Time-of-flight mass spectrometer and signal processing device

Abstract

A time-of-flight mass spectrometer (100) is provided with: an ejection unit (27) that ejects ions for each sequence; a flight tube (32); an ion detector (35); and a signal processing device (7) that generates a mass spectrum on the basis of detection values from the ion detector and outputs a display signal for displaying the mass spectrum. The signal processing device generates one-shot data for each sequence using the detection values and, after correcting the one-shot data, generates the mass spectrum through a process (S10) of integrating the corrected one-shot data. The correction includes shift correction that shifts the one-shot data in the flight time axis direction.

Description

Time-of-flight mass spectrometer and signal processing device

[0001] The present disclosure relates to a time-of-flight mass spectrometer and a signal processing device.

[0002] A time-of-flight mass spectrometer generally imparts a certain amount of kinetic energy to ions derived from sample components, causing them to fly a certain distance in space, measures the time required for the ions to fly, and calculates the mass-to-charge ratio of the ions from this time of flight (see Japanese Patent No. 6489240 (Patent Document 1)).

[0003] Patent No. 6489240

[0004] A time-of-flight mass spectrometer repeats a sequence from ejecting ions stored in an ion trap into flight space to detecting the ions in mass order with an ion detector. This allows the time-of-flight mass spectrometer to generate "one-shot data" indicating the relationship between time-of-flight (TOF) and ion intensity for each sequence. The sequence operation is repeated without changing the TOF range or sampling interval. Therefore, the time-of-flight mass spectrometer can generate a TOF spectrum by simply accumulating the generated multiple one-shot data.

[0005] However, the TOF spectrum generated in this manner does not take into account the "statistical variation of ion intensity signals along the time-of-flight axis" that occurs in each sequence operation. This can cause excessive broadening of the peak width of the TOF spectrum or a decrease in the intensity of the peak top. Mass spectra generated based on the TOF spectrum are affected by the TOF spectrum and have reduced accuracy. These results directly affect the evaluation of instrument performance. In other words, excessive broadening of the peak width is considered to be a decrease in resolution, and a decrease in the intensity of the peak top is considered to be a decrease in sensitivity.

[0006] The present disclosure has been made to solve such problems, and aims to provide users with mass spectra in which the statistical variation of ion intensity signals in the TOF axis direction is reduced.

[0007] A time-of-flight mass spectrometer according to one aspect of the present disclosure is a time-of-flight mass spectrometer that repeatedly stores ions in an ion trap and ejects ions from the ion trap for each sequence. The time-of-flight mass spectrometer includes an ejection unit that ejects ions for each sequence, a flight tube that defines a flight space through which the ions fly, an ion detector that detects ions that have completed their flight in the flight space among the ions ejected from the ejection unit, and a signal processing device that generates a mass spectrum based on detection values ​​from the ion detector and outputs a display signal for displaying the mass spectrum. The signal processing device generates one-shot data for each sequence, which indicates the relationship between ion intensity and time-of-flight, using the detection values, corrects the one-shot data, and then generates a mass spectrum by integrating each of the corrected one-shot data. The correction includes a shift correction that shifts the one-shot data along the time-of-flight axis.

[0008] According to the present disclosure, a mass spectrum can be generated in which the statistical variation of ion intensity signals in the TOF axis direction is reduced.

[0009] FIG. 1 is a schematic diagram of a time-of-flight mass spectrometer according to the present embodiment; FIG. 2 is a diagram illustrating the concept of one-shot data corresponding to each of three sequences; FIG. 3 is a diagram illustrating the concept of a reference spectrum; FIG. 4 is a diagram illustrating how one-shot data is shifted in data point intervals in the TOF axis direction; FIG. 5 is a diagram comparing a simple integrated spectrum without shift correction, a reference spectrum, and a TOF spectrum with shift correction; FIG. 6 is a flowchart illustrating the processing procedure of a signal processing device; FIG. 7 is a flowchart illustrating the processing procedure related to Modification 1; FIG. 8 is a diagram illustrating several examples of integrated spectra with shift correction, generated by processing related to Modification 1; FIG. 9 is a diagram illustrating a waveform obtained by taking the difference between two moving averages with different numbers of points for certain one-shot data; and FIG. 10 is a diagram illustrating an example of a reference spectrum related to Modification 2.

[0010] Hereinafter, embodiments of the present disclosure will be described in detail with reference to the drawings. In the drawings, the same or corresponding parts are designated by the same reference numerals, and description thereof will not be repeated.

[0011] [Overall Configuration of Time-of-Flight Mass Spectrometer 100] Figure 1 is a schematic diagram of a time-of-flight mass spectrometer 100 according to this embodiment. The time-of-flight mass spectrometer 100 is, for example, a quadrupole (Q)-time-of-flight (TOF) mass spectrometer. Note that a tandem time-of-flight mass spectrometer, such as a tandem quadrupole (QQ) or tandem flight (TOF-TOF) type, may also be used as the time-of-flight mass spectrometer. The time-of-flight mass spectrometer 100 can detect TOF signals of ions over a wide range, from low mass (low m / z) to high mass (high m / z), in a single analysis.

