Adaptive Search Mass Spectrometer Spectral Analysis

Abstract

The method of analyzing a spectrum includes identifying a set of sample peaks in a sample spectrum, where the sample peaks are associated with fragments of the sample, each having a sample fragment mass. A reference spectrum is selected using one or more reference peaks corresponding to fragments of the reference, each having a reference fragment mass. A mass difference between the selected sample and reference peaks can be determined, and a group exchange can be selected based on the mass difference. For example, a group exchange represents a change in mass of the sample or reference fragment associated with the selected peak. The selected peak is shifted by the mass difference, and a fit value to the reference spectrum is determined. The fit value characterizes the similarity between each set of sample and reference peaks in response to the group exchange and the corresponding peak shift.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 226,603, filed July 28, 2021, entitled "ADAPTIVE SEARCH MASS SPECTROMETER SPECTRAL ANALYSIS," the contents of which are incorporated herein by reference in their entirety.

[0002] [Copyright Notice] A portion of the disclosure of this patent document contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure as it appears in the Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever. [Technical Field]

[0003] This application relates to mass spectrometry and related spectral analysis, and more generally to spectroscopic data analysis for sample matching and identification of unknown substances, including, but not limited to, spectral analysis of mass spectrometry systems, including gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) systems, and other or more generalized spectral data analysis. [Background technology]

[0004] Spectral analysis is a powerful tool for sample matching and substance identification, including identifying the chemical composition of unknown substances in a particular sample. In a gas chromatography-mass spectrometry (GC-MS) system, the gas chromatograph utilizes a capillary column to separate molecules or molecular fragments (components) based on their physical and chemical properties, such as size, weight, length, diameter, film thickness, and other topological characteristics. Differences in these properties determine the relative affinity of various molecules for the stationary phase in the column, rather than the mobile phase, and drive separation based on retention time as the sample travels down the length of the column.

[0005] The goal is similar in liquid chromatography-mass spectrometry (LC-MS) systems, where different molecular fragments or components of a liquid mixture are partitioned between a stationary phase and a mobile phase and then separated along the length of the column or based on their retention time within the column. In practice, additional technical challenges may exist based on the liquid composition of the sample, for which various techniques have been developed. These include adsorption chromatography, partition chromatography, ion-exchange chromatography, size-exclusion chromatography, affinity chromatography, or reversed-phase (partition) chromatography, which utilizes a nonpolar (e.g., hydrophobic) stationary phase and a polar mobile phase (e.g., a mixture of water and another polar solvent).

[0006] Different molecules elute from the GC or LC stage at different times based on their retention time, which depends on their different molecular (chemical and physical) properties. A downstream mass spectrometer (MS) system captures molecules or their fragments from the upstream GC or LC system and exposes them to an electron beam of energy and intensity selected to ionize the different molecules or (more commonly) break them down into ionized fragments. The ionized fragments are electromagnetically accelerated and subjected to a strong magnetic field in the mass analyzer, which bends the migration paths of the molecules (if present) and fragments along different paths based on their different mass-to-charge ratios.

[0007] The magnetic field separates the migrating ionized fragments by mass, producing a spectral signature of the sample that is identified by a detector. The detector identifies the separated fragments by mass and provides data for calculating their relative amounts or abundances. Generally, different molecules tend to fragment into different components, and different spectra can be matched to identify unknown molecules or their fragments in an unknown sample. However, many substances can have numerous different organic and / or inorganic fragments, each with multiple common configurations and variations of the same or different masses. Therefore, identifying the original molecular composition of an unknown sample (or a significant fragment of the sample) can pose significant technical challenges based on the many variations that may be observed in the spectrum.

[0008] One approach to this problem involves performing spectroscopy on a set of "known" substances to create a library of reference spectral data. In each reference spectrum, the distribution of mass peaks represents the relative measured abundance of various fragments, which may be obtained from the reference molecule by spectroscopy. Spectral data obtained from an unknown sample can be compared to the library of reference spectra to find matches based on the similarity of the mass peaks. Many such libraries of reference spectral data are available for use in comparison, for example, from Wiley Science Solutions (John Wiley & Sons, Inc., Hoboken, NJ) and other sources.

[0009] Unfortunately, especially for molecules that fragment into multiple organic or inorganic components that may or may not have similar masses, there may be a wide range of different reference spectra from which to select an appropriate "match." Regardless of chemical composition, different fragments may also have similar masses. Additionally, baseline shifts and other systematic effects may exist, and if the sample and reference spectra are not acquired on the same instrument, systematic variations in mass peak distributions may appear. Therefore, a single mass spectrometry spectrum may not provide a definitive identification of the sample molecule(s) and all associated fragments that are the subject of spectroscopic analysis. Consequently, improved mass spectrometry techniques are desired that do not suffer from the exact same limitations as prior art techniques. Summary of the Invention

[0010] A method of adaptive searching for use in mass spectrometer analysis includes identifying or otherwise confirming a set of sample peaks in a sample spectrum. The sample peaks are associated with molecular fragments (or components) of the sample. The method includes selecting a reference spectrum having a set of reference peaks associated with molecular fragments of a reference. Each of the sample's molecular fragments has a sample fragment mass, and each of the reference's molecular fragments has a reference fragment mass. Comparison of the sample spectrum and the reference spectrum can be used to provide a basis for calculating one or more fit values ​​or similarity metrics that aid in identifying the sample with the reference. Visual comparison can also be useful, as can the calculated similarity metrics. A list of similar calculated results or fit values ​​can be provided for a number of references available in a library or database of reference spectra, for example, by ranking the results according to the similarity metric or by otherwise identifying reference spectra with relatively high similarity metrics (e.g., similarity scores).

[0011] Depending on the application, the method may also include determining a mass difference of a set of selected sample peaks in the sample spectrum compared to a selected reference peak in the reference spectrum, and selecting a group exchange based on the mass difference. A group exchange represents a change in sample fragment mass associated with one or more of the set of selected sample peaks compared to a reference fragment mass associated with a fragment in the set of selected reference peaks. Multiple exchanges are possible. These candidate group exchanges allow for adjustment and adaptation of a ranked "hit list" (i.e., a ranked list) of candidate reference spectra based on their respective similarity metrics.

[0012] One or more peaks in the reference spectrum can be shifted by a mass difference associated with a candidate group exchange determined to be likely or possible in the unknown sample compared to the reference molecule. An updated or adjusted fit value can be determined by recalculating a similarity metric of the sample spectrum with respect to the shifted reference spectrum, where the fit value characterizes the similarity between the set of sample and reference peaks shifted in response to the group exchange.

[0013] Also encompassed are computer-based systems, including memory and processor components configured to perform these methods and display the sample spectrum, original reference spectrum, and shifted reference spectrum along with their respective fit values ​​and associated data on a user interface. Also included are computer products with machine-readable code stored on a non-transitory medium, the code being executable by a computer processor to perform the methods or operate the systems.

