Calibration of analytical instruments

Abstract

A method includes measuring a first physicochemical property of analyte ions to generate a dataset, and identifying a first group of analyte ions within the dataset. Each analyte ion in the first group has a value for an attribute corresponding to a first value or a first range of the attribute. The method further includes selecting a first calibration from a plurality of different calibrations associated with the first value or the first range of the attribute, and using the first calibration to calibrate the measured first physicochemical property of the first group of analyte ions.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority and benefit to UK Patent Application No. 2005715.4, filed on 20 April 2021. The entire contents of this application are incorporated herein by reference. Technical Field

[0003] This invention provides a method for calibrating analytical instruments such as mass spectrometers and / or ion mobility spectrometers. Background Technology

[0004] Analytical instruments such as mass spectrometers and / or ion mobility spectrometers are typically calibrated by ionizing a calibration compound and then measuring the physicochemical properties of the resulting ion (such as mass-to-charge ratio or ion mobility drift time). The measured physicochemical property values ​​are compared with reference physicochemical property values, and the difference between the measured and reference values ​​is determined. This difference is then used to determine the calibration for the instrument.

[0005] When the analyte is subsequently analyzed using an analytical instrument, it is ionized, and the physicochemical properties of the resulting analyte ions are measured using the instrument. Calibration is then used to correct the measured physicochemical property values ​​of the analyte ions.

[0006] The applicant believes there is still room for improvement in the methods for calibrating analytical instruments. Summary of the Invention

[0007] According to one aspect, a method is provided that includes:

[0008] The first physicochemical properties of the analyte ions are measured in order to generate a dataset;

[0009] Identify a first group of analyte ions within a dataset, wherein each analyte ion in the first group has a value of an attribute, the value corresponding to a first value, or within a first range of the attribute;

[0010] Select a first calibration associated with the first value or the first range of the attribute from a plurality of different calibrations; and

[0011] The first calibration is used to calibrate the measured first physicochemical properties of the first set of analyte ions.

[0012] Various embodiments relate to a method for calibrating analytical instruments (such as mass spectrometers and / or ion mobility spectrometers), wherein multiple different calibrations can be used to calibrate a dataset (such as mass spectrometry and / or ion mobility spectrometry). According to various embodiments, each of the multiple different calibrations is associated with a different value or range of at least a first ionic property (such as a specific charge state), a value or range of a second physicochemical property (such as ion mobility), and / or a value or range of an initial ion energy. In various embodiments, a set or more groups of analyte ions are identified in the dataset (spectrum) such that ions within each group share the same value, or fall within a range of the (first) property. The dataset (spectrum) is then calibrated by calibrating each group of ions within the dataset separately using calibrations associated with the value or range of the (first) ionic property of said group.

[0013] Therefore, various implementations involve a calibration method in which multiple different calibrations can be performed on a dataset, and in which a specific calibration for a set of ions within the dataset is selected based on one or more determined properties of those ions.

[0014] The various implementation schemes contrast with conventional techniques that use a single calibration on the dataset. The applicant has recognized that using multiple different calibrations on the dataset can produce more accurate calibrations.

[0015] As will be described in more detail below, this is because the initial conditions of ions with the same intrinsic value of a first physicochemical property (such as mass-to-charge ratio) can vary depending on the ion's property values ​​(such as charge state, second physicochemical property (ion mobility) value, and / or initial ion energy), and these differences in initial conditions can cause differences in the measured first physicochemical properties (such as time of flight) of ions with the same intrinsic value of a first physicochemical property (mass-to-charge ratio).

[0016] In this regard, the applicant has first recognized that it is possible to identify different groups of ions within a dataset, wherein ions in each group share the same or similar property values ​​(and thus initial conditions) (even where at least some of the groups overlap in terms of the first physicochemical properties), and secondly, by using different calibrations for each group, differences in initial conditions (and thus differences in the first physicochemical properties measured) can be taken into account.

[0017] Therefore, the accuracy of calibration can be improved by identifying one or more groups of analyte ions within a dataset (where each group includes ions with the same or similar property values) and selecting a calibration associated with the property values ​​of each group.

[0018] Therefore, it will be understood that various implementation schemes provide an improved method for calibrating analytical instruments.

[0019] The method may include:

[0020] Identify different second groups of analyte ions within the dataset, wherein each analyte ion in the second group has a value of the (first) attribute, the value corresponding to a second different value of the (first) attribute, or a second different range of the (first) attribute;

[0021] Select a second calibration from the plurality of different calibrations that is associated with the second value or the second range of the (first) attribute; and

[0022] The second calibration is used to calibrate the measured physicochemical properties of the second set of analyte ions.

[0023] According to one aspect, a method is provided that includes:

[0024] The first physicochemical properties of the analyte ions are measured in order to generate a dataset;

[0025] The first calibration is used to calibrate the measured first physicochemical properties of the first group of analyte ions; and

[0026] The first physicochemical properties of the different second group of analyte ions were calibrated using a second different calibration.

[0027] The analyte ions in the first group may each have a value of a first attribute, the value corresponding to a first value of the first attribute, or falling within a first range of the first attribute. The analyte ions in the second group may each have a value of the first attribute, the value corresponding to a second different value of the first attribute, or falling within a second different range of the first attribute.

[0028] The analyte ions in the first group may each have a value of a second (different) property, the value corresponding to a first value of the second property, or falling within a first range of the second property. The analyte ions in the second group may each have a value of the second property, the value corresponding to a second different value of the second property, or falling within a second different range of the second property.

[0029] The method may include using one or more third different calibrations to calibrate one or more different third groups of the measured first physicochemical properties of the analyte ions.

[0030] The method may include using multiple different calibrations to calibrate the dataset to obtain a calibrated dataset.

[0031] The method may include determining multiple different calibrations of the analytical instrument, wherein each of the multiple different calibrations is associated with a corresponding different value or range of the (first) attribute.

[0032] Each of the multiple different calibrations can also be associated with a corresponding different value or range of the second attribute.

[0033] According to one aspect, a method is provided that includes:

[0034] To ionize the calibrator in order to generate ions;

[0035] The first physicochemical properties of the ions were measured using analytical instruments.

[0036] For each reference value in the first set of reference values ​​for the first physicochemical property, determine the difference between the reference value and a measured value of the first physicochemical property associated with the reference value, and use the difference to determine a first calibration for the analytical instrument; and

[0037] For each reference value in the second set of reference values ​​for the first physicochemical property, the difference between the reference value and the measured value of the first physicochemical property associated with the reference value is determined, and the difference is used to determine a second calibration for the analytical instrument.

[0038] The reference values ​​in the first set of reference values ​​may correspond to ions having values ​​of the (first) attribute, wherein the value corresponds to a first value of the (first) attribute, or a first range of the (first) attribute. The reference values ​​in the second set of reference values ​​may correspond to ions having values ​​of the (first) attribute, wherein the value corresponds to a second different value of the (first) attribute, or a second different range of the (first) attribute.

