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24/7 Automated Behavior
Tracking for Rodent Safety
Pharmacology and
Phenotyping
Sponsored by:
InsideScientific is an online educational environment
designed for life science researchers. Our goal is to aid in
the sharing and distribution of scientific information
regarding innovative technologies, protocols, research
tools and laboratory services.
Thank you to our event sponsor
Presenters:
David Craig
Actual Analytics
dcraig@actualanalytics.com
Sara Wells, PhD
MRC Harwell
s.wells@har.mrc.ac.uk
Will Redfern, PhD
AstraZeneca
will.redfern@astrazeneca.com
24/7 Automated Behavior
Tracking for Rodent Safety
Pharmacology and Phenotyping
David Craig
CEO
Actual Analytics
Copyright 2015 - David Craig, Actual Analytics, and InsideScientific. All rights reserved
Actual Analytics
• Founded in 2010
• Staffed by Ph.D’s in computer vision, machine
learning, neuroscience & biology
• Founded to transform the industry
• Committed to excellent Innovation
contact:
David Craig: dcraig@actualanalytics.com
+44 (0) 7803 162005
The Journey
We have worked with Astra Zeneca and the
MRC under two “Crack-It” projects with the
assistance of the NC3R’s we express our
profound gratitude to all three for their
significant support, engagement and vision.
contact:
David Craig: dcraig@actualanalytics.com
+44 (0) 7803 162005
The Product
ActualHCA (Home Cage Analyser)is the only
product that permits scientists to gather 24x7
data and automated analysis of the complex
behaviours of group housed rodents, identity
retained, in their real home cage, with major
3Rs benefits
contact:
David Craig: dcraig@actualanalytics.com
+44 (0) 7803 162005
Preliminary Validation of a Home
Cage Automated Behavioural
Monitoring System in Rats
Will Redfern
PhD, FSB, FBPhS, DSP
Translational Safety
Drug Safety & Metabolism
AstraZeneca
Copyright 2015 – Will Redfern and InsideScientific. All rights reserved
Disclaimer
The views expressed are those of the presenter and do not necessarily
reflect the views of AstraZeneca plc.
This presentation should not be interpreted as an endorsement of any
technology product mentioned, neither AstraZeneca plc nor the
presenter have any financial or commercial interest with the
manufacturers of any such product, nor is there any other conflict of
interest.
Attrition of candidate drugs during development
Cook et al. (2014) analysed the
causes of failure of candidate
drugs in AstraZeneca during
2005-10 (safety; efficacy;
strategic portfolio decisions).
They found that ~60% of drug
project closures were safety-
related.
David Cook et. al., Lessons learned
from the fate of AstraZeneca’s drug
pipeline: a five-dimensional
framework. Nature Reviews Drug
Discovery (2014) 13: 419-431.
Safety-related
attrition
Attrition due to inadequate safety – Why?
Shortcoming Impact Solution?
1. Lack of early detection of
safety signals
‘Doomed’ compounds enter in vivo toxicology phase
Improve frontloaded screening: in silico
and in vitro
2. Lack of detection of safety
hazards preclinically
‘Doomed’ compounds enter clinical development
Improve quality and increase information
content of safety pharmacology and
toxicology studies
3. Lack of confidence, knowledge,
or precision in preclinical-
clinical translation
Defective risk assessment: ‘Doomed’ compounds
may be let through, anticipating a large safety
margin; ‘safe’ compounds may be stopped,
anticipating an inadequate safety margin.
Improve risk assessment and decision-
making by better understanding of the
translation of the preclinical signals to
humans.
Attrition due to inadequate safety – Why?
Shortcoming Impact Solution?
1. Lack of early detection of
safety signals
‘Doomed’ compounds enter in vivo toxicology phase
Improve frontloaded screening: in silico
and in vitro
2. Lack of detection of safety
hazards preclinically
‘Doomed’ compounds enter clinical development
Improve quality and increase information
content of safety pharmacology and
toxicology studies
3. Lack of confidence, knowledge,
or precision in preclinical-
clinical translation
Defective risk assessment: ‘Doomed’ compounds
may be let through, anticipating a large safety
margin; ‘safe’ compounds may be stopped,
anticipating an inadequate safety margin.
Improve risk assessment and decision-
making by better understanding of the
translation of the preclinical signals to
humans.
*Redfern WS et al. (2013) Functional Assessments in Repeat-dose Toxicity Studies: The Art of the Possible. Toxicology Research 2: 209-234.
Impact of adverse effects of drugs
by organ function throughout the
pharmaceutical life cycle…
The various toxicity domains have been ranked first by contribution to products
withdrawn from sale, then by attrition during clinical development.
Phase
‘Nonclinical’ Phase I Phase I-III Phase III / MKTG Post-Marketing Post-Marketing
Information: Causes of attrition Serious ADRs Causes of attrition ADRs on label Serious ADRs Withdrawal from sale
Source: Car (2006) Sibille et al. (1998) Olson et al. (2000) BioPrint® (2006) Budnitz et al. (2006) Stevens & Baker (2008)
Sample size: 88 CDs stopped 1,015 subjects 82 CDs stopped 1,138 drugs 21,298 patients 47 drugs
Cardiovascular: 27% 9% 21% 36% 15% 45%
Hepatotoxicity: 8% 7% 21% 13% 0% 32%
Haematology/BM: 7% 2% 4% 16% 10% 9%
NERVOUS SYSTEM 14% 28% 21% 67% 39% 2%
Immunotox; photosensitivity: 7% 16% 11% 25% 34% 2%
Gastrointestinal: 3% 23% 5% 67% 14% 2%
Reprotox: 13% 0% 1% 10% 0% 2%
Musculoskeletal: 4% 0% 1% 28% 3% 2%
Respiratory: 2% 0% 0% 32% 8% 2%
Renal: 2% 0% 9% 19% 2% 0%
Genetic tox: 5% 0% 0% 0% 0% 0%
Carcinogenicity: 3% 0% 0% 1% 0% 0%
Other: 0% 0% 4% 16% 2% 2%
Adapted from Redfern WS et al. SOT 2011
1-9% 10-19% >20%0%
  
Studying adverse effects of drugs on the nervous system
• Neuronal-astrocyte co-cultures
• In vitro electrophysiology (ion channels; neurones; slices)
IN VITRO
IN VIVO
POST
MORTEM
• Behavioural/neurological
• Neurophysiological recordings (EEG; ERG; EMG; BAER; nerve conduction velocity)
• Neurochemical (in vivo microdialysis; biomarkers)
• Neuroimaging (MRI; MRS; PET; SPECT)
• Neurohistopathology/ immunohistochemistry
Redfern WS & Wakefield ID (2006)
Safety Pharmacology. In Toxicological
Testing Handbook: Principles,
Applications and Data Interpretation, 2nd
Edn., pp. 33-78, D Jacobson-Kram & K
Keller (eds.). New York: Informa
Healthcare.
