Predicting Toxicity -An Unfinished Case Story Ph.d. Student Jeppe Skytte Spicker.
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Transcript of Predicting Toxicity -An Unfinished Case Story Ph.d. Student Jeppe Skytte Spicker.
Predicting Toxicity
-An Unfinished Case StoryPh.d. Student Jeppe Skytte Spicker
Merck’s Estimated loses from Law suits regarding Vioxx:
50 BILLION DOLLARS!!(Jyllands-Posten 14. december 2005, erhverv og Økonomi, side 6)
Drug profiling
Database on “profiles” of
known compounds
Drug profiling
New, unknown compound
Project aims:
1. Make a prediction method or a classifier for toxicity
2. Gain mechanistic insight of toxicity
Assignment (work):
• You have tissue from rats treated with 15 different compounds.
– You have pathology reports on toxicological findings in the rat. – Five of the compounds do not induce a toxic response, the
remaining ten does. – The ten remaining compounds all induces various forms of
toxicity which all manifests as cell death in the liver.
• You have 10 minutes to formulate your approach and some interesting questions. Afterwards we will discuss your suggestions in forum.
Questions:
• Is it possibly to predict? (good performance)• Can I separate subclasses?• How few genes are needed? • (How large is the fold change?)• Do these genes make biological sense?• Can I get any mechanistic insight by putting the
genes into biological context (pathways)?
Approach to classifier:
• Make independent feature selection (t-test/ANOVA)
• KNN LGO (leave group out)
FINDING THE SIGNIFICANT GENES IS ONLY 1% OF THE WORK!
• Find an expert on the biology (It is not a weakness if that expert comes from a completely different planet)
• Make sure that person is (as) interested in the problem (as you) (Identify a win-win situation)
• Ask the person if what you are looking at is interesting and relevant FROM THE VERY BEGINNING!
• Never stop looking for future partners (for collaboration)
Which list do you like?Probe Set ID Gene Title GO Biological Process Description
1368399_a_at plasma glutamate carboxypeptidase proteolysis and peptidolysis peptide metabolism tissue regeneration
1368609_at solute carrier family 10 (sodium/bile acid cotransporter family), member 1
transport sodium ion transport organic anion transport bile acid transport
1371400_at thyroid hormone responsive protein regulation of transcription from RNA polymerase II promoter lipid metabolism
1372306_at ethylmalonic encephalopathy 1 (predicted)
1387053_at flavin containing monooxygenase 1 electron transport transport
1387328_at Cytochrome P450, subfamily IIC (mephenytoin 4-hydroxylase)
electron transport xenobiotic metabolism
Or?Probe Set ID Gene Title GO Biological Process Description
1369983_a_at plasma glutamate carboxypeptidase proteolysis and peptidolysis peptide metabolism tissue regeneration
1003714_at solute carrier family 6 (sodium/bile acid cotransporter family), member 6b
transport sodium ion transport organic anion transport bile acid transport
1603689_at HSP90 (Heat shock protein) response to cellular stress
1337206_at CYP2B6 xenobiotic metabolismlipid metabolism
1053873_at flavin containing monooxygenase 1 electron transport transport
1387328_at Cytochrome P450, subfamily IIC (mephenytoin 4-hydroxylase)
electron transport xenobiotic metabolism
The Mother of Take-Home Messengers:
THE MOST IMPORTANT THING IN DATA ANALYSIS, IS NOT THE
DATA ANALYSIS, BUT THE QUESTION!