US-UK Collab: Mycobacterial Transmission Dynamics in Agricultural Systems: Integrating Phylogenetics, Epidemiology, Ecology, and Economics

Lead Research Organisation: University of Glasgow
Department Name: College of Medical, Veterinary &Life Sci

Abstract

Mathematical modeling of disease transmission is an important tool in studying infectious disease control; however, parameter estimation from field data is often difficult to quantify, especially with complex diseases. Whole-genome sequencing has become faster and more affordable in recent years, thanks to Next-Generation Sequencing techniques. As large databases of sequenced pathogen isolates become available, infectious disease epidemiologists will be able to use these databases, which are more fine-grained than previous serotyping methods, to improve our understanding of transmission dynamics. However, a general methodology is not yet available for such detailed data in bacteria with slow transmission timescales. This project proposes to develop a quantitative methodology for incorporating whole genome sequence (WGS) data into bacterial transmission models. For this, isolates will be used from mycobacterial infections in agricultural systems in the US and UK. Mycobacterial infections, including Mycobacterium avium subsp. paratuberculosis (MAP) and M. bovis (bovine tuberculosis or bTB), are usually studied in simple one-host systems. Mycobacterial disease is extremely difficult to control due to long latent periods, poor diagnostic sensitivity, wildlife and environmental reservoirs of infection, and heterogeneous strain infectiousness. The key to controlling these diseases is believed to be an integrated approach to understand the pathways through which pathogen transmission occurs at all levels in an ecosystem: within animals, between individual animals, between livestock and wildlife, and between livestock and the environment. A generalized, multi-scale methodology is proposed for determining transmission dynamics using WGS data and phylodynamics. These dynamics will be incorporated into predictive models of disease transmission and control within an economic framework, to help decision-makers make informed control choices.

Technical Summary

We will develop a new multi-scale model of infection transmission and control which will be used to better understand the principles, dynamics, and impacts of multi-host infections (particularly mycobacterial infections) at multiple levels. These models will be developed in an integrated, phylodynamic parameter estimation framework, using mathematical models that incorporate both our detailed farm and phylogenetic data. In particular, our work will provide a general framework for modeling infection dynamics of slow-moving pathogens within livestock herds and the connection to both wildlife populations and environmental reservoirs that can affect the dynamics of transmission and control. Our work will be based on unique and innovative data collection methods and data analyses. We will test our methods using expansive isolate collections and precise data on two mycobacterial infections: Mycobacterium avium subsp. paratuberculosis (MAP), the cause of Johne's disease (JD) in ruminants, and Mycobacterium bovis (M. bovis), the causal agent of bovine tuberculosis (bTB). Bovine tuberculosis will be studied in cattle and white-tailed (WT) deer (Odocoileus virginianus) in the US and compared to bTB in cattle and Eurasian badgers (Meles meles) in the UK, while MAP will be studied in dairy cattle and their environment in both the US and UK. These infections are active in complex ecosystems and affect human populations through direct contact, economic impact, and potential contamination of the food supply. By comparing across pathogens, we can examine the impact of the difference between wildlife reservoirs (M. bovis) and environmental reservoirs (MAP), with their differing mutation rates4 while determining the general principles involved in integrating WGS and epidemiological models.

Planned Impact

Transformative research in phylodynamics and disease ecology is proposed to improve our understanding of bacterial infection dynamics by developing 1) a generalized methodology for incorporating WGS data into transmission models, 2) a generalized ecosystem approach to modeling infectious diseases with agricultural production and economic components, and 3) research methods for modeling transmission dynamics in complicated multi-scale systems. This project will integrate innovative phylodynamic techniques with novel data collection and analysis across various scales in the US and UK to determine the minimum necessary data requirements for this model type. The results will allow for design of cost-effective data collection programs, which will be valuable in develop countries but essential in many livestock-dependent low-income countries.

phylodynamic framework at the core of this work will have broad use in public health policy and practices through identifying important factors in multi-host, systems; the generality of the framework will allow it to be adapted broadly to bacterial diseases affecting humans and animals. This interdisciplinary work will promote a cross-fertilization of ideas amongst students, researchers and faculty in molecular biology, epidemiology, ecology, and economics. The molecular biologists, epidemiologists, ecologists and economists in the team will collaborate closely to develop the techniques for this work. Other research-related education and outreach activities specific to this work will include workshops at NIMBioS, short-courses on transmission for veterinarians, and an intensive graduate-level course on endemic disease modeling. Furthermore, members of the group actively participate in science educational programs for 7th-9th grade girls in the Ithaca, NY community and in education for school-age children in the UK, as well as professional development classes in many countries.