Studying adverse effects of drugs on the nervous system
• Neuronal-astrocyte co-cultures
• In vitro electrophysiology (ion channels; neurones; slices)
IN VITRO
IN VIVO
POST
MORTEM
• Behavioural/neurological
• Neurophysiological recordings (EEG; ERG; EMG; BAER; nerve conduction velocity)
• Neurochemical (in vivo microdialysis; biomarkers)
• Neuroimaging (MRI; MRS; PET; SPECT)
• Neurohistopathology/ immunohistochemistry
Redfern WS & Wakefield ID (2006)
Safety Pharmacology. In Toxicological
Testing Handbook: Principles,
Applications and Data Interpretation, 2nd
Edn., pp. 33-78, D Jacobson-Kram & K
Keller (eds.). New York: Informa
Healthcare.
Global nervous system safety assessment:
The Irwin test / Functional Observatory Battery
• A manual, multi-parameter assessment of nervous system function in rodents
• Involves observations in the home cage and in an arena,
as well as manual interaction
• Limited to ‘snapshot’ observations at specified time points pre- and post-dose
Plus: any miscellaneous
observations; body weight gain
overnight post-dose
Redfern WS et al. (2005) J Pharmacol Toxicol Methods 52: 77-82 Ewart L et al. (2013) J Pharmacol. Toxicol. Methods 68: 30-43.
• posture
• gait
• straub tail
• body tone
• ptosis
• exophthalmos
• grip strength
• traction response
• tremor
• twitches
• convulsions
Neurological
Autonomic
• salivation
• acrimation
• piloerection
• abnormal
urination
• abnormal
defaecation
• abnormal
respiration
• pupil size
• rectal temp
• touch response
• palpebral reflex
• startle reflex
• pinna reflex
• righting reflex
Sensorimotor
Behavioural
• arousal
• activity
• vocalisation
• aggressiveness
• Sniffing
• Stereotypy
• rearing
• bizarre behaviour
Locomotor activity
Automated measurement of ambulatory activity and
rearing in a novel arena, usually over 30-60 min.
Habituation to the novelty of the arena occurs during the
monitoring period, and upon re-testing.
• Methodology
- 3 dimensional matrix of infrared beams OR videotracking
- Beam breaks OR videotracking used to quantify movement
- Rats have to be single-housed during the measurement period
• Activity in a novel arena
- Novel environment to measure spontaneous locomotor activity
- Two phases of locomotion: initial exploratory phase
(duration dependent on rat strain/age/conditions) followed by
habituation phase
• Home cage activity
- Home cage: avoids novel environment – no anxiety component
- 24 hour continuous monitoring/circadian rhythms
- Higher activity during dark phase/darkness Redfern WS & Wakefield ID (2006) Safety Pharmacology. In Toxicological Testing
Handbook: Principles, Applications and Data Interpretation, 2nd Edn., pp. 33-78, D Jacobson-
Kram & K Keller (eds.). New York: Informa Healthcare.
Locomotion Activity
Spontaneous Locomotor Activity
Spontaneous locomotor activity in a novel
arena provides 2 levels of baseline activity:
initial high exploratory-related locomotor
activity followed by low baseline activity
due to habituation.
Novelty Phase
- 0 to 10 min of assessment
Habituation Phase
-10 to 30 min of assessment
0
5
10
0 (0-5) (5-10) (10-15) (15-20) (20-25) (25-30)
TotalDistanceMoved(m)
TestTrials(time from startof assessmentinmin)
Spontaneous Locomotor Activity Profile
Control
Habituation
Phase
Novelty
Phase
Asymptotic
Level
Chu A et al. (1999) Proc US Gen Safety Pharmacol Soc
Spontaneous Locomotor Activity Profiles
0
5
10
0 (0-5) (5-10) (10-15) (15-20) (20-25) (25-30)
Test Trials (time from start of assessment in min)
TotalDistanceMoved(m)
Control Sedative
Habituation
Phase
Novelty
Phase
Asymptotic
Level
Spontaneous Locomotor Activity
Chu A et al. (1999) Proc US Gen Safety Pharmacol Soc
Novelty Phase
high baseline activity in this phase
is suitable for the detection of
sedative effects
Spontaneous Locomotor Activity Profiles
0
5
10
0 (0-5) (5-10) (10-15) (15-20) (20-25) (25-30)
Test Trials (time from start of assessment in min)
TotalDistanceMoved(m)
Control Stimulant Sedative
Habituation
Phase
Novelty
Phase
Asymptotic
Level
Spontaneous Locomotor Activity
Novelty Phase
high baseline activity in this phase
is suitable for the detection of
sedative effects
Habituation Phase
drug-induced activity stimulation
becomes readily detectable when
baseline activity is low
Chu A et al. (1999) Proc US Gen Safety Pharmacol Soc
So, is it time
for new
technology?
What if...?
• You could monitor the ambulatory activity of each individual
rat within a group in a standard home cage over 24 hours,
or longer...?
• Also monitor their temperature...?
• Achieve this without surgery...?
• Detect convulsions and other ‘abnormal’ behaviours...?
• Achieve all this without having to modify the home cage...?
• Do this in a standard IVC cage rack, which you could wheel anywhere...?
But how...?