[0012] The time-of-flight mass spectrometer 100 includes a vacuum chamber 2 , a power supply unit 4 , an introduction unit 5 , a control unit 6 , and a signal processing unit 7 .

[0013] The control unit 6 controls various electrical components, including electrodes, arranged in the vacuum chamber 2, and the power supply unit 4. The power supply unit 4 applies a predetermined voltage to each of the various electrical components in the vacuum chamber 2 based on commands from the control unit 6. The control unit 6 is configured, for example, by a microcomputer.

[0014] The signal processing device 7 includes a processor 71 , a memory 72 , an input / output I / F 73 , a display 74 , and an input device 75 .

[0015] The processor 71 is typically an arithmetic processing unit such as a CPU (Central Processing Unit) or an MPU (Micro Processing Unit). The processor 71 performs various processes by reading and executing programs stored in the memory 72. The processor 71 is configured to be able to communicate with the control unit 6.

[0016] The memory 72 is realized by a storage device such as a read-only memory (ROM), a random access memory (RAM), or a hard disk drive (HDD). The ROM can store programs executed by the processor 71. The RAM can temporarily store data used during execution of the programs by the processor 71 and can function as a temporary data memory used as a work area. The HDD is a non-volatile storage device. A semiconductor storage device such as a flash memory may be used in addition to or instead of the HDD. The programs and / or data may be stored in an external storage device accessible by the processor 71.

[0017] The input / output interface (I / F) 73 is an interface for exchanging various types of data between the processor 71 and an external device connected to the input / output interface 73. The external device includes a display 74, an input device 75, and a control unit 6. The display 74 displays, for example, the processing results of the processor 71. The input device 75 is typically composed of a touch panel, a keyboard, a mouse, etc. The input device 75 accepts input operations by the user to the processor 71.

[0018] The control unit 6 and the signal processing device 7 may be integrated. For example, the control unit 6 may be provided with the functions of the signal processing device 7.

[0019] The vacuum chamber 2 is partitioned into an ionization chamber 200, a first vacuum chamber 201, a second vacuum chamber 202, a third vacuum chamber 203, and a fourth vacuum chamber 204. The pressure inside the ionization chamber 200 is approximately atmospheric pressure. The first vacuum chamber 201, the second vacuum chamber 202, the third vacuum chamber 203, and the fourth vacuum chamber 204 are evacuated by vacuum pumps (not shown). The control unit 6 controls the vacuum pumps so that the degree of vacuum increases in the order of the first vacuum chamber 201, the second vacuum chamber 202, the third vacuum chamber 203, and the fourth vacuum chamber 204.

[0020] An electrospray ionization (ESI) source 21 is disposed in the ionization chamber 200. A liquid sample containing a target component is supplied to the ESI source 21. The ESI source 21 sprays the liquid sample into the ionization chamber 200 while imparting an electric charge to the liquid sample. This ionizes compounds in the sample liquid, and various ions derived from the sample diffuse into the ionization chamber 200. Of the ions in the ionization chamber 200, those to be analyzed are directed from the first vacuum chamber 201 to the fourth vacuum chamber 204 along the ion optical axis C1 by control described below.

[0021] However, the method for ionizing compounds is not limited to this. For example, a method using other ion sources, such as an atmospheric pressure chemical ion source, may be used. An ion source that ionizes gaseous or solid samples, rather than liquid samples, may also be used.

[0022] Ions in the ionization chamber 200 are sent to the first vacuum chamber 201 through the desolvation tube 22 and focused by the ion guide 23. The ions focused by the ion guide 23 are sent from the first vacuum chamber 201 to the second vacuum chamber 202 via the skimmer 24. The ions sent to the second vacuum chamber 202 are focused by the ion guide 25. The ions focused by the ion guide 25 are sent from the second vacuum chamber 202 to the third vacuum chamber 203.

[0023] The third vacuum chamber 203 is equipped with a quadrupole mass filter 26 and a collision cell 27. The collision cell 27 is equipped with a multipole ion guide 28, an entrance lens electrode 36, and an exit lens electrode 37. The collision cell 27 functions as an ion trap that accumulates ions. The time-of-flight mass spectrometer 100 according to this embodiment repeats the accumulation of ions in the ion trap and the ejection of ions from the ion trap for each sequence.

[0024] The ions sent to the third vacuum chamber 203 are introduced into the quadrupole mass filter 26. A voltage corresponding to the ions to be analyzed is applied to the quadrupole mass filter 26.

[0025] Therefore, of the ions introduced into the quadrupole mass filter 26, only ions having a specific mass-to-charge ratio (m / z) corresponding to the applied voltage pass through the quadrupole mass filter 26. Ions that pass through the quadrupole mass filter 26 are called "precursor ions." The precursor ions are introduced into the collision cell 27. The inlet unit 5 supplies a CID (Collision Induced Dissociation) gas to the collision cell 27. The precursor ions introduced into the collision cell 27 collide with the CID gas and are dissociated. As a result, various product ions are generated within the collision cell 27.

