Leo Brueggeman, Daniel Himmelstein, Sergio Baranzini
http://slides.com/leoo/lincs#/
Drugs
Symptoms
Side Effects
http://www.lincscloud.org/
How to best define set of genes affected by a drug?
Perturbagen
Gold Signatures
Non-gold Signatures
(replicable and distinct)
MCF7:6H
NEU:6H
MCF7:24H
NEU:24H
Consensus Signature
*Signature is array of probe-wise z scores
A
A
B
B
C
C
D
D
E
E
A
A
B
B
C
C
D
D
E
E
A = 0.59
B = 0.43
C = 0.40
D = 0.60
E = -0.2
------------
total = 1.84
A
A
B
B
C
C
D
D
E
E
A = 0.59
B = 0.43
C = 0.40
D = 0.60
E = -0.2
------------
total = 1.84
A = 0.59/1.84 = .32 x Sig A
B = 0.43/1.84 = .23 x Sig B
C = 0.40/1.84 = .21 x Sig C
D = 0.60/1.84 = .32 x Sig D
E = -0.20/1.84 = -.10 x Sig E
total = 1.0
-----------------
A
A
B
B
C
C
D
D
E
E
A = 0.59
B = 0.43
C = 0.40
D = 0.60
E = -0.2
------------
total = 1.84
A = 0.59/1.84 = .32 x Sig A
B = 0.43/1.84 = .23 x Sig B
C = 0.40/1.84 = .21 x Sig C
D = 0.60/1.84 = .32 x Sig D
E = -0.20/1.84 = -.10 x Sig E
total = 1.0
-----------------
Consensus
Signature
(sum weighted signatures)
http://www.drugbank.ca/
DrugBank Drug
Consensus Signature
Perturbagen A
Perturbagen B
Gold Sig's A
Gold Sig's B
Variation within the data:
Correlation between transcriptional profiles treated by the same drug varies widely
Number of gold signatures per drug varies between 0 and ~ 1000
Question: Do drugs with more gold signatures have fewer significant genes?
There are 72 cell lines represented in the gold signatures
There are 72 cell lines represented in the gold signatures
MCF7: breast carcinoma (m)
VCAP: prostate carcinoma (m)
A549: lung non small cell carcinoma
PC3: prostate carcinoma (m)
HA1E: immortalized normal kidney
HCC535: lung carcinoma
A375: melanoma
HT29: colon adenocarcinoma
HEPG2: liver carcinoma
There are 72 cell lines represented in the gold signatures
prostate carcinoma (m)
immortalized normal kidney
melanoma
prostate carcinoma (m)
liver carcinoma
lung carcinoma
lung non small cell carcinoma
breast carcinoma (m)
colon adenocarcinoma
muscle myoblast
primary adipocyte stem cell
iPSc differentiated neurons
iPSc differentiated neural progenitors
Number of LINCS perturbagens mapped to each DrugBank drug varies between 1 and 7
Question: Where on 'correlation continuum' do merged perturbagens lie?
0
0.3
0.15
Unrelated Perturbagens
Merged Perturbagens
Identical Perturbagens
Question: Where on 'correlation continuum' do merged perturbagens lie?
0
0.3
0.15
Unrelated Perturbagens
Merged Perturbagens
Identical Perturbagens
DB07
DB04
Pert D
Pert E
[0.05]
Pert D Signatures
Pert E Signatures
Pert D Consensus
Pert E Consensus
Question: Where on 'correlation continuum' do merged perturbagens lie?
0
0.3
0.15
Unrelated Perturbagens
Merged Perturbagens
Identical Perturbagens
DB01
Pert A B C
[ 1 , 0.5, 0.4]
[ 0.5, 1, 0.1 ]
[ 0.4, 0.1, 1 ]
DB07
DB04
Pert D
Pert E
[0.05]
Pert D Signatures
Pert E Signatures
Pert D Consensus
Pert E Consensus
Question: Where on 'correlation continuum' do merged perturbagens lie?
0
0.3
0.15
Unrelated Perturbagens
Merged Perturbagens
Identical Perturbagens
DB01
Pert A B C
[ 1 , 0.5, 0.4]
[ 0.5, 1, 0.1 ]
[ 0.4, 0.1, 1 ]
DB07
DB04
Pert D
Pert E
[0.05]
DB09
Pert F
Pert D Signatures
Pert E Signatures
Pert D Consensus
Pert E Consensus
Pert F Sig Subset 2
Pert F Sig Subset 1
[0.3]
Pert F-2 Consensus
Pert F-1 Consensus
Number of LINCS perturbagens mapped to each DrugBank drug varies between 1 and 7
Correlation
Application of LINCS Data