Time-domain analysis of signals used in charge detection mass spectrometry

Abstract

A charge detection mass spectrometer (CDMS) includes an electrostatic linear ion trap (ELIT), a processor, and a memory storing instructions executable by the processor to (a) control the ELIT to trap ions, (b) collect ion measurement information as the trapped ions oscillate back and forth through the ELIT, the ion measurement information including the charge induced by the ions on the charge detector of the ELIT during each passage of the ions through the ELIT and the timing of the induced charges relative to each other, (c) process the ion measurement information in the time domain of each of a plurality of sequential time windows to determine the charge magnitude of the ions during each time window, and (d) determine the charge magnitude of the trapped ions based on the charge magnitude value of each time window.

Description

[0001] Cross-references to related applications

[0002] This international patent application claims the benefit and priority of U.S. Provisional Patent Application No. 62 / 969,325, filed on February 3, 2020, the disclosure of which is hereby incorporated herein by reference in its entirety.

[0003] Government rights

[0004] This invention was developed with government support under license number GM1311100 granted by the National Institutes of Health in the United States. The U.S. government holds specific rights to this invention. Technical Field

[0005] This disclosure generally relates to charge detection mass spectrometry instruments, and more specifically to performing mass and charge measurements using such instruments. Background Technology

[0006] Charge detection mass spectrometry (CDMS) is a particle analysis technique in which the mass of an ion is determined by simultaneously measuring its mass-to-charge ratio (often referred to as "m / z") and charge. In some CDMS instruments, an electrostatic linear ion trap (ELIT) is used to perform such measurements. Summary of the Invention

[0007] This disclosure may include one or more features listed in the appended claims, and / or one or more of the following features and combinations thereof. In one aspect, a charge detection mass spectrometer (CDMS) may include an electrostatic linear ion trap (ELIT), an ion source configured to supply ions to the ELIT, a charge-sensitive preamplifier having an input operatively coupled to the ELIT, at least one processor operatively coupled to the ELIT and the amplifier's output, and at least one memory storing instructions which, when executed by the at least one processor, cause the at least one processor to (a) control the ELIT to trap ions supplied by the ion source therein, (b) collect ion measurement information based on an output signal generated by the charge-sensitive preamplifier as the trapped ions oscillate back and forth through the ELIT, the ion measurement information including the charge induced by the ions on a charge detector of the ELIT during each passage of the ions through the ELIT and the timing of the induced charges relative to each other, (c) process the ion measurement information in the time domain of each of a plurality of sequential time windows to determine the charge magnitude value of the ions during each time window, and (d) determine the charge magnitude value of the trapped ions based on the charge magnitude value of each time window.

[0008] On the other hand, a method is provided for measuring ion charge in an electrostatic linear ion trap, the electrostatic linear ion trap including a charge detection cylinder positioned between two ion mirrors, wherein, during an ion trapping event, ions oscillate back and forth between the two ion mirrors, each time passing through the charge detection cylinder and inducing a corresponding charge on the charge detection cylinder, and wherein the ion measurement signal includes the magnitude of the induced charge and the timing of the induced charge during the trapping event, the ion measurement signal being recorded in an ion measurement file. The method may include (a) establishing a time window for the ion measurement signal at the beginning of the ion measurement file, (b) generating a simulated ion measurement signal for the time window of the ion measurement signal using input parameters, including estimates of signal frequency, charge value, signal phase, and duty cycle, (c) iteratively processing the variance between the time windows of the ion measurement signal and the simulated ion measurement signal by adjusting the values ​​of the input parameters until the variance converges, (d) recording the charge value generated from (c), (e) advancing the time window of the ion measurement signal by an incremental time amount, (f) repeating (b)–(d) until the time window reaches the end of the ion measurement file, and (g) determining the charge of the ion based on the charge value of each time window. Attached Figure Description

[0009] Figure 1 This is a simplified diagram of a CDMS system including an embodiment of an electrostatic linear ion trap (ELIT) with control and measurement components coupled thereto.

[0010] Figure 2A yes Figure 1 The diagram shows an enlarged view of the ion mirror M1 of ELIT, where the mirror electrode of M1 is controlled to generate an ion transport electric field.

[0011] Figure 2B yes Figure 1 The diagram shows an enlarged view of the ion mirror M2 of ELIT, where the mirror electrode of M2 is controlled to generate an ion-reflecting electric field.

[0012] Figure 3 yes Figure 1 A simplified illustration of a processor embodiment shown in the figure.

[0013] Figures 4A-4C yes Figure 1 A simplified diagram of the ELIT illustrates the sequential control and operation of ion mirrors to capture at least one ion within the ELIT, and to cause the ion(s) to oscillate back and forth between the ion mirrors and pass through a charge detection cylinder to measure and record multiple charge detection events.

[0014] Figure 5This is a simplified flowchart illustrating an embodiment of the process for analyzing signal measurements contained in an ion measurement event file in the time domain to determine the frequency and charge magnitude (z) of ions oscillating back and forth by a charge detection cylinder via ELIT during an ion capture event.

[0015] Figure 6 It is a graph of the signal versus time, which depicts one cycle of the analog signal used for axial ion trajectories in an electrostatic linear ion trap.

[0016] Figure 7 yes Figure 6 The extended curve of the analog signal, where the duty cycle varies between 40% and 60%.

[0017] Figure 8 yes Figure 6 Another extended graph of the analog signal, where the frequency varies between 10 kHz and 15 kHz.

[0018] Figure 9 yes Figure 6 The extended curve of the analog signal is shown, which illustrates the modified variation superimposed on it, where the modified variation introduces RC attenuation.

[0019] Figure 10 This is a simplified workflow diagram illustrating an embodiment of the cross-correlation process used to determine an initial estimate of the phase of a simulated ion signal.

[0020] Figure 11 This is a simplified workflow diagram illustrating an example of an optimization algorithm for reducing the variance between the analog ion signal and the ion measurement signal.

[0021] Figure 12 This is a graph of SRS versus the number of iterations, illustrating the relationship between the SRS and the number of iterations. Figure 11 Example convergence of the optimization algorithm.

[0022] Description of illustrative embodiments

[0023] For the purpose of promoting an understanding of the principles of this disclosure, reference will now be made to several illustrative embodiments shown in the accompanying drawings, and they will be described using specific language.

[0024] This disclosure relates to apparatus and techniques for processing time-domain ion measurement signals generated by an electrostatic linear ion trap (ELIT) of a charge detection mass spectrometer (CDMS) to simultaneously determine the ion mass-to-charge ratio and ion charge, from which the ion mass can then be determined. For the purposes of this disclosure, the phrase "charge detection event" is defined as the charge induced on the charge detector of the ELIT by detecting a single pass of an ion through the charge detector, and the phrase "ion measurement event" is defined as the set of charge detection events generated by the ion oscillating back and forth through the charge detector a selected number of times or a selected time period. As will be described in detail below, since the oscillation of ions through the charge detector is generated by controlled capture of ions within the ELIT, the phrase "ion measurement event" may alternatively be referred to herein as an "ion capture event" or simply a "capture event," and the phrases "ion measurement event," "ion capture event," "capture event," and variations thereof should be understood to be synonymous with each other.