[0014] In any of these examples, the sample spectrum can be obtained from a mass spectrometer system, such as a gas chromatography-mass spectrometry (GC-MS) system or a liquid chromatography-mass spectrometry (LC-MS) system. The reference spectrum can be obtained from a similar system and stored in a library or database. One or both of the sample spectrum and the reference spectrum can be output to a user interface (UI), such as a graphical user interface (GUI), along with one or more proposed (system-specified) or user-selected group exchanges and system-calculated fit values. Input can also be received at the user interface, and the input may determine the selected group exchange. A set of proposed group exchanges can also be output to the user interface, e.g., the input is used to determine the selected group exchange from the set of proposed group exchanges.

[0015] In any of these examples, a total mass value representing the molecular ion mass of the sample may be provided at the user interface. For example, the total mass value may be based on a sample peak in a sample spectrum provided as search input. The total mass value may be used to select a reference spectrum, determine a mass difference, or select a group exchange. A user may also provide input at the user interface, such as to update or change the total mass value. In some of these applications, a null or zero total mass value and other parameters may be output, displayed, or provided to the user interface, and input received at the user interface may be used to determine the total mass value.

[0016] In any of these examples, the group exchange can represent the exchange of an atomic group within a molecular fragment associated with a selected sample peak for a different atomic group within a molecular fragment associated with a selected reference peak. The group exchange can also represent the exchange of an entire molecular fragment associated with a selected sample peak for an entire molecular fragment associated with a selected reference peak.

[0017] In any of these examples, one or more additional group exchanges can be selected that represent one or more additional mass differences between the sample fragment mass associated with the sample peak and the reference fragment mass associated with the reference peak. The one or more additional sample or reference peaks can be shifted by one or more additional mass differences, e.g., the fit value characterizes the similarity between the sample and reference spectra including the additional shifted sample or reference peaks responsive to the one or more additional group exchanges.

[0018] In any of these examples and embodiments, the sample spectrum and reference spectrum can be obtained from a more generalized molecular or atomic spectral data analysis system, such as a visible or ultraviolet (UV) spectroscopy system, an infrared (IR) spectroscopy system, a Raman spectroscopy system, or a nuclear magnetic resonance (NMR) spectroscopy system. In these applications, the sample and reference fragment masses can be related to sample and reference fragments, e.g., the masses of emitting fragments in IR, visible, or UV spectroscopy, the masses of molecular fragments in vibrational or rotational states that are responsive in Raman spectroscopy, or the masses of other nuclear or molecular fragments that have a different nuclear spin response in NMR spectroscopy. [Brief explanation of the drawings]

[0019] [Figure 1] FIG. 1 is a schematic diagram of a mass spectrometry system with an adaptive search analysis processor. [Figure 2]FIG. 2 is a block diagram of a method for adaptive searching mass spectrometer spectral analysis. [Figure 3] FIG. 3 is a block diagram of an adaptive system for mass spectrometer spectral analysis. [Figure 4A] FIG. 4A is a diagram of a user interface showing a representative spectrum suitable for adaptive search analysis. [Figure 4B] FIG. 4B is an illustration of a user interface showing the match between a representative sample and reference spectrum. [Figure 5A] FIG. 5A is an illustration of a user interface showing the discrepancy between a representative sample and reference spectrum. [Figure 5B] FIG. 5B is an illustration of a user interface showing improved agreement between a representative sample and a shifted reference spectrum based on delta mass analysis. [Figure 6] FIG. 6 is a diagram of a user interface showing a representative sample spectrum, a shifted reference spectrum, and an unshifted reference spectrum. [Figure 7A] FIG. 7A is a diagram of the user interface showing a representative sample spectrum of unknown molecular weight. [Figure 7B] FIG. 7B is an illustration of a user interface showing a reference spectrum that matches the sample spectrum of FIG. 7A. [Figure 8A] FIG. 8A is an illustration of a user interface showing a shifted reference spectrum that matches the sample spectrum of FIG. 7A. [Figure 8B] FIG. 8B is an illustration of a user interface showing a representative sample spectrum along with a selected reference spectrum based on user input. [Figure 9] FIG. 9 is a chart showing the process flow steps in an adaptive search that starts with a sample spectrum and looks for potential matches within a library of reference spectra. DETAILED DESCRIPTION OF THE INVENTION

[0020] The present disclosure, as described herein, relates to spectral analysis for mass spectrometry, and more generally to adaptive search techniques for spectral analysis. Depending on the application, these techniques enable the analysis of a sample spectrum (or "molecular fingerprint") of a typical unknown sample or substance to determine the sample's exact mass and to find, identify, or select a reference spectrum that falls within a mass threshold. The sample mass is calculated, and a selected isotope pattern is shifted to determine what structural fragment substitutions (group exchanges) or additions are required to generate a sample spectrum based on the reference spectrum (or vice versa). [introduction]

[0021] This adaptive search technique allows for the shifting of only specific fragment patterns. The search identifies similar compounds that may have fragment groups present or absent in the reference spectrum compared to the sample or unknown spectrum. For example, the presence or absence of specific molecular fragments in the reference spectrum may cause some reference peak positions to differ from those of the unknown sample by a mass difference or delta mass (ΔM). Mass and mass difference are typically defined in atomic mass units (AMU), but the choice of scale is arbitrary. Mass spectrometry also commonly uses u (AMU) or m / z (mass per unit charge), where the charge is typically understood to be 1. Multiple ionized fragments have a smaller bending radius and can be captured based on that. Noise suppression algorithms, as known in the art, can also be utilized.

[0022] Using adaptive analysis, one or more reference peaks can be shifted by a mass difference ΔM to achieve a better (improved) matching score or fit value (calculated similarity metric). Based on the better matching score or fit value, similar compounds can be presented in the user interface as a hit list (e.g., a ranked list of a subset of potential matches). Dotted lines or other indicia can be used on the display of the user interface to indicate the shifts performed by the adaptive search, e.g., to show the reference spectra before and after the shift on a window in the graphical user interface.

[0023] This allows the user to "map" a reference spectrum onto the sample, or vice versa, and identify the best (or better) match. User input (e.g., by entering a total mass value, mass difference, or simply clicking a specific button or link associated with a "hit") may be used to aid in the selection of a reference spectrum or group exchange, or to indicate potential matches with relatively high match values. This technique is applicable to both gas chromatography (GC) and liquid chromatography (LC) mass spectral (GC-MS or LC-MS) analysis, as well as other forms of spectral analysis with mass peaks or other spectral features that are amenable to similar adaptive search algorithms based on compositional differences between the reference and sample spectra. [Mass spectrometer system overview]

[0024] Figure 1 is a schematic diagram of a mass spectroscopy system (or mass spectrometer) 100 in data communication with an adaptive search analysis (ASA) processor 170. In the gas chromatography-mass spectroscopy (GC-MS) configuration of Figure 1, the spectroscopy system 100 includes a gas chromatograph or chromatography (GC) system 110 and a mass spectrometer or spectroscopy (MS) system 130. Alternatively, the spectroscopy system 100 can utilize a liquid chromatography-mass spectroscopy (LC-MS) configuration having a liquid chromatograph or chromatography (LC) system 110 connected to a mass spectrometer 130, or a separate spectroscopy system 100 can be used for the initial separation of sample molecules.