SPONSOR
submits a
technological
challenge
NC3Rs
invites
innovators
to enter the
competition
INNOVATORS
submit proposed
solutions
EXPERT PANEL
selects winning
solutions(s)
NC3Rs
fund
development
project
INNOVATOR,
SPONSOR
AND NC3Rs
deliver the
technological
solution
https://www.crackit.org.uk/
CRACK IT is a funding competition (Challenges) and technology
partnering hub (Solutions) designed to accelerate the
development, application and commercialisation of
technologies with 3Rs potential as they emerge from the
research base.
CRACK IT has been developed to facilitate active collaboration
between the pharmaceutical, chemical and consumer products
industries, contract research organisations, small and medium
enterprises (SMEs) and the academic sector.
• Challenge set by AZ (Will Redfern) in 2011
• Remit was to monitor activity, behaviour and
temperature of individual rats when group-
housed in standard home cages, 24/7, for up to
a month
• Winning solution awarded to Actual Analytics
(Edinburgh)
• Project got underway in 2012
• AZ’s in-kind contribution has been intellectual
input and annotation of video to train the
behavioural recognition software
• Aims also to include detection of convulsions
Rodent Big Brother Project
Automated home cage behavioural monitoring system funded by NC3Rs CRACK IT scheme
Rodent Big Brother Project
Automated home cage behavioural monitoring system funded by NC3Rs CRACK IT scheme
• Positional information and temperature via a
subcutaneous RFID microchip, detected by a
baseplate reader under the cage
• Behaviour captured via a high-res camera using
IR lighting, analysed automatically by
behavioural recognition software
• A prototype system was installed at AstraZeneca
Alderley Park (UK) in 2014
• We are undertaking a full road-testing,
evaluation and pharmacological validation
• Intention is to incorporate into early
investigative toxicology studies in rats
Features of the home cage 24 h monitoring system
RFID chip on fingertip...
...injected subcutaneously
Infrared
lighting panel
IVC home cage Baseplate RFID chip reader
(under home cage)
Side-view
video camera
Mini-computer and
power supply
(Part of)
cage rack
Features of the home cage 24 h monitoring system
VIDEO CAPTURE
• High quality video
capture for manual
analysis by expert
• Automated analysis of
common behaviours by
behavioural recognition
software
• Additional behaviours
can be annotated for
training the software
Infrared
lighting panel
IVC home cage Baseplate RFID chip reader
(under home cage)
Side-view
video camera
Mini-computer and
power supply
(Part of)
cage rack
Features of the home cage 24 h monitoring system
BASEPLATE READER
• Automated acquisition
of ambulatory activity
• Automated acquisition
of subcutaneous
temperature
• RFID data used to ‘ID
tag’ each animal in the
video
Ongoing video annotation and validation work
Manual Annotation of Video
• Capture of light-dark phase
video from different individual
animals
• Careful manual annotation of
individual behaviours to train
behavioural recognition
software
Mechanical Update – Camera Stand-off
• Do all modules capture continuous 24/7
baseplate and video data without drop-
out/crashes?
• Are 24 h activity and temperature data
equivalent between modules?
• Do X-Y data from baseplate tally with manual X-Y
data using ‘bird’s eye view’ camera?
• Do activity and subcutaneous temperature show
a 24 h periodicity?
• Do peaks in baseplate-derived activity data tally
with peaks in automated motion detection?
• Is temperature data accurate?
• Can the system detect changes in temperature
induced by non-pharmacological means
(eg, single-housing rats)?
• Can the system detect changes in activity
induced by non-pharmacological means (eg,
cage change)?
• Can the system detect pharmacologically-
induced changes in activity and temperature?
• Do software-derived behavioural data tally with
manual video analysis?
User Acceptance Testing & Validation
Manual analysis of behaviours in a single rat over 22 h
Performed as part of behavioural annotation of video
Top 10 Most Common Behaviours Measured
Behaviour Number of events
Scratching 593
Rearing 579
Walking 475
Chewing hind paw 334
Licking/chewing coat 298
Immobile 266
Face washing 205
Eating from forepaws 203
Feeding from hopper 190
Drinking 177
• These annotated episodes are being
used to train the behavioural
recognition software. Others will be
added when sufficient episodes have
been captured on video and
annotated.
• Episodes of convulsions will be
captured from an ongoing epileptic
rat model (ie, no additional animals
used).
Manual analysis of behaviours in a single rat over 22 h
Performed as part of behavioural annotation of video
Actigram plot of a single animal over 2 consecutive days
A circadian cycle is evident; work ongoing to verify accuracy of
above data manually.
Group mean temperature and activity data over 3 days
• Data derived via the
baseplate RFID chip
readers over 3
consecutive days
• Six Rats housed in
two cages
(3 rats per cage)
Periodogram showing peak in frequency distribution
of activity at a 24 h frequency
Differences between dark phase and light phase group
mean activity for 3 baseplates (n = 5 rats).
Baseplates
24 h Periodicity of activity data
24 h Periodicity of activity data
Periodogram showing peak in frequency distribution
of activity at a 24 h frequency
Differences between dark phase and light phase group
mean activity for 3 baseplates (n = 5 rats).
Baseplates
Filter algorithms currently being
refined to minimise registering of
micromovements between adjacent
antennae in baseplate during periods
of low ambulatory activity.
Effects of single-housing on subcutaneous temperature
• Decrease in subcutaneous temperature
immediately upon housing singly after
being housed in groups of 3
• Possible causes: group housing or rats
enables intermittent ‘huddling’ with two
cage mates, and may achieve a higher
ambient temperature (with two
additional rats generating heat)
• Illustrates just one of several
physiological stressors associated with
single housing (not to mention the
psychological stressors).
Single vs. Group Housed Rats
Advantages
This is a technological breakthrough.
This data collection wasn’t possible before now...
 Enables continuous 24 h monitoring over days and weeks
 Increases the information content of existing study types
 Animals are housed in social groups
 Non-invasive (other than a subcutaneously injected RFID microchip)
 No modifications to standard housing cages required
 Modules fit inside standard IVC cage rack, so do not require a dedicated room
 Can be incorporated into existing study types (without the use of additional animals)
 Future developments include automated detection of convulsive behaviours
Potential applications
Preclinical Safety Assessment
• The original intent for this technology.
