. These methods can be used to estimate unknown parameters and provide a rigorous statistical analysis of series of possible transmission events between individuals or groups of individuals that give rise to epidemics.

Publications

10 25 50
 
Description Research conducted with the support of this grant led to the development of new way of thinking about integrating genetic and epidemiological data in order to reconstruct so-called transmission trees - connected diagrams that illustrate 'who infected who' in the course of an epidemic. This methodology and has been articulated in a number of highly cited papers.
Exploitation Route Our research has arguably stimulated complementary research undertaken at Imperial College by Jombart and his group, Samuel Soubeyrand at INRA in Avignon.
Sectors Agriculture, Food and Drink

 
Description Our methodology has been used in the analysis of both the 2001 and 2007 FMDV outbreaks in the UK (for the 2007 outbreak see for example Cottam et al. (2008) Plos Pathogens 4, 1-9)
First Year Of Impact 2008
Sector Agriculture, Food and Drink
 
Description Training - Triage Nurses at Endulen Hospital
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact Our phlebotomists have trained several triage nurses at Endulen Hospital in study enrolment procedure. This includes validation systems for temperatures and weight which increase the accuracy of the measurement they can use for all patients and outpatients at Endulen Hospital
 
Description INRA International fellowship to Dr Gael Thebaud
Amount € 70,000 (EUR)
Organisation French National Institute of Agricultural Research 
Department INRA-Génétique Cellulaire, FRANCE
Sector Public
Country France
Start  
 
Description OIE/FAO Laboratory Network for FMD 
Organisation Botswana Vaccine Institute
Country Botswana 
Sector Public 
PI Contribution The Pirbright Institute currently coordinates a global network of fourteen International Reference Laboratories for FMD.
Collaborator Contribution The Network of OIE/FAO FMD Reference Laboratories has been established with two principal goals: 1) To understand global virus distribution patterns and use these data to inform vaccine recommendations and 2) To harmonise and improve the quality of laboratory testing carried out by international and national reference laboratories. These activities require sharing and joint evaluation of surveillance information from laboratory diagnosis, serotyping, genetic characterisation and vaccine matching tests and harmonisation of standards for diagnostic procedures.
Impact Outputs from the network provide vital information to international organisations involved in the control of FMD (such as OIE and FAO), as well as specific regional and national programmes to control FMD
Start Year 2006
 
Description OIE/FAO Laboratory Network for FMD 
Organisation Department of Livestock Development
Country Thailand 
Sector Public 
PI Contribution The Pirbright Institute currently coordinates a global network of fourteen International Reference Laboratories for FMD.
Collaborator Contribution The Network of OIE/FAO FMD Reference Laboratories has been established with two principal goals: 1) To understand global virus distribution patterns and use these data to inform vaccine recommendations and 2) To harmonise and improve the quality of laboratory testing carried out by international and national reference laboratories. These activities require sharing and joint evaluation of surveillance information from laboratory diagnosis, serotyping, genetic characterisation and vaccine matching tests and harmonisation of standards for diagnostic procedures.
Impact Outputs from the network provide vital information to international organisations involved in the control of FMD (such as OIE and FAO), as well as specific regional and national programmes to control FMD
Start Year 2006
 
Description OIE/FAO Laboratory Network for FMD 
Organisation FGBI Federal Centre for Animal Health
Country Russian Federation 
Sector Public 
PI Contribution The Pirbright Institute currently coordinates a global network of fourteen International Reference Laboratories for FMD.
Collaborator Contribution The Network of OIE/FAO FMD Reference Laboratories has been established with two principal goals: 1) To understand global virus distribution patterns and use these data to inform vaccine recommendations and 2) To harmonise and improve the quality of laboratory testing carried out by international and national reference laboratories. These activities require sharing and joint evaluation of surveillance information from laboratory diagnosis, serotyping, genetic characterisation and vaccine matching tests and harmonisation of standards for diagnostic procedures.
Impact Outputs from the network provide vital information to international organisations involved in the control of FMD (such as OIE and FAO), as well as specific regional and national programmes to control FMD
Start Year 2006
 
Description OIE/FAO Laboratory Network for FMD 
Organisation French Agency for Food, Environmental and Occupational Health & Safety (ANSES)
Country France 
Sector Public 
PI Contribution The Pirbright Institute currently coordinates a global network of fourteen International Reference Laboratories for FMD.
Collaborator Contribution The Network of OIE/FAO FMD Reference Laboratories has been established with two principal goals: 1) To understand global virus distribution patterns and use these data to inform vaccine recommendations and 2) To harmonise and improve the quality of laboratory testing carried out by international and national reference laboratories. These activities require sharing and joint evaluation of surveillance information from laboratory diagnosis, serotyping, genetic characterisation and vaccine matching tests and harmonisation of standards for diagnostic procedures.
Impact Outputs from the network provide vital information to international organisations involved in the control of FMD (such as OIE and FAO), as well as specific regional and national programmes to control FMD
Start Year 2006
 
