EMBL-EBI Powerpoint Presentation

21.11.2012
5
Visualising Molecular Interactions
(Standards and Formats)
Sandra Orchard
EMBL-EBI
EBI is an Outstation of the European Molecular Biology Laboratory.

Who wants to use interaction data?
1. Protein biochemists studying one or a family of protein –
detail orientated, down to specific residues at interacting
interfaces
2. Cell biologists – interested in processes, pathways, and
additional interactions → new biology. Often interested in
binding domains.
3. Network biologists – tend to want coverage rather than
accuracy
2

What are the issues with interaction data?
1. Users tend not to understand the data – if they see
A – B
this will be interpreted as a direct, experimentally
verified interaction.
2. Users do not take data confidence into account –
will naively regard all data as of equal strength

Interaction Databases
Deep Curation
IntAct – active curation, broad species coverage, all molecule types
MINT – active curation, broad species coverage, PPIs
DIP – active curation, broad species coverage, PPIs
MatrixDB – active curation, extracellular matrix molecules only
MPACT - ceased curation, limited species coverage, PPIs
BIND – ceased curating 2006/7, broad species coverage, all
molecule types – information becoming dated
Shallow curation
BioGRID – active curation, limited number of model organisms
HPRD – ? active curation, human-centric, modelled interactions
MPIDB – active curation, microbial interactions, soon to be closed,
data to IntAct

Why are data standards essential
• Prior to 2003, many databases= many formats. Onus on
the user to reformat when merging data
• File conversion inevitably leads to data loss
• Many formats compromised tool development – each tool
developed tended to be database specific
5

HUPO-PSI
• Global representative body for MS proteomics
• Initiated multi-lab tissue profiling studies – data
incompatibility between groups compromised
comparability
• MS and MI interactions standards developed to enable
these comparisons
6

What constitutes a PSI standard
• Documents that make up each individual standard
• Minimal reporting requirements => MIAPE document
• XML Data exchange format
• Domain-specific controlled vocabulary

MIMIx

PSI-MI standard format
• XML schema, tab-delimited option (MITAB) and
detailed controlled vocabularies
• Jointly developed by major data providers:
BIND, CellZome, DIP, GSK, HPRD, Hybrigenics, IntAct, MINT, MIPS, Serono, U. Bielefeld, U.
Bordeaux, U. Cambridge, and others
• PSI-MI XML Version 1.0 published in February 2004
The HUPO PSI Molecular Interaction Format - A community standard for the representation of
protein interaction data.
Henning Hermjakob et al, Nature Biotechnology 2004, 22, 176-183.
• Version 2.5/MITAB2.5 published in October 2007
Broadening the Horizon – Level 2.5 of the HUPO-PSI Format for Molecular Interactions;
Samuel Kerrien et al. BioMed Central. 2007.
9

PSI-MI standard format benefits
• Collecting and combining data from different sources
has become easier
• Standardized annotation through PSI-MI ontologies
• Tools from different organizations can be chained,
e.g. analysis of IntAct data in Cytoscape.
Home page
http://www.psidev.info/MI
10

PSIMITAB Extended Columns
+
+
2.5 2.6 2.7
11
MITAB2.5 columns (15):
• ID(s) interactor A & B
• Alt. ID(s) interactor A & B
• Alias(es) interactor A & B
• Interaction detection
method(s)
• Publication 1st author(s)
• Publication Identifier(s)
• Taxid interactor A & B
• Interaction type(s)
• Source database(s)
• Interaction identifier(s)
• Confidence value(s)
MITAB2.6 columns (+21):
• Experimental role(s) A&B
• Biological role(s) A&B
• Properties (CrossReference) A&B
• Type(s) of interactors A&B
• HostOrganism
• Expansion method(s)
• Annotations A&B
• Parameters
• Creation/update date
• Checksums A, B & interaction
• Negative
MITAB2.7 columns (+6):
• Features A&B
• Stoichiometry A&B
• Participant detection
method A&B

PSI-MI XML3.0?
• New data stretching the format to its limits
• Cooperative binding – e.g. allostery
• Dynamic data, captured over a series of time points, [agonist] etc
Need to indicate ordered series of events – currently can be
achieved as a hack.
Discussion topic for 2013 PSI-MI meeting (April, Liverpool)
www.psidev.info
Will aim for backward compatibility,
12

Using interaction data
• Data from IMEx databases is richly annotated – much of
this is not used in network analysis
• As model organism interactomes move to completeness,
data quality may become more of an issue than quantity
• Passage of data from
Primary databases → compilation databases → analysis tools
results in loss of information
•May wish to rethink pipelines to ensure more
sophisticated user requirements are met
13

Cell cycle – Arabidopsis thalia

www.ebi.ac.uk/ols
Controlled
vocabularies

Additional benefits
• MITAB format – released 2007 by popular demand. Tab-delimitated
organisation of data.
• PSICQUIC – query access that runs across all interaction databases
using PSI formats
• Interaction confidence – it becomes possible to score interactions
across multiple databases
• Access to R Bioconductor statistics packages
• Growth industry in “composite” databases – do no new curation but
merge the output of resources producing data in PSI format.
• IMEx