[0039] The reference values ​​within the first set of reference values ​​may correspond to ions having values ​​of a second (different) property, said value corresponding to a first value of the second property, or within a first range of the second property. The reference values ​​within the second set of reference values ​​may correspond to ions having values ​​of the second property, said value corresponding to a second different value of the second property, or within a second different range of the second property.

[0040] The method may include:

[0041] For each of the third set of multiple reference values ​​for the first physicochemical property, the difference between the reference value and the measured value of the first physicochemical property associated with the reference value is determined, and the difference is used to determine a third calibration for the analytical instrument.

[0042] The reference values ​​within the third set of reference values ​​may correspond to ions having the value of the (first) property, wherein the value corresponds to a third different value of the (first) property, or a third different range of the (first) property. The reference values ​​within the third set of reference values ​​may correspond to ions having the value of the second property, wherein the value corresponds to a third different value of the second property, or a third different range of the second property.

[0043] The first physicochemical property may include mass-to-charge ratio, time of flight, ion mobility and / or collision cross-section.

[0044] The first physicochemical property may include mass-to-charge ratio and / or time of flight, and the step of measuring the first physicochemical property of the ion may include mass analysis of the ion to generate a mass spectrometer and / or time-of-flight spectrum.

[0045] The step of measuring the first physicochemical property of the ion may include mass analysis of the ion using a time-of-flight (“ToF”) mass analyzer.

[0046] The first and / or second attributes may include a second (optionally different) physicochemical property. At least one (such as the first) attribute may include a second different physicochemical property (i.e., a physicochemical property that is different from (not the same as) the first physicochemical property).

[0047] The first and / or second attributes may include charge state. Ions within each group may have the same charge state, and each group may correspond to different charge states.

[0048] The first and / or second properties may include mass-to-charge ratio, time of flight, ion mobility, and / or collision cross-section.

[0049] Ions within each group may have ion mobility values ​​and / or collision cross sections within the same range, and each group may correspond to different ranges of ion mobility and / or collision cross sections.

[0050] Ions within each group may have mass-to-charge ratios and / or flight times within the same range, and each group may correspond to different ranges of mass-to-charge ratios and / or flight times.

[0051] The first and / or second attribute may include energy.

[0052] The first attribute may include ion mobility value and / or collision cross section, and the second attribute may include mass-to-charge ratio and / or time of flight.

[0053] According to one aspect, an analytical instrument is provided, which is configured to perform the methods described above.

[0054] The analytical instruments may include a mass spectrometer and / or an ion mobility spectrometer.

[0055] According to one aspect, a method is provided that includes:

[0056] Ion groups were measured using a time-of-flight mass spectrometer (“ToFMS”).

[0057] Identifying ions with specific properties and / or characteristics; and

[0058] Calibration is applied based on the aforementioned attributes and / or characteristics. Attached Figure Description

[0059] Various embodiments of the invention will now be described by way of example only and with reference to the accompanying drawings, in which:

[0060] Figure 1 The analytical instruments are illustrated according to various implementation schemes.

[0061] Figure 2 A schematic illustration of a time-of-flight (“ToF”) quality analyzer according to various implementation schemes;

[0062] Figure 3 The data demonstrate the mass accuracy and mass-to-charge ratio of single-charged ions, double-charged ions, and triple-charged ions measured using a time-of-flight mass spectrometer (“ToF-MS”).

[0063] Figure 4 A conceptual representation of a multidimensional drift time-m / z dataset;

[0064] Figure 5 This is a flowchart illustrating calibration methods according to various implementation schemes; and

[0065] Figure 6 This is a flowchart illustrating methods for determining multiple calibrations according to various implementation schemes. Detailed Implementation

[0066] Figure 1 Schematic illustration of analytical instruments, such as mass spectrometers and / or ion mobility spectrometers, according to various implementation schemes. For example... Figure 1 As shown, the analytical instrument includes an ion source 10, one or more functional components 20 disposed downstream of the ion source 10, and an analyzer 30 disposed downstream of the ion source 10 and the one or more functional components 20.

[0067] like Figure 1 As shown, the analytical instrument can be configured such that ions can be provided to the analyzer 30 from the ion source 10 via one or more functional components 20.

[0068] Ion source 10 may be configured to generate ions, for example, by ionizing a calibrator or analyte. Ion source 10 may include any suitable ion source, such as those selected from the group consisting of: (i) electrospray ionization (“ESI”); (ii) atmospheric pressure photoionization (“APPI”); (iii) atmospheric pressure chemical ionization (“APCI”); (iv) matrix-assisted laser desorption / ionization (“MALDI”); (v) laser desorption / ionization (“LDI”); (vi) atmospheric pressure ionization (“API”); (vii) silicon-on-silicon desorption / ionization (“DIOS”); (viii) electron beam desorption / ionization (EBD). Impact (“EI”) ion source; (ix) Chemical ionization (“CI”) ion source; (x) Field ionization (“FI”) ion source; (xi) Field desorption (“FD”) ion source; (xii) Inductively coupled plasma (“ICP”) ion source; (xiii) Fast atomic bombardment (“FAB”) ion source; (xiv) Liquid phase secondary ion mass spectrometry (“LSIMS”) ion source; (xv) Desorption electrospray ionization (“DESI”) ion source; (xvi) Nickel-63 radioactive ion source; (xvii) Atmospheric pressure matrix-assisted laser desorption / ionization ion source. Sources; (xviii) Thermal spray ion source; (xix) Atmospheric sampling glow discharge ionization (“ASGDI”) ion source; (xx) Glow discharge (“GD”) ion source; (xxi) Impactor ion source; (xxii) Real-time direct analysis (“DART”) ion source; (xxiii) Laser spray ionization (“LSI”) ion source; (xxiv) Ultrasonic spray ionization (“SSI”) ion source; (xxv) Matrix-assisted inlet ionization (“MAII”) ion source; (xxvi) Solvent-assisted inlet ionization (“SAII”) ion source; (xxvii) Desorption electrospray ionization (“DESI”) ion source; (xxviii) Laser ablation electrospray ionization (“LAESI”) ion source; (xxix) Surface-assisted laser desorption ionization (“SALDI”) ion source; (xxx) Low-temperature plasma (“LTP”) ion source; (xxxi) Helium plasma ionization (“HePI”) ion source; (xxxii) Rapid evaporation ionization mass spectrometry (“REIMS”) ion source; and / or (xxxiii) Laser-assisted rapid evaporation ionization mass spectrometry (“LA-REIMS”) ion source.

[0069] In various specific embodiments, ion source 10 includes an electrospray ionization (“ESI”) ion source.