[0026] The product ions are temporarily accumulated in the collision cell 27 by the action of an ion trap formed by the ion guide 28 , entrance lens electrode 36 , and exit lens electrode 37 .

[0027] The ions accumulated in the collision cell 27 are emitted as a group of ion packets from the collision cell 27 toward the fourth vacuum chamber 204. The collision cell 27 is an example of an emission section. An ion transport optical system 29 consisting of a plurality of electrodes is disposed between the third vacuum chamber 203 and the fourth vacuum chamber 204. The ions emitted from the collision cell 27 are guided by the ion transport optical system 29 and introduced into the fourth vacuum chamber 204.

[0028] The fourth vacuum chamber 204 is provided with an orthogonal accelerator 30, a flight tube 32, a reflector 38, and an ion detector 35. The reflector 38 includes a reflectron 33 and a back plate 34. The flight tube 32 defines a flight space 320 in which ions fly.

[0029] Ions introduced into the orthogonal acceleration unit 30 in the X-axis direction are accelerated in the Z-axis direction and enter the flight space 320. An electric field that causes the ions to fly back along path C2 is formed in the flight space 320. Ions flying from the orthogonal acceleration unit 30 toward the reflector 38 make a U-turn due to the action of the reflected electric field formed by the reflector 38 and re-enter the flight space 320. The ions then reach the ion detector 35.

[0030] In the orthogonal acceleration unit 30, ions with smaller mass-to-charge ratios are accelerated at a higher speed. Therefore, the time of flight (TOF) of ions from the ion trap through the orthogonal acceleration unit 30 to the ion detector 35 varies depending on the mass-to-charge ratio of the ions. This separates ions according to their mass-to-charge ratio. The ion detector 35 detects ions in order of mass. The ion detector 35 is connected to the signal processing device 7 via an analog-to-digital (A / D) converter 8. The ion detector 35 outputs an ion intensity signal corresponding to the amount of ions incident on the ion detector 35 to the signal processing device 7 via the analog-to-digital (A / D) converter 8.

[0031] The signal processing device 7 uses the ion intensity signal obtained from the ion detector 35 to generate "one-shot data" that indicates the relationship between ion intensity and time of flight (TOF).

[0032] The time-of-flight mass spectrometer 100 repeatedly executes a sequence from ejecting ions stored in the collision cell 27 to detecting the ions in mass order with the ion detector 35. This generates a number of "one-shot data" corresponding to the number of executed sequences. The TOF range and sampling interval are the same for each sequence.

[0033] The signal processing device 7 generates a TOF spectrum using the generated multiple one-shot data. Furthermore, the signal processing device 7 calculates the mass-to-charge ratio based on the time-of-flight of the ions, and generates a mass spectrum using the calculation result and the TOF spectrum. The signal processing device 7 displays the generated mass spectrum on the display 74. For example, by looking at the mass spectrum displayed on the display 74, a user can understand the relationship between the mass-to-charge ratio and the ion intensity.

[0034] [One-Shot Data] Figure 2 shows the concept of one-shot data corresponding to each of the three sequences. In each of the graphs shown in Figure 2 (A) to (C), the vertical axis represents intensity and the horizontal axis represents time of flight (TOF). In Figure 2, the ion intensity corresponding to the TOF axis value (TOF value) t is expressed as S(t).

[0035] The amount of ions ejected from the ion trap in one sequence is limited. Therefore, the distribution of ion intensities appearing in one one-shot data is highly dependent on probability. In other words, peaks originating from a sample cannot necessarily be detected simultaneously in one sequence. Therefore, it is conceivable to generate a TOF spectrum by integrating multiple one-shot data.

[0036] Each of the multiple one-shot data sets has a common TOF range and sampling interval. Therefore, a TOF spectrum can be formed by simply accumulating multiple one-shot data sets. However, the TOF spectrum generated in this manner does not take into account the "statistical variation in ion intensity signals in the TOF axis direction" that occurs in each sequence operation. This can cause excessive broadening of the peak width of the TOF spectrum or a decrease in the peak top intensity. These factors ultimately directly affect the evaluation of instrument performance. In other words, excessive broadening of the peak width is considered to be a decrease in resolution, and a decrease in the peak top intensity is considered to be a decrease in sensitivity.

[0037] Therefore, in this embodiment, we propose an appropriate signal processing method for improving the essential performance of TOF spectra. This method includes the following signal processing steps: (1) generating a reference spectrum from a spectrum obtained by accumulating one-shot data, (2) correcting the TOF variation of each one-shot data by referring to the TOF value and intensity ratio of the reference spectrum, and (3) generating a TOF spectrum by accumulating the corrected one-shot data.

[0038] The signal processing device 7 generates a TOF spectrum by executing these signal processing steps (1) to (3). FIG. 3 is a diagram showing the concept of a reference spectrum. FIG. 4 is a diagram showing how one-shot data is shifted in the TOF axis direction at data point intervals. FIG. 5 is a diagram comparing a simple integrated spectrum without shift correction, a reference spectrum, and a TOF spectrum with shift correction. FIG. 6 is a flowchart for explaining the processing procedure of the signal processing device 7.

