TY - JOUR
T1 - A combined pre-clinical meta-analysis and randomized confirmatory trial approach to improve data validity for therapeutic target validation
AU - Kleikers, Pamela W. M.
AU - Hooijmans, Carlijn
AU - Goeb, Eva
AU - Langhauser, Friederike
AU - Rewell, Sarah S. J.
AU - Radermacher, Kim
AU - Ritskes-Hoitinga, Merel
AU - Howells, David W.
AU - Kleinschnitz, Christoph
AU - Schmidt, Harald H. H. W.
PY - 2015/8/27
Y1 - 2015/8/27
N2 - Biomedical research suffers from a dramatically poor translational success. For example, in ischemic stroke, a condition with a high medical need, over a thousand experimental drug targets were unsuccessful. Here, we adopt methods from clinical research for a late-stage pre-clinical meta-analysis (MA) and randomized confirmatory trial (pRCT) approach. A profound body of literature suggests NOX2 to be a major therapeutic target in stroke. Systematic review and MA of all available NOX2(-/y) studies revealed a positive publication bias and lack of statistical power to detect a relevant reduction in infarct size. A fully powered multi-center pRCT rejects NOX2 as a target to improve neurofunctional outcomes or achieve a translationally relevant infarct size reduction. Thus stringent statistical thresholds, reporting negative data and a MA-pRCT approach can ensure biomedical data validity and overcome risks of bias.
AB - Biomedical research suffers from a dramatically poor translational success. For example, in ischemic stroke, a condition with a high medical need, over a thousand experimental drug targets were unsuccessful. Here, we adopt methods from clinical research for a late-stage pre-clinical meta-analysis (MA) and randomized confirmatory trial (pRCT) approach. A profound body of literature suggests NOX2 to be a major therapeutic target in stroke. Systematic review and MA of all available NOX2(-/y) studies revealed a positive publication bias and lack of statistical power to detect a relevant reduction in infarct size. A fully powered multi-center pRCT rejects NOX2 as a target to improve neurofunctional outcomes or achieve a translationally relevant infarct size reduction. Thus stringent statistical thresholds, reporting negative data and a MA-pRCT approach can ensure biomedical data validity and overcome risks of bias.
U2 - 10.1038/srep13428
DO - 10.1038/srep13428
M3 - Article
C2 - 26310318
SN - 2045-2322
VL - 5
JO - Scientific Reports
JF - Scientific Reports
M1 - 13428
ER -