Pathways Integration Tool (PINT)

Category Cross-Omics>Pathway Analysis/Gene Regulatory Networks/Tools

Abstract The Pathways Integration Tool (PINT) was designed to assist users to conduct Biological Pathway Integration (BPI), and to explore the possible phenotypic outcomes under a particular physiological or pathological condition.

PINT can integrate standard Systems Biology Markup Language (SBML) files. Since these files may be obtained from different sources, any inconsistency in component names can be revised by using an annotation editor after uploading a pathway model.

This integration function greatly simplifies the building of a complex model from small models.

To get new users started, about 190 curated public models of human pathways were collected by PINT.

Relevant models can be selected and sent to its Workbench by using a user-friendly query interface, which also accepts a gene list derived from high-throughput experiments.

The models on the Workbench, from either a public or a private source, can be integrated and painted. The painting function is useful for highlighting important genes or their expression level on a merged pathway diagram, so that the biological significance can be revealed.

The PINT Biological Pathway Integration (BPI) function --

The main function of BPI is how multiple pathway models can be integrated in order to generate a merged model, in which Not only is the original pathway information in each model preserved, but also the initially unavailable inter-pathway relations can be rebuilt.

Hence, PINT has been implemented with a set of functions to assist users to complete the following steps:

1) Users upload their pathway models into the BPI system;

2) The BPI system pools the users’ pathway models together;

3) The BPI system then finds the pairwise relation(s) among pathway models;

4) The BPI system rebuilds the inter-model connections; and

5) The BPI system removes the redundant nodes and edges from the merged model.

PINT Website usage --

The PINT website provides an integrated environment for users to perform the functions that are required for Biological Pathway Integration (BPI).

On the PINT web-site, these functions are categorized into four (4) web pages:

Start, Upload, Browse, and Workbench (see these menu bar items on the PINT web-site).

Users may search for pathway models to start with, upload private pathway models or gene-symbol lists (for highlighting entities on merged diagrams), browse available models in PINT and select pathway models to perform the core BPI functions, respectively.

Uploaded models and gene-symbol lists will be cached in PINT temporarily and cleaned at the end of each week.

The PINT public models and users private models --

PINT provides ~190 human pathway models for new users to try BPI immediately. These models were prepared based on two (2) data sources:

1) First, the manufacturers used CellDesigner - (see G6G Abstract Number 20159) to re-build ~30 human pathway models from the pathway diagrams provided by BioCarta - (see G6G Abstract Number 20264).

2) Second, the manufacturers retrieved ~160 human pathway models through parsing the human pathway information from a pathway XML file downloaded from the Pathway Interaction Database (PID) - (see G6G Abstract Number 20245).

Also, users can upload their own private models into PINT on the ‘Upload’ page, located on the manufacturer’s web-site.

Pathway models to be uploaded can be either downloaded from BioModels - (see G6G Abstract Number 20295) or Panther - (see G6G Abstract Number 20065), or created by CellDesigner (version 3.5.1 or later) or SBMLeditor (under implementation).

Furthermore, every PINT public pathway model can be downloaded in the SBML format, and then re-uploaded and re-annotated as a user’s private model.

This operation is useful when integrating pathway models that contain fusion genes and their products, as demonstrated in an example on the PINT ‘Documentation’ page, located on the manufacturer’s web-site.

Selecting Pathway models --

Both the public and private pathway models already in PINT can be browsed or searched by the user.

The PINT ‘Browse’ page (located on the manufacturer’s web-site) lists alphabetically the public and private pathway models respectively. Also, the PINT ‘Start’ page (located on the manufacturer’s web-site) provides users with several search options.

Users can type in keywords (e.g. gene symbol, synonym), or upload a long list of keywords. Users may also search for reactions involving a user-specified entity.

This reaction-search function, very similar to the PID-style query, allows users to take an entity as the ‘center point’, and to wander along relevant reactions further upward or downward, and thus enables users to quickly find upstream and downstream pathway models.

From the results returned by PINT after a ‘search’ or ‘browse’ operation, users may choose and send pathway models to the PINT Workbench to perform BPI.

Integrating pathway models (PINT Workbench) --

The PINT Workbench provides the core BPI functions that allow users to visualize pairwise relations among pathway models, choose a subset of them for integration, visualize the merged diagram, highlight entities on the merged diagram and download the merged model for reuse in PINT or other SBML model editing/visualization tools.

PINT Relation graph --

The core Biological Pathway Integration (BPI) functions of PINT can be activated if a number of Pathway models have been submitted to the Workbench.

On the activated Workbench, there is a Relation graph, a list of pathway models, and options to display or export a merged model. The Relation graph shows the pairwise relations among the models listed in the PINT Workbench.

Each number in this graph indicates how many nodes two (2) potentially linkable pathway models have in common.

When a number is clicked, PINT can generate a merged diagram of two relevant models for preview, where identical nodes commonly found in both models are shaded in yellow.

Users can then decide whether such a merged model is interesting or Not, and choose relevant distinct models for integration at a later stage.

Highlighting entities on a merged diagram (Painting, PINT Workbench) --

The Biological Pathway Integration (BPI) conducted by PINT relies on putatively identical nodes (PIN) sets, but Not on any gene or protein expression data.

This means that merged models generated in this manner are just hypothetical and may need further experimental evidence to support their biological significance.

Therefore, PINT provides a ‘painting’ function that can highlight entities based on the user’s gene-symbol lists, expression data or the tissue/histology information retrieved from UniGene.

This function can Not only assist users to explore if their experimental data are consistent with a merged model but also help users to determine if a merged model makes biological sense.

Thus, based on painted diagrams, bench biologists may use their expertise to decide whether the hypothetical pathway represented by a merged model is interesting, and therefore design more experiments to investigate its features.

Alternatively, they may decide to try other combinations of models to perform another round of pathway integrations and see if experimental evidence can support other merged models.

The diagram painting function can also be used to highlight entities in other biological context, such as selective pressure in evolution, etc.

Overall, PINT is a useful tool Not only in studying the regulatory circuit in a given cell/tissue types, but also in viewing the changes of Pathway flux when dynamic information is available.

Moreover, PINT can also be used to integrate models across states (e.g. different environments) or even across organisms (e.g. in a metagenomic context). In the latter case, the pathways across dependent species in different environments can be explored.

System Requirements

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Manufacturer Web Site Pathways Integration Tool (PINT)

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G6G Abstract Number 20646

G6G Manufacturer Number 104244