[0039] [Processing Procedure] The processing procedure of the signal processing device 7 will be explained below according to the flowchart shown in Fig. 6, with reference to Fig. 3 to Fig. 5 as necessary. Note that, as an example, it is assumed that trypsinogen (molecular weight 24,000 Da) is analyzed in the time-of-flight mass spectrometer 100 and a spectrum is formed by applying this method.

[0040] When the time-of-flight mass spectrometer 100 receives an instruction from the user to start analysis, it executes the processes described below as part of a series of analytical processing steps and derives a TOF spectrum as the analysis result. Furthermore, the time-of-flight mass spectrometer 100 creates a mass spectrum based on the TOF spectrum and displays the created mass spectrum on the display 74. The processes of generating a reference spectrum and correcting the one-shot signal are executed as internal processes of the signal processing device 7 included in the time-of-flight mass spectrometer 100. After issuing an instruction to start analysis to the time-of-flight mass spectrometer 100, the user checks the mass spectrum displayed on the display 74.

[0041] For example, when the user selects an optional function such as "high resolution / high sensitivity mode" during the process of setting the analysis conditions before performing the analysis, the signal processing device 7 executes processing based on the processing procedure described below.

[0042] First, the user selects the m / z range in which they wish to confirm the mass spectrum of trypsinogen with high resolution and high sensitivity, and issues an instruction to start analysis to the time-of-flight mass spectrometer 100. The signal processing device 7 sets the analysis conditions in accordance with the user's instructions (step S1). Based on the m / z range, the signal processing device 7 determines the TOF range (t1 to t2) in which data will be acquired by the digitizer.

[0043] Next, the signal processing device 7 instructs the control unit 6 to perform an analysis operation. This initiates a sequence for generating one-shot data in the vacuum chamber 2. This sequence is repeatedly executed within the TOF range set in step S1. The developer or user sets the number of times the sequence will be repeated in the time-of-flight mass spectrometer 100 in advance. The signal processing device 7 generates one-shot data for each sequence and generates an accumulated spectrum by accumulating each of the generated one-shot data (step S2). The signal processing device 7 stores each of the generated one-shot data in the memory 72.

[0044] Next, the signal processing device 7 generates a reference spectrum using the accumulated spectrum (step S3). Specifically, the signal processing device 7 generates the reference spectrum by smoothing the accumulated spectrum. The signal processing device 7 smooths the accumulated spectrum, for example, using a moving average technique. Statistical variations exist in each one-shot data. However, by accumulating each one-shot data, the isotope pattern derived from trypsinogen can be confirmed from the "accumulated spectrum." Furthermore, the isotope pattern derived from trypsinogen appears more clearly in the "reference spectrum." As described above, the signal processing device 7 generates the reference spectrum by accumulating each one-shot data generated for each sequence.

[0045] The waveform of the reference spectrum is conceptually shown in Fig. 3. In Fig. 3, the ion intensity corresponding to the value t on the TOF axis is expressed as T(t).

[0046] In the signal processing according to the present disclosure, the reference spectrum is “correction reference data” for correcting each of the multiple one-shot data. As will be described below, the signal processing device 7 corrects each of the multiple one-shot data using the reference spectrum.

[0047] The signal processing device 7 may use an unsmoothed "integrated spectrum" as the "reference spectrum." In other words, smoothing is not essential in the present disclosure. Here, an example is shown in which data having a width in the time-of-flight axis direction, like the reference spectrum, is used as the "correction reference data." However, data that does not have a width in the time-of-flight axis direction and that indicates only the peak-top intensity, or data that indicates the peak-top intensity and the "valley" intensity, may also be used as the "correction reference data."

[0048] Next, the signal processing device 7 sets one of the multiple one-shot data generated in step S2 as one-shot data to be corrected (step S4). Next, the signal processing device 7 calculates the correlation strength between the reference spectrum and the set one-shot data (step S5). To calculate the correlation strength, the signal processing device 7 may use, for example, the cross-correlation function C(s) shown in Equation 1.

[0049]

[0050] In Equation 1, "t" is a value on the TOF axis, and "t1" and "t2" are values ​​that define the TOF range (t1 to t2). These are also shown in FIGS. 3 and 4. In Equation 1, "s" is a variable that indicates the amount of shift of the one-shot data in the TOF axis direction. If there is no shift amount, "s=0". When "s=0", the correlation strength between the reference spectrum and the one-shot data is calculated in a state where t1 of the one-shot data to be corrected is superimposed on the position t1 of the reference spectrum (in other words, in a state where t2 of the one-shot data to be corrected is superimposed on the position t2 of the reference spectrum).

