BioSS and MRI: Computers and Cattle, Statistics and Sheep Iain McKendrick (BioSS Principal Consultant, Animal Health and Welfare) 5th December 2007
Jan 15, 2016
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
Consultancy Activities
• ‘Collaborative’ consultancy– Identifying improvements for MRPs, finding
solutions, facilitating knowledge transfer
– Substantial contributions to individual projects
– Blends into research
Consultancy Activities
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
Experiments and Analysis
Field Study Design and
Analysis
Information about O157 and its epidemiology and hence viability of different control methods
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
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
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
? ??
Research Programme
In vitro Adherence
Experiments and Analysis
Cattle Challenge
Experiments and Analysis
In vivo Infection Models
Between Animal
Infection Models
Field Study Design and
Analysis
Information about O157 and its epidemiology and hence viability of different control methods
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