Description OIE/FAO Laboratory Network for FMD 
Organisation Lanzhou Veterinary Research Institute
Country China 
Sector Learned Society 
PI Contribution The Pirbright Institute currently coordinates a global network of fourteen International Reference Laboratories for FMD.
Collaborator Contribution The Network of OIE/FAO FMD Reference Laboratories has been established with two principal goals: 1) To understand global virus distribution patterns and use these data to inform vaccine recommendations and 2) To harmonise and improve the quality of laboratory testing carried out by international and national reference laboratories. These activities require sharing and joint evaluation of surveillance information from laboratory diagnosis, serotyping, genetic characterisation and vaccine matching tests and harmonisation of standards for diagnostic procedures.
Impact Outputs from the network provide vital information to international organisations involved in the control of FMD (such as OIE and FAO), as well as specific regional and national programmes to control FMD
Start Year 2006
 
Description OIE/FAO Laboratory Network for FMD 
Organisation Lombardy and Emilia Romagna Experimental Zootechnic Institute (IZSLER)
Country Italy 
Sector Public 
PI Contribution The Pirbright Institute currently coordinates a global network of fourteen International Reference Laboratories for FMD.
Collaborator Contribution The Network of OIE/FAO FMD Reference Laboratories has been established with two principal goals: 1) To understand global virus distribution patterns and use these data to inform vaccine recommendations and 2) To harmonise and improve the quality of laboratory testing carried out by international and national reference laboratories. These activities require sharing and joint evaluation of surveillance information from laboratory diagnosis, serotyping, genetic characterisation and vaccine matching tests and harmonisation of standards for diagnostic procedures.
Impact Outputs from the network provide vital information to international organisations involved in the control of FMD (such as OIE and FAO), as well as specific regional and national programmes to control FMD
Start Year 2006
 
Description OIE/FAO Laboratory Network for FMD 
Organisation National Agri-Food Quality and Health Service (SENASA)
Country Argentina 
Sector Public 
PI Contribution The Pirbright Institute currently coordinates a global network of fourteen International Reference Laboratories for FMD.
Collaborator Contribution The Network of OIE/FAO FMD Reference Laboratories has been established with two principal goals: 1) To understand global virus distribution patterns and use these data to inform vaccine recommendations and 2) To harmonise and improve the quality of laboratory testing carried out by international and national reference laboratories. These activities require sharing and joint evaluation of surveillance information from laboratory diagnosis, serotyping, genetic characterisation and vaccine matching tests and harmonisation of standards for diagnostic procedures.
Impact Outputs from the network provide vital information to international organisations involved in the control of FMD (such as OIE and FAO), as well as specific regional and national programmes to control FMD
Start Year 2006
 
Description OIE/FAO Laboratory Network for FMD 
Organisation National Centre for Foreign Animal Diseases (NCFAD)
Country Canada 
Sector Public 
PI Contribution The Pirbright Institute currently coordinates a global network of fourteen International Reference Laboratories for FMD.
Collaborator Contribution The Network of OIE/FAO FMD Reference Laboratories has been established with two principal goals: 1) To understand global virus distribution patterns and use these data to inform vaccine recommendations and 2) To harmonise and improve the quality of laboratory testing carried out by international and national reference laboratories. These activities require sharing and joint evaluation of surveillance information from laboratory diagnosis, serotyping, genetic characterisation and vaccine matching tests and harmonisation of standards for diagnostic procedures.
Impact Outputs from the network provide vital information to international organisations involved in the control of FMD (such as OIE and FAO), as well as specific regional and national programmes to control FMD
Start Year 2006
 
Description OIE/FAO Laboratory Network for FMD 
Organisation Onderstepoort Veterinary Institute
Country South Africa 
Sector Academic/University 
PI Contribution The Pirbright Institute currently coordinates a global network of fourteen International Reference Laboratories for FMD.
Collaborator Contribution The Network of OIE/FAO FMD Reference Laboratories has been established with two principal goals: 1) To understand global virus distribution patterns and use these data to inform vaccine recommendations and 2) To harmonise and improve the quality of laboratory testing carried out by international and national reference laboratories. These activities require sharing and joint evaluation of surveillance information from laboratory diagnosis, serotyping, genetic characterisation and vaccine matching tests and harmonisation of standards for diagnostic procedures.
Impact Outputs from the network provide vital information to international organisations involved in the control of FMD (such as OIE and FAO), as well as specific regional and national programmes to control FMD
Start Year 2006
 