[0025] refer to Figure 1 The illustration shows an embodiment of a CDMS system 10 including an electrostatic linear ion trap (ELIT) 14, which has control and measurement components coupled thereto. In the illustrated embodiment, the CDMS system 10 includes an ion source 12 operatively coupled to the inlet of the ELIT 14. The ion source 12 illustratively includes any conventional device or apparatus for generating ions from a sample, and may further include one or more devices and / or instruments for separating, collecting, filtering, splitting, and / or normalizing or shifting the charge state of ions according to one or more molecular properties. As an illustrative example, the ion source 12 may include a conventional electrospray ionization source, a matrix-assisted laser desorption / ionization (MALDI) source, etc., coupled to a conventional mass spectrometer inlet; this illustrative example should not be considered as limiting in any way. The mass spectrometer can have any conventional design, including, but not limited to, time-of-flight (TOF) mass spectrometers, reflectance mass spectrometers, Fourier transform ion cyclotron resonance (FTICR) mass spectrometers, quadrupole mass spectrometers, triple quadrupole mass spectrometers, magnetic sector mass spectrometers, etc. In any case, the ion outlet of the mass spectrometer is operatively coupled to the ion inlet of the ELIT 14. The sample from which the ions are generated can be any biological or other material.

[0026] In the illustrated embodiment, ELIT 14 illustratively includes a charge detector CD surrounded by a grounded chamber or cylinder GC and operatively coupled to opposing ion mirrors M1, M2, respectively positioned at their opposite ends. Ion mirror M1 is operatively positioned between ion source 12 and one end of charge detector CD, and ion mirror M2 is operatively positioned at the opposite end of charge detector CD. Each ion mirror M1, M2 defines a corresponding ion mirror region R1, R2 therein. The regions R1, R2 of ion mirrors M1, M2, the charge detector CD, and the space between charge detector CD and ion mirrors M1, M2 together define a centrally passing longitudinal axis 20, which schematically represents the ideal ion travel path through ELIT 14 and ion mirrors M1, M2, as will be described in more detail below.

[0027] In the illustrated embodiment, voltage sources V1 and V2 are electrically connected to ion mirrors M1 and M2, respectively. Each voltage source V1 and V2 illustratively includes one or more switchable DC voltage sources that can be controlled or programmed to selectively generate N programmable or controllable voltages, where N can be any positive integer. Reference will be made below. Figure 2A and Figure 2B An illustrative example of such voltages is provided to establish one of two different operating modes for each ion mirror M1, M2, as will be described in detail below. In any case, under the influence of an electric field selectively established by voltage sources V1, V2, ions extend near the center within ELIT 14 and move along the longitudinal axis 20 of the charge detector CD and ion mirrors M1, M2.

[0028] The diagram illustrates voltage sources V1 and V2 electrically connected to a conventional processor 16 via P signal paths. The processor 16 includes a memory 18 storing instructions that, when executed by the processor 16, cause the processor 16 to control the voltage sources V1 and V2 to generate desired DC output voltages for selectively establishing ion transport and ion reflection electric fields TEF and REF, respectively, within regions R1 and R2 of the respective ion mirrors M1 and M2. P can be any positive integer. In some alternative embodiments, either or both of the voltage sources V1 and V2 can be programmable to selectively generate one or more constant output voltages. In other alternative embodiments, either or both of the voltage sources V1 and V2 can be configured to generate one or more time-varying output voltages of any desired shape. It will be understood that in alternative embodiments, more or fewer voltage sources may be electrically connected to mirrors M1 and M2.

[0029] The charge detector CD is illustratively provided in the form of a conductive cylinder, electrically connected to the signal input of the charge-sensitive preamplifier CP, and the signal output of the charge-sensitive preamplifier CP is electrically connected to the processor 16. Voltage sources V1 and V2 are illustratively controlled in a manner described in detail below to selectively capture ions entering the ELIT 14 and cause them to oscillate back and forth between ion mirrors M1 and M2, so that the captured ions repeatedly pass through the charge detector CD. With ions captured within the ELIT 14 and oscillating back and forth between ion mirrors M1 and M2, the charge-sensitive preamplifier CP is illustratively operable in a conventional manner to detect the charge (CH) induced on the charge detection cylinder CD when ions pass through the charge detection cylinder CD between ion mirrors M1 and M2, thereby generating a corresponding charge detection signal (CHD). The charge detection signal CHD is illustratively recorded in the form of oscillation period values, and at this point, each oscillation period value represents ion measurement information for a single corresponding charge detection event. During the corresponding ion measurement event (i.e., during the ion capture event), multiple such oscillation period values ​​are measured and recorded for the captured ions, and the resulting multiple recorded oscillation period values—i.e., the set of ion measurement information recorded for the ion measurement event—are processed as described below to determine the ion charge, mass-to-charge ratio, and / or mass value. Multiple ion measurement events can be processed in this manner, and the mass-to-charge ratio and / or mass spectrum of the sample can be illustratively constructed therefrom.

[0030] Now for reference Figure 2A and Figure 2B It shows that they are respectively in Figure 1 The embodiments of ion mirrors M1 and M2 of ELIT 14 are depicted. Illustratively, ion mirrors M1 and M2 are identical to each other, as each includes a cascaded arrangement of four spaced-apart conductive mirror electrodes. For each ion mirror M1, M2, a first mirror electrode 301 has a thickness W1 and defines a channel of diameter P1 passing through it at its center. An end cap 32 is fixed or otherwise coupled to the outer surface of the first mirror electrode 301 and defines an aperture A1 passing through it at its center, which serves as an ion inlet and / or outlet to and / or from the corresponding ion mirror M1, M2. In the case of ion mirror M1, the end cap 32 is coupled to... Figure 1 The ion outlet of the ion source 12 shown in the diagram is or is part of it. The aperture A1 of each end cap 32 illustratively has a diameter P2.

[0031] The second mirror electrode 302 of each ion mirror M1, M2 is spaced apart from the first mirror electrode 301 by a space of width W2. Similar to mirror electrode 301, the second mirror electrode 302 has a thickness W1 and defines a channel with a diameter P2 passing through its center. The third mirror electrode 303 of each ion mirror M1, M2 is also spaced apart from the second mirror electrode 302 by a space of width W2. The third mirror electrode 303 has a thickness W1 and defines a channel with a width P1 passing through its center.

[0032] The fourth mirror electrode 304 is spaced apart from the third mirror electrode 303 by a space of width W2. The fourth mirror electrode 304 illustratively has a thickness of W1 and is formed by the corresponding ends of a grounded cylinder GC disposed around the charge detector CD. The fourth mirror electrode 304 defines an aperture A2 passing through its center, which is illustratively conical in shape and linearly increases from a diameter P3 defined at the inner surface of the grounded cylinder GC to a diameter P1 at the outer surface of the grounded cylinder GC (which is also the inner surface of the corresponding ion mirrors M1, M2) between the inner and outer surfaces of the grounded cylinder GC.

[0033] In some embodiments, the space defined between mirror electrodes 301-304 may be a void, i.e., a vacuum gap, and in other embodiments, such a space may be filled with one or more non-conductive materials, such as a dielectric. Mirror electrodes 301-304 and end cap 32 are axially aligned, i.e., collinear, such that the longitudinal axis 22 passes centrally through each aligned channel and also centrally through apertures A1, A2. In embodiments where the space between mirror electrodes 301-304 comprises one or more non-conductive materials, such materials will similarly define the corresponding channels therethrough, which are axially aligned, i.e., collinear, with the channels defined by mirror electrodes 301-304, and these channels illustratively have a diameter of P2 or greater. Illustratively, P1 > P3 > P2, although other relative diameter arrangements are possible in other embodiments.

[0034] A region R1 is defined between apertures A1 and A2 of ion mirror M1, and another region R2 is similarly defined between apertures A1 and A2 of ion mirror M2. Regions R1 and R2 are illustratively identical to each other in shape and volume.