[0051] When "s" is a value greater than or less than 0, the correlation strength between the reference spectrum and the one-shot data is calculated in a state in which the one-shot data is shifted in the TOF axis direction relative to the reference spectrum by the shift amount determined by "s". Here, the unit of the shift amount, i.e., the data point interval, is defined as "Δt". Δt is a discrete value. Therefore, when the correlation strength is actually calculated, the integral in Equation 1 is replaced by a sum. Note that Δt depends on the sampling rate of the digitizer.

[0052] 4 shows how the one-shot data is shifted in the TOF axis direction at data point intervals Δt. Note that while Fig. 4 shows how the one-shot data is shifted in the positive direction of the TOF axis, in signal processing the one-shot data is shifted in both the positive and negative directions to calculate the correlation strength between the reference spectrum and the one-shot data.

[0053] Peak detection is not performed in calculating the correlation strength. This is because the correlation between the one-shot data and the reference spectrum is determined as a spectral pattern without relying on a specific signal peak. However, the signal processing device 7 removes unnecessary baseline noise signals before calculating the correlation strength.

[0054] When a cross-correlation function such as that shown in Equation 1 is used, the calculation result based on the cross-correlation function will be a value other than zero when a peak in the reference spectrum and a peak in the one-shot data overlap at a TOF value corresponding to a data point. Furthermore, if the intensity information of the reference spectrum is considered as a weight, the calculation result based on the cross-correlation function will be a larger value when the one-shot data overlaps with a peak of high intensity in the reference spectrum.

[0055] After the correlation strength is calculated in step S5, the signal processing device 7 executes a shift process (step S6). This changes the degree of overlap of the one-shot data with respect to the reference spectrum by Δt. Thereafter, the signal processing device 7 repeatedly executes steps S4 to S6, provided that the shift amount does not exceed the upper limit (NO in step S7). This allows the correlation strength to be calculated while changing the degree of overlap of the one-shot data with respect to the reference spectrum.

[0056] In step S6, a shift process is performed in the positive direction of the TOF axis by Δt until the shift amount reaches the upper limit value, and then a shift process is performed in the negative direction of the TOF axis by Δt until the shift amount reaches the "lower limit value corresponding to the upper limit value." Therefore, in step S5, in addition to the correlation strength when the one-shot data is not shifted in the TOF axis direction, the correlation strength is also calculated when the shift amount is ±2Δt, ±3Δt, ... (s = ±2Δt, ±3Δt, ...). In this way, the signal processing device 7 shifts the one-shot data within a predetermined range in both the positive and negative directions of the time-of-flight axis.

[0057] For example, the width of adjacent peaks in the isotope pattern may be used as the range of the shift amount in each of the positive and negative directions. This is because the statistical variation in the TOF axis direction of one-shot data is considered to occur at most between adjacent peaks in the isotope pattern. Here, the width of adjacent peaks in the isotope pattern is, for example, the difference between "ti1" and "ti2" shown in FIG. 3. Therefore, it is conceivable to set the range of the shift amount (the upper and lower limit values) to "ti2-ti1."

[0058] The range of the shift amount is not limited to the width of adjacent peaks of the isotope pattern. However, the larger the shift amount, the greater the possibility that the deviation between the integrated spectrum formed after correction of the one-shot data and the isotope pattern of the reference spectrum will be. Therefore, the developer or user must carefully determine the range of the shift amount. In this embodiment, for all one-shot data, the range of the shift amount in each of the positive and negative directions may be set to a value corresponding to 10Δt, and the correlation strength between the reference spectrum and the one-shot data may be calculated for each shift amount.

[0059] If the shift amount reaches the upper limit (or lower limit) (YES in step S7), the signal processing device 7 determines correction data based on the "optimal shift amount" (step S8). More specifically, the signal processing device 7 compares the correlation strengths calculated for each shift amount for the one-shot data (step S5). The signal processing device 7 selects the shift amount that maximizes the correlation strength, and adopts the one-shot data obtained by shifting the original one-shot data in the TOF axis direction by the selected shift amount as correction data. Here, the signal processing device 7 determines the shift amount so as to minimize the deviation between the peak of the reference spectrum and the peak of the one-shot data. The correction performed by the signal processing device 7 includes a shift correction that shifts the one-shot data in the time-of-flight axis direction. Furthermore, the signal processing device 7 determines the magnitude of the deviation between the peak of the reference spectrum and the peak of the one-shot data based on the correlation strength between the reference spectrum and the one-shot data.

[0060] Next, the signal processing device 7 determines whether or not correction data corresponding to each of all the one-shot data has been acquired (step S9). If correction data corresponding to each of all the shot data has not been acquired, the signal processing device 7 returns to step S4. The signal processing device 7 repeats the processes of steps S4 to S8 until correction data corresponding to each of all the shot data has been acquired. In this way, the signal processing device 7 acquires correction data corresponding to each of all the one-shot data. Note that the shift amount that maximizes the correlation strength may be a completely different value for each one-shot data.

[0061] Calculating the correlation strength through the processing of steps S5 and S6 is equivalent to calculating the similarity between the signal detection pattern of a single one-shot data piece and that of a reference spectrum for each shift amount, and therefore, absolute values ​​can be compared. For example, if the correlation strength between the one-shot data shifted by +2Δt and the reference spectrum is greatest compared to the other shift amounts, it can be considered that the one-shot data shifted by +2Δt should have been acquired as data shifted by +2Δt if there were no detection error in the hardware.

