Controversy In Pharmacogenomics - Harvard University...Alejandra M. De Jesús-Soto, Mark R....
Transcript of Controversy In Pharmacogenomics - Harvard University...Alejandra M. De Jesús-Soto, Mark R....
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Controversy In Pharmacogenomics Alejandra M. De Jesús-Soto, Mark R. Ruprecht, Patricia Vera-González
Principal Investigator: Rafael Irizarry, PhD Graduate Assistant: William Townes, MS
Harvard T.H. Chan School of Public Health
Summer Program in Biostatistics & Computational Biology
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Outline
● Background and Introduction
● Analysis and Comparison of Results
● Takeaway/Conclusion
● Future Work
● Acknowledgements
● References
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Precision Medicine
“Doctors have always recognized that every patient is unique,
and doctors have always tried to tailor their treatments as best
they can to individuals. You can match a blood transfusion to a
blood type — that was an important discovery. What if
matching a cancer cure to our genetic code was just as easy,
just as standard? What if figuring out the right dose of medicine
was as simple as taking our temperature?” - President Obama, January 30, 2015
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Great Insight...
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… Only one problem
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Obtaining Samples
Cell Lines
Biological Replicates
● Retrieve and genetically transform cell cultures derived from various tissue
● Expose samples to drugs ● Record Drug Response
(sensitivity) ● Quantify the
effectiveness of the drug (does it work?)
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How They Did It... ● 471 cell lines shared between both data sets for 64 gene mutations
● Compared drug sensitivity between CGP and CCLE for 15 drugs
● IC50: Drug concentration necessary to inhibit 50% of growth
Drugs by Study
Haibe-Kains et al. (2013)
Cell Lines by Study
Haibe-Kains et al. (2013) Barretina, J. et al. (2012).
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Close But not Quite... ● Ranked the response of the 471 shared cell lines and computed the Spearman’s
rank correlations for the IC50 values.
moderate correlation r = 0.61 ·
fair correlation r = 0.53
Haibe-Kains, et al. (2013). Haibe-Kains, et al. (2013).
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Our Interpretation of The Problem
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Fig 1. IC50 value correlations between datasets by cell line and across drug.
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Haibe-‐Kains et al. (2013) -‐-‐ Left Our results -‐-‐ Right
Fig 2. IC50 value comparisons between our analysis and Haibe-‐Kains et al. (2013).
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Comparison between Spearman Correlation Coefficients
Fig 3. Scatterplot of drug IC50 value correlations comparing ours and the literature’s.
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Fig 4. IC50 value distributions by dataset.
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-log1
0[IC
.50]
(CC
LE)
-log10[IC.50] (CGP)
Fig 5. Adjusted IC50 value correlations by cell line and across drug.
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Correlation table across studies 2
*Adj = Adjusted
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“8”
Barretina, J. et al. (2012)
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0 2 4 6 8
−20
−10
05
Cell Line Raw Data
Dose Level (in uM)
% G
row
th In
hibi
tion
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−8 −6 −4 −2 0 2
−20
−10
05
Drug Ineffective
log2(Dose)
% G
row
th In
hibi
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0% Inhibition
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0 2 4 6 8
−80
−60
−40
−20
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Cell Line Raw Data
Dose Level (in uM)
% G
row
th In
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−8 −6 −4 −2 0 2
−80
−60
−40
−20
0
Drug Effective
log2(Dose)
% G
row
th In
hibi
tion
IC50 Line
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Genomic features
Biomarkers for specific drugs
Takeaway/Conclusion
Heavy (63%)
censorship 1185/1878 Cell Lines
Clinical Trials
Challenges in pharmacogenomic
analyses
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Future Work
Obtain gene expressions of both studies from raw .CEL Riles
Compare genomic features between studies across all cell lines
Better statistical summary of the curves for drug responses
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Acknowledgments ● Dana-Farber Cancer Institute ● Rafael Irizarry, PhD ● William Townes, MS ● Summer Program in Biostatistics and
Computational Biology ● Jessica Boyle, Heather Mattie, Olivia Orta Dr. Rebecca Betensky ● Harvard T.H. Chan School of Public Health
#SPB
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References Barretina, Caponigro, Stransky et al. The Cancer Cell Line Encyclopedia enables predictive
modelling of anticancer drug sensitivity. Nature. 2012 Mar 28;483(7391):603-7. doi: 10.1038/nature11003.
Garnett, Mathew J., et al. "Systematic identification of genomic markers of drug sensitivity in cancer cells." Nature 483.7391 (2012): 570-575.
Haibe-Kains, Benjamin, et al. "Inconsistency in large pharmacogenomic studies." Nature 504.7480 (2013): 389-393.
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Controversy In Pharmacogenomics Alejandra M. De Jesús-Soto, Mark R. Ruprecht, Patricia Vera-González
Principal Investigator: Rafael Irizarry, PhD Graduate Assistant: William Townes, MS
Harvard T.H. Chan School of Public Health
Summer Program in Biostatistics & Computational Biology
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Dichotomization of IC50 Values by Drug 3