• Can slot into existing study types: safety
pharmacology studies and repeat-dose toxicology
studies
• Will detect the previously undetectable: 24 h
activity, 24 h temperature, 24 h behavioural analysis,
and the occurrence of convulsions outside normal
manual monitoring hours
• Could identify ‘at risk’ individuals to back-up/pre-
warn welfare decision-making
Drug withdrawal phenomena
• Different classes of drugs with dependence potential
cause different patterns of effects on cessation of
treatment. However, these usually include changes
in activity, behaviour, temperature and food intake.
CNS Drug Discovery
• Can slot into existing disease models
• Will detect 24 h activity,
24 h temperature, 24 h behavioural
analysis, and the occurrence of convulsions
outside normal manual monitoring hours
Academic Research: Disease Models
• Various applications -- could identify ‘at risk’ individuals
to back-up welfare decision-making
Academic Research: Circadian Rhythms, Ageing
• Various applications
Academic Research: Phenotyping
• New CRISPR technology opens up the availability of
transgenic rat strains
Acknowledgements
AstraZeneca Alderley Park, Cheshire, UK
Karen Tse
Claire Grant
Dave Simpson
Liz Beard
Karen Sefton
Lauren Leslie (1-year placement student, University of Glasgow)
Victoria Rimmer (1-year placement student, University of Manchester)
NC3Rs London, UK
Kathryn Chapman
Cathy Vickers
Vicky Robinson
Publications to date:
Redfern WS, Armstrong JD, Heward J, Allison B, Lukins T, Grant C, Leslie L, Craig DJ, Vickers C, Chapman K. (2014) Rodent Big Brother: Development and validation of a home cage automated
behavioural monitoring system for use in repeat-dose toxicity studies in rats. Eurotox 50th Annual Congress, Edinburgh, UK.
Leslie L, Armstrong JD, Heward J, Allison B, Lukins T, Sillitto, R, Grant C, Craig DJ, Vickers C, Chapman K, Redfern WS. (2014) Rodent Big Brother: Development and validation of a home cage
automated behavioural monitoring system for use in safety pharmacology studies in rats. Safety Pharmacology Society 14th Annual Meeting, Washington, DC, USA.
Actual Analytics Edinburgh, UK
Douglas Armstrong
David Craig
Tim Lukins
James Heward
Rowland Sillitto
Agis Chartsias
Emma O’Callaghan
University of Strathclyde Glasgow, UK
Judith Pratt
Advancements in Home-Cage
Phenotyping Methods for
Group-Housed Mice
Sara Wells, PhD
Director,
Mary Lyon Centre
MRC Harwell
Copyright 2015 – Sara Wells and InsideScientific. All rights reserved
MRC Harwell
Genetics of Disease
Sponsors
Seeking refinement in the
characterisations of mouse models
NC3Rs
New technologies to support
refinement
Project Funders
Actual Analytics
Technology Specialists
Developers
Using new technologies to
solve difficult problems
 Dynamic and progressive research facility
 Extensive resources for mouse research
 Provide a national and international lead
in laboratory animal science
MRC Harwell : An International Centre for Mouse Genetics
Commitment to Reduction, Refinement and Reproducibility
 Open in 2004 -- Capacity for 55k mice at any
one time
 Significant molecular biology and pathology
capabilities
 Currently running efficiently at full capacity
MRC Harwell : Facts and Figures
In 2014 alone:
 230k regulated procedures
 125 transgenic models
 321 lines exported
MRC Harwell : Facts and Figures
Science-led Service Delivery
Building a comprehensive functional catalogue
of a mammalian genome
The International Mouse
Phenotyping Consortium (IMPC)
www.mousephenotype.org
IMPC – The Context
• The function of the majority of genes in the mouse
(and human) genomes is unknown
• KOs have been generated and analysed in about 35% of mouse genes
• Data for these genes is patchy – dependent on the interests and experience of
the investigator. There is an increased attention on reproducibility and reliability.
• Develop approaches for broad based phenotyping, to provide a comprehensive
picture of disease states and to integrate with human and clinical genetics.
• IRDiRC (rare disease); Biobank;100,000 genomes; MRC Mouse Network
Neuroscience and Medical Research
8,000,000+
people living in the UK
with a neurobehavioural
condition
1,000,000+
people who are
disabled because of
their condition
350,000+
people require help
for most of their
daily activities
(Neurological Alliance)
Using Mice to Research Genes
Mice are widely used in
genetic research
> 95% of mouse genes are similar to humans
Mouse physiology and
anatomy is similar to humans
How Does One Assess Well-Being?
 Digging  Climbing  Nesting
Normal behaviours...
How Does One Assess Well-Being?
How can you measure signs of neurological disease?
How can you measure signs of neurological disease?
 Hyperactivity  Social Isolation
Abnormal behaviours...
 Disrupted Sleep
Measuring Mouse Behaviour
The challenge! It changes during the day! They are active during the night!
Day Night Day Night
Mice like other mice and not new places!
Activity can be
measured by
wheel-running or
video tracking
AnxietyHoused Alone
The environment
of the test can be
stressful
The Challenge!!!
1. Monitor mouse behaviour 24 hours a day
2. In their home-cages
3. With their cage-mates
The Goal:
1. Refine tests by reducing stress factors
2. Gain vital scientific information
3. Record more data from less mice
CRACKIT Program...
Rodent Little Brother
– monitoring groups of mice
without them knowing
• High resolution cameras
and advanced computer
processing
Rodent Little Brother
– monitoring groups of mice
without them knowing
• High resolution cameras
and advanced computer
processing
• RFID chips monitored by
base plates for days and
weeks
Measuring Signs
of Neurological
Disease
• Social isolation
• Hyperactivity/
hypoactivity
• Sleep
disturbances
C3H H males 4 week old (n=9; 3 X 3 boxes) 3 day data.AverageDistance(mm)
Monitoring Complex Behaviours
The Challenge! • Need to automate the system
• Requires computer recognition of specific behaviours
• We need to train the software first
Video Capture Annotation Machine Learning
Future Aims and Targets
Analyse complex behaviours
• Grooming
• Play
• Mating
• Social interactions
Gather much data from individual mice
• Novel behaviours
• No environmental factors
• Unknown to the mouse
Thank You!