[0035] As described above, the charge detector CD is illustratively provided in the form of an elongated conductive cylinder positioned between corresponding ion mirrors M1 and M2 and spaced apart by a width W3. In one embodiment, W1 > W3 > W2, and P1 > P3 > P2, although other relative width arrangements are possible in alternative embodiments. In any case, the longitudinal axis 20 illustratively extends centrally through the channel defined by the charge detection cylinder CD, such that the longitudinal axis 20 extends centrally through the combination of ion mirrors M1 and M2 and the charge detection cylinder CD. In operation, the ground cylinder GC is illustratively controlled to a ground potential, such that the fourth mirror electrode 304 of each ion mirror M1, M2 is always at a ground potential. In some alternative embodiments, the fourth mirror electrode 304 of any or both of the ion mirrors M1, M2 can be set to any desired DC reference potential, or a switchable DC or other time-varying voltage source.

[0036] exist Figure 2A and Figure 2B In the illustrated embodiment, voltage sources V1 and V2 are each configured to generate four DC voltages D1-D4 and supply voltages D1-D4 to a corresponding mirror electrode 301-304 of the respective ion mirrors M1 and M2. In some embodiments where one or more of the mirror electrodes 301-304 are always maintained at a ground potential, one or more such mirror electrodes 301-304 may alternatively be electrically connected to the ground reference of the respective voltage sources V1 and V2, and the corresponding one or more voltage outputs D1-D4 may be omitted. Alternatively or additionally, in embodiments where any two or more of the mirror electrodes 301-304 are controlled to the same non-zero DC value, any two or more such mirror electrodes 301-304 may be electrically connected to a single voltage output of voltage outputs D1-D4, and redundant output voltages in output voltages D1-D4 may be omitted.

[0037] By selectively applying voltages D1-D4, each ion mirror M1, M2 is illustratively positioned in ion transport mode ( Figure 2A ) and ion reflection mode ( Figure 2B It can be controlled and switched between ion transport modes ( ) Figure 2A In the ion reflection mode, voltages D1-D4 generated by corresponding voltage sources V1 and V2 establish ion transport electric fields (TEF) within their corresponding regions R1 and R2. Figure 2B In this process, voltages D1-D4 generated by corresponding voltage sources V1 and V2 establish ion reflection electric fields (REF) within their respective regions R1 and R2. For example... Figure 2AAs illustrated in the example, once ions from ion source 12 enter region R1 of ion mirror M1 through inlet aperture A1, the ions are focused onto the longitudinal axis 20 of ELIT 14 by an ion transport electric field TEF established in region R1 of ion mirror M1 via selective control of voltages D1-D4 of V1. As a result of the focusing effect of the transport electric field TEF in region R1 of ion mirror M1, ions exiting region R1 of ion mirror M1 through aperture A2 of grounded chamber GC acquire a narrow trajectory to enter and pass through charge detector CD, i.e., to maintain a path close to longitudinal axis 20 as ions travel through charge detector CD. The same ion transport electric field TEF can be selectively established in region R2 of ion mirror M2 via similar control of voltages D1-D4 of voltage source V2. In the ion transport mode, ions entering region R2 from the charge detection cylinder CD through the aperture A2 of M2 via the ion transport electric field TEF in region R2 are focused onto the vertical axis 20, causing the ions to leave the aperture A1 of the ion mirror M2.

[0038] like Figure 2B As illustrated in the example, by selectively controlling the voltages D1-D4 of V2, an ion reflection electric field REF is established in region R2 of ion mirror M2 to decelerate and stop ions from entering ion region R2 from the charge detection cylinder CD through the ion inlet aperture A2 of M2, thereby accelerating the stopped ions in the opposite direction, causing them to return through aperture A2 of M2 and enter the end of the charge detection cylinder CD adjacent to M2—as depicted by ion trajectory 42—and focusing the ions onto the central longitudinal axis 20 within region R2 of ion mirror M2 to maintain the narrow trajectory of ions returning through the charge detector CD to ion mirror M1. The same ion reflection electric field REF can be selectively established in region R1 of ion mirror M1 by similarly controlling the voltages D1-D4 of voltage source V1. In ion reflection mode, the ion reflection electric field REF established within region R1 decelerates and stops ions entering region R1 from the charge detection cylinder CD through aperture A2 of M1. The ions are then accelerated in the opposite direction, returning through aperture A2 of M1 and entering the end of the charge detection cylinder CD adjacent to M1. The ions are focused onto the central longitudinal axis 20 within region R1 of the ion mirror M1 to maintain a narrow trajectory for the ions returning through the charge detector CD to the ion mirror M1. Ions that traverse the length of ELIT 14 and are reflected by the ion reflection electric field REF in ion regions R1 and R2 in a manner that allows them to continue traversing back and forth between ion mirrors M1 and M2 via the charge detection cylinder CD (as just described) are considered to be trapped within ELIT 14.

[0039] The example set of output voltages D1-D4 generated by voltage sources V1 and V2, respectively, are used to control the corresponding ion mirrors M1 and M2 to the aforementioned ion transport and reflection modes, as shown in Table I below. It will be understood that the following values ​​of D1-D4 are provided only as examples, and other values ​​of one or more of D1-D4 may be used alternatively.

[0040]

[0041] Although ion microscopes M1 and M2 and charge detection cylinder CD are in Figure 1-2B The illustration shows a cylindrical channel defined therethrough, but it will be understood that in alternative embodiments, one or both of the ion mirrors M1, M2, and / or the charge detection cylinder CD may define a non-cylindrical channel therethrough, such that one or more channels through which the longitudinal axis 20 passes at the center represent a non-circular cross-sectional area and profile. In still other embodiments, regardless of the shape of the cross-sectional profile, the cross-sectional area of ​​the channel defined by the ion mirror M1 may differ from that of the channel defined by the ion mirror M2.

[0042] For reference Figure 3 , showed Figure 1 An embodiment of the processor 16 illustrated in the figure is shown. In this embodiment, the processor 16 includes a conventional amplifier circuit 40 having an input that receives a charge detection signal CHD generated by a charge-sensitive preamplifier CP and an output electrically connected to the input of a conventional analog-to-digital (A / D) converter 42. The output of the A / D converter 42 is electrically connected to the processor 50 (P1). The amplifier 40 is conventionally operable to amplify the charge detection signal CHD generated by the charge-sensitive preamplifier CP, and the A / D converter is in turn conventionally operable to convert the amplified charge detection signal into a digital charge detection signal CDS.

[0043] Figure 3The processor 16 illustrated in the figure further includes a conventional comparator 44 having a first input receiving a charge detection signal CHD generated by a charge-sensitive preamplifier CP, a second input receiving a threshold voltage CTH generated by a threshold voltage generator (TG) 46, and an output electrically connected to the processor 50. The comparator 44 is conventionally operable to generate a trigger signal TR at its output, which depends on the magnitude of the charge detection signal CHD relative to the magnitude of the threshold voltage CTH. For example, in one embodiment, the comparator 44 is operable to generate an “inactive” trigger signal TR at or near a reference voltage (e.g., ground potential) whenever CHD is less than CTH, and to generate an “active” TR signal at or near the power supply voltage of circuits 40, 42, 44, 46, 50, or otherwise distinguishable from the inactive TR signal, when CHD is at or above CTH. In an alternative embodiment, comparator 44 is operable to generate an "inactive" trigger signal TR at or near the supply voltage as long as CHD is less than CTH, and an "active" trigger signal TR at or near the reference potential when CHD is at or above CTH. Those skilled in the art will recognize that other different trigger signal values ​​and / or different trigger signal polarities may be used to establish the "inactive" and "active" states of the trigger signal TR, provided that processor 50 can distinguish such different trigger signal values ​​and / or different trigger signal polarities, and will understand that any such other different trigger signal values ​​and / or different trigger signal polarities are intended to fall within the scope of this disclosure. In any case, comparator 44 may additionally be designed in a conventional manner to include a desired amount of hysteresis to prevent rapid switching of the output between the reference voltage and the supply voltage.