At the completion of the project, a methodology will have been developed for multi-scale generalized systems modeling of multi-host infectious diseases in an ecosystem that includes livestock, environmental, wildlife, and economic components with a particular application in mycobacterial diseases and their control. A large impact is expected in core phylogenetic and mathematical epidemiology areas, including multi-scale modeling and inference from WGS data. In the process high school, undergraduates, graduate students and post-doctoral fellows will have been trained and enthused in the use of this approach.

Publications

10 25 50

Related Projects

Project Reference Relationship Related To Start End Award Value
BB/M01262X/1 01/09/2014 14/09/2017 £379,635
BB/M01262X/2 Transfer BB/M01262X/1 15/09/2017 14/08/2019 £109,862
 
Description Analysis of the evolutionary dynamics of M bovis in Michigan deer cattle and elk has shown that elk are unlikely to have had an impact on the amount of Bovine Tb in Michigan cattle. There are considerable tensions between hunting lobbies and the cattle industry in Michigan. Elk are a 'flagship' hunting species in Michigan, and demonstrating in our detailed studies with novel deep sequence data, that there is no evidence for elk to have a role in transmission to cattle helps to refine policies towards controlling Tb.
Exploitation Route The approaches could be used for epidemiological analyses of other slowly evolving pathogens especially other mycobacteria.
Sectors Agriculture, Food and Drink,Education,Healthcare

 
Description Dr. Salvador's secondment at USDA-APHIS allowed her to learn about the bioinformatics pipeline being used to process M bovis data; in that time she worked on and contributed to the development of a revised pipeline for use in processing M. avium paratuberculosis or MAP sequence data. This new pipeline was then adopted by USDA-APHIS for the routine processing of their MAP sequence data used for epidemiological investigations.
First Year Of Impact 2016
Sector Agriculture, Food and Drink
Impact Types Policy & public services

 
Description Member of Defra's Science Advisory Council
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Impact As a member of Defra's Science Advisory Council, I provide comments on a wide variety of Defra science-related policies and draw upon both my personal research experience, but also the broader research community at the Roslin Institute
URL https://www.gov.uk/government/organisations/science-advisory-council/about/our-governance#members
 
Description BBSRC-Ireland (SFI) joint funding of research
Amount £651,477 (GBP)
Funding ID BB/P010598/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 07/2017 
End 06/2020
 
Title Bioinformatics pipeline for generation of whole genome sequence data 
Description Development of bioinformatics pipeline that is being used at the National Veterinary Science Laboratory (USDA) in Ames Iowa for generation of data on M. Avium Paratuberuclosis sequences (and use in analysing Johne's Disease outbreak data). 
Type Of Material Improvements to research infrastructure 
Year Produced 2015 
Provided To Others? Yes  
Impact While it is to be used for analysis of disease outbreaks, it is too early to quantify this as yet. 
 
Title Bioinformatics pipeline for generation of whole genome sequence data 
Description Development of bioinformatics pipeline that is being used at the National Veterinary Science Laboratory (USDA) in Ames Iowa for generation of data on M. Avium Paratuberuclosis sequences (and use in analysing Johne's Disease outbreak data).  
Type Of Material Computer model/algorithm 
Year Produced 2015 
Provided To Others? Yes  
Impact It is in active use within USDA-APHIS for handling data from MAP outbreaks, however this outcome is not at this moment quantified. 
 
Description Collaboration with Dr. Suelee Robbe-Austerman USDA-APHIS 
Organisation U.S. Department of Agriculture USDA
Department Animal and Plant Health Inspection Service
Country United States 
Sector Public 
PI Contribution From our project, we aided in the development of bioinformatics tools in partnership with USDA-APHIS that they are using for analysing collected mycobacterial sequences at USDA-APHIS.
Collaborator Contribution Our partners have provided free access to their sequence databases, as well as contextual information and advice.
Impact As a result we have recently submitted a new US-UK EEID proposal (decision pending) that builds on the previous work.
Start Year 2014
 
Description Development of a workshop on Mycobacterial infection transmission 
Organisation Cornell University
Department College of Veterinary Medicine
Country United States 
Sector Academic/University 
PI Contribution With members of my research team, contributed to the development and delivery of a combined symposium/workshop, which provided research insights (in the symposium) and training over 3 days in the workshop, on the use of tools to interpret deep sequence data generated from mycobacteria. The inaugural workshop and symposium was held from May 22nd to 24th 2018, with future iterations intended.
Collaborator Contribution The workshop organisation was led by Wageningen, with contributions from all partners on the development of training materials and delivery of the workshop
Impact The symposium was attended by approximately 80 individuals with a range of backgrounds including academic, professional and government oriented. The workshop/training courses were attended by 50 individuals (in two groups of 25). There is a commitment, subject to further funding, of repeating the workshop/collaboration in future years (expected to occur every two years).
Start Year 2018
 