[0070] The analytical instrument may include a chromatographic separation device or other separation device upstream of (and coupled to) the ion source 10. Figure 1(Not shown in the image). The chromatographic separation apparatus may include a liquid chromatography apparatus or a gas chromatography apparatus. Alternatively, the separation apparatus may include: (i) a capillary electrophoresis (“CE”) separation apparatus; (ii) a capillary electrochromatography (“CEC”) separation apparatus; (iii) a substantially rigid ceramic-based multilayer microfluidic substrate (“ceramic plate”) separation apparatus; or (iv) a supercritical fluid chromatography separation apparatus.

[0071] The analyzer 30 can be configured to analyze ions in order to determine (measure) one or more of their physicochemical properties, such as their mass-to-charge ratio, time of flight, drift time (ion mobility), and / or collision cross section (CCS).

[0072] The analyzer 30 may include a mass analyzer (configured to determine the mass-to-charge ratio or time of flight of ions) and / or an ion mobility analyzer (configured to determine the ion mobility drift time or collision cross section (CCS)).

[0073] In the case where analyzer 30 includes a mass analyzer, the mass analyzer may include any suitable mass analyzer, such as a mass analyzer selected from the group consisting of: (i) a quadrupole mass analyzer; (ii) a 2D or linear quadrupole mass analyzer; (iii) a Paul or 3D quadrupole mass analyzer; (iv) a Penning trap mass analyzer; (v) an ion trap mass analyzer; (vi) a magnetic sector mass analyzer; (vii) an ion cyclotron resonance (“ICR”) mass analyzer; (viii) a Fourier transform ion cyclotron resonance (“FTICR”) mass analyzer; (ix) an electrostatic mass analyzer arranged to generate an electrostatic field with a quadrupole logarithmic potential distribution; (x) a Fourier transform electrostatic mass analyzer; (xi) a Fourier transform mass analyzer; (xii) a time-of-flight mass analyzer; (xiii) an orthogonal acceleration time-of-flight mass analyzer; and (xiv) a linear acceleration time-of-flight mass analyzer.

[0074] In various specific implementations, the analyzer 30 includes a time-of-flight quality analyzer.

[0075] One or more functional components 20 may include any suitable such components, devices and functional elements of the analytical instrument (mass spectrometer and / or ion mobility spectrometer).

[0076] For example, in various embodiments, one or more functional components 20 include one or more ion directors, one or more ion traps and / or one or more mass filters, such as the one or more ion directors, one or more ion traps and / or one or more mass filters, which may be selected from the group consisting of: (i) quadrupole mass filters; (ii) 2D or linear quadrupole ion traps; (iii) Paul or 3D quadrupole ion traps; (iv) Penning ion traps; (v) ion traps; (vi) magnetic sector mass filters; (vii) time-of-flight mass filters; and (viii) Wien filters.

[0077] One or more functional components 20 may include activation, collision, fragmentation or reaction devices configured to activate, fragment or react ions to produce fragment or product ions.

[0078] One or more functional components 20 may include an ion mobility separator configured to separate ions based on their ion mobility. The ion mobility separator may include a linear ion mobility separator or a closed-loop (ring-shaped) ion mobility separator.

[0079] The analytical instrument can operate in various modes, including: mass spectrometry (“MS”) mode; tandem mass spectrometry (“MS / MS”) mode; a mode in which parent or precursor ions alternately fragment or react to produce fragment or product ions, and fragmentation or reaction is minimal or non-reaction; multiple reaction monitoring (“MRM”) mode; data-dependent analysis (“DDA”) mode; data-independent analysis (“DIA”) mode; quantitative mode; or ion mobility spectrometry (“IMS”) mode.

[0080] It should be noted that Figure 1 This is for illustrative purposes only, and the analytical instrument may (and does) include features for... Figure 1 Other components, devices, and functional elements shown in the document.

[0081] like Figure 1As shown herein, the analytical instrument may include a control system 40, which may be configured to control the operation of the analytical instrument, for example, in the manner described in the various embodiments herein. The control system may include a suitable control circuitry configured to cause the instrument to operate in the manner described in the various embodiments herein. The control system may include a suitable processing circuitry configured to perform any one or more of the necessary processing and / or post-processing operations for the various embodiments described herein. In various embodiments, the control system may include a suitable computing device, a microprocessor system, a programmable FPGA (Field-Programmable Gate Array), etc.

[0082] Figure 2 A more detailed demonstration of the Time-of-Flight (“ToF”) quality analyzer 30 according to various implementation schemes.

[0083] Ions can be supplied to the mass analyzer 30 via one or more functional components 20 upstream of the mass analyzer 30. Before being introduced into the analyzer 30, the ions can be "thermothered" (so that all ions have the same thermal energy), for example by being cooled by collision with an aeration zone (of one or more functional components 20) upstream of the analyzer 30.

[0084] like Figure 2 As shown, the mass analyzer 30 may include an accelerating electrode 31 (such as a pusher and / or puller electrode), an accelerating region 32, a field-free region or drift region 33, and an ion detector 34 disposed at the exit region of the field-free region or drift region 33.

[0085] It should be noted here that Figure 2 This is for illustrative purposes only, and other time-of-flight (“ToF”) quality analyzer arrangements, such as reflector arrangements and multiple reflection time-of-flight (“mr-ToF”) arrangements, may be used. Therefore, although... Figure 2 Not shown, but in various embodiments, the mass analyzer 30 may also include a reflector (in which case the detector 34 may optionally be located near the accelerating electrode 31) and / or one or more ion mirrors.

[0086] Ions from one or more upstream stages 20 of the instrument can be arranged to enter an acceleration zone 32, where they can be driven into a field-free or drift zone 33 by applying a voltage pulse to an accelerating (pusher) electrode 31. The ions can be accelerated to a velocity determined by the energy applied by the voltage pulse and the ion's mass-to-charge ratio. Ions with a relatively low mass-to-charge ratio achieve relatively high velocities and arrive at the ion detector 34 before ions with a relatively high mass-to-charge ratio.

[0087] Ions can arrive at ion detector 34 after a time determined by their velocity and travel distance, making it possible to determine the mass-to-charge ratio of the ions. Each ion or ion group arriving at detector 34 can be sampled by detector 34, and the signal from detector 34 can be digitized. The processor can then determine values ​​indicating the time of flight and / or mass-to-charge ratio (“m / z”) of the ions or ion groups. Data from multiple ions can be collected and combined to generate a dataset including time-of-flight (“ToF”) spectra and / or mass spectra.

[0088] According to various embodiments, for each ion or ion group arriving at detector 34, detector 34 will generate one or more signals, which can then be digitized and converted into time-intensity pairs, i.e., data values ​​including time-of-flight values ​​and intensity values. In these embodiments, multiple such time-intensity pairs can be collected and combined to generate a dataset including time-of-flight (“ToF”) spectra and / or mass spectra.

[0089] Various implementation schemes involve calibrating analytical instruments (such as...) Figure 1 Methods for calibrating analytical instruments. Various embodiments involve methods for calibrating analytical instruments, including mass analyzers, such as time-of-flight (“ToF”) mass analyzers, such as… Figure 2 Time-of-flight ("ToF") quality analyzer.

