Histograming of different ion surfaces in peak-detecting analog / digital converters

Abstract

Time-of-flight mass spectrometry methods, which include: Digitizing an initial signal output by an ion detector to generate an initial digitized signal; Detecting one or more peaks in the first digitized signal and determining a first area S0 of the one or more peaks and a first arrival time T0 of the one or more peaks, thereby forming a first list of data pairs; and Determine whether the first surface S0 is a first threshold surface S max exceeds or does not exceed the first threshold area S max a peak area that indicates an essentially simultaneous arrival of two ions which the ion detector cannot resolve, and where, when it is determined that the first area S0 is the first threshold area S maxdoes not exceed, the procedure further comprises recording the first area S0 and the first arrival time T0 or data derived from the first area S0 and the first arrival time T0 in a first histogram, and wherein, if it is determined that the first area S0 is the first threshold area S max The procedure includes not including the first area S0 and the first arrival time T0, or data derived from the first area S0 and the first arrival time T0, in the first histogram.

Description

Field of invention

[0001] The present invention relates generally to mass spectrometry and in particular to a method for mass spectrometry, a control system for a mass spectrometer and a mass spectrometer. background

[0002] Peak-detecting analog-to-digital converters (ADCs) are known and are described, for example, in US-8063358 B2 (Micromass). Peak-detecting analog-to-digital converters have proven to be a useful device for improving the dynamic range, resolution, and mass accuracy of orthogonal acceleration-time-of-flight mass spectrometer instruments (oa-ToF-MS instruments).

[0003] Although these improvements have led to better measurements, the approach is not without some disadvantages.

[0004] A disadvantage of the known approach (and all ADC-based systems) is the loss of accurate intensity and time measurements when the vertical range of the analog-to-digital converter (ADC) is exceeded, i.e., when the ADC suffers from saturation effects. This is a particular problem for time-of-flight analyzers with asymmetric arrival time distributions (ATDs) and for ion detectors with asymmetric ion response profiles, since the asymmetries lead to timing shifts when the analog signals exceed the ADC's vertical range.

[0005] The approach described in US-8063358 B2 converts a detected ion peak into an intensity and arrival time value, resulting in improved performance compared to other altitude-based approaches because the ion signals saturate and exceed the vertical range of the analog-to-digital converter. While these improvements cause the system to fail in a more controlled manner, it is ultimately still limited.

[0006] A second disadvantage, specific to the approach described in US-8063358 B2), concerns the peak detection process's inability to distinguish between multiple closely spaced ion response signals. In these situations, two or more closely spaced ion arrival events are interpreted by the peak detection process as a single ion arrival event, and a single arrival time and intensity value is assigned to both events. This problem occurs more frequently when the ion response profiles are comparable to or larger than the analyzer arrival time distribution (ATD).

[0007] WO 2010 / 136765 A1 discloses a method for processing mass spectral data, wherein mass spectral data are filtered out as noise when it is determined that the area of ​​an ion peak is smaller than a threshold peak area.

[0008] US 2014 / 005954 A1) discloses a method for processing LC-ToF-MS data in which a 2D dataset is generated and 2D features in the dataset are detected to generate a list of regions of interest. For each region of interest, a corrected time-of-flight measurement and a corrected intensity are derived, which may include suppressing or rejecting detected peaks caused by interfering species and / or overlapping regions of interest.

[0009] Further methods for mass spectrometry or for data processing in connection therewith are disclosed in US 2012 / 109537 A1 and US 2012 / 126110 A1.

[0010] It is desirable to create an improved method for mass spectrometry. Summary

[0011] According to one aspect, a method for mass spectrometry is created that includes: Digitizing an initial signal output by an ion detector to generate an initial digitized signal; Detecting one or more peaks in the first digitized signal and determining a first surface S0 of the one or more peaks and a first arrival time T0 of the one or more peaks, thereby forming a first list of data pairs; and determining whether the first surface S0 is a first threshold surface S max exceeds or does not exceed the first threshold area S max a peak area that indicates an essentially simultaneous arrival of two ions which the ion detector cannot resolve, and where, when it is determined that the first area S0 is the first threshold area S maxdoes not exceed, the procedure further comprises recording the first area S0 and the first arrival time T0 or data derived from the first area S0 and the first arrival time T0 in a first histogram, and wherein, if it is determined that the first area S0 is the first threshold area S max The procedure includes not including the first area S0 and the first arrival time T0, or data derived from the first area S0 and the first arrival time T0, in the first histogram.