Description Development of a workshop on Mycobacterial infection transmission 
Organisation University of Wageningen
Country Netherlands 
Sector Academic/University 
PI Contribution With members of my research team, contributed to the development and delivery of a combined symposium/workshop, which provided research insights (in the symposium) and training over 3 days in the workshop, on the use of tools to interpret deep sequence data generated from mycobacteria. The inaugural workshop and symposium was held from May 22nd to 24th 2018, with future iterations intended.
Collaborator Contribution The workshop organisation was led by Wageningen, with contributions from all partners on the development of training materials and delivery of the workshop
Impact The symposium was attended by approximately 80 individuals with a range of backgrounds including academic, professional and government oriented. The workshop/training courses were attended by 50 individuals (in two groups of 25). There is a commitment, subject to further funding, of repeating the workshop/collaboration in future years (expected to occur every two years).
Start Year 2018
 
Description US/UK EEID Project 
Organisation Cornell University
Department Department of Population Medicine and Diagnostic Sciences
Country United States 
Sector Academic/University 
PI Contribution Modelling of Bovine Tuberculosis epidemiology, use of bacterial deep sequencing in phylodynamic analyses
Collaborator Contribution Modelling of Johne's disease epidemioloy, economics models
Impact None as yet
Start Year 2014
 
Description BBSRC, Defra, NC3Rs Bovine tuberculosis Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact This workshop was organized by BBSRC-Defra-NC3Rs in order to bring researchers working on bovine tuberculosis (bTB) together to promote knowledge exchange, networking and to contribute to the development of a number of roadmaps for bTB. I presented a poster entitled "The use of Next Generation Sequencing to understand bovine Tuberculosis transmission in a multi-host system".
Year(s) Of Engagement Activity 2017
 
Description Bovine Tuberculosis Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact The 2015 Bovine Tuberculosis workshop at the University of Glasgow, led by Rowland Kao, engaged with a mix of (primarily) scientists and veterinarians engaged in production of evidence to support policy (including researchers from the UK, Republic of Ireland, Spain, France, the US and New Zealand). It covered cutting edge research themes in modelling, data science, pathogen sequencing and immune-epidemiology & transcriptomics. It helped to spark multiple conversations on the integration of new technologies into bovine Tb control.
Year(s) Of Engagement Activity 2015
URL https://www.gla.ac.uk/researchinstitutes/bahcm/events/headline_415441_en.html
 
Description Bovine Tuberculosis Workshop 2015 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact The 2015 Bovine Tuberculosis workshop at the University of Glasgow, co-organized by Liliana Salvador, engaged with a mix of (primarily) scientists and veterinarians engaged in production of evidence to support policy (including researchers from the UK, Republic of Ireland, Spain, France, the US and New Zealand). It covered cutting edge research themes in modelling, data science, pathogen sequencing and immune-epidemiology & transcriptomics. It helped to spark multiple conversations on the integration of new technologies into bovine Tb control.
Year(s) Of Engagement Activity 2015
URL https://www.gla.ac.uk/research/az/boydorr/meetingsevents/2015-bovinetuberculosis/
 
Description Conference aimed at mixed academic, practitioner and policy-maker audience (Minnesota) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact International conference on One Health research, where I spoke of the potential role of whole genome sequencing as a tool for uncovering complex interactions in pathogens affecting multiple species, and using our ongoing work on bovine Tuberculosis in cattle and badgers as the key exemplar. There was both a short question and answer following my talk, as well as a panel discussion where I, together with a mixed group of speakers discussed the potential for "Science in Action: Big Data Methods and Approaches" - in order to highlight new data approaches that have the potential to shift paradigms in use of science to inform policy and practice. As a result I also had several informal discussions on the potential for whole genome sequencing as a new tool in epidemiology.
Year(s) Of Engagement Activity 2016
URL http://www.wifss.ucdavis.edu/wp-content/uploads/documents/OneHealth/iCOMOSPROGRAMFINAL.pdf
 
