Accelerating Candidate Gene Discovery through Ontological Indexing of Large Scale Data Repositories

Simon Twigger, Ph.D.

MCW Department ofPhysiology

Human & Molecular Genetics Center

http://rgd.mcw.edu

Meet the client

Rat researchers ask...

What tissue is this gene expressed in?What expression data is known for SD (aka

SD/NHsd, Harlan Sprague Dawley,

Sprague Dawley) rats?

Are any of these genes associated

with my phenotype?Has this gene been seen in the brain?What rat expression studies have

been done on Mammary Cancer(aka breast neoplasms/breast

cancer/cancer of the breast, breast carcinoma...)?

Has anyone done any expression studies using congenic rats?

Biological Data Warehouse

Really important piece of data...

Problem...

WherWhere, e,

what,what,when?when?

+

(one) Solution?

WhereWhere, ,

what,what,when?when?

+

How to create the index?

Examine One by One?

Analysis of anterior pituitary glands of ACI, Copenhagen, and Brown Norway males following treatment with the synthetic estrogen diethylstilbestrol (DES).

Copenhagen = COPBrown Norway = BN

NCBO ontology services

http://bioportal.bioontology.org/annotator

Open Biomedical Annotator

http://www.bioontology.org/wiki/index.php/Annotator_Web_service

• Datasets

• Series• Sample

s

• Datasets

• Series• Sample

s

Initial Ontologies & Workflow

Phase 1Small Scale Testing

http://gminer.mcw.edu/

Initial Test Load:

30 Rat Dataset records (GDS) out of 23632 Series records (GSE) out of 750587 Sample records (GSM) out of 7288

RubyOnRails web application to view data

Parallel Annotation Workflow

Concurrent Annotation Results

August October

Cloud-enabled Workflow?

Results/Demo

Initial Observations - Synonyms

DES

Ept6Searching with synonyms can be great:Ept6 = ACI.COP-(D3Mgh16-D3Rat119)/ShulDES = Diethylystilbestrol

Initial Observations - Synonyms

Searching with synonyms can cause problems:Estrogen-induced pituitary tumorigenesis = EPTEthanolaminephosphotransferase activity = EPT

Initial Observations 2Rat Strain symbols

AT, AN, AS, A, B, CDG (1000 x g)C (˚C)TX (Abbreviation for Texas)

...pituitary gland of the ACI, Copenhagen and Brown Norway Rat.

...16 month-old Sprague-Dawley females that......expression data from female SD rats with access to

lifelong......Strain or Line: F344/NCrl ...

...dahl Salt-sensitive (S) rat and S.R(9)x3A congenic rat....

...kidneys from Dahl salt-sensitive males...

Train classifier on real strain phrases? Look for relevant neighboring terms?

Initial Observations - Anatomy

In GEO recordsIn GEO records Corresponding MA termCorresponding MA termWhite Adipose Tissue White FatBrown Adipose Tissue Brown Fat

Ulnar bone Ulna boneSkeletal Muscle Set of Skeletal Muscle

Anterior Pituitary Anterior Pituitary GlandCalvarial Bone ChondrocraniumLeft Ventricle Heart Left Ventricle

Potential synonyms that could be added to MA

Phase 2All Rat Affy Samples

1 ontology (Anatomy)

0 Rat Dataset records (GDS)479 Series records (GSE)12,012 Sample records (GSM)

Larger scale data load

Targeted Indexing

Mouse AdultGross Anatomy

Ontology

Results/Demo

Linking annotations to data

Tm2d1

RGD1306410

Svs4

Hbb

Scgb2a1

Alb

Tm2d1

RGD1306410

Svs4

HbbScgb2a

1Alb

+

Hbb is_expressed_in rat kidneyTm2d1 is_expressed_in rat kidney

Human (U133, U133v2.), Mouse (430, U74, U95) and Rat (U34a/b/c, 230, 230v2)62,000 samples x ca. 25,000 genes/sample = 1.5B data points

Linking annotations to data

Probeset results on GMiner

Gabdr

Probeset results on GMiner

RDF Data integration

Triple StoreTriple Store

OpenRDF Sesame

Virtuoso Open Source

Rat Genes& xrefs

Probeset toRGD ID

Probesetto MA

Mouse AnatomyOntology

Ongoing•Work on term recognition, strains, etc.

•Evaluation of Probeset-to-Anatomy results

•Curation interface to add additional terms

•RDF formats, Triple Store implementation

•Integrate Strain and tissue results into RGD

Education & Outreach

Meet the student

You!

Heavy ScientificProblem

Ontologies More knowledge

through

education =

bigger lever!

Researchers

Video #3 is being shot this week

Future Videos

Target is the scientist!

• Solve common tasks• Use annotation tools• Evaluate annotations

• Intro to specific ontologies• Interview ontology teams

• Ideas?• What does your community need?

Acknowledgements

• Joey Geiger - Development of GMiner

• Jennifer Smith - Video creation, data curation

• Rajni Nigam - Rat Strain Ontology

• Clement Jonquet - NCBO OBA tools

• Trish Whetzel - Video script feedback

• Mark Musen & NIH Roadmap Initiative - Our Funding!

Links

• http://twigger.hmgc.mcw.edu/ncbo/ Project webpage

• http://gminer.mcw.edu Web application

• http://github.com/mcwbbc/gminer Gminer Code

• http://github.com/simont/MCW-RDF RDFizer code

simont@mcw.edu