A systems biology approach to integrating pathogen evolution and epidemiology
Lead Research Organisation:
University of Glasgow
Department Name: Institute of Biomedical & 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.
Organisations
- University of Glasgow (Lead Research Organisation)
- Botswana Vaccine Institute (Botswana) (Collaboration)
- FGBI Federal Centre for Animal Health (Collaboration)
- French Agency for Food, Environmental and Occupational Health & Safety (ANSES) (Collaboration)
- Lombardy and Emilia Romagna Experimental Zootechnic Institute (IZSLER) (Collaboration)
- National Agri-Food Quality and Health Service (SENASA) (Collaboration)
- Onderstepoort Veterinary Institute (Collaboration)
- Lanzhou Veterinary Research Institute (Collaboration)
- Project Directorate on Foot and Mouth Disease (Collaboration)
- Department of Livestock Development (Collaboration)
- U.S. Department of Agriculture USDA (Collaboration)
- Veterinary and Agrochemical Research Centre (Collaboration)
- National Centre for Foreign Animal Diseases (NCFAD) (Collaboration)
- Pan American Foot-and-Mouth Disease Center (Panaftosa) (Collaboration)
- The Pirbright Institute (Project Partner)
People |
ORCID iD |
Daniel Haydon (Principal Investigator) |
Publications
Wright C
(2011)
Beyond the Consensus: Dissecting Within-Host Viral Population Diversity of Foot-and-Mouth Disease Virus by Using Next-Generation Genome Sequencing
in Journal of Virology
Thébaud G
(2010)
The relationship between mutation frequency and replication strategy in positive-sense single-stranded RNA viruses.
in Proceedings. Biological sciences
Orton RJ
(2013)
Observing micro-evolutionary processes of viral populations at multiple scales.
in Philosophical transactions of the Royal Society of London. Series B, Biological sciences
Morelli MJ
(2013)
Evolution of foot-and-mouth disease virus intra-sample sequence diversity during serial transmission in bovine hosts.
in Veterinary research
Morelli MJ
(2012)
A Bayesian inference framework to reconstruct transmission trees using epidemiological and genetic data.
in PLoS computational biology
Cottam EM
(2008)
Transmission pathways of foot-and-mouth disease virus in the United Kingdom in 2007.
in PLoS pathogens
Cottam EM
(2008)
Integrating genetic and epidemiological data to determine transmission pathways of foot-and-mouth disease virus.
in Proceedings. Biological sciences
Cottam EM
(2009)
Analysis of Foot-and-mouth disease virus nucleotide sequence variation within naturally infected epithelium.
in Virus research
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 |