[0012] One embodiment relates to the histograming of different ion surfaces in peak-detecting analog / digital converters and represents a new method for operating a mass spectrometer, in particular a time-of-flight mass spectrometer, in which digitized ion signals are detected for peaks, wherein only ions that exhibit responses in a certain range are histogramed.

[0013] US 2014 / 005954 A1 does not disclose how unwanted flight time measurements and intensities are detected and suppressed or discarded.

[0014] The step of determining whether the first surface S0 is the first threshold surface S maxWhether or not the limit is exceeded can be performed in bursts, i.e., during a single acquisition of mass spectral data, which refers to, for example, the application of a single orthogonal acceleration pulse to an orthogonal acceleration electrode of a time-of-flight mass analyzer.

[0015] The step of determining whether the first surface S0 is the first threshold surface S max Whether or not the threshold is exceeded can be determined before histograming data pairs consisting of arrival time and area.

[0016] The step of determining whether the first surface S0 or the first intensity I0 is the first threshold surface S max Whether or not the limit is exceeded can be determined prior to histograming mass spectral data from separate acquisitions to form or create a composite mass spectrum.

[0017] If it is determined that the first surface S0 is the first threshold surface S maxIf the threshold is exceeded, the procedure may further include filtering out, attenuating, discarding or not including the first area S0 and the first arrival time T0 in the first histogram.

[0018] The method may further include filtering out, attenuating, or otherwise discarding one or more data pairs from the first list, thereby forming a second reduced list, wherein a data pair from the first list is filtered out, attenuated, or otherwise discarded if it is determined that the first area S0 of a peak in a data pair in the first list is smaller than a second threshold area S min is.

[0019] The procedure can also convert the first arrival time T0 into a second arrival time T. n and a third arrival time T n+1 include.

[0020] The procedure can also store the second arrival time T n and / or the third arrival time Tn+1 comprising two or more substantially adjacent or contiguous predetermined time classes or storage locations.

[0021] According to an unclaimed embodiment: (i) will be the second arrival time T n stored in a time class or memory location that is immediately before or contains the first arrival time T0; and / or (ii) the third arrival time T n+1 is stored in a predetermined time class or memory location that immediately follows or contains the first arrival time T0.

[0022] The method can also convert the first peak area S0 into a second peak area S0 and a third peak area S n+1 include.

[0023] The method can also store the second peak area S n and / or the third peak area S n+1comprising two or more substantially adjacent or contiguous predetermined time classes or storage locations.

[0024] According to an unclaimed embodiment: (i) the second peak area S n stored in a time class or memory location that is immediately before or contains the first arrival time T0; and / or (ii) the third peak area S n+1 is stored in a predetermined time class or memory location that immediately follows or contains the first arrival time T0.

[0025] In an unclaimed embodiment: (i) the first peak area S0 follows the relation S0 = S n + S n+1 ; and / or (ii) S0T0 follows the relationship S n ·T n + S n+1 · T n+1 = S0 ·T0

[0026] The method can also involve replacing the first arrival time T0 and the first peak area S0 of at least some of the peaks with the second arrival time T. n and the second peak area S0 and the third arrival time T n+1 and the third peak area S n+1 include.

[0027] The method can also convert the first intensity I0 into a second intensity I n and a third intensity I n+1 include.

[0028] The method can also store the second intensity I n and / or the third intensity I n+1 comprising two or more substantially adjacent or contiguous predetermined time classes or storage locations.