[0090] In time-of-flight (“ToF”) mass analyzer (and other) setups, a calibration characteristic curve, such as a calibration curve, can be used to determine the mass-to-charge ratio based on the measured time of flight. Alternatively, a conversion characteristic curve, such as a conversion curve, can be used to determine the mass-to-charge ratio based on the measured time of flight, and then a calibration characteristic curve, such as a calibration curve, can be used to determine a calibrated (more accurate) mass-to-charge ratio value.

[0091] In a standard setup, a single calibration curve is typically used to calibrate the dataset (mass spectrometer) across its entire (mass-to-charge ratio) range.

[0092] However, various implementations involve a method for calibrating analytical instruments in which a dataset (such as a mass spectrometer) can be calibrated using multiple different calibrations (such as by using multiple different calibration curves). The applicant has recognized that using multiple different calibrations on the dataset (mass spectrometer) can produce a more accurate calibration.

[0093] This is because the initial conditions of ions with the same intrinsic values ​​of first physicochemical properties (such as the same intrinsic mass-to-charge ratio) can vary depending on the ion's property values ​​(such as charge state, second physicochemical property values ​​(such as ion mobility) and / or initial ion energy), and these differences in initial conditions can cause differences in the measured first physicochemical properties (such as time of flight) of ions with the same intrinsic values ​​of first physicochemical properties.

[0094] For example, the initial position or positional distribution of ions with the same mass-to-charge ratio within the acceleration region 32 (relative to the acceleration electrode 31) may vary depending on the ion's property values ​​(such as charge state, secondary physicochemical properties such as ion mobility, and / or initial ion energy), and these differences in initial position or positional distribution may cause differences in the measured flight time (and thus the measured mass-to-charge ratio) of ions with the same intrinsic mass-to-charge ratio.

[0095] In this regard, the applicant has first recognized that it is possible to identify different groups of ions within a dataset (such as mass spectrometry) in which ions in each group share the same or similar property values ​​(and thus initial conditions) (even if at least some of the groups overlap in terms of first physicochemical properties (such as mass-to-charge ratio), and secondly, by using different calibrations for each group, differences in initial conditions (and thus differences in the first physicochemical properties measured) can be taken into account and corrected.

[0096] Therefore, according to various embodiments, a first physicochemical property of the analyte ions is measured to generate a dataset, and at least a first group of analyte ions is identified within the dataset. Each analyte ion in the first group may have a value for an attribute corresponding to a first value, or within a first range of said attribute. A first calibration associated with the first value or first range of the attribute is then selected from a plurality of different calibrations, and the first calibration is used to calibrate the measured first physicochemical property of the first group of analyte ions.

[0097] For example, the time of flight and / or mass-to-charge ratio of analyte ions can be measured to generate time-of-flight spectra and / or mass spectra, and at least a first group of analyte ions can be identified within said spectra. The analyte ions within the first group may each have values ​​for attributes (such as charge state, second physicochemical properties (such as ion mobility) and / or initial ion energy) corresponding to a first value or within a first range of attributes. A first calibration associated with the first value or first range of attributes can then be selected from a plurality of different calibrations, and the first calibration can be used to calibrate the measured time of flight and / or mass-to-charge ratio of the first group of analyte ions.

[0098] According to various embodiments, multiple different calibrations are provided, each of which is associated with a different value or range of an ionic property (such as a specific charge state), a value or range of a second physicochemical property (such as ion mobility), and / or a value or range of an initial ion energy. In various embodiments, multiple groups of analyte ions are identified within a dataset such that ions within each group share the same value, or a range of said property. Each group of ions is then calibrated separately using a calibration associated with the value or range of the ionic property of said group.

[0099] Therefore, a second group, a third group, and / or another different group of analyte ions can also be identified within the dataset. The analyte ions within the second group, the third group, and / or another group may each have a value for a property corresponding to a second, third, and / or another different value, or a second, third, and / or another different range of said property. A second, third, and / or another calibration associated with the second, third, and / or another value or a second, third, and / or another range of the property can then be selected from a plurality of different calibrations, and the second, third, and / or another calibration can be used to calibrate the measured first physicochemical properties of the second, third, and / or another group of analyte ions.

[0100] For example, a second, third, and / or another group of analyte ions can also be identified within the time-of-flight spectrum and / or mass spectrometry. A second, third, and / or another calibration associated with a second, third, and / or another value or range of the property can then be selected from several different calibrations, and the measured time of flight and / or mass-to-charge ratio of the second, third, and / or another group of analyte ions can be calibrated using the second, third, and / or another calibration.

[0101] Therefore, various implementations involve a calibration method in which multiple different calibrations of a dataset are possible, and in which a specific calibration for a set of ions within the dataset is selected based on the determined properties of those ions. By identifying one or more sets of analyte ions within the dataset (where each set includes ions with the same or similar property values) and selecting a calibration associated with the property values ​​of each set, calibration accuracy can be improved. Thus, various implementations allow for improved (quality) precision.

[0102] In various other implementations, ions can be identified as belonging to a particular group based on more than one attribute. For example, for multidimensional data (such as mass-to-charge ratio (m / z) - mobility), different calibrations can be applied to different regions of the multidimensional (such as m / z - mobility) space.

[0103] Therefore, the method may include identifying a first group of analyte ions within a dataset, wherein each analyte ion in the first group has a value of a first attribute, the value corresponding to a first value or within a first range of the first attribute, and wherein each analyte ion in the first group has a value of a second (different) attribute, the value corresponding to the first value or within a first range of the second attribute. The method may include selecting a first calibration from a plurality of different calibrations that is associated with a first value or first range of the first attribute and with a first value or first range of the second attribute.

[0104] The method may include identifying different second groups of analyte ions within a dataset, wherein each analyte ion in the second group has a value of a first attribute, the value corresponding to a second different value, or a second different range of the first attribute, and wherein each analyte ion in the second group has a value of a second attribute, the value corresponding to a second different value, or a second different range of the second attribute. The method may include selecting a second calibration from a plurality of different calibrations that associates a second value or a second range of the first attribute with a second calibration and a second calibration that associates the second value or second range of the second attribute with a second calibration.

[0105] The method may include identifying different third group analyte ions in a corresponding manner.

[0106] In these embodiments, the first attribute and the second attribute may each include any of the attributes described herein. In various embodiments, at least one (such as the first) attribute includes a second distinct physicochemical property (i.e., a physicochemical property that is different from (not identical to) the first physicochemical property). In various embodiments, the first attribute includes ion mobility values ​​and / or collision cross-sections, and the second attribute includes mass-to-charge ratio and / or time of flight.

[0107] Various implementation schemes are particularly suitable for high-quality precision systems, such as multi-reflection time-of-flight (“mr-ToF”) arrangements.