[0025] 1, gas chromatograph 110 includes a carrier gas inlet 112 configured to accept a carrier gas stream (e.g., hydrogen, helium, nitrogen, argon, or other carrier gas suitable for use as a mobile phase) and a sample port 115 configured to introduce an unknown substance or sample into the carrier gas stream. The carrier gas and sample propagate through a column 120 (e.g., an open tubular or capillary column, or a packed column with a solid, inert support material) which may be coated with a thin film of liquid defining a stationary phase.

[0026] The different molecular components of the sample are separated based on their retention time within the column 120, which depends on their relative affinity for the mobile and stationary phases, which in turn depends on temperature, which is controlled by placing the column 120 in an oven or similar temperature-controlled enclosure 122.

[0027] The separated sample components exit column 120 via transfer line 125 and are transported to mass spectrometer system 130. Mass spectrometer system 130 includes an ionization chamber 140 with a filament 142 and an electron trap 145. Ionization chamber 140 is configured such that for electrons that leave filament 142 with sufficient energy to ionize and separate sample components into fragments, excess electrons are captured in trap 145.

[0028] Typically, the electron energy can be controlled to exceed the ionization potential to provide additional energy to break down sample components into ionized molecular fragments. A DC potential 175 is applied to accelerate the ionized fragments as they travel through the mass analyzer 150, where a strong magnetic field is applied to bend the fragments along different paths based on their different mass-to-charge ratios. The fragments are spatially separated along different paths and counted by a detector 155 connected to a local processor or controller 160 adapted for data processing and control of the spectroscopy system 100.

[0029] Counting the fragments accumulated along different paths provides evidence of the relative abundance of each mass-resolved fragment in the sample molecule accumulated (integrated) over a given time frame. Alternatively, real-time data accumulation and analysis can be applied. Typically, the highest peak value observed in the spectrum is the focus of adaptive search, but lower values ​​corresponding to less abundant fragments may also be representative components of the sample molecule and may be the subject of the same or similar analysis.

[0030] During operation, the spectroscopy system 100 acquires a sample spectrum from an unknown substance, including a set of sample peaks, each having a characteristic sample fragment mass and associated with the abundance of different fragments in the sample. The local spectrometer controller 160 is in data communication with an adaptive search and analysis (ASA) processor 170, for example, via a wired or wireless network communication link 165. The link 165 may be adapted for either real-time or asynchronous communication between the spectroscopy controller 160 and the ASA processor 170.

[0031] The ASA processor 170 is provided in communication with a user interface 180 and has access to a reference spectral library or database (DB) 190. Suitable databases 190 include, but are not limited to, mass spectral (MS) databases, gas chromatography-mass spectrometry (GC-MS) spectral databases, and liquid chromatography-mass spectrometry (LC-MS) spectral databases. Suitable examples include, for example, the Wiley Registry and other important collections on mass spectrometry, the Knowitall Mass Spectral Database Collection, the National Institute of Standards and Technology (NIST) and National Institutes of Health (NIH) mass spectral libraries, the Library of Biologically and Environmentally Important Organic Compounds (ISIDOROV), mass spectra of designer drugs, geochemicals, petrochemicals, and biomarkers (SPECDATA), mass spectra of drugs, toxicants, pesticides, pollutants, and their metabolites, LIPIDS mass spectral data, mass spectral libraries of pesticides including linear retention indices (LRIs), mass spectra of flavors and fragrances of natural and synthetic compounds, the Fatty Acid Methyl Esters (FAMES) mass spectral library, mass spectra of bioactive compounds, and mass spectra of volatiles in foods (SPECDATA). In other applications, the techniques described herein can also be applied to infrared (IR) spectral data (e.g., IR, Fourier transform IR (FT-IR), attenuated total reflectance (ATR) IR spectroscopy, and other IR spectral libraries including Sadtler and Hummel spectra; nuclear magnetic resonance (NMR) spectral databases including hydrogen or proton (H NMR) and carbon (C NMR) spectra and NMR spectra of other atomic nuclei; Raman spectral databases (e.g., Wiley high-quality Raman spectra featuring Sadtler data); and ultraviolet-visible (UV-Vis) spectral databases.These and other suitable spectral databases are available from, for example, Wiley Science Solutions and other sources, as discussed above.

[0032] ASA processor 170 can be configured to identify a set of sample peaks in a sample spectrum obtained by spectroscopy system 100, each sample peak being associated with a sample molecule or fragment thereof having a characteristic sample molecule or fragment mass. ASA processor 170 can then select one or more reference spectra from database 190 for comparison with the sample spectrum. User interface 180 may describe any or all of the specific examples of user interfaces 180A-180H or 180J as described herein. Similarly, any example of user interfaces 180A-180H or 180J may be embodied by user interface 180.

[0033] Each sample spectrum captured and selected for analysis includes a set of reference peaks associated with fragments of a particular reference material. Each reference fragment has its own characteristic reference fragment mass, typically measured in either atomic mass units (AMU or u) or mass per unit charge (m / z). Generally, the sample and reference spectra selected for analysis should be acquired using substantially similar spectroscopic systems, e.g., the GC-MS or LC-MS spectroscopic system 100 according to FIG. 1. Given the wide range of commercially available (and custom-designed) GC-MS and LC-MS systems available, even under favorable conditions, the ASA processor 170 can also be adapted to account for systematic differences between the sample and reference spectra, e.g., by modulating the spectral peaks to account for mass-based sensitivity differences or systematic shifts in mass.

[0034] As an improvement over existing techniques, ASA processor 170 is also configured to adapt and account for differences in chemical composition between the sample and reference spectra based on adaptive group exchange analysis. To accomplish this, ASA processor 170 determines the mass difference between selected sample and reference peaks using group exchange to adjust for the mass difference, as described herein, and improves the match between the sample and reference spectra based on group exchange.

[0035] 1 are merely representative. In other examples, a different spectral processing system 100 can be used, such as an optical, ultraviolet, infrared, Raman, or nuclear magnetic resonance spectroscopy system 100. In these examples, the database 190 can provide access to reference spectra from multiple types of systems, so that similar types of reference data can be found for use in the analysis, and the output to the user interface 180 can be adapted accordingly. [Analysis using mass difference between peaks]

[0036] Figure 2 is a block diagram of a method 200 for adaptive mass spectrometer analysis, executed, for example, by the ASA processor 170 shown in Figure 1. In this particular example, the method 200 includes one or more processing steps selected from identifying or validating a set of sample peaks in a sample spectrum (step 210), selecting a reference (REF) spectrum (step 220), determining the mass difference (ΔM) between the selected sample and reference spectra (step 230), selecting at least one group exchange (XCHG) taking into account the mass difference (step 240), shifting the selected peaks according to the mass difference (step 250), and determining fit values ​​of the sample and reference spectra including the shifted peaks, such that the fit values ​​are responsive to the group exchange (step 260).

[0037] The fitness value may then be output to a graphical user interface configured for user access (step 270). Method 200 may also be performed iteratively, for example, to test different group exchanges until an improved fitness value is obtained, e.g., a value higher than the previous iteration, or a fitness value above a threshold, or a fitness value within a predetermined appropriate range. Alternatively, the steps of method 200 may be performed in any order or combination, with or without the additional process steps described herein.