For additional information on the ActualHCA
24x7 automated home cage monitoring system,
and other video tracking solutions for
behavioural research please visit:
http://www.actualanalytics.com/
InsideScientific is an online educational environment
designed for life science researchers. Our goal is to aid in
the sharing and distribution of scientific information
regarding innovative technologies, protocols, research
tools and laboratory services.

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24x7 Automated Behavior Tracking For Rodent Safety Pharmacology & Phenotyping

  • 1. 24/7 Automated Behavior Tracking for Rodent Safety Pharmacology and Phenotyping Sponsored by:
  • 2. InsideScientific is an online educational environment designed for life science researchers. Our goal is to aid in the sharing and distribution of scientific information regarding innovative technologies, protocols, research tools and laboratory services.
  • 3. Thank you to our event sponsor
  • 4. Presenters: David Craig Actual Analytics dcraig@actualanalytics.com Sara Wells, PhD MRC Harwell s.wells@har.mrc.ac.uk Will Redfern, PhD AstraZeneca will.redfern@astrazeneca.com
  • 5. 24/7 Automated Behavior Tracking for Rodent Safety Pharmacology and Phenotyping David Craig CEO Actual Analytics Copyright 2015 - David Craig, Actual Analytics, and InsideScientific. All rights reserved
  • 6. Actual Analytics • Founded in 2010 • Staffed by Ph.D’s in computer vision, machine learning, neuroscience & biology • Founded to transform the industry • Committed to excellent Innovation contact: David Craig: dcraig@actualanalytics.com +44 (0) 7803 162005
  • 7. The Journey We have worked with Astra Zeneca and the MRC under two “Crack-It” projects with the assistance of the NC3R’s we express our profound gratitude to all three for their significant support, engagement and vision. contact: David Craig: dcraig@actualanalytics.com +44 (0) 7803 162005
  • 8. The Product ActualHCA (Home Cage Analyser)is the only product that permits scientists to gather 24x7 data and automated analysis of the complex behaviours of group housed rodents, identity retained, in their real home cage, with major 3Rs benefits contact: David Craig: dcraig@actualanalytics.com +44 (0) 7803 162005
  • 9. Preliminary Validation of a Home Cage Automated Behavioural Monitoring System in Rats Will Redfern PhD, FSB, FBPhS, DSP Translational Safety Drug Safety & Metabolism AstraZeneca Copyright 2015 – Will Redfern and InsideScientific. All rights reserved
  • 10. Disclaimer The views expressed are those of the presenter and do not necessarily reflect the views of AstraZeneca plc. This presentation should not be interpreted as an endorsement of any technology product mentioned, neither AstraZeneca plc nor the presenter have any financial or commercial interest with the manufacturers of any such product, nor is there any other conflict of interest.
  • 11. Attrition of candidate drugs during development Cook et al. (2014) analysed the causes of failure of candidate drugs in AstraZeneca during 2005-10 (safety; efficacy; strategic portfolio decisions). They found that ~60% of drug project closures were safety- related. David Cook et. al., Lessons learned from the fate of AstraZeneca’s drug pipeline: a five-dimensional framework. Nature Reviews Drug Discovery (2014) 13: 419-431. Safety-related attrition
  • 12. Attrition due to inadequate safety – Why? Shortcoming Impact Solution? 1. Lack of early detection of safety signals ‘Doomed’ compounds enter in vivo toxicology phase Improve frontloaded screening: in silico and in vitro 2. Lack of detection of safety hazards preclinically ‘Doomed’ compounds enter clinical development Improve quality and increase information content of safety pharmacology and toxicology studies 3. Lack of confidence, knowledge, or precision in preclinical- clinical translation Defective risk assessment: ‘Doomed’ compounds may be let through, anticipating a large safety margin; ‘safe’ compounds may be stopped, anticipating an inadequate safety margin. Improve risk assessment and decision- making by better understanding of the translation of the preclinical signals to humans.
  • 13. Attrition due to inadequate safety – Why? Shortcoming Impact Solution? 1. Lack of early detection of safety signals ‘Doomed’ compounds enter in vivo toxicology phase Improve frontloaded screening: in silico and in vitro 2. Lack of detection of safety hazards preclinically ‘Doomed’ compounds enter clinical development Improve quality and increase information content of safety pharmacology and toxicology studies 3. Lack of confidence, knowledge, or precision in preclinical- clinical translation Defective risk assessment: ‘Doomed’ compounds may be let through, anticipating a large safety margin; ‘safe’ compounds may be stopped, anticipating an inadequate safety margin. Improve risk assessment and decision- making by better understanding of the translation of the preclinical signals to humans. *Redfern WS et al. (2013) Functional Assessments in Repeat-dose Toxicity Studies: The Art of the Possible. Toxicology Research 2: 209-234.
  • 14. Impact of adverse effects of drugs by organ function throughout the pharmaceutical life cycle…
  • 15. The various toxicity domains have been ranked first by contribution to products withdrawn from sale, then by attrition during clinical development. Phase ‘Nonclinical’ Phase I Phase I-III Phase III / MKTG Post-Marketing Post-Marketing Information: Causes of attrition Serious ADRs Causes of attrition ADRs on label Serious ADRs Withdrawal from sale Source: Car (2006) Sibille et al. (1998) Olson et al. (2000) BioPrint® (2006) Budnitz et al. (2006) Stevens & Baker (2008) Sample size: 88 CDs stopped 1,015 subjects 82 CDs stopped 1,138 drugs 21,298 patients 47 drugs Cardiovascular: 27% 9% 21% 36% 15% 45% Hepatotoxicity: 8% 7% 21% 13% 0% 32% Haematology/BM: 7% 2% 4% 16% 10% 9% NERVOUS SYSTEM 14% 28% 21% 67% 39% 2% Immunotox; photosensitivity: 7% 16% 11% 25% 34% 2% Gastrointestinal: 3% 23% 5% 67% 14% 2% Reprotox: 13% 0% 1% 10% 0% 2% Musculoskeletal: 4% 0% 1% 28% 3% 2% Respiratory: 2% 0% 0% 32% 8% 2% Renal: 2% 0% 9% 19% 2% 0% Genetic tox: 5% 0% 0% 0% 0% 0% Carcinogenicity: 3% 0% 0% 1% 0% 0% Other: 0% 0% 4% 16% 2% 2% Adapted from Redfern WS et al. SOT 2011 1-9% 10-19% >20%0%   
  • 16. Studying adverse effects of drugs on the nervous system • Neuronal-astrocyte co-cultures • In vitro electrophysiology (ion channels; neurones; slices) IN VITRO IN VIVO POST MORTEM • Behavioural/neurological • Neurophysiological recordings (EEG; ERG; EMG; BAER; nerve conduction velocity) • Neurochemical (in vivo microdialysis; biomarkers) • Neuroimaging (MRI; MRS; PET; SPECT) • Neurohistopathology/ immunohistochemistry Redfern WS & Wakefield ID (2006) Safety Pharmacology. In Toxicological Testing Handbook: Principles, Applications and Data Interpretation, 2nd Edn., pp. 33-78, D Jacobson-Kram & K Keller (eds.). New York: Informa Healthcare.