[0029] Each predetermined time class or memory location can have a width, the width falling within a range selected from the following group: (i) < 1 ps; (ii) 1-10 ps; (iii) 10-100 ps; (iv) 100-200 ps; (v) 200-300 ps; (vi) 300-400 ps; (vii) 400-500 ps; (viii) 500-600 ps; (ix) 600-700 ps; (x) 700-800 ps; (xi) 800-900 ps; (xii) 900-1000 ps; (xiii) 1-2 ns; (xiv) 2-3 ns; (xv) 3-4 ns; (xvi) 4-5 ns; (xvii) 5-6 ns; (xviii) 6-7 ns; (xix) 7-8 ns; (xx) 8-9 ns; (xxi) 9-10 ns; (xxii) 10-100 ns; (xxiii) 100-500 ns; (xxiv) 500-1000 ns; (xxv) 1-10 µs; (xxvi) 10-100 µs; (xxvii) 100-500 µs; (xxviii) > 500 µs.

[0030] According to one embodiment: (i) the first signal comprises an output signal, a voltage signal, an ion signal, an ion current, a voltage pulse or an electron current pulse; and / or (ii) the ion detector includes a microchannel plate, a photomultiplier or an electron multiplier device; and / or (iii) the ion detector includes a current / voltage converter or amplifier for generating a voltage pulse in response to the arrival of one or more ions at the ion detector.

[0031] The procedure may further include applying an amplitude threshold to the first digitized signal before determining the first area S0 or the first intensity I0 of the one or more peaks and the first arrival time T0 of the one or more peaks, in order to filter out at least some noise peaks from the first digitized signal.

[0032] The procedure may further include smoothing the first digitized signal using a moving average, a boxcar integrator, a Savitsky-Golay or Hites-Biemann algorithm before determining the first area S0 or the first intensity I0 of the one or more peaks and the first arrival time T0 of the one or more peaks.

[0033] The procedure may further include determining or obtaining a second differential or a second difference of the first digitized signal prior to determining the first area S0 or the first intensity I0 of the one or more peaks and the first arrival time T0 of the one or more peaks.

[0034] The step of determining the first arrival time T0 of one or more peaks may include determining one or more zero crossing points of the second differential of the first digitized signal.

[0035] The procedure may also include: Determining or setting a start time T 0start an ion arrival event corresponding to a digitization interval immediately before or after the time at which the second difference of the first digitized signal falls below zero or another value; and Determining or setting an end time T 0end of an ion arrival event corresponding to a digitization interval that lies immediately before or after the time at which the second difference of the first digitized signal rises above zero or some other value.

[0036] The procedure may also include: (i) Determining the peak area of ​​one or more peaks present in the first digitized signal corresponding to one or more ion arrival events, wherein the step of determining the peak area of ​​one or more peaks present in the first digitized signal is a determination of the area of ​​one or more peaks present in the first digitized signal that is generated by the start time T 0start and / or through the end times T 0end is limited, includes; and / or (ii) Determining the moment of one or more peaks present in the first digitized signal corresponding to one or more ion arrival events, wherein the step of determining the moment of one or more peaks present in the first digitized signal corresponding to one or more ion arrival events is determining the moment of a peak that is due to the start time T 0startand / or through the end times T 0end is limited, includes; and / or (iii) Determining the center time of one or more peaks present in the first digitized signal corresponding to one or more ion arrival events; and / or (iv) Determining the mean or representative time of one or more peaks present in the first digitized signal that correspond to one or more ion arrival events.

[0037] The method may further include receiving the first signal over a detection period, the length of which is selected from the following group: (i) < 1 µs, (ii) 1-10 µs, (iii) 10-20 µs, (iv) 20-30 µs, (v) 30-40 µs, (vi) 40-50 µs, (vii) 50-60 µs, (viii) 60-70 µs, (ix) 70-80 µs, (x) 80-90 µs, (xi) 90-100 µs, (xii) 100-110 µs, (xiii) 120-130 µs, (xiv) 130-140 µs, (xv) 140-150 µs, (xvi) 150-160 µs, (xvii) 160-170 µs, (xviii) 170-180 µs, (xix) 180-190 µs, (xx) 190-200 µs, (xxi) 200-250 µs, (xxii) 250-300 µs, (xxiii) 300-350 µs, (xxiv) 350-400 µs, (xxvi) 450-500 µs, (xxvii) 500-1000 µs and (xxviii) > 1 ms; the method may further include subdividing the acquisition time period into n time classes or storage locations, where n is selected from the following group: (i) < 100, (ii) 100-1000, (iii) 1000-10000, (iv) 10000-100000, (v) 100000-200000, (vi) 200000-300000, (vii) 300000-400000, (viii) 400000-500000, (ix) 500000-600000, (x) 600000-700000, (xi) 700000-800000, (xii) 800000-900000, (xiii) 900000-1000000 and (xiv) > 1000000; wherein each time class or storage location may be of substantially the same length, width or duration.