Description OIE/FAO Laboratory Network for FMD 
Organisation Pan American Foot-and-Mouth Disease Center (Panaftosa)
Country Brazil 
Sector Charity/Non Profit 
PI Contribution The Pirbright Institute currently coordinates a global network of fourteen International Reference Laboratories for FMD.
Collaborator Contribution The Network of OIE/FAO FMD Reference Laboratories has been established with two principal goals: 1) To understand global virus distribution patterns and use these data to inform vaccine recommendations and 2) To harmonise and improve the quality of laboratory testing carried out by international and national reference laboratories. These activities require sharing and joint evaluation of surveillance information from laboratory diagnosis, serotyping, genetic characterisation and vaccine matching tests and harmonisation of standards for diagnostic procedures.
Impact Outputs from the network provide vital information to international organisations involved in the control of FMD (such as OIE and FAO), as well as specific regional and national programmes to control FMD
Start Year 2006
 
Description OIE/FAO Laboratory Network for FMD 
Organisation Project Directorate on Foot and Mouth Disease
Country India 
Sector Public 
PI Contribution The Pirbright Institute currently coordinates a global network of fourteen International Reference Laboratories for FMD.
Collaborator Contribution The Network of OIE/FAO FMD Reference Laboratories has been established with two principal goals: 1) To understand global virus distribution patterns and use these data to inform vaccine recommendations and 2) To harmonise and improve the quality of laboratory testing carried out by international and national reference laboratories. These activities require sharing and joint evaluation of surveillance information from laboratory diagnosis, serotyping, genetic characterisation and vaccine matching tests and harmonisation of standards for diagnostic procedures.
Impact Outputs from the network provide vital information to international organisations involved in the control of FMD (such as OIE and FAO), as well as specific regional and national programmes to control FMD
Start Year 2006
 
Description OIE/FAO Laboratory Network for FMD 
Organisation U.S. Department of Agriculture USDA
Department Agricultural Research Service
Country United States 
Sector Public 
PI Contribution The Pirbright Institute currently coordinates a global network of fourteen International Reference Laboratories for FMD.
Collaborator Contribution The Network of OIE/FAO FMD Reference Laboratories has been established with two principal goals: 1) To understand global virus distribution patterns and use these data to inform vaccine recommendations and 2) To harmonise and improve the quality of laboratory testing carried out by international and national reference laboratories. These activities require sharing and joint evaluation of surveillance information from laboratory diagnosis, serotyping, genetic characterisation and vaccine matching tests and harmonisation of standards for diagnostic procedures.
Impact Outputs from the network provide vital information to international organisations involved in the control of FMD (such as OIE and FAO), as well as specific regional and national programmes to control FMD
Start Year 2006
 
Description OIE/FAO Laboratory Network for FMD 
Organisation Veterinary and Agrochemical Research Centre
Country Belgium 
Sector Public 
PI Contribution The Pirbright Institute currently coordinates a global network of fourteen International Reference Laboratories for FMD.
Collaborator Contribution The Network of OIE/FAO FMD Reference Laboratories has been established with two principal goals: 1) To understand global virus distribution patterns and use these data to inform vaccine recommendations and 2) To harmonise and improve the quality of laboratory testing carried out by international and national reference laboratories. These activities require sharing and joint evaluation of surveillance information from laboratory diagnosis, serotyping, genetic characterisation and vaccine matching tests and harmonisation of standards for diagnostic procedures.
Impact Outputs from the network provide vital information to international organisations involved in the control of FMD (such as OIE and FAO), as well as specific regional and national programmes to control FMD
Start Year 2006
 
Description Keynote presentation - 7th International Symposium on Emerging and re-emerging Pig Diseases, Kyoto, Japan 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presented a talk outlining our research findings - entitled: "King D.P., Logan G., Freimanis G. L., Wright C. F., King D. J., Knowles N. J., Wadsworth J., Lasecka L., Bachanek-Bankowska K., Di Nardo A., Orton R. and Haydon D. T. Using sequence data to understand the epidemiology of foot-and-mouth disease" at the 7th International Symposium on Emerging and re-emerging Pig Diseases, Kyoto, Japan, June 2015.
Year(s) Of Engagement Activity 2015
URL http://emerging2015.com