[0108] In these (and other) arrangements, the initial conditions (position / spatial distribution) of ions at the accelerating electrode 31 may limit the mass accuracy (rather than the ToF itself). This is because, even if the ions arriving at the accelerating electrode 31 are fully thermalized (i.e. have the same thermal energy), the initial conditions may vary depending on the different properties of the ions.

[0109] For example, in time-of-flight mass spectrometers (“ToF-MS”) (and elsewhere), ions are typically introduced into the analyzer 30 from a gas-filled RF confinement device (such as an RF ion guide). This device can be used to adjust the ion beam to improve the spectrometer’s resolution and transmission characteristics.

[0110] The initial conditions of the ions can be subtly dependent on the properties of the ions within the ion beam, particularly such as mass, charge state (z), mass-to-charge ratio (“m / z”), ion mobility, energy, and combinations of these properties. Although such variations in initial conditions may have a negligible effect on the resolution and sensitivity characteristic curves of the instrument, the applicant recognizes that they can significantly affect mass-to-charge ratio (“m / z”) calibration.

[0111] For example, when measuring doubly charged ions, calibration based on monocharged ions may not be optimal. This is because ions with different charge states (but the same mass-to-charge ratio (“m / z”)) will arrive at the accelerating electrode 31 with different spatial distributions.

[0112] This is because after thermalization, all ions will have the same energy (corresponding to the temperature of the thermally heated gas). Kinetic energy is the sum of mass (m) and the square of velocity (v). 2 This is proportional to the mass-to-charge ratio ("m / z"). Therefore, larger ions (larger masses) will have smaller velocities (v) and thus smaller spatial distributions in the gas-filled zone prior to the (ToF) mass analyzer 30. This subsequently means that, for ions with the same mass-to-charge ratio ("m / z"), those with larger charges (z) (and thus larger masses (m)) will have smaller spatial distributions compared to those with smaller charges (and thus smaller masses).

[0113] Therefore, the conventional assumption that ions with the same mass-to-charge ratio (“m / z”) will have the same time of flight does not hold in this case (because ions with different charges but the same mass-to-charge ratio (“m / z”) have different initial positions).

[0114] Therefore, it will be understood that the mean time of flight of an ion swarm in a ToF analyzer depends not only on its mass-to-charge ratio (“m / z”). The mean time of flight also depends on the initial phase space within the acceleration region 32. Due to the nature of RF confinement, this in turn depends on other ion properties, such as charge state, ion mobility, and axial energy. Even for thermally charged ions, this can cause a time-of-flight difference of hundreds of ppb for ions with the same mass-to-charge ratio (“m / z”) but different charge states. (This problem becomes even worse for non-thermally charged ions, as will be further described below).

[0115] Figure 3 This is illustrated in the figure, which shows the mass accuracy and mass-to-charge ratio data of single-charged, double-charged, and triple-charged ions measured using time-of-flight mass spectrometry. (As shown by...) Figure 3 It is evident that the precision of monocharged ions, doubly charged ions, and tricharged ions differs. Furthermore, due to... Figure 3 As can be seen, each group of ions can use a different calibration curve. Figure 3 Accurate calibration is performed using the solid line in the middle.

[0116] Various implementation schemes are also applicable, or alternatively, particularly to lower precision instruments, especially where all ions may not be fully thermalized before reaching the (ToF) mass analyzer 30.

[0117] As the trend toward smaller, cheaper instruments continues, performance inevitably suffers. Typically, one of the first performance metrics affected is mass accuracy. This may be the case, for example, in instruments with relatively short inflation zones prior to the mass analyzer 30.

[0118] An example of such an instrument is described, for instance, in PCT / GB2019 / 051510, the entire contents of which are incorporated herein by reference. In this example, the segmented quadrupole ion director 320 may be relatively short, and therefore the ions reaching the mass analyzer 304 may not be fully thermalized. The degree of thermalization can affect mass calibration and can depend on factors such as charge state, ion mobility, and implantation energy.

[0119] For example, ions with higher ion mobility will be less affected by the thermal gas and will therefore have higher energy and thus a larger spatial distribution before the (ToF) mass analyzer 30.

[0120] Therefore, the conventional assumption that ions with the same mass-to-charge ratio (“m / z”) will have the same time of flight does not hold (because ions with different ion mobilities but the same mass-to-charge ratio (“m / z”) have different initial positions).

[0121] Therefore, it is beneficial to calibrate these ions according to their properties and / or characteristics. These effects may also occur in, for example, higher-performance instruments with targets of lower mass accuracy.

[0122] Various implementations can also be applied to arrangements where ions are input to mass analyzer 30 (or one or more upstream functional stages 20) with different energies, i.e., arrangements where ions have different input energies. For example, in experiments in which the energy of ions is switched or altered (e.g., ramped) in a fragmentation device such as a collision cell (e.g., a “shotgun” experiment, e.g., as described in US 6717130, the entire contents of which are incorporated herein by reference), ions leaving the fragmentation device (collision cell) may have different residual energies and therefore different spatial distributions before the (ToF) mass analyzer 30.

[0123] Therefore, the conventional assumption that ions with the same mass-to-charge ratio (“m / z”) will have the same time of flight does not hold (because ions with different input energies but the same mass-to-charge ratio (“m / z”) have different initial positions).

[0124] As described above, in various implementation schemes, different ion groups (such as different charge states, different regions of mobility, different multidimensional data regions, and different input energies) in the analyte ion data are identified, and different calibrations are used for each different group.

[0125] In various embodiments, one or more groups within the groups may overlap in terms of the first physicochemical property (mass-to-charge ratio (“m / z”)). That is, ions within different groups may be distributed within the same or overlapping range of the first physicochemical property. However, the applicant has recognized multiple ways in which ions within each group can be identified.

[0126] For example, when the attribute is charge state, for one-dimensional data (such as mass-to-charge ratio (m / z)), peak detection can be used on mixed spectra to distinguish which ions are single-charged, double-charged, triple-charged, etc. For example, single-charged ions may have isotopes with a 1 Da interval, double-charged ions may have isotopes with a 1 / 2 Da interval, triple-charged ions may have isotopes with a 1 / 3 Da interval, and so on. Ions for each charge state can be grouped together, and different calibrations can be used for each group of ions.

[0127] For two-dimensional data (such as m / z mobility), different charge states can be distinguished based on their characteristic m / z mobility distribution.

[0128] When the property is ion mobility, different calibrations can be applied to different regions of mobility or different regions of the m / z mobility space.

[0129] More generally, for multidimensional data (such as m / z mobility data), different calibrations can be applied to different regions of the multidimensional data (such as different regions of the m / z mobility space).

[0130] Therefore, for example, such as Figure 4 As shown, a first calibration can be used for region 1 (which has a first range of mass-to-charge ratio and a first range of ion mobility drift time), and a second different calibration can be used for region 2 (which has a second different (overlapping) range of mass-to-charge ratio and a second different (overlapping) range of ion mobility drift time). More generally, in such data, different calibrations can be used for different ranges of mass-to-charge ratio (m / z), different ranges of ion mobility drift time, or different m / z mobility regions of the data.

