Multi-MS Dark Matter Detection via Dynamic Triggering
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current mass spectrometry techniques, such as Data-Dependent Analysis (DDA) and Data-Independent Acquisition (DIA), are limited in their ability to comprehensively identify proteins and peptides in complex biological samples, often missing low-abundance compounds due to incomplete databases and inadequate structural determination, especially for unknown metabolites known as 'dark matter' in untargeted LCMS experiments.
Innovation Solution
A system comprising multiple mass spectrometers connected via a data system, where one mass spectrometer performs Data-Independent Acquisition (DIA) and generates inclusion or exclusion lists for targeted MS2 or MSN scans on other instruments, allowing for dynamic triggering of more informative scans and chromatographic offsets to analyze retention times and precursor masses across multiple instruments, utilizing different fragmentation methods for enhanced structural information.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If Data-Dependent Acquisition (DDA) is used to select and isolate single ion species for fragmentation, then identification of abundant proteins and peptides is improved, but detection of low-abundance compounds is lost
Solution Approach 1:
The patent segments the mass spectral analysis into multiple independent experiments: a first DIA experiment for comprehensive fragment ion data collection, and a second targeted experiment for structural determination of selected precursors. This segmentation allows each experiment to optimize for its specific purpose while collectively addressing both abundant and low-abundance compound detection
Solution Approach 2:
The first DIA experiment serves as a preliminary action that generates inclusion/exclusion lists and identifies candidate precursors before the second targeted experiment. This preliminary data collection enables the second experiment to focus resources on specific low-abundance compounds that require further structural characterization
2Loss of information
If Data-Independent Acquisition (DIA) is used to fragment all ion species across full m/z range, then coverage of low-abundance compounds is improved, but structural determination capability is insufficient
Solution Approach 1:
The patent divides the analysis into two segments: the first DIA experiment provides comprehensive coverage by fragmenting all ions, while the second targeted experiment provides detailed structural determination for selected precursors using optimized fragmentation conditions and multiple collision energies
Solution Approach 2:
The inclusion/exclusion lists generated from the first DIA experiment serve as an intermediary that bridges the comprehensive coverage of DIA and the targeted structural determination of the second experiment. These lists identify which precursors require further analysis, enabling selective follow-up on low-abundance compounds
3Device complexity
If a single mass spectrometer is used to perform both comprehensive scanning and detailed analysis, then device complexity is reduced, but analysis time and productivity decrease
Solution Approach 1:
The patent merges the capabilities of two mass spectrometers through a data system, combining the comprehensive scanning capability of the first instrument with the targeted analysis capability of the second instrument. This virtual merging allows parallel operation and data integration without requiring physical consolidation of hardware
Solution Approach 2:
The system implements feedback by using data from the first DIA experiment to dynamically generate inclusion/exclusion lists that guide the second targeted experiment. This real-time feedback loop allows the second instrument to adjust its analysis priorities based on actual findings from the first instrument, optimizing resource allocation and analysis throughput
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach enables a more comprehensive analysis of biological samples by dynamically triggering additional mass spectrometric analyses based on real-time data, improving the detection of unknown compounds and providing a greater level of structural information than single-method analyses, thereby addressing the limitations of existing techniques.
Implementation Method 1
The ion source which may, without limitation, comprise an electrospray, thermospray or Atmospheric Pressure Chemical Ionization (APCI) source generates a plume of ions
Implementation Method 2
a quadrupole mass filter, a quadrupole ion trap or a quadrupole mass analyzer
Implementation Method 3
Ion fragmentation can be provided by various methodologies and mechanisms including collision-induced dissociation (CID), infrared multiphoton dissociation (IRMPD)
Implementation Method 4
a time-of-flight (TOF) mass analyzer
Implementation Method 5
a Fourier Transform Ion Cyclotron Resonance (FT-ICR) mass analyzer
Data Source
AI summary
A system comprises: first and second mass spectrometers; at least one liquid chromatograph configured to simultaneously supply a first stream of chromatographic eluate derived from a sample to the first mass spectrometer and a second stream of chromatographic eluate to the second mass spectrometer; and a computer or electronic controller electronically coupled to both of the first and second mass spectrometers and comprising computer-readable instructions operable to: input a mass spectrometric analysis of a chromatographic fraction of the sample obtained by the first mass spectrometer; determine whether an additional mass spectrometric analysis of the chromatographic fraction of the sample is required, based on the mass spectrometric analysis of the chromatographic fraction obtained by the first mass spectrometer; and, if the determination is affirmative, cause the second mass spectrometer to perform, after a time delay, the additional mass spectrometric analysis of the chromatographic fraction of the sample.