[0044] Processor 50 is illustratively operable to generate a threshold voltage control signal THC and supply THC to threshold generator 46 to control its operation. In some embodiments, processor 50 is programmed or programmable to control the generation of threshold voltage control signal THC in a manner that controls threshold voltage generator 46 to generate CTH with a desired magnitude and / or polarity. In other embodiments, a user may provide instructions to processor 50 in real time, for example via a downstream processor, such as via a virtual control and visualization unit, to control threshold voltage generator 46 to generate threshold voltage control signal THC in a manner that controls CTH with a desired magnitude and / or polarity. In any case, in some embodiments, threshold voltage generator 46 is illustratively implemented in the form of a conventional controllable DC voltage source configured to generate an analog threshold voltage CTH with polarity and magnitude defined by the digital threshold control signal THC in response to the threshold control signal THC in digital form, for example in the form of a single serial digital signal or multiple parallel digital signals. In some alternative embodiments, the threshold voltage generator 46 may be provided in the form of a conventional digital-to-analog (D / A) converter that generates an analog threshold voltage CTH in response to a serial or parallel digital threshold voltage TCH, the analog threshold voltage CTH having a magnitude defined by a digital threshold control signal THC, and in some embodiments having a polarity defined by the digital threshold control signal THC. In some such embodiments, the D / A converter may form part of the processor 50. Those skilled in the art will recognize other conventional circuitry and techniques for selectively generating a threshold voltage CTH of a desired magnitude and / or polarity in response to one or more control signals THC in digital and / or analog form, and will understand that any such other conventional circuitry and / or techniques are intended to fall within the scope of this disclosure.

[0045] In addition to the aforementioned functions performed by processor 50, as referenced above Figure 2A , Figure 2BThe processor 50 is further operable to control voltage sources V1 and V2 to selectively establish ion transport and reflection fields, respectively, within regions R1 and R2 of ion mirrors M1 and M2. In some embodiments, the processor 50 is programmed or programmable to control voltage sources V1 and V2. In other embodiments, voltage sources V1 and / or V2 may be user-programmed or otherwise controlled in real time, for example, via a downstream processor 52, such as via a virtual control and visualization unit. In any case, in one embodiment, the processor 50 is illustratively provided in the form of a field-programmable gate array (FPGA), which is user-programmed or otherwise instructed to collect and store charge detection signals CDS for charge detection events and for ion measurement events, generate one or more threshold control signals TCH, determine or derive the magnitude and / or polarity of a threshold voltage CTH based on the one or more threshold control signals TCH, and control voltage sources V1 and V2. In this embodiment, reference is made to... Figure 1 The described memory 18 is integrated into the FPGA programming and forms part of the FPGA programming process. In an alternative embodiment, the processor 50 may be provided as one or more conventional microprocessors or controllers and one or more accompanying memory cells having instructions stored therein that, when executed by the one or more microprocessors or controllers, cause the one or more microprocessors or controllers to operate as just described. In other alternative embodiments, the processing circuitry 50 may be implemented purely as one or more conventional hardware circuits designed to operate as described above, or as a combination of one or more such hardware circuits and at least one microprocessor or controller operable to execute the instructions stored in memory to operate as described above.

[0046] Figure 3 An embodiment of the processor 16 depicted further illustratively includes a second processor 52 coupled to the first processor 50 and also coupled to at least one memory unit 54. In some embodiments, the processor 52 may include one or more peripheral devices, such as a display monitor, one or more input and / or output devices, although in other embodiments, the processor 52 may not include any such peripheral devices. In any case, the processor 52 is illustratively configured, i.e. programmed, to perform at least one process for analyzing ion measurement events. Data in the form of charge magnitude values ​​and charge timing data (i.e., the timing of the charges sensed by the ions on the charge detection cylinder relative to each other) received by the processor 50 via the charge detection signal CDS is illustratively transmitted directly from the processor 50 to the processor 52 for processing and analysis upon completion of each ion measurement event.

[0047] In some embodiments, processor 52 is illustratively provided in the form of a high-speed server, operable to perform both collection / storage and analysis of such data. In such embodiments, one or more high-speed memory units 54 may be coupled to processor 52 and operable to store data received and analyzed by processor 52. In one embodiment, the one or more memory units 54 illustratively include at least one local memory unit for storing data that processor 52 is using or will use, and at least one permanent storage memory unit for long-term storage of data. In one such embodiment, processor 52 illustratively has four Intel® Xeon... TM The processor (e.g., E5-465L v2, 12 cores, 2.4 GHz) is provided in the form of a Linux® server (e.g., OpenSuse Leap 42.1). In this embodiment, an improvement of over 100x in average analysis time for a single ion measurement event file is achieved compared to a conventional Windows® PC (e.g., i5-2500K, 4 cores, 3.3 GHz). Similarly, the processor 52 of this embodiment, together with one or more high-speed / high-performance memory units 54, illustratively provides an improvement of over 100x in data storage speed. Those skilled in the art will recognize that one or more other high-speed data processing and analysis systems can be implemented as processor 52, and will understand that any one or more such other high-speed data processing and analysis systems are intended to fall within the scope of this disclosure. In alternative embodiments, processor 52 may be provided in the form of one or more conventional microprocessors or controllers and one or more accompanying memory units having instructions stored therein that, when executed by one or more microprocessors or controllers, cause one or more microprocessors or controllers to operate as described herein.

[0048] In the illustrated embodiment, memory unit 54 illustratively has instructions stored therein, executable by processor 52, to analyze ion measurement event data generated by ELIT 14 to determine ion mass spectrometry information of the analyzed sample. In one embodiment, processor 52 is operable to receive ion measurement event data from processor 50 in the form of charge magnitude values ​​and charge detection timing information measured during each of a plurality of charge detection events (as defined above) constituting an "ion measurement event" (as defined above), and processes such charge detection events constituting such an ion measurement event to determine ion charge and mass-to-charge ratio data, and then determines ion mass data therefrom. Multiple ion measurement events can be processed in a similar manner to create mass spectrometry information of the analyzed sample.

[0049] As referenced above Figure 2A and Figure 2B Briefly described, voltage sources V1 and V2 are illustratively controlled by processor 50, for example via processor 52, to selectively establish ion transport and ion reflection electric fields in region R1 of ion mirror M1 and region R2 of ion mirror M2, guiding ions introduced from ion source 12 through ELIT 14, and then causing individual ions to be selectively captured and confined within ELIT 14, such that the captured ions repeatedly pass through charge detector CD as they oscillate back and forth between M1 and M2. Reference Figures 4A-4C , showed Figure 1 A simplified diagram of ELIT 14 is provided, illustrating an example of the sequential control and operation of ion mirrors M1 and M2 of ELIT 14. In the following example, processor 52 will be described as controlling the operation of voltage sources V1 and V2 according to its program, although it will be understood that the operation of voltage source V1 and / or voltage source V2 can be at least partially controlled virtually by processor 50.