[0038] Identifying the set of sample peaks in the sample spectrum (step 210) involves identifying the set of peaks and associating the reference peaks with molecular fragments of the sample substance (e.g., an unknown substance). Each sample peak is associated with the mass of the sample fragment and a peak height or magnitude that is related to the relative contribution or abundance of that fragment within the fragmented sample molecules passing through the mass spectrometer during a selected sampling period.

[0039] Selecting a reference spectrum (step 220) can be performed via data communication with a database of such spectra, e.g., library or database 190 according to FIG. 1. Each sample spectrum contains a set of reference peaks associated with fragments of a particular (known) reference substance. Each reference fragment has its own characteristic (known) reference fragment mass and a peak magnitude or height that represents the relative abundance of that fragment in the fragmented reference molecule used to obtain the reference spectrum.

[0040] Typically, the reference and sample peaks do not all match, either in fragment mass (representing the total atomic or molecular weight of the fragment) or in relative height (representing the partial composition of the sample or reference material). In this adaptive method for mass spectrometer spectral analysis, the mass difference of one or more selected sample peaks in a sample spectrum compared to one or more selected reference peaks in a selected reference spectrum can be determined (step 230).

[0041] The mass differences are analyzed to identify and select one or more group exchanges (step 240). For example, a group exchange can represent a change in the chemical composition of a sample fragment associated with a selected sample peak, resulting in an observed mass difference compared to a reference component associated with a selected reference peak.

[0042] In some instances, a group exchange represents the exchange of an atomic group within a molecular fragment associated with a selected sample peak for a different atomic group within a molecular fragment associated with a selected reference peak, or may represent the removal of a group or the exchange of an entire molecular fragment associated with a selected sample peak for a molecular fragment associated with a selected reference peak.

[0043] Shifting the selected peak (step 250) can be accomplished by shifting the selected sample peak by the mass difference associated with the selected group exchange, or by shifting the selected reference peak by the mass difference, which can be either positive or negative along the mass scale of the spectrum, depending on whether the selected group exchange increases or decreases the respective fragment mass.

[0044] Determining a fit value (step 260) can be performed on the sample spectrum with respect to any selected reference spectrum, including those with shifted sample or reference peaks, such that the fit value is responsive to group exchange. The fit value can be defined to characterize the similarity between the sample and reference spectra according to a statistical measure or other metric, such as the convolution of their respective spectral functions or the dot product of vectors representing the peaks of the sample and reference spectra, respectively. Alternatively, a likelihood function or alternative measure of similarity can be used. Other examples of similarity metrics are described, for example, in K.X. Wan et al., "Comparing similar spectra: from similarity index to spectral contrast angle," J.Am.Soc. Mass Spectrometry, Vol. 13, No. 1, pp. 85-88 (2002), and C.J. Hargreaves et al., "The Earth Mover's Distance as a Metric for the Space of Inorganic Compositions," Chem. Mater., 2020, 32, 24 10610-10620 (American Chemical Society, December 2, 2020), which are incorporated herein by reference.

[0045] One or both of the sample and reference spectra can be output to a graphical user interface, such as interface 180, which can display a screen like that shown in FIG. 1 (step 270). Depending on the application, the fit values ​​and calculation method or the selected group exchange (or both) can also be output to the interface. Input can also be received from the user interface (step 280), e.g., the input determines the selected group exchange. In certain examples, a set of proposed or suggested group exchanges can be output to the user interface based on the identified mass difference. In these applications, the input may determine the selected group exchange from among the set of proposed group exchanges, e.g., based on user preference or user selection. Thus, a user can make a selection based on the sample spectrum and other analytical results displayed in the user interface and the availability of other analytical data developed to test hypotheses regarding the structure and composition of the unknown molecule being analyzed.

[0046] In some instances, one or more additional peaks in the sample or reference spectrum can be shifted (step 250) by a mass difference (step 250) that represents an additional group exchange (step 240). In these instances, the fit value (step 260) can characterize the similarity between the sample and reference spectra that include the additional shifted sample or reference peaks in response to the additional instances of group exchange.

[0047] In some examples, one or more additional group exchanges can be selected (step 240) to represent one or more additional mass differences (step 230) determined in the sample component masses associated with the sample peaks compared to the reference peak component masses associated with the reference peaks. In these examples, the fit value characterizes the similarity between the sample and reference spectra in response to the additional group exchanges, as one or more additional peaks in the sample or reference spectra are shifted by the additional mass differences.

[0048] In some applications, the sample and reference spectra are obtained from a mass spectrometry system, such as the GC-MS or LC-MS system 100 described above, and database 190. In these examples, sample peaks are typically associated with molecular fragments of the sample, and reference peaks are typically associated with molecular fragments of the reference. In other examples, the sample and reference spectra can be obtained from optical, ultraviolet, infrared, Raman, or nuclear magnetic resonance spectroscopy systems, and both the spectral content and other output to the user interface can be adapted accordingly. [Analysis system overview]

[0049] Figure 3 is a block diagram of an adaptive system for mass spectrometer spectral analysis 300. As shown in Figure 3, the system 300 includes an adaptive search and analysis (ASA) processor 170 in communication with a user interface 180 and a spectral library or database (DB) 190, such as the example shown in Figure 1.

[0050] ASA processor 170 includes memory 310, a computer processor or microprocessor (μP) 320, and an interface 330 for data communication with user interface 180 and spectral database 190. Memory 310 includes a non-transitory machine-readable data storage medium configured to store computer code executable on processor 320 to perform adaptive search analysis, for example, in accordance with system 100 of FIG. 1 or method 200 of FIG. 3.

[0051] 4A is an illustration of user interface 180A showing a representative spectrum 410 suitable for the adaptive spectral analysis described herein. In this particular example, the exact mass of the unknown sample appears in the spectrum in peak 415, representing an unfragmented unknown or sample molecule with a total mass value of 220 mass units (AMU or u), as indicated by highest mass peak 418. This value is used in the adaptive search to select a reference spectrum for comparison.

[0052] 4B is a diagram of user interface 180B showing matches (or potential matches) between representative sample and reference spectra. Figure 4B is a "butterfly" diagram with sample spectrum 410 upright and reference spectrum 420 inverted along the same baseline or x-axis. A hit list (or similar ranked list) 440 may be provided to identify a subset of candidate spectra that are selected based on a (e.g., relatively high) similarity metric.

[0053] Interface 180B may also display a diagram, image, or similar graphic 450 representing the chemical structure of the selected (or candidate) reference molecule, along with an additional information panel or window 455 containing one or more corresponding data fields, such as chemical name, chemical formula, classification, CAS (American Chemical Society) registry number, and / or other database / library name or identifier, as well as estimated mass, nominal mass, or exact mass (if known), estimated or nominal retention index (e.g., estimated Kovats retention index), and other information describing the match of the reference molecule or candidate.

[0054] For example, the appropriate field group F0 may be represented in window 455 as follows: Name / CS Registration Number / Classification / DB Name / Kovats (Estimated) / Mass / Formula [F0] Each data field can be given an associated name and value. Rather than selecting from among these (or all) representative properties, the user can select data fields from the original data file, from another (preferred) set of properties from an attachment, or from a selected set of molecular substructures (e.g., to identify candidate ΔM substitutions).

