hERG false positive, negative

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lazy
lazy's picture
hERG false positive, negative

Hi
I see often the term "false / positive" or "false / negative" in hERG assay. What do they mean? My understanding is the following:
False/positive: positive in hERG assay (drug inhibited hERG) but no effect on in vivo study
False/negative: negative in hERG assay (drug no effect on hERG) but QT prolongation in the in vivo study
 

g a
g a's picture
Hi Lazy

Hi Lazy
False positive nad false negative are common statistical terms.......
False Positive means
the error of rejecting the null hypothesis given that it is actually true; e.g., someone is being accused  of a crime that they did not actually commit.
where as False negative is
 the error of failing to reject the null hypothesis given that the alternative hypothesis is actually true; e.g., you commited a crime but court can not prove you guilty.

varsha
varsha's picture
hi lazy.

hi lazy.
False positives and false negatives are terms that accunt for variability that you may see in  in vitro assays, drug screen and so forth.
False positives show an effect in an assay when they do not really affect your protein. False positives could be taken care of by repeating the assay (independent biological replicates, for example) or by doing the screen at least three times. If you do not see the effect in the replicates you may eliminate them as  false positives. You may also check the effect of the drug in a different assay. If the first assay was  inhibition of enzyme activity, the second might be the inhibition of post translation modification or subcellular localization. Depending upon your protein of interest, you may design such an experiment. If you see the effect in both kinds of assays you may be sure of the drug being a true positive
 
False negatives may arise due to lack of co factors in vitro  and you may need to optimize that. in vivo false negatives may arise due to permeability differences. So the drug may be active in an in vitro rxn but not in the cell line or in the animal. In this case you may need to optimize the assay accordingly.
Hope this info helps.
Good luck!
 
 

The FFM
The FFM's picture
Lazy

Lazy
I think you pretty much have your definitions correct
 
False positive - drug blocks hERG but has no torsadogenic propensity in vivo
False negative  - drug is torsadogenic in vivo but does not block hERG.
For the false negatives you will try hard to find one that does not hit other modulators of cardiac repolarization even if they are weak acting on hERG
you will find Pgs 268 - 277 of the book "the hERG cardiac potassium channel Structure, Function and Long QT Syndrome, Novartis Foundation Symposium (Novartis Foundation Symposia)"  very useful
[ISBN-10: 0470021403; ISBN-13: 978-0470021408, Wiley; 1 edition (April 8, 2005)]
The link above should take yo to an excerpt from google books.  Ohterwise get it from your library or purchase it from amazon here www.amazon.com/gp/product/0470021403