[0050] like Figure 4A As illustrated in the diagram, the ELIT control sequence begins with processor 52 controlling voltage source V1 to establish an ion transport field within region R1 of ion mirror M1, thus controlling ion mirror M1 to ion transport operation mode (T). It also controls voltage source V2 to similarly establish an ion transport field within region R2 of ion mirror M2, thus controlling ion mirror M2 to ion transport operation mode (T). As a result, ions generated by ion source 12 enter ion mirror M1, and when they enter charge detection cylinder CD, they are focused onto the vertical axis 20 by the ion transport field established in region R1. The ions then pass through charge detection cylinder CD and enter ion mirror M2, where the ion transport field established in region R2 of M2 focuses the ions onto the vertical axis 20, causing the ions to pass through the exit aperture A1 of M2, as shown. Figure 4A The ion trajectory depicted in Figure 60 is illustrated.

[0051] Now for reference Figure 4B After a selected time period has elapsed since both ion mirrors M1 and M2 have been operating in ion transport mode and / or until successful ion transport has been achieved, processor 52 is illustratively operable to control voltage source V2 by establishing an ion reflection field within region R2 of ion mirror M2, controlling ion mirror M2 to ion reflection mode (R), while maintaining ion mirror M1 in ion transport mode (T) as shown. As a result, at least one ion generated by ion source 12 enters ion mirror M1 and is focused onto longitudinal axis 20 by the ion transport field established in region R1, causing the at least one ion to pass through ion mirror M1 and enter charge detection cylinder CD, as just referenced. Figure 4AThen, (one or more) ions pass through the charge detection cylinder CD and enter the ion mirror M2, where an ion reflection field established in region R2 of M2 reflects (one or more) ions, causing them to travel in the opposite direction and return to the charge detection cylinder CD, as described above. Figure 4B The ion trajectory in Figure 62 is illustrated.

[0052] Now for reference Figure 4C After an ion-reflecting electric field has been established in region R2 of ion mirror M2, processor 52 is operable to control voltage source V1 to control ion mirror M1 into ion-reflecting operation mode (R) by establishing an ion-reflecting field in region R1 of ion mirror M1, while maintaining ion mirror M2 in ion-reflecting operation mode (R) to trap (one or more) ions within ELIT 14. In some embodiments, processor 52 is illustratively operable, i.e., programmed, to control ELIT 14 in a "random trapping mode" or a "continuous trapping mode," wherein ELIT 14 has already been... Figure 4B After the selected time period is operated in the state shown in the diagram—that is, where M1 is in ion transport mode and M2 is in ion reflection mode—the processor 52 can operate to control the ion mirror M1 to the reflection operation mode (R). Until the selected time period has elapsed, ELIT 14 is controlled to... Figure 4B The system operates as illustrated in the diagram. In other embodiments, the processor 52 is operable, i.e., programmed, to control the ELIT 14 in a "triggered capture mode," which illustratively carries a significantly greater probability of capturing a single ion compared to a random capture mode. In the "triggered capture mode," after an ion has been detected as passing through the charge detection cylinder CD, the processor 52 is operable to control the ion mirror M1 to a reflective operating mode (R).

[0053] In any case, when both ion mirrors M1 and M2 are controlled in ion reflection operation mode (R) to trap ions within ELIT 14, the opposing ion reflection fields established in regions R1 and R2 of ion mirrors M1 and M2, respectively, cause the ions to oscillate back and forth between ion mirrors M1 and M2, each time passing through the charge detection cylinder CD, as shown. Figure 4C The ion trajectory 64 depicted in the diagram is illustrated and described above. In one embodiment, the processor 50 is operable to maintain Figure 4C The operating state illustrated in Figure 4 continues until the ions pass through the charge detection cylinder CD a selected number of times. In an alternative embodiment, after controlling M1 (and M2 in some embodiments) to the ion reflection operating mode (R), the processor 50 is operable to maintain the operating state illustrated in Figure 4 for the selected time period. In any embodiment, in Figure 4CThe number of cycles or time spent in the illustrated state can be illustratively programmed, for example via instructions stored in memory 54, or via user interface control. In any case, ion detection event information generated each time an ion passes through the charge detection cylinder CD is temporarily stored in processor 50, for example in the form of an ion measurement file, which can illustratively have predefined data or sample length. The total number of charge detection events stored in processor 50 when an ion has passed through the charge detection cylinder CD a selected number of times or has oscillated back and forth between ion mirrors M1 and M2 for a selected time period defines an ion measurement event. When an ion measurement event is completed, the stored ion detection event defining the ion measurement event—for example, an ion measurement event file—is passed to processor 52 or retrieved by processor 52. Figures 4A-4C The sequence shown in the diagram is then returned to Figure 4A The sequence illustrated in the figure, wherein voltage sources V1 and V2 are controlled as described above, to control ion mirrors M1 and M2 to ion transport operation modes (T) respectively by establishing ion transport fields in regions R1 and R2 of ion mirrors M1 and M2 respectively. Then, the sequence illustrated is repeated the same number of times as desired.

[0054] To date, the Fast Fourier Transform (FFT) algorithm has been used to analyze ion measurement event files in the frequency domain. In such implementations, the mass-to-charge ratio (m / z) of the ion is calculated from the fundamental oscillation frequency (f0) of the signal using a calibration constant (C) (Equation 1), and the charge of the ion is determined by the magnitude of the fundamental frequency peak in the FFT.

[0055] Equation 1:

[0056] .

[0057] Since only the fundamental frequency is used in determining the ion charge, the signal can be considered as a single sine wave. However, FFT does not use a great deal of information about the signal because higher-order harmonics are ignored. This means the signal must be measured for a longer period to achieve charge-state resolution. A more complete representation of the waveform reduces amplitude uncertainty, thereby improving charge accuracy and reducing the trapping time necessary to achieve charge-state resolution. Furthermore, while peak values ​​in FFT analysis depend on factors such as the signal duty cycle, the time-domain signal amplitude is constant for a given charge, and amplitude measurements in the time domain are independent of the duty cycle. These properties make time-domain analysis advantageous for applications with transient time-varying signals, such as those found in CDMS, where the ion oscillation frequency and signal duty cycle change as ions lose energy due to collisions with the background gas and electrostatic interactions with the detection cylinder.

[0058] The following describes a process for analyzing signal measurements contained in an ion measurement event file in the time domain using FFT. This process incorporates information contained within higher-order harmonics by fitting the signal measurements to an analog waveform for more accurate measurement of ion charge. In the following description, ELIT is designed such that the time-domain charge detection signal CHD stored in the ion measurement event file is a square wave signal (i.e., with a 50% duty cycle). Although it will be understood that in alternative implementations, ELIT can be designed such that the duty cycle of the time-domain charge detection signal CHD is greater than or less than 50%. With ion measurement files containing signal measurements at a 50% duty cycle, the following algorithm improves the accuracy of charge value determination by 15% to 20% compared to FFT, reaching the statistical lower bound of the amplitude uncertainty of a square wave corrupted by Gaussian noise. The optimal charge standard deviation versus noise standard deviation achievable with a square wave is... And the number of points the waveform spends in the HI state (equivalent to the number of points spent in the LO state, respectively N) HI and N LO It is related to ) and has the following relationship:

[0059] Equation 2:

[0060] .

[0061] Now for reference Figure 5 A simplified flowchart of an embodiment of process 100 is shown, which is used to analyze signal measurements contained in an ion measurement event file in the time domain to determine the frequency and charge value (z) of an ion oscillating back and forth by a charge detection cylinder via ELIT during an ion trapping event. Based on this frequency determination, the mass-to-charge ratio (m / z) of the ion is determined from Equation 1, and the mass of the ion is determined as the product of m / z and z. Illustratively, process 100 is stored in the memory of processor 16 in the form of instructions executable by processor 16 to implement the functionality of process 100.

