Data independent acquisition of product ion spectra and reference spectra library matching
Inventors
Bonner, Ronald F. • Tate, Stephen A. • AEBERSOLD, RUDOLF • Navarro ALvarez, Pedro Jose • Rinner, Oliver • Reiter, Lukas • Gillet, Ludovic
Assignees
Eidgenoessische Technische Hochschule Zurich ETHZ • Biognosys AG • DH Technologies Development Pte Ltd
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Publication Number
US-9343278-B2
Publication Date
2016-05-17
Expiration Date
Abstract
Systems and methods are disclosed for quantitating detectable compounds of a sample. Sample product ion spectra are received for each mass selection window for each time step. The received sample product ion spectra are searched for the presence of known compounds of interest with known product ion spectra by retrieving the known product ion spectra from a library, retrieving the sample product ion spectra corresponding to the precursor mass selection window expected to contain a precursor ion corresponding to the known product ion spectra, generating product ion traces in time for the sample product ion spectra for the known product ion spectra, calculating a score for the product ion traces and product ion spectra that represents how well known product ions and sample product ions match, and calculating a quantitative value for the known compound from the product ion traces when the score exceeds a threshold value.
Core Innovation
The invention quantitates detectable compounds by receiving sample product ion spectra for each mass selection window of a plurality of precursor mass selection windows for each time step of a plurality of time steps. The sample product ion spectra are produced by separating detectable compounds in a sample over time, and analyzing the detectable compounds at each time step by performing a plurality of product ion scans for precursor mass selection windows selected across a mass range using a tandem mass spectrometer. Each precursor mass selection window has a width greater than 10 amu.
The processor searches the received product ion spectra for the presence of one or more known compounds with known product ion spectra. The searching includes retrieving the known product ion spectra from a library, retrieving the sample product ion spectra corresponding to the precursor mass selection window expected to contain a precursor ion corresponding to the known product ion spectra, and generating product ion traces in time for the sample product ion spectra for one or more of the known product ion spectra. The searching further includes calculating a score representing how well known product ions match sample product ions.
Quantitation is performed by calculating a quantitative value for a known compound from the product ion traces when the score exceeds a threshold value. The document also supports identification of modified forms by using matching sample product ions, comparing matching ions to predicted masses from known product ions together with a modification to characterize modification type and location, and extracting a spectrum from the sample product ion spectra for the identified modified form.
Claims Coverage
The document contains three independent claims: a system, a method, and a computer program product. Across these independent claims, the inventive features include time-resolved product ion scans over multiple precursor mass selection windows, library-based matching using generated product ion traces in time, score calculation for matching known product ions to sample product ions, and calculating a quantitative value when the score exceeds a threshold value.
Time-resolved tandem mass spectrometry with wide precursor mass selection windows
The system/method receives sample product ion spectra for each mass selection window of a plurality of precursor mass selection windows for each time step, where the precursor mass selection windows are selected across a mass range and each precursor mass selection window has a width greater than 10 amu.
Product ion scan matching to known product ion spectra from a library
The system/method searches received product ion spectra for one or more known compounds by retrieving known product ion spectra from a library and retrieving sample product ion spectra corresponding to the precursor mass selection window expected to contain a precursor ion corresponding to the known product ion spectra.
Generating product ion traces in time and calculating a match score
The system/method generates product ion traces in time for the sample product ion spectra for one or more of the known product ion spectra and calculates a score that represents how well known product ions of the known product ion spectra match sample product ions of the sample product ion spectra.
Quantitation based on score exceeding a threshold value
The system/method calculates a quantitative value for the known compound from the product ion traces when the score exceeds a threshold value.
Modified form identification using matching sample product ions and predicted modified ion masses
The system/method further uses one or more matching sample product ions to identify a modified form of one or more compounds of the known compounds, where matching sample ions are compared to masses predicted from known product ions and a modification to characterize the type and location of the modification.
Spectrum extraction to characterize modification type and location
The system/method extracts a spectrum from sample product ion spectra to characterize a type and location of the modification in an identified modified form.
Overall, the independent claims cover time-resolved tandem mass spectrometry with precursor mass selection windows having width greater than 10 amu, library-based searching using retrieved known product ion spectra and retrieved sample product ion spectra for expected precursor windows, generating product ion traces in time and calculating a score for matching, and calculating a quantitative value when the score exceeds a threshold. Dependent coverage extends the matching outcome to identifying modified forms by using matching sample product ions, comparing to predicted masses with a modification to characterize modification type and location, and extracting spectra to support that characterization.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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