Mining phenotype databases to identify mouse models of clinical relevance

An International Centre for Mouse Genetics

MINING PHENOTYPE DATABASES TO IDENTIFY MOUSE MODELS OF CLINICAL RELEVANCEMichelle Simon and Ann-Marie Mallon

Introduction

• Introduction – EUMODIC

• EuroPhenome (www.europhenome.org)• EMPRESS (European Mouse Phenotyping Resource of Standardised Screens) )• Data capture procedure.• Data display / Website.• Other phenotyping portals – Sanger mouse portal, K312 Portal

• IMPC • Overview of IMPC• MPI2 Consortium • Informatics Plans

• Worked Example.

• Tasks.

INTRODUCTION - EUMODIC

• EUMODIC • Pilot project to phenotype 500 mouse mutants using standardised

pipelines called EMPReSSlim (battery of simple tests to detect defects in as many body systems as possible)

• e.g. SHIRPA, Clinical Chemistry etc• Actual phenotype measurements are captured

INTRODUCTION – EUMODIC (II)

• Partners• MRC Harwell UK • Institut Clinique de la Souris France • Helmholtz Zentrum München Germany • The Wellcome Trust Sanger Institute UK • CMHD, Canada

• Each clinic has its own version of the phenotyping pipelines

• EuroPhenome (www.europhenome.org)• Raw and automatically annotated phenotype data from high

throughput projects such as EUMODIC

EuroPhenome Data Capture

SOPs Definition

Defining data Standards

Data Capture in LIMS

Data Export to Centralised DB

Validation and QC

EMPRESS (EUROPEAN MOUSE PHENOTYPING RESOURCE OF STANDARDISED SCREENS)

EMPRESS

• Experimental Procedures designed by Scientists

• Standard operating procedures (SOPs).

• SOPs stored in EMPReSS RDBMS

• Standardised Mouse Phenotyping (across centres and consortiums)• Defined measured parameters with bounds• Defined derived parameters• Environmental and other Metadata recorded• Ontology Annotation (Mammalian Phenotype and Entity Quality

PATO approaches)

EMPRESS

http://empress.har.mrc.ac.uk/• Comprehensive database of standardised phenotyping protocols.

Search procedures

EMPRESS

Four different phenotyping pipelines

Procedures

EMPReSS

Unique Empress Identifier

Different Parameters

Measurement types and

increments

Ontology Annotation - Mammalian Phenotype

EMPReSS SLIM, Primary Phenotyping Screen

21 different procedures

Phenotype Data Capture

Automatic data annotation of significant phenodeviants with MP ontology terms

EuroPhenome Data Annotation Model

Mutant Cohort

Data for 1 parameter or derived parameter

Compared to the control cohort or running baseline control

Statistical Analysis (Mann U

Whitney/T-test or

Fishers Exact)

Mean, SD, SE and P

value calculated

If P value is significant

annotate with MP term from

EMPReSS which is assigned to

that parameter

Stored in Annotati

on Database

EUROPHENOME STATISTICSN

r of L

Sep-08

Nov-08

Jan-09

Mar-09

May-09

Jul-09

Sep-09

Nov-09

Jan-10

Mar-10

May-10

Jul-10

Sep-10

Nov-10

Jan-11

Mar-11

May-11

Jul-11

Sep-11

Nov-11

Jan-12

Mar-12

May-12

Data in Europhenome

• 502Lines

•2,505

• 30,276 Mice

HMGU MRC_Harwell WTSI ICS CMHD0

Centre

f Alle

Number of Lines with significant annotations by Procedure

Dysmorp

hology

Non-Inva

sive b

lood pressu

Calorim

Simplifi

GTTDEX

AX-Ray

Open-field

Modified SH

Grip-St

rength

Rotarod

Acoustic S

tartle

Hot Plat

Indirect

ophthalmosco

Slit La

Clinica

l Chem

Haemato

FACs A

nalysis

Immunoglo

Heart w

eight/ti

bia len

Fasted

Clinica

l Chem

Body Weig

EUROPHENOME (Gene Search)

An International Centre for Mouse Genetics www.europhenome.org

PHENOTYPE SEARCH

PHENOMAP

SANGER MOUSE PORTAL

http://www.sanger.ac.uk/mouseportal

International Mouse Phenotyping Consortium (IMPC)

IMPC 22 Academic, Government Institutes

MRC Harwell (Steve Brown, current Chair Steering Comm.; Tom Weaver)

Sanger Institute (Allan Bradley, Dave Adams, Karen Kennedy)

NIH KOMP2 BASH, Baylor (Monica Justice) DTCC (UC Davis (Kent Lloyd), TCP,

Charles River, Children’s Hospital Oakland RI)

Jackson Lab (Karen Svenson) Toronto Centre for Phenogenomics (Colin

McKerlie) Helmholtz Zentrum Munich (Martin Hrabe de

Angelis) Institut Clinique de la Souris (Yann Herault) Australian Phenomics Network (Adrienne

McKenzie) RIKEN BioResource Center (Yuichi Obata) MARC (Xiang Gao) CNR (Glauco Toccinni Valentini) EBI (Paul Flicek)

Secretariat (Mark Moore, Executive Director; Joerg Rossbacher)

FUNDERS MRC (Nathan Richardson, Clare

Newland) NIH (Jane Peterson, Eric Green, Jim

Battey, Colin Fletcher, Martin Guyer) Wellcome Trust (Michael Dunn, Clare

McVicker) Infrafrontier (Martin Hrabe de

Angelis) Genome Canada (Cindy Bell) European Commission (Observer

status) Canadian Institutes of Health

Research, CIHR (Jane Aubin)

What is IMPReSS?

• IMPReSS: International Mouse Phenotyping Resource of Standardised Screens

• Launched Tue 13th March 2012• The successor of EMPReSS - Inherits historical Pipelines, adds IMPC

Pipeline• New architecture, new site, plus some more features

IMPReSS – IMPC Pipeline

• Adult pipeline agree and embryonic pipeline in development

Key Concepts: 3Ps

Pipeline

Procedure

MeasuredParameter

MetadataParameter

3Ps have unique identifiers, Keys, e.g: IMPC_001_001_005_001

contains

Ontology Associations

• Ontology Associations• Structured, controlled vocabulary used worldwide by scientists to

describe phenotypes and beyond• Various Collections but MP is popular• Predefined option choices for high throughput ontology annotation

• Procedure: Open Field– Measured Parameter: Distance Travelled

» MP:0001399 - Hyperactivity » MP:0001402 - Hypoactivity » MP:0003313 - Abnormal locomotor activation

• Can compare baselines against mutants by ontologies associated with the mice to identify phenotypes and variations and can also QC submitted data

An International Centre for Mouse GeneticsHomepage http://www.mousephenotype.org/impress

Component Owner Partners

Project Management, Reporting and Community Outreach

EBI Harwell/Sanger

Tracking Database Sanger Harwell

SOP and Pheno-DCC Harwell Sanger

Annotation Pipelines Harwell Sanger/EBI

Central Data Archive EBI Sanger/Harwell

Web Portal EBI Sanger/Harwell

New Homepage for IMPC Portalhttp://www.mousephenotype.org/

Basic Search Functionality added

• Displays subset of iMITS data• Many planned improvements ahead

• download entire gene list• register for gene of interest• will link to IMPC phenotype data as available

Mining phenotype databases to identify mouse models of clinical relevance

Documents

Transcript of Mining phenotype databases to identify mouse models of clinical relevance

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