[0055] When a sample compound is found in the reference database (e.g., based on total mass and / or other sample peaks), the first (most similar) hit will typically be the compound itself, as shown in Figure 4B. In this case, sample spectrum 410 and reference spectrum 420 show the same highest (total mass) peak 418 / 428, similar peaks 415 / 425 in the remainder of the spectrum, and both mass values ​​(representing different fragments in the sample and reference spectra) and amplitudes (representing the same relative composition) match.

[0056] The quality of the match can also be described by a fit value, which provides a numerical assessment of the match (or similarity) between the sample and reference spectra. For example, the dot product of normalized vectors representing the peaks in each spectrum (sample and reference) can be used to generate a hit quality index (HQI) ranging from 0 to 1, with a maximum fit value of 1 and a minimum fit value of 0. Alternatively, a convolution of spectral functions, a likelihood function, or other mathematical measure of similarity can be used.

[0057] The list 440 displays a subset of candidate spectra that can be selected and / or ranked based on their respective similarity metrics or based on user input. The spectra are associated with a column field for a database (DB) identifier with a specific value for each column, such as a hit quality index (HQI) or other similarity metric, a user-selected or system-generated tag (TAG), and an identification (ID) number that catalogs the candidate spectrum within the database. The name of the candidate molecule may also be displayed in an appropriate industry-standard format, along with its exact (or known) mass and a graphical representation of the candidate spectrum itself, for comparison with the sample spectrum. For example, the following shows a suitable field group F1: HQI / TAG / DB / ID / Name / [Spectrum] [F1]

[0058] In these field representations, square brackets indicate fields that may contain graphical data. When a group substitution is selected, the list 440 of the selected subset of reference spectra may also include additional fields, such as a residual or adjusted hit quality index (R.HQI) (e.g., recalculated after the selected substitution), an associated ΔM value, and a description of the substitution (e.g., substitution of chlorine for another atom, or exchange of other atomic groups, in either or both graphical and textual form). If a particular spectrum contains a target molecular ion mass, that mass may be displayed in an associated field (e.g., a molecular mass or μ / z box, etc.), with a black triangle or other marker indicating the corresponding position within the (graphical) spectral field in the appropriate field group F2, described below. HQI / TAG / R.HQI / DB / ID / Name / [Spectrum] / ΔM / [ΔM] / Replace [F2]

[0059] 5A is an illustration of user interface 180C showing partial matches (and, conversely, partial mismatches) between representative sample and reference spectra. If a sample compound is not found in the reference database, the match value may change because the spectra may be less similar. For example, sample spectrum 410 and reference spectrum 420 may show similar total mass values ​​at peaks 418 and 428, respectively, but the amplitudes may vary, and other sample peaks 415 and reference peaks 425 may be less similar, as shown in FIG. 5A.

[0060] Depending on the fit values ​​and the sample and reference spectra compared and displayed on the user interface, the adaptive search results may or may not be confident that there is a good match between the (unknown) sample material and the (known) reference material, e.g., shown by graphic 455 along with total molecular weight and other identifying information in display window 455. In such cases, the user interface may also be configured to accept a total mass value, e.g., as input from the user, to select another reference spectrum or to determine a mass difference between the selected sample and reference peaks suitable for delta mass / group exchange analysis.

[0061] In situations where a representative sample of an unknown substance and one or more reference spectra partially match, the user interface allows the user to perform an adaptive search to find a better match with an improved fit. This adaptive search component is configured to compare the spectrum of the unknown sample to find similar compounds that may have molecular groups present, missing, or exchanged. The presence, absence, or exchange of groups causes some peak positions in the reference spectrum to differ relative to the spectrum of the unknown substance due to a change in mass or "delta mass" (ΔM).

[0062] The adaptive search function allows the user to shift some peaks by a selected ΔM to achieve a better match score or fit value. These changes may result in different similar compounds appearing at the top of the hit list (ranked subset or list) 440, identifying the highest similarity score. To mark shifts performed by the adaptive search, dotted lines or other indicia are used in a window in the user interface to indicate the shift of the reference fragment mass in the reference spectrum before and after the shifting process. These dotted lines or other indicia may also be selectively displayed in response to the user clicking or selecting a designated button or icon in the hit list 440, or in response to a similar input, to configure the display of the search results on the interface. Indicia may include color coding, parallel labels, tabular displays, or other similar indicia, indicators or indicia that identify or indicate the relationship between the shifted and unshifted mass peaks, or other spectral data.

[0063] FIG. 5B is an illustration of user interface 180D showing an improved match between a representative sample spectrum 410 and a shifted reference spectrum 430 based on delta mass / group exchange analysis. As shown in FIG. 5B, a mass difference (e.g., ΔM 26 u, or other designated value) is determined between selected peaks in the sample and reference spectra and used to select or suggest the missing group or group exchange corresponding to the mass difference. After the exchange (in one particular case, a cyclohexyl ring replaces a butyl group), the fit value increases substantially, reflecting a better match (improved fit) between the sample and shifted reference peaks 415 and 435, respectively, and more similar total mass peaks 418 and 438.

[0064] This is an example of a suitable ΔM exchange representative of adaptive search techniques. In other examples, the exchange ΔM, as well as the resulting matches between the sample and shifted reference peaks, can provide an indication of match quality, for example, in a visual or graphical comparison, independent of a hit quality index (HQI) or match value or similarity metric determined by an interface (e.g., one used to generate the ranked list 440).

[0065] See also additional examples below. Depending on the application, suitable output to user interfaces 180A-180D, 180E or 180F-180H and 180J (below) can include the mass difference (ΔM) between the selected peaks, information identifying the selected sample and reference peaks for which the mass difference was determined, and suggested group exchanges or substitutions that result in a difference (e.g., a higher fit value) after shifting the selected peak by the mass difference.

[0066] FIG. 6 is a diagram of the user interface 180E showing a representative sample (unknown) spectrum 410, a shifted reference spectrum 430, and an unshifted reference spectrum 420. As shown in FIG. 6, the mass difference between the sample peak 415 and the unshifted reference peak 425 is determined, e.g., ΔM=26u. This mass difference corresponds to a group exchange representing different molecular fragments of the (unknown) sample and the (known) reference. After the exchange, the reference peak 425 is shifted to a new value 435 to better match the sample peak 415. The total mass peak 428 in the reference spectrum is also shifted by the same amount to a new value 438 to match the total mass peak 418 of the sample.

[0067] 6 , reference peaks 425, 428 of reference spectrum 420 are shifted by a mass difference ΔM to generate shifted reference spectrum 430 having shifted peaks 435, 438 that better match sample peaks 415, 418 and result in a higher match value compared to sample spectrum 410. For convenience, the reference may typically be shifted to match the sample. Similarly, sample peaks 415, 418 of sample spectrum 410 may be shifted to match (unshifted or uncorrected) peaks 425, 428 of (unshifted) reference spectrum 420 based on the mass difference ΔM and the same corresponding group exchange. Thus, this technique can be performed on either basis (shifting either the sample or reference spectrum), depending on the application and user preference.