PSICQUIC
• Proteomics Standards Initiative Common QUery InterfaCe.
• Community effort to standardise the way to access and retrieve data
from Molecular Interaction databases.
• Widely implemented by independent interaction data resources.
• Based on the PSI standard formats (PSI-MI MITAB) - PSICQUIC-view
and PSICQUIC webservices now support MITAB 2.6 and 2.7
• Not limited to protein-protein interactions, also e.g.
• Drug-target interactions
• Simplified pathway data
• A registry listing resources implementing PSICQUIC
• Documentation: http://psicquic.googlecode.com

PSICQUIC
http://www.ncbi.nlm.nih.gov/pubmed/21716279

PSICQUIC Registry
• 25 sources
• >150,000,000 interactions
http://www.ebi.ac.uk/Tools/webservices/psicquic/registry/registry?action=STATUS

PSICQUIC Registry - Tagging
Content
protein-protein
small molecule-protein
nucleic acid-protein
Interaction representation
evidence
clustered
Curation standards
mimix curation
imex curation
rapid curation
Source
internally curated
text mining
predicted
imported
Complex expansion
spoke
matrix
bipartite

PSICQUIC view
• Simple and complex queries
• Link back to the original source for more details
• Clustering of queries across providers
• Visualization of graphical network
http://www.ebi.ac.uk/Tools/webservices/psicquic/view/

IntAct, PSICQUIC and Cytoscape

PSICQUIC – the downside
• PSICQUIC gives access to multiple databases and large
amounts of data
• Many data types can be searched – experimental
(physical/genetic/functional), inferred, predictive,
• User has problems easily differentiating the data types
• Many databases do not curate data but repackage and
represent (APID, iREFindex, I2D, InnateDB, STRING) – the
same information will appear multiple times
23

Data distribution best practise
• Flexibility in standard usage leads to non-standard usage
• Data merged by identifier – if this differs, the same
interaction will not merge
• uniprotkb:P51587 will not merge with P51587
• Ongoing work through HUPO-PSI to standardise what
data goes in each column and have reference identifier
(Proteins- UniProt, standard inchi key – small molecules)
in designated columns to allow merging.
• http://code.google.com/p/psicquic/wiki/DataDistributionBe
stPractices
24

IMEx
• Consortium of 9 molecular interaction databases
dedicated to producing high quality, annotated data,
curated to the same standards
• Data is curated once at a single centre then exchanged
between partners
• Users need only go to a single site to obtain all data
• www.imexconsortium.org

26
www.imexconsortium.org

IntAct goals & achievements
1. Publicly available repository of molecular interactions
(mainly PPIs) - ~310K binary interactions taken from
>5,600 publications (October 2012)
2. Data is standards-compliant and available via our
website, for download at our ftp site or via PSICQUIC
http://www.ebi.ac.uk/intact
ftp://ftp.ebi.ac.uk/pub/databases/intact
www.ebi.ac.uk/Tools/webservices/psicquic/view/main.xhtml
3. Provide open-access versions of the software to allow
installation of local IntAct nodes.
27

http://www.ebi.ac.uk/intact
IntAct – Home Page
28

First search from the home page…
Visualisation – table view
Interaction
Score
Choice of UniProtKB
or Dasty View
Taxonomy
PubMed/IMEx ID
Details of
interaction
Expansion
method
29

30
Visualisation – table view

31
Visualisation – network view

Cytoscape Web
• Currently V1 installed – no further development as
technology change announced immediately afterwards
• Development will start on beta version on V2 in New Year
32

Applying a better graph layout…
Visualisation – network view
Master headline

Highlighting network properties…
Visualisation – network view
Master headline

PSICQUIC plugin for Cytoscape 2.8.3
Cytoscape
File Import
Network from Web Services...

PSICQUIC plugin for Cytoscape 2.8.3
• Does not import MITAB 2.6/2.7 fields (experimental and biological roles of
participants, expansion method, host taxID, participant detection
method...).
• Visualization has room for improvement.
• Reference attributes for visual features need to be referenced to humanreadable
ones.

PSICQUIC plugin for Cytoscape 3
Cytoscape
File Import Network Public Databases...

PSICQUIC plugin for Cytoscape 3
• Does not import MITAB 2.6/2.7 fields (experimental and biological roles of
participants, expansion method, host taxID, participant detection
method...).
• Minor issues with some MITAB 2.5 fields (interaction type, publication 1 st
author, source database).
• Visualization has room for improvement.
• Some bugs while merging and querying.

xgmml format from IntAct / PSICQUIC View
• Includes MITAB 2.6/2.7 fields with some minor issues (fields with multiple
values can have exporting problems, participant detection method).
• Visualization is pretty dull, lots of room for improvement.
• Issues with non-readable attributes should be fixed in the next few days (or
have been fixed already).

40
Current IntAct support:
European Commission grants PSIMEx
(FP7-HEALTH-2007-223411)
APO-SYS (FP7-HEALTH-2007-200767)
Affinomics (241481)

?
?
? ?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
41