  • 17. Studying adverse effects of drugs on the nervous system • Neuronal-astrocyte co-cultures • In vitro electrophysiology (ion channels; neurones; slices) IN VITRO IN VIVO POST MORTEM • Behavioural/neurological • Neurophysiological recordings (EEG; ERG; EMG; BAER; nerve conduction velocity) • Neurochemical (in vivo microdialysis; biomarkers) • Neuroimaging (MRI; MRS; PET; SPECT) • Neurohistopathology/ immunohistochemistry Redfern WS & Wakefield ID (2006) Safety Pharmacology. In Toxicological Testing Handbook: Principles, Applications and Data Interpretation, 2nd Edn., pp. 33-78, D Jacobson-Kram & K Keller (eds.). New York: Informa Healthcare.
  • 18. Global nervous system safety assessment: The Irwin test / Functional Observatory Battery • A manual, multi-parameter assessment of nervous system function in rodents • Involves observations in the home cage and in an arena, as well as manual interaction • Limited to ‘snapshot’ observations at specified time points pre- and post-dose
  • 19. Plus: any miscellaneous observations; body weight gain overnight post-dose Redfern WS et al. (2005) J Pharmacol Toxicol Methods 52: 77-82 Ewart L et al. (2013) J Pharmacol. Toxicol. Methods 68: 30-43. • posture • gait • straub tail • body tone • ptosis • exophthalmos • grip strength • traction response • tremor • twitches • convulsions Neurological Autonomic • salivation • acrimation • piloerection • abnormal urination • abnormal defaecation • abnormal respiration • pupil size • rectal temp • touch response • palpebral reflex • startle reflex • pinna reflex • righting reflex Sensorimotor Behavioural • arousal • activity • vocalisation • aggressiveness • Sniffing • Stereotypy • rearing • bizarre behaviour
  • 20. Locomotor activity Automated measurement of ambulatory activity and rearing in a novel arena, usually over 30-60 min. Habituation to the novelty of the arena occurs during the monitoring period, and upon re-testing.
  • 21. • Methodology - 3 dimensional matrix of infrared beams OR videotracking - Beam breaks OR videotracking used to quantify movement - Rats have to be single-housed during the measurement period • Activity in a novel arena - Novel environment to measure spontaneous locomotor activity - Two phases of locomotion: initial exploratory phase (duration dependent on rat strain/age/conditions) followed by habituation phase • Home cage activity - Home cage: avoids novel environment – no anxiety component - 24 hour continuous monitoring/circadian rhythms - Higher activity during dark phase/darkness Redfern WS & Wakefield ID (2006) Safety Pharmacology. In Toxicological Testing Handbook: Principles, Applications and Data Interpretation, 2nd Edn., pp. 33-78, D Jacobson- Kram & K Keller (eds.). New York: Informa Healthcare. Locomotion Activity
  • 22. Spontaneous Locomotor Activity Spontaneous locomotor activity in a novel arena provides 2 levels of baseline activity: initial high exploratory-related locomotor activity followed by low baseline activity due to habituation. Novelty Phase - 0 to 10 min of assessment Habituation Phase -10 to 30 min of assessment 0 5 10 0 (0-5) (5-10) (10-15) (15-20) (20-25) (25-30) TotalDistanceMoved(m) TestTrials(time from startof assessmentinmin) Spontaneous Locomotor Activity Profile Control Habituation Phase Novelty Phase Asymptotic Level Chu A et al. (1999) Proc US Gen Safety Pharmacol Soc
  • 23. Spontaneous Locomotor Activity Profiles 0 5 10 0 (0-5) (5-10) (10-15) (15-20) (20-25) (25-30) Test Trials (time from start of assessment in min) TotalDistanceMoved(m) Control Sedative Habituation Phase Novelty Phase Asymptotic Level Spontaneous Locomotor Activity Chu A et al. (1999) Proc US Gen Safety Pharmacol Soc Novelty Phase high baseline activity in this phase is suitable for the detection of sedative effects
  • 24. Spontaneous Locomotor Activity Profiles 0 5 10 0 (0-5) (5-10) (10-15) (15-20) (20-25) (25-30) Test Trials (time from start of assessment in min) TotalDistanceMoved(m) Control Stimulant Sedative Habituation Phase Novelty Phase Asymptotic Level Spontaneous Locomotor Activity Novelty Phase high baseline activity in this phase is suitable for the detection of sedative effects Habituation Phase drug-induced activity stimulation becomes readily detectable when baseline activity is low Chu A et al. (1999) Proc US Gen Safety Pharmacol Soc
  • 25. So, is it time for new technology?
  • 26. What if...? • You could monitor the ambulatory activity of each individual rat within a group in a standard home cage over 24 hours, or longer...? • Also monitor their temperature...? • Achieve this without surgery...? • Detect convulsions and other ‘abnormal’ behaviours...? • Achieve all this without having to modify the home cage...? • Do this in a standard IVC cage rack, which you could wheel anywhere...? But how...?