[0131] The implementation scheme can also be applied to parallel-accumulation serial fragmentation (PASEF) type experiments or similar experiments, in which different fragment ion groups are obtained from different parent ions, and in which fragment ion groups are separated within a drift time corresponding to the drift time interval of the parent ions. In this case, different calibrations can be used for each group of fragment ions.

[0132] Figure 5 This is a flowchart illustrating methods for calibrating analytical instruments according to various implementation schemes.

[0133] like Figure 5 As shown in the diagram, according to various implementation schemes, the analyte is ionized to generate analyte ions (…). Figure 5 (Step 60 in the text). This can be accomplished using ion source 10.

[0134] The analyte ions can then be measured using analytical instruments to determine their physicochemical properties, such as mass-to-charge ratio, time of flight, drift time (ion mobility), and / or collision cross-section (CCS). (Alternatively, the analytical instrument may be used to measure the physicochemical properties of product or fragment ions derived from the calibration ions.) Thus, the first physicochemical properties may include mass, mass-to-charge ratio, time of flight, ion mobility, drift time (ion mobility), and / or collision cross-section (CCS).

[0135] This may include passing ions from ion source 10 through one or more functional components 20 and into analyzer 30. The analyzer 30 can then analyze the ions (and / or product or fragment ions derived from the ions) for example, to generate mass spectra and / or ion mobility spectra of the analyte ions (and / or product or fragment ions derived from the analyte ions). Figure 5 Step 61 in the process.

[0136] Therefore, the dataset may include mass spectrometry and / or ion mobility spectrometry, and the use of analytical instruments to measure the physicochemical properties of ions (and / or product or fragment ions derived from ions) may include the use of analytical instruments to generate mass spectrometry and / or ion mobility spectrometry of analyte ions (and / or product or fragment ions derived from analyte ions).

[0137] Analytical instruments can be used to measure a single physicochemical property, in which case the dataset can be a one-dimensional dataset, such as mass spectrometry and / or ion mobility spectrometry. Alternatively, analytical instruments can be used to measure multiple physicochemical properties, in which case the dataset can be a multidimensional dataset, such as a two-dimensional mass-to-charge ratio and ion mobility dataset. For example, a two-dimensional mass-to-charge ratio and ion mobility dataset can be obtained by separating ions in an ion mobility separator before analyzing the ions in the mass analyzer 30.

[0138] Once the dataset is obtained, at least a first group of ions can be identified within it. In various implementations, multiple distinct groups of ions can be identified within the dataset. Some, most, or all of the ions in the dataset can be assigned to a single group. Each ion assigned to a group can be assigned to only a single group.

[0139] All analyte ions within a group may each have the same value for a property, or may each have a value for a property within a specific range of that property. Therefore, analyte ions in the first group will each have a value for a property corresponding to a first value, or within a first range of that property; analyte ions in the second group may each have a value for a property corresponding to a second value, or within a second range of that property; analyte ions in the third group may each have a value for a property corresponding to a third value, or within a third range of that property, and so on.

[0140] Each of the values ​​(first value, second value, third value, etc.) may be different. Each of the ranges (first range, second range, third range, etc.) may be different. Some, most, or all of the ranges may be dissimilar (non-overlapping), and / or some, most, or all of the ranges may partially overlap.

[0141] (First) Attributes may include a second distinct physicochemical property (i.e., a physicochemical property that is not the same as the first physicochemical property), such as mass, charge, mass-to-charge ratio, time of flight, (ion mobility) drift time and / or collision cross section (CCS).

[0142] In various specific embodiments, the attribute includes charge (charge state). In these embodiments, the first group of ions may include ions having a specific charge (such as one of mono, di, tri, etc. charged ions). Therefore, identifying the first group of ions within the dataset may include identifying ions having a specific charge (such as one of mono, di, tri, etc. charged ions) within the dataset. Similarly, the second (third) group of ions may include ions with a different charge (such as another of mono, di, tri, etc. charged ions). Therefore, identifying the second (third) group of ions within the dataset may include identifying ions with a different charge (such as one of mono, di, tri, etc. charged ions) within the dataset.

[0143] As described above, the steps of identifying a group of analyte ions within a dataset may include subjecting the dataset (spectrum) to a peak detection algorithm to identify different groups of ions within the dataset, such as monocharged ions and / or dicharged ions and / or tricharged ions, etc. Figure 5(Step 62 in the original text). Alternatively, the step of identifying a group of analyte ions may include using measured second physicochemical properties (such as (ion mobility) drift time and / or collision cross section (CCS)) within the dataset to identify different ion groups.

[0144] In various specific embodiments, the attributes may include (ion mobility) drift time and / or collision cross-section (CCS). In these embodiments, the first group of ions may include ions having (ion mobility) drift time values ​​and / or collision cross-section (CCS) within a specific range. Therefore, identifying the first group of ions within a dataset may include identifying ions within the dataset having (ion mobility) drift time values ​​and / or collision cross-section (CCS) within a specific range.

[0145] Similarly, the second (third) group of ions may include ions having drift time values ​​and / or collision cross sections (CCS) within a specific range. Therefore, identifying the second (third) group of ions within the dataset may include identifying ions having drift time values ​​and / or collision cross sections (CCS) within the dataset.

[0146] As described above, this can be accomplished by using the measured (ion mobility) drift time and / or collision cross section (CCS) to identify different ion groups within the dataset (where the (ion mobility) drift time and / or collision cross section (CCS) of the ions are measured when the first physicochemical property (mass-to-charge ratio) of the analyte ions is measured).

[0147] For multidimensional data (such as m / z mobility data), different calibrations can be applied to different regions of the multidimensional data (such as different regions of the m / z mobility space).

[0148] Therefore, all analyte ions within a group may each have the same value for a first property (such as ion mobility and / or collision cross-section), or may each have a value for the first property within a specific range of the first property. All analyte ions within a group may also each have the same value for a second, different property (such as mass-to-charge ratio and / or time of flight), or may each have a value for the second property within a specific range of the second property.

[0149] Each identified group of analyte ions can then be calibrated using a group-specific calibration. This may include correcting for the measured first physicochemical properties of the ions within each group using a calibration associated with the group.

[0150] Therefore, for example, such as Figure 5As shown, a single-charged ion can be calibrated using a calibration associated with a single-charged ion (step 63), a double-charged ion can be calibrated using a calibration associated with a double-charged ion (step 64), a triple-charged ion can be calibrated using a calibration associated with a triple-charged ion (step 65), and so on.

[0151] The results of these multiple calibrations can be combined to produce a final calibration dataset (step 66). Therefore, in various embodiments, multiple calibrations (including at least a first calibration and a second calibration) can be used to calibrate the dataset (the measured first physicochemical property) to obtain a calibration dataset.