[0062] In addition, if no significant maximum value is observed in the correlation strength for each shift amount of one-shot data and the correlation strength value is small overall, it is not preferable to determine the correction data based on the maximum correlation strength. Therefore, a threshold value for determining the correlation strength may be set, and if the correlation strength for each shift amount is equal to or less than the threshold value, the one-shot data in question may be excluded from the subsequent processing (step S10: accumulation of correction data and spectrum formation).

[0063] Next, the signal processing device 7 generates a TOF spectrum by integrating all the corrected data (step S10). In other words, the signal processing device 7 generates a TOF spectrum by executing a process of integrating each corrected one-shot data. However, since the shift amount of each corrected data is different, both ends of the TOF axis of the integrated spectrum are truncated, and only the TOF range common to all the corrected data is used as the TOF spectrum.

[0064] 5 shows the TOF spectrum obtained through the above processing procedure, together with the accumulated spectrum and the reference spectrum. As is clear from FIG. 5, the TOF spectrum obtained through the above processing procedure has improved resolution and S / N compared to the accumulated spectrum and the reference spectrum. The inventors of the present disclosure have confirmed that the TOF spectrum according to this embodiment has about two times the resolution and about three times the S / N compared to a conventional accumulated spectrum obtained by simply accumulating multiple one-shot data without shift correction, for example.

[0065] After step S10, the signal processing device 7 generates a mass spectrum using the mass-to-charge ratio and the TOF spectrum (step S11). In this way, the signal processing device 7 corrects the one-shot data, then performs a process of integrating each of the corrected one-shot data, and finally generates a mass spectrum using the TOF spectrum obtained by this process.

[0066] Next, the signal processing device 7 executes a display process (step S12). More specifically, the signal processing device 7 outputs a display signal for displaying the mass spectrum generated in step S11 to the display 74. As a result, the mass spectrum is displayed on the display 74.

[0067] In response to a user instruction, the signal processing device 7 may output a display signal for displaying the TOF spectrum to the display 74. In this case, the TOF spectrum is displayed on the display 74. Alternatively, the signal processing device 7 may output a display signal for displaying the mass spectrum and the TOF spectrum to the display 74.

[0068] As described above, according to this embodiment, corrected data in which the TOF variation of one-shot data has been corrected is accumulated, making it possible to obtain a spectrum in which the statistical variation of the detection signal derived from the sample is reduced. In other words, according to this embodiment, a high-resolution, high-sensitivity spectrum can be obtained for the sample to be analyzed. This makes it possible to provide the user with a mass spectrum in which the statistical variation of the ion intensity signal in the TOF axis direction is reduced.

[0069] [Modification 1] Modification 1 will be described with reference to Fig. 7 and Fig. 8. Fig. 7 is a flowchart for explaining a processing procedure related to Modification 1. Fig. 8 is a diagram showing several examples of shift-corrected accumulated spectra generated by processing related to Modification 1.

[0070] The flowchart shown in FIG. 7 adds steps S91 to S93 to the flowchart shown in FIG. 6 . In Modification 1, after determining YES in step S9, the signal processing device 7 determines whether the convergence condition is met (step S91). If the convergence condition is not met, the signal processing device 7 does not immediately generate a TOF spectrum by integrating all the correction data, but instead uses the spectrum obtained by integrating all the correction data as a reference spectrum (step S92). In other words, the "reference spectrum" is replaced with the "spectrum obtained by integrating all the correction data." Furthermore, the signal processing device 7 replaces each "correction data" with the corresponding "one-shot data" (step S93).

[0071] Thereafter, the signal processing device 7 returns to step S4 and repeats steps S4 to S9 based on the replaced one-shot data. The signal processing device 7 repeats this series of processes until the convergence condition is met. In the first modification, since this series of processes is repeated, a higher correction effect is achieved compared to the processing procedure shown in FIG.

[0072] The convergence condition (step S91) may be, for example, "the shift amount of 80% of the one-shot data group is equal to or less than a predetermined threshold." In this case, when the shift amount (positive or negative shift amount) of 80% of the one-shot data group is equal to or less than the predetermined threshold, the signal processing device 7 proceeds to step S10. Note that, for example, "half the range of shift amounts" may be adopted as such a "threshold." For example, when the range of shift amounts is a value corresponding to 10 Δt, the threshold is 5 Δt.

[0073] 8 shows examples of integrated spectra generated when the number of repetitions is 1, 3, and 10. The integrated spectrum generated when the number of repetitions is 3 has sharper peaks than the integrated spectrum generated when the number of repetitions is 1.

[0074] As described above, according to the first modification, a higher correction effect can be achieved, and therefore the peak resolution can be further increased, compared to the processing procedure shown in Fig. 6. In the example shown in Fig. 8, it is considered that the convergence condition is satisfied with about three repetitions, and therefore even if the number of repetitions is increased beyond three, the corrected integrated spectrum does not change significantly.