Description Ecology and Evolution of Infectious Diseases Conferences 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact I have participated in the International EEID conference where I presented a poster entitled "The use of Whole-Genome-Sequencing to understand bovine Tuberculosis cross-species transmission patterns in Michigan, USA" an gave a lightning talk entitled: "Investigating bacterial transmission at the wildlife/livestock interface using genomic data: bovine tuberculosis in Michigan, USA", in 2016 and 2017, respectively.
Year(s) Of Engagement Activity 2016,2017
URL https://eeid2017.eemb.ucsb.edu/
 
Description Editorial for the Veterinary Record 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I wrote an invited editorial piece for the Veterinary Record, to comment on a published paper on the impact of badger culling. The content of the editorial was a particular paper in the VR, however it was informed by my own research including the linked awards.
Year(s) Of Engagement Activity 2015
URL https://veterinaryrecord.bmj.com/content/177/16/415
 
Description ISVEE conference 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Participation in the 14th Conference of the International Society for Veterinary Epidemiology and Economics: Planning Our Future. I gave a talk entitled: "Estimating bacterial cross-species transmission in Michigan", which was followed by interesting questions and discussion. The participation in this conference also originated a blog post about "Multi-disciplinary interactions under the Mexican sun - reflections from the ISVEE conference" (https://boydorrblog.wordpress.com/2015/12/06/guest-blog-multi-disciplinary-interactions-under-the-mexican-sun-reflections-from-the-isvee-conference/).
Year(s) Of Engagement Activity 2015
URL http://isvee2015.org/
 
Description ISVEE conference talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk at the ISVEE conference aimed at a mix of academics, practitioners/veterinarians and policy-makers. The talk led to further interactions with vets in Brazil's "Embrapa" (Brazilian Agricultural Research Corporation) which has since led to a funded project including Salvador and Kao as advisors.
Year(s) Of Engagement Activity 2015
URL http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=9ea51dca-5c9a-452b-a12f-1b043cc9f51f&cKey...
 
Description Invited Plenary Speaker 'ModAH 2017' 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact The Modelling in Animal Health Symposium held in Nantes, France (June 2017) was a scientific conference that included a mix of academics, professional practitioners (veterinarians) and policy-evidence civil servants. I spoke on the work involved in quantifying the role of cattle in the transmission of bovine Tb (incorporating cattle movements and sequencing data). The talk sparked further conversations with Defra evidence teams about legislation surrounding cattle movement restrictions - further commissioned work from Defra is possibly though as yet not finalised.
Year(s) Of Engagement Activity 2017
URL https://workshop.inra.fr/modah2017/
 
Description Mini-Symposium on Bovine Tuberculosis 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact This symposium, led by Rowland Kao, on the use of integrated of large datasets including pathogen sequence data and its ability to explain 'wicked' problems (i.e. multi-host pathogen systems with biased data) was held, with representatives from Government and researchers across multiple nations (UK, Republic of Ireland, USA, Spain). The discussions prompted increased international collaborations (two ongoing projects) to analyses dense datasets related to bovine Tuberculosis control.
Year(s) Of Engagement Activity 2017
URL https://www.gla.ac.uk/researchinstitutes/bahcm/news/headline_529612_en.html
 
Description Mini-Symposium on bovine tuberculosis 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact This symposium, co-organized by Liliana Salvador, on the use of integrated of large datasets including pathogen sequence data and its ability to explain 'wicked' problems (i.e. multi-host pathogen systems with biased data) was held, with representatives from Government and researchers across multiple nations (UK, Republic of Ireland, USA, Spain). The discussions prompted increased international collaborations (two ongoing projects) to analyses of dense datasets related to bovine Tuberculosis control. Liliana also gave a talk entitled: "Bovine tuberculosis in Michigan: the role of of elk in disease transmission".
Year(s) Of Engagement Activity 2017
URL https://www.gla.ac.uk/researchinstitutes/bahcm/news/headline_529612_en.html
 
Description Presentation to Meeting of the USAHA Tuberculosis Scientific Advisory Subcommittee 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Highlighted uses of modern genetic technology combined with mathematical models to understand tuberculosis epidemiology

Have had several continued email and phone conversations with persons within the USDA and other state organisations regarding this research area.
Year(s) Of Engagement Activity 2013,2014
URL http://www.usaha.org/Portals/6/Committees/tuberculosis/presentations/2014-Palmer-TBSAS.pdf
 
Description TEDx talk - The Science of Networks 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I gave a TEDx talk on the science of networks, including referring to the difficulties of identifying links between communities in multi-host pathogen systems (using bovine Tb as an exemplar) and also the effects of community separation on the polarisation of debate (again using bovine Tb in cattle and badgers as an example).
Year(s) Of Engagement Activity 2017
URL http://tedxuniversityofglasgow.com/speakers