[0062] Process 100 begins at step 102, where the time window counter N is initialized to 1 (or some other constant value). Process 100 is illustratively designed to analyze the signal measurements contained in the ion measurement event file by analyzing the signal measurements in each of a plurality of sequential time windows of the measurement event file. As long as the frequency and duty cycle of the signal measurements remain substantially unchanged within each time window, this file windowing method advantageously reduces the influence of time-varying frequencies and duty cycles on the measurement amplitude, thereby allowing the approximation of these parameters to be constant over the duration of each window. In an example implementation, where the ion measurement event file is approximately 100 ms in length and contains approximately 1000 signal measurement cycles, the time windows are illustratively selected to be each 10 ms in length, with each of the 10 time windows containing 100 signal measurement cycles.

[0063] Following step 102, process 100 proceeds to step 104, where processor 16 is operable to perform an FFT analysis on a first time window of signal measurements contained in the ion measurement event file (hereinafter referred to as the ion measurement signal IMS), and to determine the fundamental oscillation frequency (Fi) of the first time window of the IMS signal in a conventional manner as described above. FFT ) and charge value (CH FFT In one example implementation, CH FFT Multiply by 2.955 ADC bits / e to obtain the time-domain signal amplitude in ADC bits for later use in process 100.

[0064] After step 104, process 100 proceeds to step 106, where processor 16 is operable to generate a simulated ion signal (SIS) for the Nth time window using input parameters F, CH, PH, and DC, where F is the frequency, CH is the charge value, PH is the phase, and DC is the duty cycle.

[0065] In one example implementation, the SIS is generated in ELIT by simulating the trajectory of a 130 eV / z ion with m / z of 25600 TH using the Beeman algorithm (a modified velocity Verlet algorithm) in Fortran with an electric field calculated using SIMION 8.1 at 10.02306 kHz. The signal of this ion is generated by superimposing the ion trajectory onto a potential array, where the charge detection cylinder has +1 and all other electrodes remain grounded. This generates a signal 160 normalized to +1 according to Green's reciprocity theorem, as shown below. Figure 6The example depicts this. Signal 160 is decomposed into two parts: a negative transition 160A and a positive transition 160B. One cycle of the signal is fitted using two dual-dose sigmoid curves from OriginPro 2018. One curve is used for the positive transition 160B (for when ions enter the detection cylinder) and a different curve is used for the negative transition 160A (for when ions leave the cylinder), according to the following equation.

[0066] Equation 3:

[0067]

[0068] Where t is time, p is a general fitting parameter for the S-curve, and l1 and l2 describe the rise or fall time of the SIS waveform 160. These values ​​are used... Additive adjustments are made to change the duty cycle of the positive transition, while the negative transition remains constant, such as... Figure 7 The example depicts a waveform 160 with a duty cycle varying from 40% (trace 170A) to 60% (trace 170C), with a nominal 50% duty cycle (trace 170B) shown for comparison.

[0069] In equation 3, f scaling This is the desired frequency divided by the nominal frequency (e.g., 10.02306 kHz) used in the analysis function that initially created the waveform. An example of such an analysis function is... Figure 8 The diagram shows that signal 160 varies between a lower frequency 180A (e.g., 10 kHz) and a higher frequency 180B (e.g., 15 kHz). T is the duration of the wave period, the time elapsed since the start of the last wave period is t-t0, and A is the amplitude. The phase is adjusted by adding the phase time to t0, which shifts the waveform by a specified time. Variables h1 and h2 describe the rate at which the wave transitions between LO to HI or HI to LO states. The smaller the h value, the rounder the resulting waveform, while the higher the h value, the steeper the transition. Variable h scaling h is adjusted multiplicatively to adjust the transition slope. The minimum and maximum values ​​of these curves are constrained to 0 and +1, respectively, so they can be concatenated end-to-end to generate a periodic waveform. The SIS waveform is then scaled to an amplitude of 1500 ADC bits and centered at zero.

[0070] Implementation of the discrete-time first-order recursive relation for a high-pass filter Applied to SIS waveform 160 to apply RC attenuation 190 recorded on an existing mass spectrometer, such as Figure 9 The example depicts this. The RC decay point i of the SIS waveform function is generated by multiplying the decay constant by the symmetric numerical derivative of the waveform according to the following equation.

[0071] Equation 4:

[0072] .

[0073] By applying a square wave generated by a function generator to an antenna near a charge detection cylinder on a spectrometer, and fitting the square wave in the time domain with different RC values ​​to find the value that gives the best fit, the optimal value is determined. Constant. Variable This represents the time for a single ADC sample (400 ns).

[0074] Refer again Figure 5 In step 106 of process 100, for the first passage of the simulated ion signal SIS within the first time window (N = 1), F = F FFT CH = CH FFT The pH is zero, and the DC estimate corresponding to the duty cycle of ions traveling along an axial trajectory at 130 eV / z is 49.2%. Further illustratively, in step 106, a cross-correlation is performed between the first time windows of the IMS and SIS, as shown in... Figure 10 The example in process 200 is illustrated in the diagram. In this process 200, the initial SIS (where PH = 0) is cross-correlated with the IMS by shifting the SIS by one sampling point (e.g., 400 ns) and then calculating the variance between the IMS and SIS at each phase, for example, using a conventional residual sum of squares (SRS). The minimum value of the resulting correlation function (where the IMS and SIS phases match the nearest acquisition point) is then illustratively used as an initial non-zero estimate of the PH phase in the SIS signal.

[0075] As the simulated ion signal (SIS) is generated and filled within the initial input parameter values, as just described, process 100 proceeds from step 106 to step 108, where processor 16 is operable to determine the variance between the IMS and the SIS. In one embodiment, the signal variance is determined using a conventional residual sum of squares (SRS) according to the following equation, where, in one implementation, M = 25,000 acquisition points (the number of points in a 10 ms window of the IMS file), although in alternative implementations, M can be any positive integer.

[0076] Equation 5:

[0077]

[0078] In alternative embodiments, other conventional variance determination equations and / or procedures may be used.

[0079] In any case, after step 108, process 100 proceeds to step 110, where processor 16 is operable to determine whether the variance process executed in step 108 has converged. Illustratively, convergence at step 110 is achieved by comparing the result of equation 5 with the result of a previous execution of equation 5. During the first execution of step 110, there will only be a single execution of equation 5, so process 100 follows the "No" branch of step 110 to step 112, where processor 16 is operable to execute an optimization algorithm configured to reduce the variance between IMS and SIS.

[0080] In step 108, the variance between the IMS and SIS determined for each combination of input parameters is illustratively used to generate a cost function, which can be minimized in step 112 using any of a variety of conventional optimization algorithms. In one example implementation, the conventional gradient descent method is illustratively used as the optimization algorithm. This particular optimization method is advantageous in this context because a significant throughput improvement can be achieved by employing a fast first-order approximation algorithm. This makes it possible to accelerate the analysis method to keep up with real-time data acquisition without significantly increasing computational cost. In alternative embodiments, one or more other conventional optimization algorithms may be used.

[0081] In gradient descent optimization, IMS and SIS are compared by calculating the SRS between them for a specific set of input parameters. Then, the input parameters are varied by relatively small amounts to determine the numerical partial derivatives of the SRS with respect to each input parameter. After the partial derivatives are calculated, in step 114, the input parameters are multiplied by their respective partial derivatives by a unique learning rate for each input parameter based on their respective convergence rates. To adjust. If It is the parameter vector at iteration n, and If is a vector of learning rates, then the gradient descent equation for step n+1 can be written as follows (Equation 6). Here, F, DC, PH, CH, and S represent the frequency, duty cycle, phase, amplitude, and transition slope parameters used in noiseless waveform synthesis, respectively.

