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Improving the internal validity of
experiments in focal ischaemia
Malcolm MacleodCentre for Clinical Brain Sciences, University of Edinburgh
1026
1026 interventions in experimental stroke
O’C
olli
ns
et
al A
nn N
euro
l 2006
1026603
1026 interventions in experimental stroke
Tested in focal ischaemia
O’C
olli
ns
et
al A
nn N
euro
l 2006
1026883374
1026 interventions in experimental stroke
Effective in focal ischaemia
O’C
olli
ns
et
al A
nn N
euro
l 2006
1026883550
97 18
1026 interventions in experimental stroke
Tested in clinical trial
O’C
olli
ns
et
al A
nn N
euro
l 2006
1026883550
97 171 3
1026 interventions in experimental stroke
Effective in clinical trial
O’C
olli
ns
et
al A
nn N
euro
l 2006
What’s my problem?
• I want to improve the outcome for my patients with stroke
• To get that, I want to conduct high quality clinical trials of interventions which have a reasonable chance of actually working in humans
• But which of the remaining 929 interventions should I choose?
It’s not just my problem …
“…you will meet with several observations and experiments which, though communicated for true
by candid authors or undistrusted eye-witnesses, or perhaps recommended by your own experience,
may, upon further trial, disappoint your expectation, either not at all succeeding, or at least varying much
from what you expected”
Robert Boyle (1693)Concerning the Unsuccessfulness of Experiments
• One which describes some biological truth in the system being studied
• Internal validity: the extent to which an experiment accurately describes what happened in that model system
• Can be inferred by extent of reporting of measures to avoid common biases
What is a Valid Experiment?
• One which considers all available supporting animal data
• One which considers the likelihood of publication bias
• One which tests a drug under circumstances similar to those in which efficacy has been demonstrated in animal models
What is a Valid Translational strategy?
Potential sources of bias in animal studies
• Internal validityProblem Solution
Selection Bias Randomisation
Performance Bias Allocation Concealment
Detection Bias Blinded outcome assessment
Attrition bias Reporting drop-outs/ ITT analysis
False positive report bias Adequate sample sizes
Aft
er
Cro
ssle
y e
t al, 2
008,
Wach
old
er,
2004
Internal validityDopamine Agonists in models
of PD
Ferg
uso
n e
t al, in d
raft
Internal validityDopamine Agonists in models
of PD
Ferg
uso
n e
t al, in d
raft
Internal validityDopamine Agonists in models
of PD
Ferg
uso
n e
t al, in d
raft
Internal ValidityRandomisation and blinding in studies of
hypothermia in experimental stroke
van d
er
Worp
et
al B
rain
2007
Randomisation
Yes No
Blinded outcome
assessment
Yes NoEffi
cacy
47%39%47%37%
Effi
cacy
Stem cells in experimental stroke
Lees
et
al, in d
raft
Infarct Volume
Internal ValidityRandomisation, allocation concealment and
blinding in studies of Stem cells in experimental stroke
Neurobehavioural score
Lees
et
al, in d
raft
Internal Validity NXY-059
Macl
eod
et
al, 2
008
Internal ValidityAttrition bias
Internal ValidityFalse positive reporting bias
• The positive predictive value of any test result depends on– p (α)– Power (1-ß)– Pre-test probability of a positive result
aft
er
Wach
old
er,
2004
Internal ValidityFalse positive reporting bias
• The positive predictive value of any test result depends on– p (α) (0.05)– Power (1-ß) (0.30)– Pre-test probability of a positive result
(0.50)
Positive predictive value = 0.67i.e. only 2 out of 3 statistically positive studies
are truly positive
aft
er
Wach
old
er,
2004
Chances that data from any given animal will be non-
contributory
Number of animals Power % animals wasted
4 18.6% 81.4%
8 32.3% 67.7%
16 56.4% 43.6%
32 85.1% 14.9%
assume simple two group experiment seeking 30% reduction in infarct volume, observed SD
40% of control infarct volume
Chances of wasting an animal
Number of animals per group
0 10 20 30 40
% a
nim
als
was
ted
0
20
40
60
80
100
BetterWorse
Pre
cisi
on
• All outcomes– 29 publications– 109 experiments– 1596 animals– Improved outcome by 31% (27-35%)
External Validity Publication Bias for FK506
Macl
eod
et
al, JC
BFM
200
5
External Validity Hypertension in studies of NXY-059 in experimental
stroke
Macl
eod
et
al, S
troke
in
pre
ss
Infarct volume:– 9 publications– 29 experiments– 408 animals– 44% (35-53%) improvement
Hypertension:– 7% of animal studies– 77% of patients in the
(neutral) SAINT II study
External Validity Hypertension in studies of tPA in experimental
stroke
Pere
l et
al B
MJ 2007
Comorbidity
“Normal” BP
Effi
cacy
-2%25%
Infarct Volume:– 113 publications– 212 experiments– 3301 animals– Improved outcome by 24% (20-28)
Hypertension:– 9% of animal studies– Specifically exclusion criterion in (positive)
NINDS study
Quality of Translation tPA and tirilazad
• Both appear to work in animals
• tPA works in humans but tirilazad doesn’t
• Time to treatment: tPA:– Animals – median 90 minutes– Clinical trial – median 90 minutes
• Time to treatment: tirilazad– Animals – median 10 minutes– Clinical trial - >3 hrs for >75% of patients
Sena e
t al, S
troke
2007;
Pere
l et
al B
MJ 200
7
Chose your patients – tPA: Effect of time to treatment on
efficacy
Pere
l et
al B
MJ 2007
; La
nce
t 2
004
Publication bias
Randomisation Co-morbidity
bias
Reported efficacy
How much efficacy is left?
26%32% 20% 5%
AnimalStudies
Systematic Review
AndMeta-analysis
• how powerful is the treatment?
• what is the quality of evidence?
• what is the range of evidence?
• is there evidence of a publication bias?
• What are the conditions of maximum efficacy?
Clinical Trial
Summarising data from animal experiments
Resources and acknowledgements
• www.camarades.info/index_files/papers.htm• www.camarades.info/index_files/talks.htm• www.camarades.info/index_files/resources.htm
• Chief Scientist Office, Scotland
• Emily Sena, Evie Ferguson, Jen Lees, Hanna Vesterinen
• David Howells, Bart van der Worp, Uli Dirnagl, Philip Bath
