Translational research: bench to where? John P.A. Ioannidis Professor and Chairman, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece Professor of Medicine (adjunct), Tufts University School of Medicine, Boston, USA
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Translational research: bench to where? John P.A. Ioannidis Professor and Chairman, Department of Hygiene and Epidemiology, University of Ioannina School.
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Translational research: bench to where?
John P.A. IoannidisProfessor and Chairman, Department of Hygiene and Epidemiology,
University of Ioannina School of Medicine, Ioannina, GreeceProfessor of Medicine (adjunct), Tufts University School of Medicine,
Boston, USA
Definitions
• Translational research = conveying and making use of information from the bench to the bedside and from the bedside to the bench
• The bench should be extended to include the computer and the cyberspace
• The bedside should be extended to include the streets
Translation of major basic science promises
• Medical progress depends on important discoveries from basic biomedical research
We have limited empirical data on: how frequently these promises are materialized reach the stage of clinical application reach the stage of routine clinical use what is the time frame for this translation
Highly-promising basic science publications
25, 190 articles (published in 1979-1983 in Nature, Science, Cell, JEM, JCI, JBC)
562 articles (retrieved key word search)
153 potentially eligible articles (full text)
101 original articles that made clear promises for immediate clinical translation
The rate of publishing an RCT or positive RCT
decreased after 12-15 yrs had elapsed from the promise
Translation into clinical research
RCT Positive RCT
Current Licensed Clinical Use
Of the 27 technologies that had a published RCT:
only 5 (actually 4) are in licensed clinical use one 1 is in wide clinical use
• Just in the year 2002 studies were published addressing the relationship of the APOE epsilon polymorphism with familial Alzheimer’s disease; sporadic Alzheimer’s disease; colorectal cancer; fatty liver; atherosclerosis; hyperlipidemia; acute ischemic stroke; spina bifida; coronary artery disease; normal tension glaucoma; hypertension; Parkinson’s disease, diabetic nephropathy; pre-eclampsia; hepatitis C-related liver disease; cerebrovascular disease; coronary artery disease post-renal transplantation; non-specified cognitive impairment; childhood nephrotic syndrome; spontaneous abortion; multiple sclerosis; alcohol withdrawal; cognitive dysfunction after coronary artery surgery; alcoholic chronic pancreatitis; alcoholic cirrhosis; macular toxicity from chloroquine; macular edema; aortic valve stenosis; vascular dementia; type II diabetes mellitus; and migraine.
ROC curve of luciferase activity ratios for epidemiological associations for the same
gene variants
0,0 0,2 0,4 0,6 0,8 1,0
0,0
0,2
0,4
0,6
0,8
1,0
Ioannidis and Kavvoura Genet Med 2006
Invoking external evidence in support: too perfectly agreeable to be true
• We screened 46 studies on microarrays addressing major cancer outcomes in humans
• We scrutinized the comments made in the discussion regarding external evidence that supported or was against the findings of specific genes or groups thereof in the identified molecular signatures
• Supportive comments outnumbered comments against the research findings by 9 to 1 (270 vs. 29)
• 17% of the comments did not even pertain to the same gene as found in the study
• 53% did not pertain even to the same disease
Ioannidis, Polyzos and Trikalinos Eur J Cancer 2007
Waves of evidence
microcosms
Post-study odds of a true finding are small
• When effect sizes are small
• When studies are small
• When field are “hot” (many furtively competitively teams work on them)
• When there is strong interest in the results
• When databases are large
• When analyses are more flexible Ioannidis JP. PLoS Medicine 2005
A research finding cannot reach credibility over 50% unless
u<R
i.e., bias must be less than the pre-study odds
Readily available, available, hidden, and very well hidden data
Kyzas, Loizou, Ioannidis. JNCI 2005
What do we want after all?
• The written editorial policies of the 25 most-cited journals ask routinely for novelty, importance and significance as criteria for acceptance of manuscripts; only one (JAMA) mentions the need to discuss limitations