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SUMMARY:Reconciling the discordance between Mendelian randomization studie
 s and the results of recent cardiovascular outcome trials - Dr Brian Feren
 ce\, Wayne State University School of Medicine
DTSTART:20160518T110000Z
DTEND:20160518T120000Z
UID:TALK66234@talks.cam.ac.uk
CONTACT:Narinder Bansal
DESCRIPTION:The drug discovery and development process is increasing being
  focused on developing therapies that attempt to recapitulate the phenotyp
 e of polymorphisms that are associated with the risk of disease.  Mendelia
 n randomization studies play an important role in providing genetic valida
 tion for these potential therapeutic targets.  Indeed\, as new therapies a
 re designed to recapitulate the phenotype of polymorphisms that are associ
 ated with the risk of disease\, in future it is likely that randomized tri
 als will be designed to recapitulate the naturally randomized genetic evid
 ence.  However\, demonstration that the phenotype mediated by a polymorphi
 sm is causally associated with the risk of disease is merely the first ste
 p in accurately anticipating the results of randomized trials designed to 
 evaluate the clinical efficacy these therapies.  Important further steps i
 nclude estimating the quantitative magnitude of the effect of the polymorp
 hism on the risk of disease per unit change in the causal intermediate bio
 marker\; evaluating the effect of the polymorphisms alone and in combinati
 on with polymorphisms that mimic the stand of care using factorial Mendeli
 an randomization\; estimating the effect of short-term exposure to changes
  in the causal intermediate biomarker\; and identifying populations who ar
 e most likely to benefit.  Failure to adequately consider these issues can
  result in unexpected null trial results leading to a discordance between 
 the results of randomized trials and those anticipated by Mendelian random
 ization studies.  We shall illustrate these principles by comparing the re
 sults of Mendelian randomization studies with the results of recent random
 ized trials evaluating statins\, ezetimibe\, PCSK9 inhibitors\, CETP inhib
 itors and fibrates\; and use these principles to propose the optimal trial
  design to evaluate therapies that lower Lp(a).  
LOCATION:Thomas and Dorothy Strangeways Room\, Strangeways Research Labora
 tory\, Wort’s Causeway\, Cambridge\, CB1 8RN
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