  • 27. SPONSOR submits a technological challenge NC3Rs invites innovators to enter the competition INNOVATORS submit proposed solutions EXPERT PANEL selects winning solutions(s) NC3Rs fund development project INNOVATOR, SPONSOR AND NC3Rs deliver the technological solution https://www.crackit.org.uk/ CRACK IT is a funding competition (Challenges) and technology partnering hub (Solutions) designed to accelerate the development, application and commercialisation of technologies with 3Rs potential as they emerge from the research base. CRACK IT has been developed to facilitate active collaboration between the pharmaceutical, chemical and consumer products industries, contract research organisations, small and medium enterprises (SMEs) and the academic sector.
  • 28. • Challenge set by AZ (Will Redfern) in 2011 • Remit was to monitor activity, behaviour and temperature of individual rats when group- housed in standard home cages, 24/7, for up to a month • Winning solution awarded to Actual Analytics (Edinburgh) • Project got underway in 2012 • AZ’s in-kind contribution has been intellectual input and annotation of video to train the behavioural recognition software • Aims also to include detection of convulsions Rodent Big Brother Project Automated home cage behavioural monitoring system funded by NC3Rs CRACK IT scheme
  • 29. Rodent Big Brother Project Automated home cage behavioural monitoring system funded by NC3Rs CRACK IT scheme • Positional information and temperature via a subcutaneous RFID microchip, detected by a baseplate reader under the cage • Behaviour captured via a high-res camera using IR lighting, analysed automatically by behavioural recognition software • A prototype system was installed at AstraZeneca Alderley Park (UK) in 2014 • We are undertaking a full road-testing, evaluation and pharmacological validation • Intention is to incorporate into early investigative toxicology studies in rats
  • 30. Features of the home cage 24 h monitoring system RFID chip on fingertip... ...injected subcutaneously
  • 31. Infrared lighting panel IVC home cage Baseplate RFID chip reader (under home cage) Side-view video camera Mini-computer and power supply (Part of) cage rack Features of the home cage 24 h monitoring system VIDEO CAPTURE • High quality video capture for manual analysis by expert • Automated analysis of common behaviours by behavioural recognition software • Additional behaviours can be annotated for training the software
  • 32. Infrared lighting panel IVC home cage Baseplate RFID chip reader (under home cage) Side-view video camera Mini-computer and power supply (Part of) cage rack Features of the home cage 24 h monitoring system BASEPLATE READER • Automated acquisition of ambulatory activity • Automated acquisition of subcutaneous temperature • RFID data used to ‘ID tag’ each animal in the video
  • 33. Ongoing video annotation and validation work Manual Annotation of Video • Capture of light-dark phase video from different individual animals • Careful manual annotation of individual behaviours to train behavioural recognition software Mechanical Update – Camera Stand-off
  • 34. • Do all modules capture continuous 24/7 baseplate and video data without drop- out/crashes? • Are 24 h activity and temperature data equivalent between modules? • Do X-Y data from baseplate tally with manual X-Y data using ‘bird’s eye view’ camera? • Do activity and subcutaneous temperature show a 24 h periodicity? • Do peaks in baseplate-derived activity data tally with peaks in automated motion detection? • Is temperature data accurate? • Can the system detect changes in temperature induced by non-pharmacological means (eg, single-housing rats)? • Can the system detect changes in activity induced by non-pharmacological means (eg, cage change)? • Can the system detect pharmacologically- induced changes in activity and temperature? • Do software-derived behavioural data tally with manual video analysis? User Acceptance Testing & Validation
  • 35. Manual analysis of behaviours in a single rat over 22 h Performed as part of behavioural annotation of video Top 10 Most Common Behaviours Measured Behaviour Number of events Scratching 593 Rearing 579 Walking 475 Chewing hind paw 334 Licking/chewing coat 298 Immobile 266 Face washing 205 Eating from forepaws 203 Feeding from hopper 190 Drinking 177 • These annotated episodes are being used to train the behavioural recognition software. Others will be added when sufficient episodes have been captured on video and annotated. • Episodes of convulsions will be captured from an ongoing epileptic rat model (ie, no additional animals used).
  • 36. Manual analysis of behaviours in a single rat over 22 h Performed as part of behavioural annotation of video
  • 37. Actigram plot of a single animal over 2 consecutive days A circadian cycle is evident; work ongoing to verify accuracy of above data manually.
  • 38. Group mean temperature and activity data over 3 days • Data derived via the baseplate RFID chip readers over 3 consecutive days • Six Rats housed in two cages (3 rats per cage)
  • 39. Periodogram showing peak in frequency distribution of activity at a 24 h frequency Differences between dark phase and light phase group mean activity for 3 baseplates (n = 5 rats). Baseplates 24 h Periodicity of activity data
  • 40. 24 h Periodicity of activity data Periodogram showing peak in frequency distribution of activity at a 24 h frequency Differences between dark phase and light phase group mean activity for 3 baseplates (n = 5 rats). Baseplates Filter algorithms currently being refined to minimise registering of micromovements between adjacent antennae in baseplate during periods of low ambulatory activity.
