Download What is a pathway?

Bayesian Factor Modelling for Omics Data
Analysis to Drug Treatments
Naruemon Pratanwanich (Ploy)
and Pietro Lio’
28 Oct 2014
Outline
• Introduction:
– Why pathway-based analysis ?
– Current tool
• Our approach: Bayesian factor modelling
• Results: comparison with state-of-the-art methods
• Applications:
– Drug repositioning
– Disease comorbidity
– Tissue comparative study
Naruemon Pratanwanich (Ploy)
Email: np394@cam.ac.uk
INTRODUCTION
Why pathway-based analysis ?
Current tool
Naruemon Pratanwanich (Ploy)
Email: np394@cam.ac.uk
What is a pathway?
Naruemon Pratanwanich (Ploy)
Email: np394@cam.ac.uk
Why pathway-based analysis ?
List of DE genes
• BRCA1
• MIR151A
• SMIM2
• ASAP1-IT1
• FGF14
Pathway profile
• GnRH signalling pathway
• Caffeine metabolism
• MAPK signaling pathway
 Each pathway is individually interpretable
 Dimension reduction
 Clarification for one gene – multiple pathways
Naruemon Pratanwanich (Ploy)
Email: np394@cam.ac.uk
BRCA1 functions in
multiple pathways
BRCA1
BRCA1
Fanconi anemia pathway
Naruemon Pratanwanich (Ploy)
PI3K-Akt signaling pathway
Email: np394@cam.ac.uk
Why pathway-based analysis ?
List of DE genes
• BRCA1
• MIR151A
• SMIM2
• ASAP1-IT1
• FGF14




Pathway profile
• GnRH signalling pathway
• Caffeine metabolism
• MAPK signaling pathway
Each pathway is individually interpretable
Dimension reduction
Clarification for one gene – multiple pathways
Modest change detection
Naruemon Pratanwanich (Ploy)
Email: np394@cam.ac.uk
Current tool
Gene set enrichment analysis (GSEA)
Do not take pathway dependency into account
GSEA
p-value = ?
Broad Institute
2005
One sample and one pathway at a time !
Naruemon Pratanwanich (Ploy)
Email: np394@cam.ac.uk
OUR APPROACH
Bayesian factor modelling
Naruemon Pratanwanich (Ploy)
Email: np394@cam.ac.uk
Drug treatments
Disease perturbations
A
B
Naruemon Pratanwanich (Ploy)
Email: np394@cam.ac.uk
Gaussian Markov
Random Fields
Naruemon Pratanwanich (Ploy)
Email: np394@cam.ac.uk
Assumptions
• Perturbation
→ Certain pathways
→ Gene expression levels
• Association strengths between genes and
pathways are different
• Pathways are NOT independent
Naruemon Pratanwanich (Ploy)
Email: np394@cam.ac.uk
Naruemon Pratanwanich (Ploy)
Email: np394@cam.ac.uk
Naruemon Pratanwanich (Ploy)
Email: np394@cam.ac.uk
Naruemon Pratanwanich (Ploy)
Email: np394@cam.ac.uk
Naruemon Pratanwanich (Ploy)
Email: np394@cam.ac.uk
RESULTS
Comparison with state-of-the-art methods
using a set of known drug-pathway pairs from
an external database
Naruemon Pratanwanich (Ploy)
Email: np394@cam.ac.uk
drug i
drug j
drug i
drug j
Most probable
responsive pathways
Pathway rank profiles
Naruemon Pratanwanich (Ploy)
Email: np394@cam.ac.uk
drug i
drug j
drug i
drug j
Most probable
responsive pathways
Pathway rank profiles
Naruemon Pratanwanich (Ploy)
Email: np394@cam.ac.uk
Bad: Drugs with a few pathways
Good: Drugs with many pathways
Naruemon Pratanwanich (Ploy)
Email: np394@cam.ac.uk
APPLICATIONS OF
PATHWAY NETWORK
Disease comorbidity
Drug repositioning
Tissue comparative study
Naruemon Pratanwanich (Ploy)
Email: np394@cam.ac.uk
Disease comorbidity
Hepatitis B
Thyroid
cancer
FCεRI
NF-κB
Naruemon Pratanwanich (Ploy)
Email: np394@cam.ac.uk
Drug repositioning
Colorectal
cancer
Naruemon Pratanwanich (Ploy)
GnRH
Email: np394@cam.ac.uk
Tissue comparative analysis
MCF7 – Breast cancer
PC3 – Prostate cancer
DE genes
Compare
FcƐRI
NF-κB
FcƐRI
Crosstalks
NF-κB
Compare
Rank 10th
Naruemon Pratanwanich (Ploy)
Rank 11,765th
Email: np394@cam.ac.uk
Conclusions
• Identify pathway responsiveness and pathway crosstalks
• Generate informative hypothesis related to molecular
processes based on pathways
• Future issues: sign flipping, interaction within pathways
Naruemon Pratanwanich (Ploy)
Email: np394@cam.ac.uk
Confirm that pathways are not independent !
FacPad
Our
method
Naruemon Pratanwanich (Ploy)
GSEA
Email: np394@cam.ac.uk
Naruemon Pratanwanich (Ploy)
Email: np394@cam.ac.uk
Naruemon Pratanwanich (Ploy)
Email: np394@cam.ac.uk