[0038] The procedure may further include the use of an analog-to-digital converter or transient recorder to digitize the first signal and optional additional signals.

[0039] According to an unclaimed embodiment: (a) the analog-to-digital converter or transient recorder comprises an n-bit analog-to-digital converter or transient recorder, where n is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or > 20; and / or (b) the analog-to-digital converter or transient recorder has a sampling or acquisition rate selected from the following group: (i) < 1 GHz, (ii) 1-2 GHz, (iii) 2-3 GHz, (iv) 3-4 GHz, (v) 4-5 GHz, (vi) 5-6 GHz, (vii) 6-7 GHz, (viii) 7-8 GHz, (ix) 8-9 GHz, (x) 9-10 GHz and (xi) > 10 GHz; and / or (c) the analog-to-digital converter or transient recorder has a digitization rate that is substantially uniform or non-uniform.

[0040] The method may further include subtracting a constant number or constant value from the first digitized signal, wherein, if a section of the first digitized signal falls below zero after the subtraction of a constant number or constant value from the first digitized signal, the method further includes resetting the section of the first digitized signal to zero.

[0041] The procedure may also include: Digitizing one or more additional signals output by the ion detector to generate one or more additional digitized signals; Detecting one or more peaks in the one or more further digitized signals and determining a first area S0 of the one or more peaks and a first arrival time T0 of the one or more peaks, thereby forming a first list of data pairs; and Determine whether the first surface S0 is a first threshold surface S max exceeds or does not, where it is determined that the first surface S0 is the first threshold surface S max does not exceed, and the procedure further includes recording the first area S0 and the first arrival time T0, or data derived from the first area S0 and the first arrival time T0, in the first histogram.

[0042] The one or more additional signals can contain at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000 or 10000 signals from the ion detector, each signal corresponding to a separate trial run or a separate acquisition.

[0043] The method can also combine or histogram the second peak area S. n and the third peak area Sn+1 , corresponding to the first digitized signal, with one or more second peak surfaces S0 and one or more third peak surfaces S n+1 , which correspond to one or more other digitized signals, to form a composite time or mass spectrum.

[0044] The procedure may also include: Determine whether the first surface S0 or the first intensity I0 constitutes a third threshold surface S' max or a third threshold intensity I' max exceeds or does not, where, if it is determined that the first area S0 or the first intensity I0 is the third threshold area S' max or the third threshold intensity I' maxdoes not exceed, and the procedure further includes recording the first area S0 or the first intensity I0 and / or the first arrival time T0 or data derived from the first area S0 or the first intensity I0 and / or the first arrival time T0 in the first histogram.

[0045] The method may further include filtering out, attenuating or otherwise discarding one or more data pairs, wherein a data pair is filtered out, attenuated or otherwise discarded if it is determined that the first area S0 or the first intensity I0 is less than a fourth threshold area S' min or a fourth threshold intensity I' min is.

[0046] According to the embodiments, the first area S0 or the first intensity I0 and / or the first arrival time T0 can be included in the first histogram if the first area S0 or the first intensity I0 is between a first (upper) area threshold S max or an (upper) intensity threshold I max and a second (lower) surface threshold S min or a second (lower) intensity threshold I min lies, optionally with the first surface S0 or the first intensity I0 also between a third (upper) surface threshold S' max or a third (upper) intensity threshold I' max and a fourth (lower) surface threshold S' min or a fourth (lower) intensity threshold I' minAccordingly, embodiments are considered in which the first area S0 or the first intensity I0 and / or the first arrival time T0 may be included in the first histogram if the first area S0 or the first intensity I0 lies within one or two distinct regions. Further embodiments are considered in which the first area S0 or the first intensity I0 and / or the first arrival time T0 may be included in the first histogram if the first area S0 or the first intensity I0 lies within one of three, four, five, six, seven, eight, nine, ten or more than ten distinct regions.

[0047] The procedure may also include determining one or more additional characteristics or metrics related to the one or more peaks.