[0152] Various embodiments also relate to methods for determining multiple calibrations for analytical instruments (such as those described above). According to various embodiments, this may include ionizing one or more calibrators to generate ions, and using the analytical instrument to measure a first physicochemical property of the ions. The method may include: for each of a first set of multiple reference values ​​for the first physicochemical property, determining a difference between the reference value and a measured value of the first physicochemical property associated with the reference value, and using the difference to determine a first calibration for the analytical instrument. The method may also include: for each of a second set of multiple reference values ​​for the first physicochemical property, determining a difference between the reference value and a measured value of the first physicochemical property associated with the reference value, and using the difference to determine a second calibration for the analytical instrument.

[0153] Figure 6 This is a flowchart illustrating methods for determining multiple calibrations for analytical instruments according to various implementation schemes.

[0154] like Figure 6 As shown in the diagram, according to these embodiments, the calibrator compound can be ionized to generate calibrator ions (…). Figure 6 (Step 70 in the text). This can be accomplished using ion source 10.

[0155] The analytical instrument can then be used to measure the first physicochemical properties of the calibrator ions (such as mass-to-charge ratio, time of flight, drift time (ion mobility), and / or collision cross-section (CCS)). (Alternatively, the analytical instrument can be used to measure the physicochemical properties of product or fragment ions derived from the calibrator ions.)

[0156] The first physicochemical property of using an analytical instrument to measure ions (and / or product or fragment ions derived from ions) may include passing calibrator ions from ion source 10 through one or more functional components 20 and into analyzer 30. The analyzer 30 may then analyze the ions (and / or product or fragment ions derived from ions), for example, to generate mass spectrometry and / or ion mobility spectrometry of the calibrator ions (and / or product or fragment ions derived from calibrator ions). Figure 6 (Step 71 in the text). Therefore, using analytical instruments to measure the first physicochemical properties of ions (and / or product or fragment ions derived from ions) may include using analytical instruments to generate mass spectrometry and / or ion mobility spectrometry of calibrator ions (and / or product or fragment ions derived from calibrator ions).

[0157] The dataset (spectrum) can undergo peak detection algorithms to determine a set of measurements, where each measurement corresponds to an ion peak (center) in the spectrum. Therefore, using analytical instruments to measure the first physicochemical properties of ions (and / or product or fragment ions derived from ions) may include determining a set of measurements.

[0158] At least a first group of ions can then be identified within the dataset. In various implementations, multiple distinct groups of ions can be identified within the dataset. All analyte ions (measurements) within a group may each have the same value for a property, or may each have a value for a property within a specific range of that property (e.g., as described above regarding...). Figure 5 (As described above). Optionally, all analyte ions (measurements) within a group may also each have the same value of a second different property, or may each have a value of the second property within a specific range of the second property (e.g., as described above).

[0159] For example, such as Figure 6 As shown, the dataset (spectrum) can identify the first group of ions (measurements) corresponding to monocharged ions, the second group of ions (measurements) corresponding to dicharged ions, and / or the third group of ions (measurements) corresponding to tricharged ions (etc.). Figure 6 Step 72 in the middle.

[0160] According to various implementation schemes, each of a plurality of reference values ​​for physicochemical properties against a selected calibration value (such as each of a plurality of reference values ​​for mass-to-charge ratio, time of flight, (ion mobility) drift time, and / or collision cross section (CCS)) can be compared with a measured value of the physicochemical properties of the ion. Specifically, the analytical instrument can assign a (single) measured value of the physicochemical property to each of the plurality of reference values ​​for the physicochemical property. In other words, for each of the plurality of reference values, the analytical instrument can find a (single) measured value in the set of measurements that corresponds (closest to) the reference value.

[0161] Therefore, for example, the analytical instrument can assign a (single) ion peak in the mass spectrometry and / or ion mobility spectrometry to each of some or all of the reference values. This can be accomplished, for example, by the control system 40 using one or more suitable algorithms.

[0162] Multiple reference values ​​may include one or more sets of reference values, for example, all reference values ​​within one set may each correspond to the same value having a property or an ion having a value within a specific range of properties (e.g., as described above). Optionally, all reference values ​​within one set may each correspond to the same value having a second different property or an ion having a value within a specific range of a second property (e.g., as described above).

[0163] Multiple different calibrations for the analytical instrument can then be determined. For each of some or all of the reference values ​​within each set of reference values, each calibration can be determined by: determining the (percentage) difference between the reference value and the measurement value assigned to said reference value, and then using these differences to determine the calibration for said set of analytical instruments. These differences can then be used to determine the calibration characteristic curves of the analytical instrument, such as calibration curves.

[0164] Calibration can be determined for each group within the identified groups in this way. Therefore, for example, as... Figure 6 As shown, a calibration can be determined for a single-charged ion (step 73), a different calibration can be determined for a dual-charged ion (step 74), a different calibration can be determined for a tri-charged ion (step 75) (and so on), until a set of multiple calibrations is obtained (step 76).

[0165] Once a set of multiple calibrations has been determined, these calibrations can be stored for later use in calibrating the instrument. As described above, calibration can be used by ionizing the analyte to produce analyte ions, and then using an analytical instrument to measure the physicochemical properties of the analyte ions (and / or product or fragment ions derived from the analyte ions). The calibration can be used to correct the measured physicochemical property values ​​of the analyte ions (and / or product or fragment ions derived from the analyte ions).

[0166] Although various implementation schemes have been described in detail above, various additional and alternative implementation schemes are possible.

[0167] For example, depending on the implementation scheme, calibration can be applied in real time or in post-processing.

[0168] Depending on the implementation, different calibrations for each group can be “dead reckoning” and / or generally applied without a complete recalibration routine. For example, calibrations can be determined only for single-charged ions, and correction factors (along with the determined calibrations for single-charged ions) can be applied when calibrating dual-charged ions. This is possible because, as... Figure 3 As shown, calibrations may differ by only one constant correction factor. Therefore, in various implementations, one or more of the multiple calibrations, or each calibration, may or may not include a (complete) calibration curve.

[0169] According to various implementation schemes, corrections can be applied without measuring the properties of the ions, but rather based on known and / or expected ions in the target experiment. Therefore, identifying each group of analyte ions within the dataset (where each group of analyte ions has a value for a property corresponding to a specific value or within a specific range of properties) may (or may not) include measuring, estimating, and / or inferring properties.

[0170] Although various implementation schemes have been described above regarding mass-to-charge ratio calibration (especially drift time and mass-to-charge ratio calibration) (e.g., using the mass scale for calibrating a ToF mass analyzer 30), these schemes can also be applied to different types of calibration. For example, in various implementation schemes, multiple calibrations can be used for drift time and ion mobility calibration.

