BEReX v.1.0

Biomedical Entity-Relationship eXplorer

User Guide

Minji Jeon1, Sunwon Lee2, Kyubum Lee2, Aik-Choon Tan3 and Jaewoo Kang1;2

1Interdisciplinary Graduate Program in Bioinformatics, Korea University, Seoul, Korea 2Department of Computer Science and Engineering, Korea University, Seoul, Korea

3Department of Medicine/Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

*The T-rex figure is adapted from the animated movie “Meet the Robinsons” (2007).

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* For bugs and inquiries, please contact:

Minji Jeon (mjjeon@korea.ac.kr) Jaewoo Kang (kangj@korea.ac.kr)

* Project website: http://infos.korea.ac.kr/berex

* BEReX is licensed under the GNU General Public License and is 100% freely available to both commercial

and academic users. See the file LICENSE.txt in the BEReX distribution package or this URL for the full text

of the license: http://www.gnu.org/licenses/gpl.html

* BEReX is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied

warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public

License for more details.

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1. System Requirements

1) OS: Windows, Mac OS X, or Linux

2) Java Runtime: JRE6 or later, or JDK1.6 or a later version is needed to run the application

3) CPU: A reasonably fast CPU will work such as Intel Core-i3 or better

4) Memory: 4GB or more is recommended

5) Storage Space: 3.12GB of extra space is required

2. Installation Guide

1) Install JRE from http://www.oracle.com/technetwork/java/javase/downloads/index.html (skip this step if you have JRE6 or later, or JDK1.6 or later)

2) Download BEReX (v.1.0) and unzip the package file:

Windows : berex-v1-windows.zip (184MB) (http://infos.korea.ac.kr/berex/Windows/berex-v1-

windows.zip)

Mac : berex-v1-mac.zip (184MB) (http://infos.korea.ac.kr/berex/Mac/berex-v1-mac.zip) Linux : berex-v1-linux.zip (184MB) (http://infos.korea.ac.kr/berex/Linux/berex-v1-linux.zip)

3) Run BEReX.bat (for Windows) / BEReX.sh.command (for Mac) / BEReX.sh (for Linux)

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3. User Interface Overview

Users can query BEReX for any combination of genes, drugs, diseases, pathways, miRNAs, transcription

factors, and gene ontology terms by using keywords. The query box and search button are located at the top

of the application window. The BEReX exploration window at the center shows the query results in a graph.

Users can interactively expand/modify the graph to construct custom pathway networks of their interest. The

tree view window at the top right shows the entity-relation information of a selected node. The window below

that shows the details of a selected node or edge and provides links to external sources such as PubMed

articles that support the relation. The window at the bottom left allows users to filter information by particular

entity types, relation types, and data sources. Finally, users can save the current graph as a file for later use

or export the graph as an image through the file menu at the top.

4. Tutorial: BCR-ABL1 Use Case

Here, we show how we generate the BCR-ABL1 network in Figure 1 (main paper). Please follow the next

steps:

1) Enter “BCR ABL1” in the query box and click on the ‘Search’ button.

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2) A sub-network that matches

the query appears in the

exploration window as shown

below. In addition to the query

nodes (BCR and ABL1),

BEReX automatically selects

a small number of additional

entities that are highly related

to the query nodes, and adds

them to the network (TP53,

SRC, UBC, and HSP90AA1).

We use a PageRank-based

scoring algorithm for

determining the relevancy.

Please note that BEReX’s

response time may be slow in

the beginning due to the time

required for the system

memory cache to warm up

(i.e., a good portion of the

working database is loaded

into the memory).

3) The tree view window at the top-right

shows the full interaction information for

the two query nodes as shown below.

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4) The information window right

below the tree view window

shows the detailed information

about a selected node or edge.

The figure below shows the

information about ABL1.

5) The window at the bottom-right shows the

shortest paths between nodes selected by a user.

The figure below shows the result after the user

selected TP53 and SRC. The shortest paths are

shown in the order of their significance determined

by our scoring algorithm. Users can add one of the

shortest paths to the current graph by double-clicking

one from the list.