[0068] FIG. 7A is a diagram of the user interface 180F showing a representative sample spectrum 410 with an unknown molecular (total) mass. As shown in FIG. 7A, this sample spectrum 410 does not contain a clear total mass peak indicating the (unknown) molecular ion mass. This can occur, for example, if few or no sample molecules reach the detector without fragmenting. Nevertheless, the total mass can be estimated from other peaks 415 in the sample spectrum 410 (e.g., by combining the masses of different fragments and looking for peaks in the distribution), and the estimated mass can be used to select a reference spectrum for delta mass / group exchange analysis.

[0069] The estimated mass may also be in the form of a user input, output to user interface 180F, or updated via interface 180F. If the total mass cannot be determined from the sample spectrum, the system can determine one from the best-matching reference spectra based on (e.g., iterative) shifts of peaks in the sample spectrum that suggest at least one mass difference ΔM, and development of a numerical evaluation of the match (or similarity) between the sample and reference spectra adjusted by the peak shifts.

[0070] 7B is an illustration of user interface 180G showing an unshifted reference spectrum 420 that matches the sample spectrum 410 of FIG. 7A. The gross mass peaks 418, 428 may or may not be distinct in either the sample spectrum 410 or the reference spectrum 420, but the estimated mass values ​​appear to be accurate. The selected reference peak 425 of the reference spectrum 420 provides a good (adequate or improved) match with the corresponding sample peak 415 in the sample spectrum 410, reflected in a high Hit Quality Index (HQI) or other fit value.

[0071] 7B also provides a comparison of the reference spectrum 420 at 441 (upright) with a ranked list 440 containing a number of additional sample spectrum "hits" 442, 443, 444, and 445, e.g., with relatively high or low similarity metrics (based on HQI or other fit values). These sample spectra can be selected based at least in part on the mass peaks of the sample spectrum and the estimated or nominal total mass (or exact value, if known), or based on a total mass entered by the user into the user interface. The selected reference spectra can also be used to test the adaptive techniques and demonstrate the reliability of the results, for example, when one of the reference spectra is known in advance to match the sample, or by comparing two identical reference spectra, or two reference spectra with known group exchanges associated with known ΔM.

[0072] FIG. 8A is an illustration of user interface 180H showing a shifted reference spectrum 430 that matches the sample spectrum 410 of FIG. 7A. In this particular example, the shifted reference spectrum 430 may be derived from one of a selected subset or ranked list 440 of reference spectra, such as the second "hit" reference spectrum 442 of FIG. 7B, in which peak 435 is shifted by a representative mass difference ΔM of 20 μm. This corresponds to a group exchange replacing a chlorine in the shifted reference spectrum 430 with a methyl group, and matches both the unknown sample spectrum 410 and the known (unshifted) reference spectrum 420 of FIG. 7B, which differs from the references shifted by the same exchange value. Thus, the mass difference shift technique can be used not only to identify unknown sample substances, but also to verify the determination of mass differences between known reference spectra.

[0073] FIG. 8B is a diagram of user interface 180J showing a representative sample spectrum 410 along with selected reference spectra 420 and 441 (upright), as well as a selected subset or list 440 of additional candidates or "hits" 442, 443, 444, 445 based, for example, on a similarity metric, user input, or a combination thereof. For example, the interface can be configured for user input including information that identifies the sample spectrum or allows the interface to access the sample spectrum. Depending on the match quality, additional user input can include an estimated or nominal total mass associated with the sample spectrum, or a mass difference (ΔM) associated with a candidate group exchange used to shift peaks in the reference spectrum for comparison with peaks in the sample spectrum. The interface can also be configured to accept candidate references for adaptive searching, for example, as identified by chemical name, CAS registry number, or other library or database reference.

[0074] In the example of Figure 8B, there may or may not be a definite total mass peak 418. The user interface 180J allows the user to select, for example, hydrogen ions (H + / H - ) or metal ions (NA + ) substitution, allowing group exchanges to be selected a priori or from a suggested list.

[0075] In the particular case of Figure 8B, adaptive analysis can, in response to user input, return a single selected reference spectrum 420 and 441 (upright) with a relatively high fit value (e.g., HQI). Multiple additional, different selected "hit" reference spectra 442, 443, 444, 445 can also be provided with relatively high or low fit values. In either case, there are multiple relatively accurate mass "hits" where sample spectra 441, 442, 443, 444, 445 match one or more reference peaks 415 in reference spectrum 410. The user can then select from among the different reference spectra 441, 442, 443, 444, 445, each corresponding to a different group exchange, for example. Improved exploration and analysis

[0076] As can be seen from the above description and the examples provided below, the present disclosure teaches an improved method for analyzing spectra produced by various mass spectrometry systems. The method includes a butterfly-type display showing the distribution of total mass and fragment mass values ​​and indicating the abundances or magnitudes associated with these mass values ​​appearing in peaks in the sample spectrum and a selected reference spectrum that can be easily compared by a user of the interface. Furthermore, the user interface facilitates the use of various similarity metrics to calculate the degree of "fit" between various representations of the selected sample and reference spectra, such as the dot product of normalized vectors representing the peaks in the sample and reference spectra, or the convolution of corresponding spectral functions, or another metric such as the Earthmover distance metric. The resulting values ​​for calculating the degree of "fit" using various similarity metrics can be displayed as part of the user interface, and optionally, an identification of the specific fit metric used can also be displayed.

[0077] Additionally, the user interface allows the user to view and select candidate values ​​for the total mass of the sample material and the mass difference (ΔM) between selected peaks in the spectrum, and display a modified sample spectrum or a selected reference spectrum that reflects the application of an additive or subtractive adjustment to either spectrum based on the ΔM value. Whether or not use of these operations provided for in the user interface results in an improved match (e.g., a match that identifies one or more target molecules in the sample tested by mass spectrometry, or simply a partial or exact match), the display of the goodness-of-fit value and ΔM-adjusted spectrum allows the user to identify fragments for further adaptive searching or other analytical techniques, thereby improving identification of the sample molecule or fragments of the sample molecule of interest. [User Interface]

[0078] 9 is a chart illustrating process flow steps in an adaptive search method 1000, starting with a sample spectrum and searching for potential matches within a library of reference spectra. As shown in FIG. 9, the process or method 1000 includes one or more steps, including but not limited to the following: These steps involve specific user input actions and display of search results, and can be performed in any order or combination on or by a computer-based system or user interface, with or without additional analysis steps.

[0079] A sample spectrum is provided (step 1010) as a subject of the adaptive search method (1000). For example, a user interface can be configured to receive the sample spectrum and display the sample spectrum on a user interface (UI), such as a graphical user interface (GUI) 180 described herein.

[0080] An adaptive search is initiated (step 1020). If available, the adaptive search can be initiated based on a molecular ion mass determined or provided from the sample spectrum (step 1025). If a molecular ion mass is not determined or provided from the sample spectrum, the adaptive search can be initiated based on a molecular ion mass or mass range determined or provided from a set of sample spectrum peaks, or a user-defined molecular ion mass.

