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Motivation
• Lokey lab - cancer research (therapeutics)
• Wet lab experiments:– Knock out genes with RNAi– Treat cells with camptothecin (DNA
damaging agent)– See if cells proceed with cell division or not
Stuff we had to start with
• List of genes known to be involved in the DNA damage checkpoint pathway (Scott, Josh, and Gene Ontology)
• Chemical sensitivity data from yeast (Boone Lab, UToronto)– Synthetic lethal interactions with DNA damaging
agents camptothecin and hydroxyurea– Genes ranked on scale of 0-3 (not sensitive - most
sensitive)
Strategy
• Start with a list of genes known to be involved in the pathway
• Utilize existing recommender programs to find additional candidates for the pathway
• Incorporate results from the different programs along with chemical sensitivity data to find the best overall candidates
Multi-species network analysis
Results were a little harder to deal with…
…leaving them out for now…
What I did
• Ran MSGR with queries:1. Known DNA damage checkpoint genes
2. Genes most sensitive to camptothecin
3. Genes most sensitive to hydroxyurea
• Combined p-values from all tests to get an overall p-value for each gene
• Ranked all returned genes by overall p-value
How to tell if my results make any sense?
• Look at known DNA-damage checkpoint genes returned– Rank– Total number
• Number of knowns returned is maximized by combining all three tests
Sensitivity of Combined Methods by P-Value
0
0.1
0.2
0.3
0.4
0.5
0.6
0.00E+00
1.00E-05
2.00E-05
3.00E-05
4.00E-05
5.00E-05
6.00E-05
7.00E-05
8.00E-05
9.00E-05
1.00E-04
P-Value
Sen
sit
ivit
y Known+Camptothecin+HydroxyureaKnown+CamptothecinKnown+HydroxyureaCamptothecin+HydroxyureaKnown DNA Damage-onlyCamptothecin-onlyHydroxyurea-onlyMSGR combined query
Precision of Combined Methods by P-Value
0
0.05
0.1
0.15
0.2
0.25
0.00E+00
1.00E-05
2.00E-05
3.00E-05
4.00E-05
5.00E-05
6.00E-05
7.00E-05
8.00E-05
9.00E-05
1.00E-04
P-Value
Pre
cis
ion
Known+Camptothecin+Hydroxyurea
Known+Camptothecin
Known+Hydroxyurea
Camptothecin+Hydroxyurea
Known DNA Damage-only
Camptothecin-only
Hydroxyurea-only
MSGR combined query
Conclusion
• Combining the MSGR results from the three queries leads to higher sensitivity but lower precision
• Single query with known DNA damage checkpoint genes seems to have best combination of precision and sensitivity