[0082] Equation 6:

[0083]

[0084] It should be noted that the transition slope S is not applicable to square waves because the transition is instantaneous, and in cases such as... Figure 5 In the process illustrated in the diagram, the transition slope is omitted in such cases. In any case, using the adjustment parameters generated from the execution of step 114, the process loops back to step 106, where processor 16 is operable to generate a new simulated ion signal (SIS). This iterative process of steps 106-114 (also by...) Figure 11 (The process 210 illustrated in the figure is depicted in an alternative form) continues until processor 16 determines in step 110 that a convergence limit has been reached. In one embodiment, this convergence limit is determined by the SRS of the current iteration (SRS). n ) and the SRS of the previous iteration (SRS) n-1 The ratio is used to set it. If SRS n / SRS n-1 If the fit is close enough to one, for example, between 0.99999999 and 1, then for more than a predetermined number of iterations, such as 50, the processor 16 is operable to determine that the fit has converged. Figure 13 illustrates an example of a portion of the best-fit waveform 240 superimposed on the noise-damaged IMS signal 230 at convergence.

[0085] Following the "Yes" branch in step 110, process 100 proceeds to step 116, where the processor is operable to determine the frequency F(N), charge value CH(N), and duty cycle DC(N) of the Nth time window of the IMS fitted to the SMS. The frequency F(N) of the Nth time window of the ion measurement signal IMS is illustratively calculated directly from the time-based transition of the signal period (e.g., approximately 100 periods in the example implementation above). The charge value CH(N) of the Nth time window of the ion measurement signal IMS is illustratively calculated as the average of the amplitudes of the periods constituting the Nth time window, and DC(N) is the most recent value of DC at convergence.

[0086] Following step 116, process 100 proceeds to step 118, where processor 16 is operable to determine whether the final time window of the ion measurement signal (IMS) has been processed. If not, process 100 proceeds to step 120, where processor 16 is operable to extend the time window by the duration. For example, 10 ms. Then, in step 122, processor 16 is operable to increment the time window counter N by 1 and set the initial values ​​for the input parameters F, CH, and DC. After analyzing the first time window (N=1), the initial guesses for subsequent windows include the best-fit frequency, duty cycle, and charge amplitude of the previous window. For each window N ≥ 2, the first 50 iterations of the iterative process in steps 106-114 illustratively preserve the phase PH used to find the next window, and then subsequent iterations optimize all parameters until convergence is achieved. This is in Figure 12 The figure is a curve of SRS versus the number of iterations. Waveform 220 shows that the first 50 iterations are relatively flat as phase PH is found, and then waveform 220 moves toward convergence.

[0087] If, in step 116, the processor 16 determines that the last time window of the IMS has been processed, then process 100 proceeds to step 124, where the processor 16 processes the frequency values ​​F(N) of multiple time windows to determine the fundamental frequency F of the ion measurement signal. IMS In some embodiments, the measurement of ion oscillations within the ELIT is not recorded immediately to allow transients caused by the switching voltages on ion mirrors M1 and M2 to subside. Subsequently, as ions oscillate back and forth between ion mirrors M1 and M2, they typically lose energy due to collisions with the background gas and electrostatic interactions with the charge detection cylinder. This energy loss leads to an increase in frequency as the ions continue to oscillate back and forth between ion mirrors M1 and M2, such as... Figure 11 This is illustrated graphically. In such an embodiment, a line is fitted to the frequency F(N) of all time windows as a function of time, and then extrapolated to the beginning of the capture event to determine F before the ions lose any energy. IMS To determine the fundamental frequency F in an illustrative way IMS This is also in Figure 11 The figure shows the fundamental frequency F. IMS Describe it as f0. Then use F. IMS The mass-to-charge ratio of the ion is calculated using Equation 1. In other embodiments with shorter trapping times and / or improved ELIT structures, the ion may not lose a considerable amount of energy during the trapping event, and in such embodiments, the fundamental frequency F0... IMS It can be calculated as the average of F(N) over N windows.

[0088] Processor 16 is further operable in step 124 to process the charge values ​​CH(N) of multiple time windows to determine the charge value CH of the ions. IMS Since the charge is constant across the IMS file, the charge CH IMS It is illustratively determined by averaging the charge value CH(N) across all N windows.

[0089] Example

[0090] FFT analysis of 1000 files, including square wave signals corrupted by Gaussian noise with a 1000 ADC bit RMSD over a duration of 100 ms, yielded a charge RMSD of 1.65e. Time-domain analysis of the same files using the technique described herein yielded an RMSD of 1.35e. Furthermore, the amplitude reported by the time-domain analysis is independent of RC attenuation, thus improving the signal-to-noise ratio by 1%. Overall, this represents a 19% improvement in charge accuracy compared to FFT. The theoretically optimal charge RMSD was achieved using time-domain analysis on a square wave with a 50% duty cycle (according to equation...). ADC position, NHI = N LO =125,000 points with a 50% duty cycle = 4 ADC bits or 1.35 basic charge). The same analysis was performed on a file containing a simulated ion signal corrupted by Gaussian noise with 1000 ADC bits RMSD, and this analysis resulted in an RMSD of 1.65e for FFT analysis and 1.45e for time-domain analysis, representing a 13% improvement in charge accuracy.

[0091] The improvement in charge accuracy of the simulated ion signal compared to the square wave can be understood by examining the Hessian matrix of the second-order partial derivatives of each parameter fitted by the algorithm.

[0092] Equation 7:

[0093]

[0094] If the Hessian matrix is ​​diagonally dominant, the optimization problem becomes well-posed, where a clear global minimum exists and uncertainties from each parameter are not coupled to each other. In such a case, the parameters are linearly independent, and the first-order gradient descent algorithm can solve these problems quickly. This is achieved in square wave signals, where the transition between the HI and LO states of the signal is instantaneous (at least within the time resolution provided by a 2.5 MHz sampling frequency). This means that the height of each transition and the time at which they occur are independent of parameters such as the amplitude, frequency, duty cycle, and phase of the signal. On the other hand, the Hessian matrix of an ion signal with a gradual transition between the HI and LO states is not diagonally dominant and has a significant contribution from mixed partial derivatives, which link the parameters and their corresponding uncertainties to each other. This means that the rise and fall times of the transition become functions of frequency, coupling the uncertainty in the frequency with the uncertainties in all other parameters (i.e., not knowing when the transition occurs means the duty cycle cannot be confidently assigned, which is compensated for by incorrect amplitude measurements). For these ill-posed optimization problems, there is no unique solution, and convergence to the minimum of the cost function is difficult when the signal is obscured by noise. The interdependence of parameters can be minimized by designing a detection system that generates a signal with a sharp transition between the LO and HI states. For example, this can be achieved by minimizing the inner diameter of the detection cylinder, thus giving the ion signal rapid rise and fall times.

[0095] In an alternative embodiment, the best-fit dual-dose sigmoid equation for the ion signal can be modified to fit the signal generated by the mass spectrometer, thereby addressing signal shape distortion caused by geometric imperfections and / or other design features of the ELIT. The more accurate the known actual instrument ion signal, the more precisely the waveform synthesis function can be applied to fit the instrument signal. While any function can be used in the waveform synthesis subroutine to fit any signal, it should be noted that the theoretical accuracy of the parameters will depend on the waveform characteristics. Finally, faster optimization algorithms or algorithms better suited for nonlinear optimization problems, such as the simplex optimizer, can be employed to fit the noiseless waveform to the signal. Furthermore, significant throughput improvements can be achieved by designing the system that generates the signal, which can be fitted with a fast first-order gradient descent algorithm with momentum, such as AMS Grad. Alternatively, the number of steps required to reach convergence can be minimized by employing a second-order optimization scheme, such as Newton's method. With these improvements, it is possible to perform time-domain analysis on the file in conjunction with real-time FFT analysis.