[0075] In the above-described second modification, step S92 is an example of a process (first process) for updating the reference spectrum by integrating each one-shot data corrected by shift correction. Step S93 is an example of a process (second process) for setting each one-shot data corrected by shift correction as a comparison target for the updated reference spectrum. Step S8 is an example of a process (third process) for determining the shift amount so as to reduce the deviation between the peak of the updated reference spectrum and the peak of the one-shot data to be compared. When the convergence condition is met, the signal processing device 7 generates a mass spectrum by integrating each one-shot data corrected in the third process.

[0076] [Modification 2] Modification 2 will be described with reference to Fig. 9 and Fig. 10. Fig. 9 is a diagram showing a waveform obtained by taking the difference between two moving averages with different number of points for one-shot data. Fig. 10 is a diagram showing an example of a reference spectrum related to Modification 2. Here, an example will be described in which a reference spectrum is generated from an integrated spectrum by taking the difference between two moving averages with different number of points.

[0077] Figure 9 shows the waveform of a 5-point moving average, the waveform of a 30-point moving average, and the difference waveform between these two waveforms. As shown in Figure 9, by taking the difference between two moving averages with different numbers of points, the peak (signal) becomes apparent. As a result, the signal and noise regions can be clearly distinguished.

[0078] Therefore, when generating a reference spectrum from an integrated spectrum, the reference spectrum may be a differential waveform between a first waveform obtained from the integrated spectrum by a moving average of a first number of points and a second waveform obtained from the integrated spectrum by a moving average of a second number of points. FIG. 10 shows a waveform W1 representing the integrated spectrum and a waveform W2 corresponding to the difference between a waveform obtained from the integrated spectrum by a moving average of 30 points and a waveform obtained from the integrated spectrum by a moving average of 100 points. Such a waveform W2 may be used as the reference spectrum. In this case, the valleys between the peaks correspond to negative weights. Therefore, according to the second modification, the difference in correlation strength values ​​for each shift amount is larger than when a reference spectrum is generated by simply applying a moving average technique to an integrated spectrum. This is useful when determining an appropriate shift amount.

[0079] [Aspects] It will be understood by those skilled in the art that the above-described embodiments are specific examples of the following aspects.

[0080] (Item 1) A time-of-flight mass spectrometer that repeatedly stores ions in an ion trap and ejects ions from the ion trap for each sequence, comprising: an ejection unit that ejects ions for each sequence; a flight tube that forms a flight space through which the ions fly; an ion detector that detects ions that have completed their flight in the flight space among the ions ejected from the ejection unit; and a signal processing device that generates a mass spectrum based on the detection values ​​of the ion detector and outputs a display signal for displaying the mass spectrum. The signal processing device generates one-shot data for each sequence that indicates the relationship between ion intensity and time-of-flight using the detection values, corrects the one-shot data, and then generates a mass spectrum by accumulating each corrected one-shot data. The correction includes a shift correction that shifts the one-shot data in the direction of the flight time axis.

[0081] According to the time-of-flight mass spectrometer described in paragraph 1, it is possible to provide a user with a mass spectrum in which the statistical variation of ion intensity signals in the TOF axis direction is reduced.

[0082] (2) In the time-of-flight mass spectrometer described in paragraph 1, the signal processing device generates a reference spectrum by integrating each one-shot data generated for each sequence, and the signal processing device determines the amount of shift in the shift correction so that the deviation between the peak of the reference spectrum and the peak of the one-shot data is small.

[0083] According to the time-of-flight mass spectrometer described in the second paragraph, the deviation between the peak of the reference spectrum and the peak of the one-shot data can be reduced.

[0084] (Item 3) In the time-of-flight mass spectrometer described in item 2, the signal processing device determines the amount of shift by performing a process of shifting the one-shot data in both the positive and negative directions of the time-of-flight axis within a predetermined range, the predetermined range being the width of adjacent peaks in the isotope pattern.

[0085] An appropriate shift amount is determined according to the time-of-flight mass spectrometer described in paragraph 3. (4) In the time-of-flight mass spectrometer described in paragraph 2 or 3, the signal processing device determines the magnitude of the shift between the peak of the reference spectrum and the peak of the one-shot data based on the correlation strength between the reference spectrum and the one-shot data.

[0086] According to the time-of-flight mass spectrometer described in item 4, the magnitude of the deviation can be determined appropriately.

[0087] (Item 5) In the time-of-flight mass spectrometer described in item 4, the signal processing device calculates the correlation strength using a cross-correlation function.

[0088] According to the time-of-flight mass spectrometer described in item 5, the correlation strength can be determined appropriately.

[0089] (Item 6) In the time-of-flight mass spectrometer described in any one of Items 2 to 5, the signal processing device generates an integrated spectrum by integrating each one-shot data generated for each sequence, and then generates a reference spectrum by smoothing the integrated spectrum.

[0090] According to the time-of-flight mass spectrometer described in item 6, noise can be removed by smoothing the integrated spectrum.

