BioSS and MRI: Computers and Cattle, Statistics and Sheep Iain McKendrick

1. BioSS and MRI: Computers and Cattle, Statistics and Sheep Iain McKendrick (BioSS Principal Consultant, Animal Health and Welfare) 5th December 2007

2. Outline • Introduction to BioSS • Overview of BioSS consultancy and research at Moredun • A sample of some of our work: E. coli O157

3. BioSS organisation • Staff (38 in total) based at, or regularly visiting • Kings Buildings, Edinburgh • the SEERAD Main Research Providers • (MRI, SCRI, RRI, MLURI, SAC) The role of BioSS is to deliver high-quality consultancy, training and research in statistics, mathematical modelling and bioinformatics.

4. BioSS organisation • BioSS activities fall into three inter-linked categories: • Consultancy • in support of the 4 research programmes • externally funded consultancy • Research • within 3 RERAD funded research themes • externally funded research • Knowledge Transfer • user-friendly software • training for scientists • postgraduate research & training • institute-led KT

5. RERAD funding • 3% of the RERAD research budget is for BioSS to “support RERAD’s research programme through specialist advice and training, and to provide research in statistics and biomathematics” • To support Programmes 1-4: £600K for consultancy £465K for research

6. Consultancy Team, AHW • Iain McKendrick (Principal Consultant; MRI) • Sarah Brocklehurst (SAC/MRI) • Ian Nevison (SAC) • Jill Sales (MRI) • Mintu Nath (MRI/SAC) • Fraser Lewis (SAC) • Other expertise available within BioSS

7. Consultancy Team, AHW • Iain McKendrick (Bacteriology) • Sarah Brocklehurst (Virology & Animal Welfare) • Ian Nevison (Experimental Design) • Jill Sales (Parasitology) • Mintu Nath (Breeding and Sustainable Systems) • Fraser Lewis (Diagnostic Tests) • BioSS staff now on-site at MRI for 4½ days per week

8. Consultancy Activities • Formal consultancy • Review of experiments or grant proposals

9. Consultancy Activities • ‘Advisory’ consultancy • Provision of on-site clinics and follow-up activities

10. Consultancy Activities • ‘Collaborative’ consultancy • Identifying improvements for MRPs, finding solutions, facilitating knowledge transfer • Substantial contributions to individual projects • Blends into research

11. Example: Dilution Counts

12. Example: Real Time PCR

13. Consultancy & Research • Consultancy • Application of existing statistical and mathematical methods • Research • Modification of existing techniques • Development of new methodology • Overlap between consultancy and research • Work to a standard publishable in international journals

14. Consultancy & Research • Research is applied to an Moredun problem • identified via consultancy where existing methodology is seen as inadequate • Research has to be strategic • of sufficient importance to be worth the use of resources • of sufficient generality to be publishable • Research underpins consultancy • Consultancy links the stats/maths and biological/veterinary research areas • We aim for all BioSS scientific staff to work both asconsultantsandresearchers

15. Other Criteria for Research • Research should fit within one of the three BioSS research themes • Statistical methodology • Statistical bioinformatics • Process and systems modelling • BioSS staff have, or can acquire, the necessary expertise • Funding is available (from SG, or elsewhere)

16. Research: E. coli O157 • Bacterium found in rumen, intestines and faeces of cattle. • Negligible effect…. Photo: Stuart Naylor (SAC)

17. In Humans… • High human public heath risk • Bloody diarrhoea or haemolytic uraemic syndrome • Wishaw outbreak, 1996 • Pennington Report, 1997 • South Wales, September 2005. Photo: BBC News

18. Research Programme In vitro Adherence Experiments and Analysis Cattle Challenge Experiments and Analysis Field Study Design and Analysis Information about O157 and its epidemiology and hence viability of different control methods

19. Research Programme MRI & BioSS SAC, MRI & BioSS SAC & BioSS In vitro Adherence Experiments and Analysis Cattle Challenge Experiments and Analysis Field Study Design and Analysis Information about O157 and its epidemiology and hence viability of different control methods

20. Field Study • Cross-sectional study of 12-30 month old beef cattle on 952 farms. • 7.9% (6.5%, 9.6%) of these animals are shedding. • With 95% confidence, at least 20% of groups of cattle contain shedding animals. Photo: Alex McKendrick

21. Field Study 2 Map: Giles Innocent, Glasgow

22. Experimental Trials • Data from 11 calves. • Experimentally challenged with huge dose (109 colony forming units). • Faeces sampled regularly post-challenge. • Data from post-mortem sampling along gastro-intestinal tract.

23. Adhesion Studies • Multiple experiments exploring the effects of flagella in promoting adherence. Photos: Arvind Mahajan, MRI

24. Research Programme In vitro Adherence Experiments and Analysis Cattle Challenge Experiments and Analysis Field Study Design and Analysis ? ? ? Information about O157 and its epidemiology and hence viability of different control methods

25. Research Programme In vitro Adherence Experiments and Analysis Cattle Challenge Experiments and Analysis Field Study Design and Analysis Between Animal Infection Models In vivo Infection Models Information about O157 and its epidemiology and hence viability of different control methods

26. rumen abomasum faeces ingestion Environmental Pool In vivoCompartmental Model • Birth/Death/Migration process.

27. Ingestion Model • Doubly stochastic Poisson process • Underlying process reflecting contact of animal with contaminated faeces. • D: density, a function of the environmental pool. • K: aggregation parameter,value of 8 derived from literature.

28. Ingestion Process

29. Mean Population Patterns

30. Assessed Strategies • Inhibitory probiotics & bacteristatic antibiotics • Reductions in birth rate. • Bactericidal antibiotics & probiotics • Increases in death rate. • Fasting of animals • Change in pH leads to higher birth rate in rumen.

31. Effect of Fasting

32. Benefits • Evaluation of scenarios which would be difficult and expensive to run experimentally. • Could avoid use of animals in initial experiments. • Informs future biological and veterinary research.

33. Problems • Excess heterogeneity in faeces compartment. • Experimental trials measure shedding longitudinally in cattle. • Possible problems with the model. • Data not particularly suitable for parameterisation.

34. H x=b x=a Continuum Model • Models growth, advection and diffusion through system.

35. Model Formulation Initial Condition: Left-hand B.C: Right-hand B.C:

36. Typical Output

37. Conclusions • Some evidence for qualitative differences between two different strains of O157. • Diffusion coefficient particularly variable. • Lack of fit • Zero counts • Curve constrained to stay too high for too long. • Consistent with colonisation (zero advection) for some bacteria in some animals.

38. Next Steps • Adapt models to allow in vivo colonisation. • Parameterisation to draw on MRI adhesion experiments • Use in vivo model parameter estimates in new between-animal model, where unknown parameters are estimated using survey data.

39. Final Points • BioSS consultancy and research activities both add value to MRI and SAC research. • Our work would lack focus without collaboration with MRI and SAC scientists. • Enormous synergies accrue from BioSS’ position outside any particular research group/organisation/programme. • I look forward to continued collaboration, both on Programme 2 activities and others (EPIC).

40. Acknowledgements • Scottish Government (RERAD) • Joanna Wood (BioSS; BBSRC) • George Gettinby, Douglas Speirs (Strathclyde) • Barti Synge, George Gunn, Chris Low and Stuart Naylor (SAC; RERAD, Defra, Wellcome) • David G.E. Smith, Arvind Mahajan (MRI; RERAD) • The IPRAVE consortium • Giles Innocent (Glasgow; Wellcome)