© 2012 IBM Corporation

Outline

 Background Introduction

 Our Methodology

 Visualization Interface

 Future Works

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© 2012 IBM Corporation

Outline

 Background Introduction

 Our Methodology

 Visualization Interface

 Future Works

3

© 2012 IBM Corporation

Drug Discovery and Development

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Available at http://www.innovation.org/drug_discovery/objects/pdf/RD_Brochure.pdf

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Federsel, Hans-Jrgen. "Handing over the baton: Connecting medicinal chemistry with process R&D." Drug News Perspect 21.4 (2008): 193-199.

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Possible solution to efficacy issue: drug indication prediction (drug repositioning)

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Drug repositioning (also known as Drug repurposing, Drug re-profiling, Therapeutic Switching and Drug re-tasking) is the application of known drugs and compounds to new indications (i.e., new diseases)

The repositioned drug has already passed a significant number of toxicity and other tests, its safety is known and the risk of failure for reasons of adverse toxicology are reduced

Drug Original Intention Reposition Viagra Hypertension Erectile dysfunction

Minoxidil Hypertension Hair loss Wellbutrin Depression Smoking cessation

Wikipedia

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Possible solution to efficacy issue: drug indication prediction (drug repositioning)

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Ashburn, Ted T., and Karl B. Thor. "Drug repositioning: identifying and developing new uses for existing drugs." Nature reviews Drug discovery 3.8 (2004): 673-683.

© 2012 IBM Corporation

Possible solution to safety issue: side effect profile prediction at an early stage   Serious drug side-effects are estimated to be the fourth leading cause of death in US, resulting in 100,000 deaths per year.

  Pharma’s worst nightmare

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Liu, Mei, et al. "Large-scale prediction of adverse drug reactions using chemical, biological, and phenotypic properties of drugs." Journal of the American Medical Informatics Association 19.e1 (2012): e28-e35.

© 2012 IBM Corporation

Potential strong associations between side-effects and indications

  Side-effects and therapeutic effects are clinical phenotypic effects of drug treatment

– They may associate with each other via underlying mechanism (even in cases where the precise pharmacological mechanism is unknown)

  Clinical phenotypic information comes from patients, not tube (in-vitro) or animals (in-vivo)

– Mimics a human phenotypic “assay” – May have less translational issue

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Duran-Frigola, Miquel, and Patrick Aloy. "Recycling side-effects into clinical markers for drug repositioning." Genome Med 4.3 (2012).

The association between drugs and their therapeutic effects measured with different assays. Captured biological complexity increases radially.

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Why Exploring the Associations Between Drug Therapeutic Indications and Side-Effects

Drugs for heart failure possibly cause impotence

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Provide explicit repositioning hypotheses

Provide clear adverse-reaction watch lists

Drugs causing postural hypotension are potential candidates for hypertension

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Outline

 Background Introduction

 Our Methodology

 Visualization Interface

 Future Works

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© 2012 IBM Corporation

Flowchart

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© 2012 IBM Corporation

Data Set

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PubChem: 881 chemical substructures

UniProt Knowledgebase:

775 protein targets

NDF-RT: 719 diseases

SIDER: 1385 side-effects

799 drugs

DrugBank: 1447 FDA-Approved Small-Molecule Drugs

http://astro.temple.edu/~tua87106/druganalysis.html

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Indication Prediction Results

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0.78 0.79 0.8 0.81 0.82 0.83 0.84

AUC

Therapeutic Indication Prediction

Side-Effect Protein Targets Chemical Structure

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Side-Effect Prediction Results

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0.61 0.63 0.65 0.67 0.69 0.71

AUC

Side-Effect Prediction

Indication Protein Targets Chemical Structure

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Association Study

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2×2 contingency table

Fisher's exact test: P-value::7.21E-12 Hypertension and impotence are highly correlated

TI+ TI-

SE+

SE- # Drugs

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Example Associations

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772,344 potential associations

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Outline

 Background Introduction

 Our Methodology

 Visualization Interface

 Future Works

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© 2012 IBM Corporation

Bipartite Graph Representation of Drug Indications and Side-Effects

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Side-effects

Therapeutic Indications

p-value

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Visualization Interface

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http://nancao.org/demos/druggraph/

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Example Clique

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© 2012 IBM Corporation

Outline

 Background Introduction

 Our Methodology

 Visualization Interface

 Future Works

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© 2012 IBM Corporation

Future Works

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How to handle drug combinations?

How to link drug with real world evidence?

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Questions?

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