[0091] (Item 7) In the time-of-flight mass spectrometer described in any one of items 2 to 6, the signal processing device repeats the first process, the second process, and the third process until a convergence condition is met, the first process is a process of updating the reference spectrum by integrating each one-shot data corrected by shift correction, the second process is a process of setting each one-shot data corrected by shift correction as a comparison target for the updated reference spectrum, and the third process is a process of determining the shift amount so as to reduce the deviation between the peak of the updated reference spectrum and the peak of the one-shot data to be compared, and when the convergence condition is met, the signal processing device generates a mass spectrum by integrating each one-shot data corrected in the third process.

[0092] According to the time-of-flight mass spectrometer described in item 7, a higher correction effect is achieved, thereby making it possible to further increase the peak resolution.

[0093] (Item 8) As a signal processing device according to another aspect, the above-described embodiment discloses the signal processing device according to any one of items 1 to 7.

[0094] According to the signal processing device described in item 8, it is possible to provide a user with a mass spectrum in which the statistical variation of ion intensity signals in the TOF axis direction is reduced.

[0095] The embodiments disclosed herein are intended to be combined as appropriate within the scope of any technical inconsistency. The embodiments disclosed herein should be considered to be illustrative and not restrictive in all respects. The scope of the present invention is defined by the claims, not by the description of the above-mentioned embodiments, and is intended to include all modifications within the meaning and scope of the claims.

[0096] 2 Vacuum chamber, 4 Power supply unit, 5 Introduction unit, 6 Control unit, 7 Signal processing unit, 8 A / D converter, 21 ESI source, 22 Desolvation tube, 23, 25, 28 Ion guide, 24 Skimmer, 26 Quadrupole mass filter, 27 Collision cell, 29 Ion transport optics, 30 Orthogonal acceleration unit, 31 Acceleration electrode, 32 Flight tube, 33 Reflectron, 34 Back plate, 35 Ion detector, 36 Entrance lens electrode, 37 Exit lens electrode, 38 Reflector, 71 Processor, 72 Memory, 73 Input / output interface (I / F), 74 Display, 75 Input device, 100 Time-of-flight mass spectrometer, 200 Ionization chamber, 201 First vacuum chamber, 202 Second vacuum chamber, 203 Third vacuum chamber, 204 Fourth vacuum chamber, 301 Push-out electrode, 302 Extraction electrode, 320 Flight space, W1, W2 waveforms.

Claims

1. A time-of-flight mass spectrometer that repeats the accumulation of ions in an ion trap and the ejection of ions from the ion trap for each sequence, comprising: an ejection unit that ejects ions for each sequence; a flight tube in which a flight space for ions to fly is formed; an ion detector that detects ions that have completed flying in the flight space among the ions ejected from the ejection unit; and a signal processing device that generates a mass spectrum based on the detection value of the ion detector and outputs a display signal for displaying the mass spectrum. The signal processing device generates one-shot data showing the relationship between ion intensity and flight time for each sequence using the detection value, and after correcting the one-shot data, generates the mass spectrum through a process of integrating each corrected one-shot data. The correction includes a shift correction for shifting the one-shot data in the flight time axis direction, a time-of-flight mass spectrometer.

2. The signal processing device generates a reference spectrum through a process of integrating each one-shot data generated for each sequence. The signal processing device determines the shift amount in the shift correction so that the shift between the peak of the reference spectrum and the peak of the one-shot data is reduced. The time-of-flight mass spectrometer according to claim 1.

3. The signal processing device determines the shift amount through a process of shifting the one-shot data within a predetermined range in each of the positive and negative directions of the flight time axis. The predetermined range is the adjacent peak width of the isotope pattern. The time-of-flight mass spectrometer according to claim 2.

4. The signal processing device determines the magnitude of the shift between the peak of the reference spectrum and the peak of the one-shot data based on the correlation strength between the reference spectrum and the one-shot data. The time-of-flight mass spectrometer according to claim 2 or claim 3.

5. The signal processing device calculates the correlation strength using a cross-correlation function. The time-of-flight mass spectrometer according to claim 4.

6. The signal processing device generates an integrated spectrum through a process of integrating each one-shot data generated for each sequence, and then generates the reference spectrum by smoothing the integrated spectrum. The time-of-flight mass spectrometer according to claim 2 or claim 3.

7. The signal processing device repeatedly performs the first process, the second process, and the third process until a convergence condition is satisfied. The first process is a process of updating the reference spectrum through a process of integrating each one-shot data corrected by the shift correction. The second process is a process of setting each one-shot data corrected by the shift correction as a comparison target with respect to the updated reference spectrum. The third process is a process of determining the shift amount so that the deviation between the peak of the updated reference spectrum and the peak of the one-shot data as the comparison target becomes small. The signal processing device generates the mass spectrum through a process of integrating each one-shot data corrected in the third process when the convergence condition is satisfied. The time-of-flight mass spectrometer according to claim 2 or claim 3.

8. The signal processing device according to any one of claims 1 to 3.

Images