[0096] Although this disclosure has been illustrated and described in detail in the foregoing figures and description, it should be considered illustrative in nature and not restrictive. It should be understood that only illustrative embodiments are shown and described, and all changes and modifications within the spirit and scope of this disclosure are intended to be protected. For example, it will be understood that the ELIT 14 illustrated in the figures and described herein is provided by way of example only, and the above concepts, structures, and techniques can be directly implemented in various alternative ELIT designs. Any such alternative ELIT design may, for example, include any one or combination of two or more ELIT regions, more, fewer, and / or different ion mirror electrodes, more or fewer voltage sources, more or fewer DC or time-varying signals generated by one or more voltage sources, one or more ion mirrors defining an additional electric field region, etc. As another example, in some alternative embodiments, Figure 5 The process illustrated in the diagram can be used solely to determine the charge value (CH) of ions during a capture event. IMS (i.e., z), and the conventional FFT method described above can be used to determine the mass-to-charge ratio (m / z). As yet another example, it can be modified... Figure 5 The process illustrated in the diagram is to account for the possible variances of frequency measurements within one or more time windows, and / or the entire ion measurement file can be processed in a manner that takes into account any such possible variances of the frequency measurements.

Claims

1. A method for measuring ion charge in an electrostatic linear ion trap, the electrostatic linear ion trap comprising a charge detection cylinder positioned between two ion mirrors, wherein, During an ion trapping event, ions oscillate back and forth between two ion mirrors, each time passing through a charge detection cylinder and inducing a corresponding charge on the cylinder. The ion measurement signal includes the magnitude and timing of the induced charge during the trapping event, and the ion measurement signal is recorded in an ion measurement file. The method includes: (a) Establish a time window for the ion measurement signal at the beginning of the ion measurement file. (b) A simulated ion measurement signal is generated using input parameters for a time window of the ion measurement signal, the input parameters including estimates of signal frequency, charge value, signal phase, and duty cycle. (c) The variance between the time windows of the ion measurement signal and the simulated ion measurement signal is iteratively processed by adjusting the values ​​of the input parameters until the variance converges. (d) Record the amount of charge generated from (c). (e) Advance the time window of the ion measurement signal by an incremental time amount. (f) Repeat (b)–(d) until the time window reaches the end of the ion measurement file, and (g) Determine the charge of the ion based on the charge value of each time window.

2. The method of claim 1, wherein (b) includes processing the ion measurement signal within a time window to determine the signal frequency and an estimate of the charge value.

3. The method according to claim 2, wherein, The time window for processing the ion measurement signal includes calculating the Fast Fourier Transform (FFT) of the time window of the ion measurement signal, and determining the estimated signal frequency and charge value based on the FFT.

4. The method according to any one of claims 1 to 3, wherein, For the first execution of the ion measurement signal within time window (b) at the beginning of the ion measurement file, the initial estimate of the signal phase is set to zero. Furthermore, (b) includes cross-correlating the simulated ion measurement signal with the time window of the ion measurement signal, and updating the estimate of the signal phase to the minimum value generated from the cross-correlation.

5. The method according to any one of claims 1 to 3, wherein (c) comprises: (1) Determine the variance between the time windows of the ion measurement signal and the simulated ion measurement signal. (2) Perform an optimization process to reduce the variance between the time windows of the ion measurement signal and the simulated ion measurement signal, and (3) Adjust the values ​​of the input parameters based on the results of the optimization process.

6. The method of claim 5, wherein (c) further comprises recording the adjusted charge value upon variance convergence. And (g) includes determining the charge value of the ion based on the adjusted charge value for each time window.

7. The method according to any one of claims 1 to 3, wherein (e) further comprises setting the input parameter to an adjusted input parameter value generated from (c).

8. The method according to any one of claims 1 to 3, wherein (d) further comprises recording the frequency values ​​generated from step (c), Furthermore, it includes determining the frequency of ion oscillations during ion capture events based on the frequency value of each time window.

9. The method according to any one of claims 1 to 3, further comprising: Calculate the Fast Fourier Transform (FFT) of the ion measurement file, and The frequency of ion oscillations during ion trapping events is determined based on FFT.

10. The method of claim 8, further comprising: The mass-to-charge ratio of ions is determined based on the ion oscillation frequency determined during the capture event, and The mass of an ion is determined based on its mass-to-charge ratio and its charge.

11. A charge detection mass spectrometer (CDMS), comprising: Electrostatic linear ion trap ELIT An ion source is configured to supply ions to the ELIT. A charge-sensitive preamplifier with an input operablely coupled to ELIT. At least one processor, operatively coupled to the output of the ELIT and the amplifier, and At least one memory storing instructions that, when executed by at least one processor, cause the at least one processor to (a) control the ELIT to capture ions supplied by the ion source therein, (b) collect ion measurement information based on an output signal generated by the charge-sensitive preamplifier as the captured ions oscillate back and forth through the ELIT, the ion measurement information including the charge induced by the ions on the charge detector of the ELIT during each pass of the ions and the timing of the induced charges relative to each other, (c) process the ion measurement information in the time domain of each of a plurality of sequential time windows to determine the charge magnitude value of the ions during each time window, and (d) determine the charge magnitude value of the captured ions based on the charge magnitude value of each time window, wherein (d) includes: (i) Establish a time window for the ion measurement signal at the beginning of the ion measurement file. (ii) A simulated ion measurement signal is generated using input parameters that serve as a time window for the ion measurement signal, including estimates of signal frequency, charge value, signal phase, and duty cycle. (iii) The variance between the time windows of the ion measurement signal and the simulated ion measurement signal is iteratively processed by adjusting the values ​​of the input parameters until the variance converges. (iv) Record the amount of charge generated from (iii). (v) Advance the time window of the ion measurement signal by an incremental time amount. (vi) Repeat steps (ii)-(iv) until the time window reaches the end of the ion measurement file, and (vii) Determine the charge of the ion based on the charge value of each time window.

12. The CDMS according to claim 11, wherein, ELIT includes a charge detection cylinder positioned between two ion mirrors, wherein during an ion trapping event, ions oscillate back and forth between the two ion mirrors, passing through the charge detection cylinder each time and inducing a corresponding charge on the cylinder, and wherein the ion measurement signal includes the magnitude of the induced charge and the timing of the induced charge during the trapping event, the ion measurement signal being recorded in an ion measurement file.

13. The CDMS according to claim 11, wherein, (iv) further includes recording the frequency values ​​generated from (c), Furthermore, the instructions stored in at least one memory further include processor-executable instructions to determine the ion oscillation frequency during an ion trapping event based on the frequency value of each time window.

14. The CDMS according to claim 11, wherein, The instructions stored in the at least one memory further include processor-executable instructions to calculate the Fast Fourier Transform (FFT) of the ion measurement file and determine the ion oscillation frequency during an ion trapping event based on the FFT.

15. The CDMS according to claim 13, wherein, The instructions stored in the at least one memory include processor-executable instructions to determine the mass-to-charge ratio of the ion based on the ion oscillation frequency determined during the capture event, and to determine the mass of the ion based on the determined mass-to-charge ratio and the determined ion charge.

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