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

BioSS and MRI: Computers and Cattle, Statistics and

Sheep

Iain McKendrick

(BioSS Principal Consultant, Animal Health and Welfare)

5th December 2007

Outline

• Introduction to BioSS

• Overview of BioSS consultancy and research at Moredun

• A sample of some of our work: E. coli O157

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.

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

• 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

RERAD funding

• 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

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

Consultancy Team, AHW

• Formal consultancy– Review of experiments or grant proposals

Consultancy Activities

• ‘Advisory’ consultancy– Provision of on-site clinics and follow-up

activities


• ‘Collaborative’ consultancy– Identifying improvements for MRPs, finding

solutions, facilitating knowledge transfer

– Substantial contributions to individual projects

– Blends into research


Example: Dilution Counts

Example: Real Time PCR

• 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

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 as consultants and researchers

Consultancy & 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)

Other Criteria for Research

• Bacterium found in rumen, intestines and faeces of cattle.

• Negligible effect….

Research: E. coli O157

Photo: Stuart Naylor (SAC)

• High human public heath risk– Bloody diarrhoea or haemolytic uraemic

syndrome– Wishaw outbreak, 1996 – Pennington Report, 1997– South Wales,

September 2005.

In Humans…

Photo: BBC News

Research Programme

In vitro Adherence

Experiments and Analysis

Cattle Challenge


Field Study Design and

Analysis

Information about O157 and its epidemiology and hence viability of different control methods

Research Programme

In vitro Adherence


Cattle Challenge



Analysis


MRI & BioSS SAC, MRI & BioSS SAC & BioSS

• 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.

Field Study

Photo: Alex McKendrick

Field Study 2

Proportion of Samples +ve

Frequency

0.900.750.600.450.300.15

40

30

20

10

0

Map: Giles Innocent, Glasgow

• 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.

Experimental Trials

• Multiple experiments exploring the effects of flagella in promoting adherence.

Adhesion Studies

1.E+03

1.E+04

1.E+05

1.E+06

1.E+07

MCI 24 - 1 h MCI 24 - 3 h MCI 25 - 1 h MCI 25 - 3 h

Bacterial Strains and Time

Mea

n a

nd

95%

Co

nfi

den

ce In

terv

al f

or

N

um

ber

of

Ad

her

ing

Bac

teri

a

Photos: Arvind Mahajan, MRI

Research Programme

In vitro Adherence


Cattle Challenge



Analysis


? ??

Research Programme

In vitro Adherence


Cattle Challenge


In vivo Infection Models

Between Animal

Infection Models


Analysis


In vivo Compartmental Model

• Birth/Death/Migration process.

Environmental Pool

rumen abomasum faeces

ingestion

11, 22 , 33 ,

p

1 2

3

• 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.

Ingestion Model

1K

C

KP

D K

Ingestion Process

Mean Population Patterns

• 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.

Assessed Strategies

Effect of Fasting

• 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.

Benefits

• Excess heterogeneity in faeces compartment.

• Experimental trials measure shedding longitudinally in cattle.

• Possible problems with the model.

• Data not particularly suitable for parameterisation.

Problems

• Models growth, advection and diffusion through system.

Continuum Model

x=a x=b

H

Initial Condition:

Left-hand B.C:

Right-hand B.C:

Model Formulation

2

2

x

n

x

nn

t

n

)()0,( 0 xxn

0),0(

x

ntn

0),( tbn

Typical Output

• 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.

Conclusions

• 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.

Next Steps

• 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).

Final Points

• 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)

Acknowledgements

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

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