[0081] A reference spectrum (or another reference spectrum) is selected (step 1030). For example, one or more candidate reference spectra can be selected from a library, database, or another set of reference spectra for comparison with the sample spectrum. This method can be successively repeated to select another reference spectrum from the set until all candidates have been considered.

[0082] Iterate through delta mass (ΔM) values ​​(step 1040). The user interface can be configured to iterate through possible ΔM values ​​over a min-max range or to use a predefined range, such as -200 to +200 AMU. Alternatively, ΔM values ​​may range from ±1 AMU to ±100 AMU, ±1 AMU to ±200 AMU, or even greater. Alternatively, the interface can calculate, estimate, or otherwise determine possible ΔM values ​​based on selected peaks representing fragment masses in the sample and reference spectra.

[0083] Peaks to be shifted are selected (step 1050). For example, peaks can be selected based on overlap between the shifted reference spectrum and the original spectrum. If there is overlap, this may indicate that shifting the selected peaks may improve the fit value. Depending on the application, the ΔM value can represent the mass difference between two atoms or molecular groups that are exchanged to shift one or more reference peaks toward or onto the sample peaks and / or cause one or more of the reference spectra to provide a better fit (higher fit value) compared to the sample spectrum.

[0084] The selected peaks are shifted (step 1060). For example, the user interface can be configured to shift one or more of the selected peaks in the reference spectrum by a delta mass (ΔM) value.

[0085] A fit value is calculated (step 1070). For example, the user interface can be configured to calculate the fit value based on a numerical comparison between the sample spectrum and a selected reference spectrum using a selected set of peaks shifted by a particular ΔM value used in the current iteration.

[0086] The delta mass (ΔM) with the best fit value is selected (step 1080). For example, the user interface can be configured to select the ΔM value with the best (e.g., highest) fit value and use it as the best match between the sample spectrum and the selected reference spectrum. The user interface can also be configured to display the calculated ΔM with the best fit value and identify or display the molecular group associated with the delta mass (ΔM) value.

[0087] Iterating through all spectra (step 1090). For example, the process or method 1000 can be repeated to select another reference spectrum from the candidate set (step 1030) until all reference spectra in the set have been analyzed. For successive iterations, the user interface can also be configured to recalculate the fit by using a different delta mass (ΔM), selecting a different peak to shift, or both.

[0088] Adaptive Display of Search Results (Step 1100). For example, the user interface can be configured to display search results, including the sample spectrum and one or more candidate reference spectra, e.g., in a hit list (or similar subset of selected reference spectra) ranked by fitness value. The user interface can also be configured to display one or more selected reference spectra, e.g., with peaks shifted based on the adaptive search results. The user interface can also be configured to display the sample and reference spectra using dotted lines or other indicia to identify shifted peaks. The interface can also adapt to user input, as described herein, and can also adapt to update any of the search results, sample spectrum, candidate reference spectra, hit list, or shifted peaks based on the user input.

[0089] Depending on the application, for example, one or more of the reference spectra in a ranked list ("hit list") may be identified as matching the sample spectrum, with or without shifted peaks. One or more of the reference spectra may also be rejected (e.g., by the user or by the user interface itself) as not being a good match, and / or one or more additional reference spectra may be added to the hit list (or similar ranked subset) based on their corresponding match values.

[0090] The process or method 1000 can be repeated by providing a new sample spectrum for analysis (step 1010), and then running the method again and displaying the new or updated results (1100). Alternatively, the display of results (step 1100) can be performed at any point during the method (1000), or the method can proceed from displaying the results (step 1100) to any step between initiating the adaptive search (step 1020) and selecting the ΔM with the best fit (step 1080) before iterating through all the spectra (step 1090).

[0091] A computer-based user interface (e.g., interface 180 of FIG. 1 ) or system (e.g., system 100 of FIG. 1 or system 300 of FIG. 3 ) can be provided to perform a method or process 1000, as described herein, that involves interaction with a user seeking to find candidate reference spectra that may be identical or closely matched to a sample spectrum of unknown composition. The user interface allows the user to input a sample spectrum and control various system actions to find candidate matching reference spectra by comparing the sample spectrum to reference spectra of known molecules collected in a library. With input available in the form of a sample spectrum, the user can initiate a search for reference spectra based on similarity, and an output is returned to the user interface display that includes a ranked subset of reference spectra that are candidates for matches or near matches.

[0092] The user interface process or method can also be performed in combination with method 200 of FIG. 2 for adaptive search mass spectrometer spectral analysis. Based on candidates returned from the adaptive search, including information about fragments appearing in the reference spectrum containing specific chemical groups, the user can adapt the search strategy by achieving a mass shift (ΔM) of the fragment represented by the mass peak in the candidate reference spectrum. The shifted peak in the spectrum can serve as the basis for calculating or iteratively recalculating a fit value to the sample spectrum. The fit value may improve with recalculation, particularly if the shifted reference spectrum is improved enough to be a strong candidate for identifying the unknown composition of the sample spectrum. [example]

[0093] The method includes identifying or confirming a set of sample peaks in a sample spectrum, where, for example, the sample peaks are associated with fragments of the sample, each having a sample fragment mass. The method includes selecting a reference spectrum having a set of reference peaks associated with reference fragments, each having a reference fragment mass, determining a mass difference of a selected sample peak of the sample spectrum compared to the selected reference peak of the reference spectrum. The method can also include selecting a group exchange based on the mass difference, where the group exchange represents a change in the sample fragment mass associated with the selected sample peak compared to the reference fragment mass associated with the selected reference peak. The method also includes shifting the selected sample peak or the selected reference peak by the mass difference. The method also includes determining a fit value of the sample spectrum with respect to the reference spectrum. For example, the fit value characterizes the similarity between the set of sample and reference peaks, including the sample or reference peak shifted in response to the group exchange.

[0094] The method for obtaining a sample spectrum from a mass spectrometer system further includes, for example, outputting one or both of the sample spectrum and the reference spectrum to a user interface.

[0095] The method further includes outputting a total mass value to a user interface, where the total mass value is determined based on the sample peak in the sample spectrum, for example, for use in selecting a reference spectrum, determining a mass difference, or selecting a group exchange.

[0096] The method further includes receiving input from a user interface, for example, the user input is used to update or change the total mass value.

[0097] The method further includes outputting one or more of the fit value and the selected group exchange to a user interface, and receiving input from the user interface, for example, the input determining the selected group exchange.

[0098] The method further includes outputting the set of one or more proposed group exchanges to a user interface, for example, the input determining a selected group exchange from among the set of proposed group exchanges.

[0099] A method in which a group exchange represents the exchange of an atomic group in a molecular fragment associated with a selected sample peak for a different atomic group in a molecular fragment associated with a selected reference peak.

[0100] Group exchange is a method that describes the exchange of a molecular fragment associated with a selected sample peak with a molecular fragment associated with a selected reference peak.

[0101] The method may further include shifting one or more additional sample peaks in the sample spectrum or one or more reference peaks in the reference spectrum by a mass difference, e.g., the fit value characterizes the similarity between the sample and reference spectra including one or more additional shifted sample or reference peaks in response to additional instances of group exchange.

