Translational research: bench to where?

1. 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

2. 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

3. 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

4. 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

5. Translation into clinical research The rate of publishing an RCT or positive RCT decreased after 12-15 yrs had elapsed from the promise RCT Positive RCT

6. 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 • ACE inhibitors/ hypertension (Nature 1980) • Pergolide mesylate/ Parkinson’s disease (Science 1979) • Recombinant IL-2/cancer (JEM 1980) • Alpha 1 antithrypsin/ emphysema (JCI 1981) • Naloxone/ shock treatment (Science 1979) Contopoulos-Ioannidis et al. Am J Med 2003 and Ioannidis JP. J Translational Med 2004

7. Translation of highly promising basic science research into clinical research occurs only sparingly and with considerable time lag What are the problems underlying this attrition?

8. Major postulated problems of current “molecular” research • Small sample sizes • Small effect sizes • Large number of biological factors • Old-epidemiology problems: confounding, misclassification All these result in questionable replication validity

9. Quanta of small effects Ioannidis, Trikalinos, and Khoury, Am J Epidemiol 2006 and Zeggini et al. Science 2007

10. Non-replicated diminishing effects Ioannidis et al, Nature Genetics 2001

12. The other side: don’t give up early… …but don’t give up on anything?

13. Counting fish in the sea of gene-disease associations

14. 12,000,000 interacting variants means… 102085 analyses

15. I need 8 slides to write all the zeros • 1000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000

16. Wisely choosing our targets: “biological plausibility”? • 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.

17. ROC curve of luciferase activity ratios for epidemiological associations for the same gene variants Ioannidis and Kavvoura Genet Med 2006

18. 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

19. Waves of evidence microcosms

20. 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

21. A research finding cannot reach credibility over 50% unless u<Ri.e., bias must be less than the pre-study odds

22. Readily available, available, hidden, and very well hidden data Kyzas, Loizou, Ioannidis. JNCI 2005

23. 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 • Cell: “unusual significance”, “raise provocative questions” • PNAS: “exceptional importance” • EMBO Journal: “manuscripts that deserve urgent publication” • Biochemistry-US: “publication of inconclusive results is discouraged” Ioannidis, J Clin Epidemiol 2007

24. How about from the bedside to the bench:Five scenarios for academic medicine

25. Academia versus/and/or industry Patsopoulos et al. BMJ 2006

26. Potential conflicts in driving translational research Patsopoulos et al. BMJ 2006

27. Brain drain and brain deficit

28. Clinical evidence and burden of disease Swingler et al. BMJ 2003

29. Medicine losing (lost) control of the basic sciences ICRAM, BMJ 2004

30. Mentoring: how to get the best of it? • In many fields <20% of faculty members have had a mentor • Women have an extra difficulty to find mentors • Academics: Solitary individual paths with no parallel

31. Choosing academic medicine for a career? You must be kidding! • Graduate degree or special fellowship with protected time • Mentor role • Start early!! • Interest declines as people progress through clinical training

32. The news from the industry:Few new chemical entities Service. Science 2004

33. In search of blockbusters Service. Science 2004

34. JCI, November 2006

35. The glacial pace of clinical translation Ioannidis, JAMA 2005, Contopoulos-Ioannidis et al. (submitted)

36. Evolution and translation of research findings does not have to be a roundtrip from bench to nowhere PLoS Clinical Trials 2006

37. Learning from the past: suggestions • Promote multidisciplinary communication • There are too many discoveries; we need more replication and more stringent and determined pursuit of replicated research promises • Foster systematic, evidence-based approaches to research. • Acknowledge in earnest the difficulty and even the failures of the scientific enterprise. • Examine what pathways have led to specific successes and failures in translation. • Synthesize evidence systematically from many studies and teams of investigators and anticipate this integration from the design phase of research. • Give credit to original ideas, good quality work and robust methodology rather than to impressive claims and magazine hype.