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6) Now, select both BCR and ABL1 by holding down the ‘SHIFT’ key and then clicking on each node. The

gene names on the two nodes will become highlighted in blue. Then, right-click on either of the two

selected nodes, which will bring up a context-menu as shown below.

7) Choose “Expand selected entity type” -> “Drug.” As a result, “imatinib” is added as below.

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8) Add two more drugs by repeating this process. If you want to add more than one entity at a time, go to

“Option” -> “Expand by” on the menu bar at the top and choose the number of entities you want added

each time. The default value is one. The resulting network is shown below. Please note that the nodes

are rearranged to improve readability.

9) Users can obtain supporting information for any relation in the current graph by clicking on an edge. For

example, the figure below shows the information window after a user clicks on the link between fasudil

and ABL1. It shows the link to the PubMed article that reports the relationship between fasudil and ABL1,

and that the source of the information is the PhamGKB database. Clicking on the PubMed link will show

the supporting article in the user’s main web browser.

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10) Now, let us add five disease/symptom nodes by following the process explained above.

11) We want to add miRNAs that interact with ABL1. This time, select only ABL1 and execute “Expand by

selected entity type” -> “miRNA” until five miRNAs are added.

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12) Add five pathways that are related to both ABL1 and BCR. Highlight both ABL1 and BCR by using ‘SHIFT

+ Click.’ Then, right-click on either ABL1 or BCR to select “Expand by selected entity type” -> “Pathway.”

Notice that RAC1 and CDC42 have been added as a result of this step. When an entity is expanded from

a set consisting of more than one node, BEReX adds a shortest path from the expanded (target) node to

each of the source nodes in the original set. For example, “Viral myocarditis pathway” has a direct link to

ABL1 (i.e., a shortest path) but has no connection to BCR. BEReX adds the highest-ranked shortest path

between them, which is in this case, “Viral myocarditis pathway” – RAC1 – BCR, among potentially many

candidate shortest paths. The relevance is determined by the PageRank-based scoring algorithm

explained in the main paper and the supplementary methods.

13) We now expand the graph for Gene Ontology terms. Select both ABL1 and BCR, and execute “Expand

by selected entity type” -> “Gene Ontology (Molecular Function).”

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14) Choose “Option” -> “Expand by” -> 5. Highlight ABL1 by clicking on it. Right-click on ABL1 and execute

“Expand by selected entity type” -> “Transcription Factor.” This will add five transcription factors as shown

below.

15) We delete RAC1, CDC42, SOS1, and MAPK14 to obtain the same network as in Figure 1. Node deletion

is done by right-clicking on the node to be deleted and clicking on “Delete this node.”

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16) Now, we want to store the current network for later use. Go to “File” -> “Save”; enter the file name for

your graph; and then click on the save button. The saved network can be loaded later through the “File”

-> “Open” menu. Note that the current version is capable of storing only the topology, not the layout, of

the graph. We will address this issue in the next version.

17) BEReX also allows graphs to be imported from and exported to a popular standard format such as PSI-

MI(Proteomics Standards Initiative-Molecular Interaction) version 2.5, SIF(Simple Interaction Format),

and GML(Graph Modeling Language). Go to “File” -> “Import/Export” to import or export a graph.

18) Users can export the current network as an image, either in EPS or JPG format. Go to “File” -> “Save as

Image”; enter the name for your image file; and then click on the save button.

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19) Users can change the graph layout through the “Option” -

> “Graph Layout” menu. Currently, BEReX supports two layouts

including the FR layout (Fruchterman-Rheingold algorithm) and the

KK layout (Kamada-Kawai algorithm).

20) Query Suggestions: BEReX provides a flexible query interface. Users can search for an entity even

when they do not know the exact names of the entities, by using wildcards such as “*” or “?”. The figure

below shows the pop-up dialog box generated by BEReX for a user query “parkin*.” From the

suggestion list, users can select the one that matches their search.

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21) Database Updates: BEReX allows users to conveniently update their databases through the “Help” ->

“Check for Updates” menu. BEReX compares the versions of the users’ databases with the version of

the database in the server. If there is an updated database available, users are allowed to update their

databases by clicking on the “Start” button in the update dialog box shown in the figure below.