[0102] The method further includes selecting one or more additional group exchanges representing one or more additional mass differences in sample fragment masses associated with the sample peaks compared to reference fragment masses associated with the reference peaks. The method further includes shifting the one or more additional sample peaks or the one or more additional reference peaks by one or more additional mass differences. The fit value characterizes the similarity between the sample and reference spectra including the one or more additional shifted sample or reference peaks in response to the one or more additional group exchanges.

[0103] A method in which sample peaks are associated with molecular fragments of the sample and reference peaks are associated with molecular fragments of the reference.

[0104] The system comprises a memory, a computer processor, and an interface in data communication with a library of reference spectra. The memory can comprise a non-transitory machine-readable data storage medium having computer code stored thereon, the computer code being executable by the processor to perform a method according to any of the above examples.

[0105] The present invention has been described with reference to exemplary embodiments. It is understood that modifications may be made and equivalents may be substituted to adapt these teachings to different materials and situations while remaining within the scope of the invention. Therefore, it is not intended that the invention be limited to the particular examples disclosed, but rather that the invention will include all embodiments falling within the scope of the appended claims.

Claims

1. 1. A computer-based method of mass spectrometry comprising: identifying a set of sample peaks within a sample spectrum, wherein the sample spectrum is a sample mass spectrometer spectrum, and the sample peaks are associated with fragments of the sample, each having a sample fragment mass; selecting a reference spectrum having a set of reference peaks associated with reference fragments, each having a reference fragment mass; determining a mass difference of a selected sample peak in the sample spectrum compared to a selected reference peak in the reference spectrum; selecting a group exchange based on the mass difference, wherein the group exchange represents a change in the sample fragment mass associated with the selected sample peak compared to the reference fragment mass associated with the selected reference peak; shifting the selected sample peak or the selected reference peak by the mass difference; determining a fit value for the sample spectrum relative to the reference spectrum, wherein the fit value characterizes a degree of similarity between a set of sample and reference peaks including the shifted sample or reference peak corresponding to the group exchange; outputting the fit and one or both of the sample spectrum and the reference spectrum to a user interface; updating the fit value on the user interface corresponding to the group exchange; determining a total mass value based at least in part on the sample peaks in the sample spectrum; outputting the total mass value to a user interface; and selecting one or more of the reference spectrum, the mass difference, or the group exchange for display on the user interface based at least in part on the total mass value; Including, method.

2. updating the total mass value based on user input received through the user interface; further comprising:

10. The method of claim 1.

3. outputting a set of one or more suggested group permutations to the user interface, wherein the group permutations are selected from among the set of suggested group permutations based on user input received through the user interface; further comprising:

10. The method of claim 1.

4. The group exchange represents the exchange of an atomic group in one of the fragments of the sample with a different atomic group in one of the fragments of the reference.

10. The method of claim 1.

5. the group exchange represents the exchange of one or all atoms of one of the sample fragments associated with the selected sample peak with one or all atoms of one of the reference fragments associated with the selected reference peak; 10. The method of claim 1.

6. shifting one or more additional sample peaks in the sample spectrum or one or more reference peaks in the reference spectrum by the mass difference; further comprising the fit value characterizes the similarity between the sample and reference spectra including the one or more additional shifted sample or reference peaks corresponding to shifting the one or more additional peaks.

10. The method of claim 1.

7. selecting one or more additional group exchanges representing one or more additional mass differences of one or more of the sample fragment masses associated with the sample peak compared to one or more of the reference fragment masses associated with the reference peak; and shifting one or more additional sample peaks or one or more additional reference peaks by said one or more additional mass differences; further comprising the fit value characterizes the similarity between the sample and reference spectra including the one or more additional shifted sample or reference peaks corresponding to the one or more additional group exchanges.

10. The method of claim 1.

8. a processor configured to perform the method of claim 1; in data communication with a data library containing a plurality of one or more of said reference spectra; User interface.

9. further configured to display a subset of reference spectra identified from the data library based on the fit value; where one or more of the following are included: The subset includes an interactive list of the identified reference spectra ranked or listed based on the fitness value; the user interface is configured to receive input for updating the fit value in response to the mass difference; the user interface is configured to receive input to update the subset in response to an update of the fitness value; or the user interface is configured to receive input for updating the subset in response to a user input. The user interface of claim 8.

10. Computer code is stored The computer code is executable by a computer processor to perform the method of claim 1. A non-transitory machine-readable data storage medium.

11. a processor and memory adapted to compare a sample spectrum from the mass spectrometer with a set of reference spectra from the library; a user interface in communication with the processor; Equipped with each of the sample spectrum and the reference spectrum includes a plurality of peaks representing fragment masses of fragments; The user interface: displaying the sample spectrum; receiving input for identifying one or more of the reference spectra from the library based on a similarity or fit metric selected to identify identical or similar fragment masses in the sample spectrum and the reference spectrum, wherein the similarity or fit metric is further selected to identify identical or similar total masses associated with one or more of the peaks in the sample and reference spectra; displaying one or more of the identified reference spectra along with the sample spectrum; receiving an input to shift one or more of the peaks in the displayed sample or reference spectrum by a change in mass value corresponding to a group exchange in the fragment; receiving an input to select or update the total mass; receiving an input to identify the one or more reference spectra based on the selected or updated gross mass; and receiving an input for updating the similarity or fit metric based on the one or more shifted peaks; It is configured as follows: A computer-based spectroscopic analysis system.

12. the user interface is configured to juxtapose the sample and reference spectra along their respective mass scales; The system of claim 11.

13. the user interface is configured to represent the original and shifted positions of the one or more peaks along a respective mass scale, as identified or linked by one or more markings; The system of claim 12.

14. The similarity or fit metric is selected from the group consisting of a dot product, a convolution, a cross-correlation, a likelihood function, and an earthmover metric that manipulates the intensities of peaks representing fragment masses. The system of claim 11.

15. the user interface is configured to receive input for selecting a change in mass value corresponding to the group exchange or for updating a change in mass value corresponding to a different group exchange. The system of claim 11.

16. the user interface is configured to receive input for shifting the one or more peaks by a selected or updated change in mass value and updating the similarity or fit metric accordingly.

16. The system of claim 15.

17. the user interface is configured to receive input to select or update a change in mass value, shift one or more of the peaks in the displayed sample or reference spectrum by the selected or updated change in mass value, and update the similarity or fit metric accordingly. The system of claim 11.

18. the user interface is configured to display a subset of the identified reference spectra selected based on the similarity or fit metric; where one or more of the following are included: the subset includes an interactive list of the identified reference spectra ranked or listed based on the similarity or fit metric; the user interface is configured to receive input for updating the similarity or fit metric in response to changes in mass values; the user interface is configured to receive input to update the subset in response to an update to the similarity or fit metric; or the user interface is configured to receive input for updating the subset in response to a user input. The system of claim 11.

19. the user interface is configured to receive input to select one or more of the peaks to shift. The system of claim 11.

20. the user interface is configured to receive input for selecting the group exchange corresponding to a change in mass value; The system of claim 11.

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