public domain 1 bel at the heart of pfizer’s systems biology infrastructure openbel workshop april...
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![Page 1: Public Domain 1 BEL at the Heart of Pfizer’s Systems Biology Infrastructure OpenBEL Workshop April 29, 2014 Carol Scalice, Business Partner, Systems Biology](https://reader036.vdocuments.site/reader036/viewer/2022062713/56649cf05503460f949bfe50/html5/thumbnails/1.jpg)
Public Domain
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BEL at the Heart of Pfizer’s Systems Biology Infrastructure
OpenBEL Workshop
April 29, 2014
Carol Scalice,
Business Partner, Systems Biology
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Public Domain
The views presented in this talk do not necessarily represent the views or opinions of Pfizer, Inc. These materials do not represent a guarantee and Pfizer, Inc. is not liable for any attempts to reuse these materials or the concepts contained herein.
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Public Domain
Outline
What have we done with BEL?
What are we working on now and where are we headed?
Q&A
![Page 4: Public Domain 1 BEL at the Heart of Pfizer’s Systems Biology Infrastructure OpenBEL Workshop April 29, 2014 Carol Scalice, Business Partner, Systems Biology](https://reader036.vdocuments.site/reader036/viewer/2022062713/56649cf05503460f949bfe50/html5/thumbnails/4.jpg)
Causal Reasoning with Transcriptional Data(Classic/Omics CRE)
• Input is set of of up- and down-regulated transcripts (e.g., between healthy and disease state).
• Output is set of hypotheses of potential molecular causes consistent with input.
• Basic concept outlined in Pollard et al. (2004).
= potential causal hypothesis
Ziemek, D. (2014) Interpreting genetics and transcriptomics data using the Causal Reasoning Engine.
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Bayes CRE: Contextual Analysis of Hypotheses
• Consider PPARG’s function in immunology and adipogenesis.
• Resulting hypotheses will include qualification of applicable context.
Zarringhalam et al,,Bioinformatics 2013
Ziemek, D. (2014) Interpreting genetics and transcriptomics data using the Causal Reasoning Engine.
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Public Domain
Causal Interaction Query
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Public Domain
Causal Interaction Query
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Public Domain
Proprietary Experimental Results
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[compound] a(PFE-c:nnnnnnn) => g(EGID:11200)
Activation
InhibitionAgonist
BindingIC50 EC50
Antagonist
![Page 9: Public Domain 1 BEL at the Heart of Pfizer’s Systems Biology Infrastructure OpenBEL Workshop April 29, 2014 Carol Scalice, Business Partner, Systems Biology](https://reader036.vdocuments.site/reader036/viewer/2022062713/56649cf05503460f949bfe50/html5/thumbnails/9.jpg)
Public Domain
Outline
What have we done with BEL?
What are we working on now and where are we headed?
Q&A
![Page 10: Public Domain 1 BEL at the Heart of Pfizer’s Systems Biology Infrastructure OpenBEL Workshop April 29, 2014 Carol Scalice, Business Partner, Systems Biology](https://reader036.vdocuments.site/reader036/viewer/2022062713/56649cf05503460f949bfe50/html5/thumbnails/10.jpg)
Precision Medicine: can we find the subset of patients who will respond to a particular drug?
• Most disease are heterogeneous. Can we find better subclasses?
• Given genetics, transcriptional and clinical data can we predict who will respond to treatment?
• Data generation is becoming cheaper and cheaper…
Ziemek, D. (2014) Interpreting genetics and transcriptomics data using the Causal Reasoning Engine.
![Page 11: Public Domain 1 BEL at the Heart of Pfizer’s Systems Biology Infrastructure OpenBEL Workshop April 29, 2014 Carol Scalice, Business Partner, Systems Biology](https://reader036.vdocuments.site/reader036/viewer/2022062713/56649cf05503460f949bfe50/html5/thumbnails/11.jpg)
Use causal knowledgebase to formalize that idea..and use upstream regulators as variables.
• For each patient, compute hypothesis profile as output.
• Each hypothesis gets a posterior probability between 0 and 1 as score.
• Followed by L1-regularized regression.
Hypothesis probability
LPS + 0.99
ERBB2 + 0.6
…
Patient GSM364633(Non-Responder)
Gene Value
t(FOXO1) +1
t(IRF7) -1
…
Patient GSM364633(Non-Responder)
Ziemek, D. (2014) Interpreting genetics and transcriptomics data using the Causal Reasoning Engine.
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Image courtesy of Dexter Pratt, Ideker Labs, UCSD
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NDEx
NDEx
BEL Compiler
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XGMML
XGMML
NDExXGMML
XGMML
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Computational Biology for Drug Discovery
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Questions
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Public Domain
PublicationsCausal Reasoning on Biological Networks: Interpreting transcriptional changesL Chindelevitch, D Ziemek, A Enayetallah, R Randhawa, B Sidders, C Brockel, E Huang
Assessing Statistical Significance in Causal GraphsL. Chindelevitch, P. Loh, A. Enayetallah, B. Berger and D. Ziemek
Modeling the Mechanism of Action of a DGAT Inhibitor Using a Causal Reasoning PlatformA. Enayetallah, D. Ziemek, M. Leininger, R. Randhawa, et al.
Novel Pancreatic Endocrine Maturation Pathways Identified by Genomic Profiling and Causal ReasoningA Gutteridge, JM Rukstalis, D Ziemek, M Tié, L Ji, et al.
Genes contributing to pain sensitivity in the normal population: an exome sequencing studyFMK Williams, S Scollen, D Cao, Y Memari, CL Hyde, B Zhang, B Sidders, D Ziemek, et al.
Molecular causes of transcriptional response: a Bayesian prior knowledge approachK Zarringhalam, A Enayetallah, A Gutteridge, B Sidders, D Ziemek