9 What is translational medicine? From: Institute of Translational Medicine, University of Texas Medical Branch
10 Animal data in stroke There are huge amounts of often confusing data Systematic review can help to make sense of itIf you select extreme bits of the evidence you can “prove” either harm or substantial benefitHowever, if you have a precise and highly significant overall effect, then it is probably realHypothermia: a systematic search identified 277 experiments in 3353 animalsBetterWorseVan der Worp et al, 2007
12 Potential sources of bias in animal studies Internal validityExternal validityPublication biasAre the models we use good models?Co-morbiditiesProblemSolutionSelection BiasRandomisationPerformance BiasAllocation ConcealmentDetection BiasBlinded outcome assessmentAttrition biasReporting drop-outs/ ITT analysisAre animal experiments falsely positive?Are clinical trials falsely negative?Do animal studies not model human disease with sufficient fidelity to be useful?
13 Blinded outcome assessment Internal Validity Randomisation and blinding in studies of hypothermia in experimental strokeBlinded outcome assessmentYesNoEfficacy è47%39%Randomisation37%Infarct Volume101 publications222 experiments3256 animalsImproved outcome by 43.5% ( )Are animal experiments falsely positive?Are clinical trials falsely negative?Do animal studies not model human disease with sufficient fidelity to be useful?Van der Worp et al, 2007
14 Internal Validity NXY-059 Infarct Volume11 publications29 experiments408 animalsImproved outcome by 44% (35-53%)Macleod et al, 2008
15 The File Drawer problem Publication bias worsebetter
16 External Validity Publication Bias for FK506 All outcomes29 publications109 experiments1596 animalsImproved outcome by 31% (27-35%)PrecisionWorseBetterMacleod et al, 2005
18 Publication bias in experimental stroke Only 11/525 publications (2.2%) reported no significant treatment effectsTrim and Fill suggested ~16% (214/1573) of experiments remain unpublishedBest estimate of magnitude of problemObserved efficacy 31.3% ( )Adjusted efficacy 23.8% ( )
19 How much efficacy is left? Publication biasRandomisationCo-morbidity bias
20 There are many other sources of bias (Sacket, 1979) Tidying up biasRepeated peaks biasSignificance biasBogus control biasHot stuff biasSelective reporting biasExcluding inconvenient outliersAdd a coupleStatistical v biological significanceBogus control bias - dropping out of treatment group on grounds of severity
21 Current performance against key quality items RandomisationBlinded Outcome AssessmentSample Size calculationStroke36%29%3%
22 How does stroke compare? RandomisationBlinded Outcome AssessmentSample Size calculationStroke36%29%3%MND31%20%<1%AD15%25%0%PD12%EAE8%Glioma14%
23 Internal validity in PD models Blinded outcome assessmentComposite qualityRooke et al, submitted
24 Estimates of affinity at cannabinoid receptors McPartland et al 2007
26 Conclusions We could, and should, do a lot better Other diseases could do much much betterLike any other process, the processes of translational medicine can be studied, systematically and methodically
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