[0171] The collision section (CCS) calibration can be determined by extracting the time of arrival (ATD) from the measurement data for each reference mass-to-charge ratio and determining the drift time for each reference mass-to-charge ratio based on the corresponding ATD. These drift time values ​​can then be plotted against the reference collision section values, and the curve can be fitted to this data. This curve can then be used to convert the measured analyte drift time values ​​into a collision section.

[0172] It will be understood that various implementation schemes provide a method that includes applying different calibrations to ions with different properties.

[0173] Various specific implementations include using a time-of-flight mass spectrometer (“ToFMS”) to measure ion clusters, identify ions with specific properties and / or characteristics, and apply calibration based on said properties and / or characteristics.

[0174] According to various implementation schemes, conventional calibration routines are modified to include ions with property ranges, wherein the calibration routine identifies ions with these different properties and calibrates ions grouped according to different properties separately. For example, the calibration routine can operate on spectra derived from mixtures of single-charged and double-charged ions and calculate different calibration curves for single-charged and double-charged sequences.

[0175] Future analyte measurements may involve determining the properties of the ions of interest to determine which calibration will be applied. Therefore, during calibration, recalibration, and mass measurements, other ion properties will be determined, and the ions will be grouped together prior to calibration and / or mass measurements.

[0176] Various implementation schemes can achieve high-quality, high-precision measurements (<100 ppb) and / or improve or maintain accuracy in smaller instruments.

[0177] Although the invention has been described with reference to preferred embodiments, those skilled in the art will understand that various changes in form and detail may be made without departing from the scope of the invention as set forth in the appended claims.

Claims

1. A method comprising: To ionize the calibrator in order to generate ions; The first physicochemical properties of the ions were measured using analytical instruments. For each reference value in a first set of reference values ​​for the first physicochemical property, a difference is determined between the reference value and a measured value of the first physicochemical property associated with the reference value, and the difference is used to determine a first calibration for the analytical instrument, wherein the reference value in the first set of reference values ​​corresponds to an ion having a value of an attribute, the value corresponding to a first value, or within a first range of the attribute; and For each reference value in the second set of reference values ​​for the first physicochemical property, a difference is determined between the reference value and a measured value of the first physicochemical property associated with the reference value, and the difference is used to determine a second calibration for the analytical instrument, wherein the reference value in the second set of reference values ​​corresponds to an ion having a value of the property, the value corresponds to a second value, or a second range of the property, the second value differing from the first value, and the second range differing from the first range. The method further includes measuring the first physicochemical properties of the analyte ions to generate a dataset; Identify a first group of analyte ions within the dataset, wherein each analyte ion in the first group has a value of the attribute, the value corresponding to the first value, or within the first range of the attribute; Select the first calibration associated with the first value or the first range of the attribute from a plurality of different calibrations including the first calibration and the second calibration; and The first calibration is used to calibrate the measured first physicochemical properties of the first set of analyte ions.

2. The method according to claim 1, further comprising: Identify a second group of analyte ions within the dataset, wherein each analyte ion in the second group has a value of the attribute, the value corresponding to a second value, or within a second range of the attribute, wherein the second group of analyte ions is different from the first group of analyte ions, the second value of the attribute is different from the first value of the attribute, and the second range of the attribute is different from the first range of the attribute; Select the second calibration associated with the second value or the second range of the attribute from the plurality of different calibrations; and The second calibration is used to calibrate the measured physicochemical properties of the second set of analyte ions.

3. The method according to claim 2, wherein Each analyte ion in the first group has a value of a second property, the value corresponding to a first value of the second property, or falling within a first range of the second property; and / or Each analyte ion in the second group has a value of the second attribute, the value corresponding to a second value of the second attribute, or within a second range of the second attribute, wherein the second value of the second attribute is different from the first value of the second attribute, and the second range of the second attribute is different from the first range of the second attribute.

4. The method of claim 2, further comprising using one or more third calibrations to calibrate the measured first physicochemical properties of one or more third groups of said analyte ions, wherein the third calibration is different from the second calibration and different from the first calibration, and the third group of analyte ions is different from the first group of analyte ions and different from the second group of analyte ions.

5. The method of claim 1, wherein the method includes calibrating the dataset using a plurality of different calibrations to obtain a calibrated dataset.

6. The method of claim 1, further comprising determining a plurality of different calibrations for the analytical instrument, wherein each of the plurality of different calibrations is associated with a corresponding different value or range of the attribute.

7. The method according to claim 1, wherein the first physicochemical property includes mass-to-charge ratio, time of flight, ion mobility and / or collision cross-section.

8. The method of claim 1, wherein the first physicochemical property includes mass-to-charge ratio and / or time of flight, and the step of measuring the first physicochemical property of the ion includes mass analysis of the ion to generate a mass spectrometer and / or time-of-flight spectrum.

9. The method of claim 8, wherein the step of measuring the first physicochemical property of the ion comprises performing mass analysis on the ion using a time-of-flight ("ToF") mass analyzer.

10. The method of claim 1, wherein the property includes a second physicochemical property, wherein the second physicochemical property is different from the first physicochemical property.

11. The method of claim 1, wherein the property includes charge state, wherein ions within each group have the same charge state, and wherein each group corresponds to a different charge state.

12. The method of claim 1, wherein the property includes ion mobility and / or collision cross-section.

13. The method of claim 12, wherein the ions within each group have ion mobility values ​​and / or collision cross sections within the same range, and wherein each group corresponds to a different range of ion mobility and / or collision cross sections.

14. The method of claim 1, wherein the property includes energy.

15. The method of claim 1, wherein the plurality of different calibrations comprises a plurality of different calibration curves.

16. An analytical instrument configured to perform the method of claim 1.

17. The analytical instrument according to claim 16, wherein the analytical instrument comprises a mass spectrometer and / or an ion mobility spectrometer.

18. A method comprising: To ionize the calibrator in order to generate ions; The first physicochemical properties of the ions were measured using analytical instruments. For each reference value in a first set of reference values ​​for the first physicochemical property, a difference is determined between the reference value and a measured value of the first physicochemical property associated with the reference value, and the difference is used to determine a first calibration for the analytical instrument, wherein the reference value in the first set of reference values ​​corresponds to an ion having a value of an attribute, the value corresponding to a first value, or within a first range of the attribute; and For each reference value in the second set of reference values ​​for the first physicochemical property, a difference is determined between the reference value and a measured value of the first physicochemical property associated with the reference value, and the difference is used to determine a second calibration for the analytical instrument, wherein the reference value in the second set of reference values ​​corresponds to an ion having a value of the property, the value corresponds to a second value, or a second range of the property, the second value differing from the first value, and the second range differing from the first range. The method further includes measuring the first physicochemical properties of the analyte ions to generate a dataset; The first calibration is used to calibrate the measured first physicochemical properties of the first set of analyte ions; and The second calibration is used to calibrate the measured first physicochemical properties of the second set of analyte ions, wherein the second calibration is different from the first calibration, and the second set of analyte ions is different from the first set of analyte ions.

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