Insilicos - Biomarker Discovery Software

August 19, 2009, Seattle - Insilicos and the Institute for Systems Biology (ISB) today announced the release of Trans-Proteomic Pipeline (TPP) version 4.3.0. This is a significant update to the software, which now contains a tool (“Mayu”) for computing the false-discovery rate (FDR) of proteomics analyses, new functionality for analysis of electron-transfer dissociation (ETD) data, and a more robust build system, making distribution of the software easier than ever on more platforms.

The TPP is an open-source proteomics software tool suite originally developed by the Institute for Systems biology (ISB). Insilicos is the primary group outside of ISB contributing to the project. For this release, Insilicos managed the software release and distribution process, at ISB's request. The TPP is a complete proteomics software suite, containing analysis software such as the well-known PeptideProphet and ProteinProphet statistical proteomics tools, and is freely available for download. Download information as well as details on the new features can be found in the 4.3.0 release announcement here.

The TPP assigns a probability to each peptide-spectrum match (PSM), but what researchers really want to control is the false discovery rate (FDR) – the proportion of incorrect identifications in their results. Mayu, developed by Lukas Reiter and Manfred Claasen of the Swiss Federal Institute of Technology, Zurich, accurately computes the FDR at the PSM, peptide, and protein levels for any dataset searched with decoys. The TPP includes a script for running Mayu after PeptideProphet. “Mayu lets you know what probability cutoff to use for a given dataset to achieve a desired FDR,” says Terry Farrah of ISB, who integrated Mayu into the TPP. “We like to achieve a protein FDR of 1%. For a small dataset, this can correspond to a PSM probability cutoff of 0.95, but for a very large dataset, perhaps 0.995. Mayu very handily tells us what cutoff to use.”

Electron-transfer dissociation (ETD) is an attractive alternative to the more common charge-induced dissociation (CID) method used to fragment peptides entering the second phase of mass spectrometry (MS2) in a proteomics experiment. ETD preferentially induces breaks at the peptide backbone, leading to cleaner MS2 spectra with the preservation of amino acid side-chain modification on the fragments. According to TPP developer David Shteynberg, “ETD fragment spectra feature charge-reduced precursor peaks, which we can use to predict accurate precursor charges up to +7 on low resolution ETD mass-spectra with existing software tools; later we must account for these charge predictions in PeptideProphet modeling.” To address this, TPP developers integrated charge state prediction software in the pipeline and Shteynberg implemented multiple charge state correction logic in the modeling component of PeptideProphet to ensure the validity of computed probabilities for multiple potential charges of the same spectrum.

While the Aebersold lab at ISB's Seattle Proteome Center originally developed the TPP, it is a collaborative, "open-source" project with several contributors from outside of the ISB including Insilicos. As the primary group outside of ISB working on the TPP, Insilicos maintains a close, ongoing working relationship with ISB. For this release, Insilicos built on their experience deploying the TPP on various Linux systems to implement a "continuous integration" build system, which automatically tests each change to the software on Windows and a variety of Linux platforms. As a result, the 4.3.0 release of the TPP has a more robust build system than ever before. Also, Insilicos included scripts with the TPP that should make a build system even easier to set up on those tested platforms. "We're always trying to improve the TPP experience both for users and for other developers," said Insilicos software engineer Natalie Tasman. "This release has important new capabilities for developers modifying the open-source TPP code, and also for anyone using the TPP for high-throughput proteomics processing on a cluster or a 'cloud' deployment such as Amazon's EC2 system."

Users are encouraged to visit the TPP's support and discussion mailing list for information and assistance with installing and using the freely-available software.

The ISB SPC's work on the TPP is funded by the National Heart, Lung, and Blood Institute under contract N01-HV-28179. Insilicos' recent work on the TPP is funded by the National Human Genome Research Institute under grant HG004537.

The Institute for Systems Biology (ISB) is an internationally renowned, non-profit research institute headquartered in Seattle and dedicated to the study and application of systems biology. Founded by Leroy Hood, Alan Aderem and Ruedi Aebersold, ISB seeks to unravel the mysteries of human biology and identify strategies for predicting and preventing diseases such as cancer, diabetes and AIDS. ISB's systems approach integrates biology, computation and technological development, enabling scientists to analyze all elements in a biological system rather than one gene or protein at a time. Founded in 2000, the Institute has grown to 14 faculty and more than 250 staff members; an annual budget of more than $35 million; and an extensive network of academic and industrial partners. For more information about ISB, visit http://www.systemsbiology.org

Insilicos LLC develops life science software for pharmaceutical development, biological research and clinical diagnostics.
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