[0048] The one or more additional characteristics or metrics associated with the one or more peaks may include: (i) the standard deviation of the one or more peaks, the full width at half maximum (FWHM) of the one or more peaks, or any other value related to the width or peak shape of the one or more peaks; and / or (ii) the kurtosis of the one or more peaks; and / or (iii) the skewness of the one or more peaks, the absolute value of the skewness of the one or more peaks, or the magnitude of the skewness of the one or more peaks.

[0049] The procedure can also determine whether one or more further characteristics or metrics constitute a first maximum threshold X. max exceeding or not, include, whereby: (i) when it is determined that one or more of the further characteristics or metrics exceed the first maximum threshold Xmax not exceeding, the procedure further includes recording the first area S0 or the first intensity I0 and / or the first arrival time T0 or data derived from the first area S0 or the first intensity I0 and / or the first arrival time T0 in the first histogram; and / or (ii) when it is determined that one or more of the further characteristics or metrics meet the first maximum threshold X max The procedure further includes filtering out, attenuating, discarding or not including the first area S0 or the first intensity I0 and / or the first arrival time T0 in the first histogram.

[0050] The procedure can also determine whether one or more additional characteristics or metrics constitute a first minimum threshold X. min exceeding or not, include, whereby: (i) when it is determined that one or more of the further characteristics or metrics meet the first minimum threshold X min The procedure further includes recording the first area S0 or the first intensity I0 and / or the first arrival time T0 or data derived from the first area S0 or the first intensity I0 and / or the first arrival time T0 in the first histogram; and / or (ii) when it is determined that one or more of the further characteristics or metrics meet the first minimum threshold X min not exceeding, the procedure further includes filtering out, attenuating, discarding or not including the first area S0 or the first intensity I0 and / or the first arrival time T0 in the first histogram.

[0051] According to another aspect, a control system for a mass spectrometer is created, whereby the control system is designed and adapted as follows: (i) Digitizing a first signal output by an ion detector to generate a first digitized signal; (ii) Detecting one or more peaks in the first digitized signal and determining a first area S0 or a first intensity I0 of the one or more peaks and a first arrival time T0 of the one or more peaks, thereby forming a first list of data pairs; and (iii) Determine whether the first surface S0 or the first intensity I0 is a first threshold surface S max or a first threshold intensity I max exceeds or does not exceed the first threshold area S max and the first threshold intensity I maxeach corresponds to a peak area and a peak intensity indicating an essentially simultaneous arrival of two ions that the ion detector cannot resolve, and wherein, when determined, the first area S0 or the first intensity I0 is the first threshold area S max or the first threshold intensity I max does not exceed, and the control system is furthermore designed and adapted to: record the first area S0 or the first intensity I0 and / or the first arrival time T0 or data derived from the first area S0 or the first intensity I0 and / or the first arrival time T0 in a first histogram.

[0052] According to another aspect, a mass spectrometer is created that includes a control system as described above.

[0053] The mass spectrometer may also include an analog / digital converter or transient recorder for digitizing the first signal.

[0054] According to an unclaimed embodiment: (a) the analog-to-digital converter or transient recorder comprises an n-bit analog-to-digital converter or transient recorder, where n is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or > 20; and / or (b) the analog-to-digital converter or transient recorder has a sampling or acquisition rate selected from the following group: (i) < 1 GHz, (ii) 1-2 GHz, (iii) 2-3 GHz, (iv) 3-4 GHz, (v) 4-5 GHz, (vi) 5-6 GHz, (vii) 6-7 GHz, (viii) 7-8 GHz, (ix) 8-9 GHz, (x) 9-10 GHz and (xi) > 10 GHz; and / or (c) the analog-to-digital converter or transient recorder has a digitization rate that is substantially uniform or non-uniform.

