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.

http://www.europhenome.org/


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

umbe

r of L

ines

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

0

100

200

300

400

500

600


Data in Europhenome

• 502Lines

•2,505

• 30,276 Mice

HMGU MRC_Harwell WTSI ICS CMHD0

20

40

60

80

100

120

140

Centre

Num

ber o

f Alle

les w

ith P

heno

type

dat

a in

EP


Number of Lines with significant annotations by Procedure

Dysmorp

hology

Non-Inva

sive b

lood pressu

re

Calorim

etry

Simplifi

ed IP

GTTDEX

AX-Ray

Open-field

Modified SH

IRPA

Grip-St

rength

Rotarod

Acoustic S

tartle

&PPI

Hot Plat

e

Indirect

ophthalmosco

py

Slit La

mp

Clinica

l Chem

istry

Haemato

logy

FACs A

nalysis

Immunoglo

bulin

Heart w

eight/ti

bia len

gth

Fasted

Clinica

l Chem

istry

Body Weig

ht0

10

20

30

40

50

60

70

80

90

100


EUROPHENOME (Gene Search)

An International Centre for Mouse Genetics www.europhenome.org








PHENOTYPE SEARCH







PHENOMAP









XRAYS




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

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









MPI2

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


Documents

Mining phenotype databases to identify mouse models of clinical relevance