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!