[0055] According to another aspect, a method for mass spectrometry is created that includes: Digitizing an initial signal output by an ion detector to generate an initial digitized signal; Detecting one or more peaks in the first digitized signal and determining a first area S0 or a first intensity I0 of the one or more peaks and a first mass or a first mass-to-charge ratio M0 of the one or more peaks, thereby forming a first list of data pairs; and Determine whether the first surface S0 or the first intensity I0 is a first threshold surface S max or a first threshold intensity I max exceeds or does not exceed the first threshold area S max and the first threshold intensity I maxeach corresponds to a peak area and a peak intensity indicating an essentially simultaneous arrival of two ions that the ion detector cannot resolve, and wherein, when determined, the first area S0 or the first intensity I0 is the first threshold area S max or the first threshold intensity I max does not exceed, and the procedure further includes recording the first area S0 or the first intensity I0 and / or the first mass or the first mass-to-charge ratio M0 or data derived from the first area S0 or the first intensity I0 and / or the first mass or the first mass-to-charge ratio M0 in a first histogram.

[0056] According to another aspect, a control system for a mass spectrometer is created, whereby the control system is designed and adapted as follows: (i) Digitizing a first signal output by an ion detector to generate a first digitized signal; (ii) Detecting one or more peaks in the first digitized signal and determining a first area S0 or a first intensity I0 of the one or more peaks and a first mass or a first mass-to-charge ratio M0 of the one or more peaks, thereby forming a first list of data pairs; and (iii) Determine whether the first surface S0 or the first intensity I0 is a first threshold surface S max or a first threshold intensity I max exceeds or does not exceed the first threshold area S max and the first threshold intensity I maxeach corresponds to a peak area and a peak intensity indicating an essentially simultaneous arrival of two ions that the ion detector cannot resolve, and wherein, when determined, the first area S0 or the first intensity I0 is the first threshold area S max or the first threshold intensity I max does not exceed, and the control system is furthermore designed and adapted to: record the first area S0 or the first intensity I0 and / or the first mass or the first mass-to-charge ratio M0 or data derived from the first area S0 or the first intensity I0 and / or the first mass or the first mass-to-charge ratio M0 in a first histogram.

[0057] According to another aspect, a method for mass spectrometry is created that includes: Digitizing an initial signal output by an ion detector to generate an initial digitized signal; Detecting one or more peaks in the first digitized signal and determining one or more characteristics or metrics associated with the one or more peaks, selected from the following group: (i) the standard deviation of the one or more peaks, the full width at half maximum (FWHM) of the one or more peaks, or another value related to the width or peak shape of the one or more peaks; and / or (ii) the kurtosis of the one or more peaks; and / or (iii) the skewness of the one or more peaks, the absolute value of the skewness of the one or more peaks, or the magnitude of the skewness of the one or more peaks; and Determine whether one or more characteristics or metrics constitute a first maximum threshold X maxexceeding or not, whereby the first maximum threshold X max corresponding to an essentially simultaneous arrival of two ions that the ion detector cannot resolve, and wherein, when it is determined that one or more characteristics or metrics exceed the first maximum threshold X max not exceeding, the procedure further includes: (i) Determining a first area S0 or a first intensity I0 of the one or more peaks and a first arrival time T0 of the one or more peaks, thereby forming a first list of data pairs; and (ii) Recording the first area S0 or the first intensity I0 and / or the first arrival time T0 or data derived from the first area S0 or the first intensity I0 and / or the first arrival time T0 in a first histogram.

[0058] According to another aspect, a method for mass spectrometry is created that includes: Digitizing an initial signal output by an ion detector to generate an initial digitized signal; Detecting one or more peaks in the first digitized signal and determining one or more characteristics or metrics associated with the one or more peaks, selected from the following group: (i) the standard deviation of the one or more peaks, the full width at half maximum (FWHM) of the one or more peaks, or another value related to the width or peak shape of the one or more peaks; and / or (ii) the kurtosis of the one or more peaks; and / or (iii) the skewness of the one or more peaks, the absolute value of the skewness of the one or more peaks, or the magnitude of the skewness of the one or more peaks; and Determining a first area S0 or a first intensity I0 of the one or more peaks and a first arrival time T0 of the one or more peaks, thereby forming a first list of data pairs; and Determine whether one or more characteristics or metrics constitute a first maximum threshold X max exceeding or not, whereby the first maximum threshold X max corresponding to an essentially simultaneous arrival of two ions that the ion detector cannot resolve, and wherein, when it is determined that one or more characteristics or metrics exceed the first maximum threshold X max not exceeding, the procedure further includes recording the first area S0 or the first intensity I0 and / or the first arrival time T0 or data derived from the first area S0 or the first intensity I0 and / or the first arrival time T0 in a first histogram.