  • 41. Effects of single-housing on subcutaneous temperature • Decrease in subcutaneous temperature immediately upon housing singly after being housed in groups of 3 • Possible causes: group housing or rats enables intermittent ‘huddling’ with two cage mates, and may achieve a higher ambient temperature (with two additional rats generating heat) • Illustrates just one of several physiological stressors associated with single housing (not to mention the psychological stressors). Single vs. Group Housed Rats
  • 42. Advantages This is a technological breakthrough. This data collection wasn’t possible before now...  Enables continuous 24 h monitoring over days and weeks  Increases the information content of existing study types  Animals are housed in social groups  Non-invasive (other than a subcutaneously injected RFID microchip)  No modifications to standard housing cages required  Modules fit inside standard IVC cage rack, so do not require a dedicated room  Can be incorporated into existing study types (without the use of additional animals)  Future developments include automated detection of convulsive behaviours
  • 43. Potential applications Preclinical Safety Assessment • The original intent for this technology. • Can slot into existing study types: safety pharmacology studies and repeat-dose toxicology studies • Will detect the previously undetectable: 24 h activity, 24 h temperature, 24 h behavioural analysis, and the occurrence of convulsions outside normal manual monitoring hours • Could identify ‘at risk’ individuals to back-up/pre- warn welfare decision-making Drug withdrawal phenomena • Different classes of drugs with dependence potential cause different patterns of effects on cessation of treatment. However, these usually include changes in activity, behaviour, temperature and food intake. CNS Drug Discovery • Can slot into existing disease models • Will detect 24 h activity, 24 h temperature, 24 h behavioural analysis, and the occurrence of convulsions outside normal manual monitoring hours Academic Research: Disease Models • Various applications -- could identify ‘at risk’ individuals to back-up welfare decision-making Academic Research: Circadian Rhythms, Ageing • Various applications Academic Research: Phenotyping • New CRISPR technology opens up the availability of transgenic rat strains
  • 44. Acknowledgements AstraZeneca Alderley Park, Cheshire, UK Karen Tse Claire Grant Dave Simpson Liz Beard Karen Sefton Lauren Leslie (1-year placement student, University of Glasgow) Victoria Rimmer (1-year placement student, University of Manchester) NC3Rs London, UK Kathryn Chapman Cathy Vickers Vicky Robinson Publications to date: Redfern WS, Armstrong JD, Heward J, Allison B, Lukins T, Grant C, Leslie L, Craig DJ, Vickers C, Chapman K. (2014) Rodent Big Brother: Development and validation of a home cage automated behavioural monitoring system for use in repeat-dose toxicity studies in rats. Eurotox 50th Annual Congress, Edinburgh, UK. Leslie L, Armstrong JD, Heward J, Allison B, Lukins T, Sillitto, R, Grant C, Craig DJ, Vickers C, Chapman K, Redfern WS. (2014) Rodent Big Brother: Development and validation of a home cage automated behavioural monitoring system for use in safety pharmacology studies in rats. Safety Pharmacology Society 14th Annual Meeting, Washington, DC, USA. Actual Analytics Edinburgh, UK Douglas Armstrong David Craig Tim Lukins James Heward Rowland Sillitto Agis Chartsias Emma O’Callaghan University of Strathclyde Glasgow, UK Judith Pratt
  • 45. Advancements in Home-Cage Phenotyping Methods for Group-Housed Mice Sara Wells, PhD Director, Mary Lyon Centre MRC Harwell Copyright 2015 – Sara Wells and InsideScientific. All rights reserved
  • 46. MRC Harwell Genetics of Disease Sponsors Seeking refinement in the characterisations of mouse models NC3Rs New technologies to support refinement Project Funders Actual Analytics Technology Specialists Developers Using new technologies to solve difficult problems
  • 47.  Dynamic and progressive research facility  Extensive resources for mouse research  Provide a national and international lead in laboratory animal science MRC Harwell : An International Centre for Mouse Genetics Commitment to Reduction, Refinement and Reproducibility
  • 48.  Open in 2004 -- Capacity for 55k mice at any one time  Significant molecular biology and pathology capabilities  Currently running efficiently at full capacity MRC Harwell : Facts and Figures
  • 49. In 2014 alone:  230k regulated procedures  125 transgenic models  321 lines exported MRC Harwell : Facts and Figures Science-led Service Delivery
  • 50. Building a comprehensive functional catalogue of a mammalian genome The International Mouse Phenotyping Consortium (IMPC) www.mousephenotype.org
  • 51. IMPC – The Context • The function of the majority of genes in the mouse (and human) genomes is unknown • KOs have been generated and analysed in about 35% of mouse genes • Data for these genes is patchy – dependent on the interests and experience of the investigator. There is an increased attention on reproducibility and reliability. • Develop approaches for broad based phenotyping, to provide a comprehensive picture of disease states and to integrate with human and clinical genetics. • IRDiRC (rare disease); Biobank;100,000 genomes; MRC Mouse Network
  • 52. Neuroscience and Medical Research 8,000,000+ people living in the UK with a neurobehavioural condition 1,000,000+ people who are disabled because of their condition 350,000+ people require help for most of their daily activities (Neurological Alliance)
  • 53. Using Mice to Research Genes Mice are widely used in genetic research > 95% of mouse genes are similar to humans Mouse physiology and anatomy is similar to humans
  • 54. How Does One Assess Well-Being?
  • 55.  Digging  Climbing  Nesting Normal behaviours... How Does One Assess Well-Being?
  • 56. How can you measure signs of neurological disease?
  • 57. How can you measure signs of neurological disease?  Hyperactivity  Social Isolation Abnormal behaviours...  Disrupted Sleep
  • 58. Measuring Mouse Behaviour The challenge! It changes during the day! They are active during the night! Day Night Day Night
  • 59. Mice like other mice and not new places! Activity can be measured by wheel-running or video tracking AnxietyHoused Alone The environment of the test can be stressful
  • 60. The Challenge!!! 1. Monitor mouse behaviour 24 hours a day 2. In their home-cages 3. With their cage-mates The Goal: 1. Refine tests by reducing stress factors 2. Gain vital scientific information 3. Record more data from less mice CRACKIT Program...
  • 61. Rodent Little Brother – monitoring groups of mice without them knowing • High resolution cameras and advanced computer processing
  • 62. Rodent Little Brother – monitoring groups of mice without them knowing • High resolution cameras and advanced computer processing • RFID chips monitored by base plates for days and weeks
  • 63. Measuring Signs of Neurological Disease • Social isolation • Hyperactivity/ hypoactivity • Sleep disturbances
  • 64.
  • 65. C3H H males 4 week old (n=9; 3 X 3 boxes) 3 day data.AverageDistance(mm)
  • 66. Monitoring Complex Behaviours The Challenge! • Need to automate the system • Requires computer recognition of specific behaviours • We need to train the software first Video Capture Annotation Machine Learning
  • 67. Future Aims and Targets Analyse complex behaviours • Grooming • Play • Mating • Social interactions Gather much data from individual mice • Novel behaviours • No environmental factors • Unknown to the mouse
  • 68. Thank You! For additional information on the ActualHCA 24x7 automated home cage monitoring system, and other video tracking solutions for behavioural research please visit: http://www.actualanalytics.com/
  • 69. InsideScientific is an online educational environment designed for life science researchers. Our goal is to aid in the sharing and distribution of scientific information regarding innovative technologies, protocols, research tools and laboratory services.