[0059] According to one embodiment, if it is determined that one or more further characteristics or metrics exceed the first maximum threshold X max The procedure further includes filtering out, attenuating, discarding or not including the first area S0 or the first intensity I0 and / or the first arrival time T0 in the first histogram.

[0060] The procedure can also determine whether one or more additional characteristics or metrics constitute a first minimum threshold X. min exceeding or not, include, whereby: (i) when it is determined that one or more of the further characteristics or metrics meet the first minimum threshold X minThe procedure further includes recording the first area S0 or the first intensity I0 and / or the first arrival time T0 or data derived from the first area S0 or the first intensity I0 and / or the first arrival time T0 in the first histogram; and / or (ii) when it is determined that one or more of the further characteristics or metrics meet the first minimum threshold X min not exceeding, the procedure further includes filtering out, attenuating, discarding or not including the first area S0 or the first intensity I0 and / or the first arrival time T0 in the first histogram.

[0061] According to another aspect, a control system for a mass spectrometer is created, whereby the control system is designed and adapted as follows: (i) Digitizing a first signal output by an ion detector to generate a first digitized signal; (ii) Detecting one or more peaks in the first digitized signal and determining one or more characteristics or metrics associated with the one or more peaks, selected from the following group: (i) the standard deviation of the one or more peaks, the full width at half maximum (FWHM) of the one or more peaks, or another value related to the width or peak shape of the one or more peaks; and / or (ii) the kurtosis of the one or more peaks; and / or (iii) the skewness of the one or more peaks, the absolute value of the skewness of the one or more peaks, or the magnitude of the skewness of the one or more peaks; and (iii) Determine whether one or more characteristics or metrics constitute a first maximum threshold X max exceeding or not, whereby the first maximum threshold X max corresponding to an essentially simultaneous arrival of two ions that the ion detector cannot resolve, and wherein, when it is determined that one or more characteristics or metrics exceed the first maximum threshold X max not exceeding, and the tax system is furthermore designed and adapted to the following: (iv) Determining a first area S0 or a first intensity I0 of the one or more peaks and a first arrival time T0 of the one or more peaks, thereby forming a first list of data pairs; and (v) Recording the first area S0 or the first intensity I0 and / or the first arrival time T0 or data derived from the first area S0 or the first intensity I0 and / or the first arrival time T0 in a first histogram.

[0062] According to another aspect, a control system for a mass spectrometer is created, whereby the control system is designed and adapted as follows: (i) Digitizing a first signal output by an ion detector to generate a first digitized signal; (ii) Detecting one or more peaks in the first digitized signal and determining one or more characteristics or metrics associated with the one or more peaks, selected from the following group: (i) the standard deviation of the one or more peaks, the full width at half maximum (FWHM) of the one or more peaks, or another value related to the width or peak shape of the one or more peaks; and / or (ii) the kurtosis of the one or more peaks; and / or (iii) the skewness of the one or more peaks, the absolute value of the skewness of the one or more peaks, or the magnitude of the skewness of the one or more peaks; and (iii) Determining a first area S0 or a first intensity I0 of the one or more peaks and a first arrival time T0 of the one or more peaks, thereby forming a first list of data pairs; and (iv) Determine whether one or more characteristics or metrics constitute a first maximum threshold X max exceeding or not, whereby the first maximum threshold X max corresponding to an essentially simultaneous arrival of two ions that the ion detector cannot resolve, and wherein, when it is determined that one or more characteristics or metrics exceed the first maximum threshold X max not exceeding, and the tax system is furthermore designed and adapted to the following: Recording the first area S0 or the first intensity I0 and / or the first arrival time T0 or data derived from the first area S0 or the first intensity I0 and / or the first arrival time T0 in a first histogram.

[0063] According to one aspect, a device for mass spectrometry is created, which includes: a time-of-flight mass spectrometer with a peak-detecting ADC in which events in a restricted response range are histogramed, and wherein the restricted response range contains a maximum value.

[0064] The answer should be related to the detected area of ​​an event.

[0065] More than one response area can be histogramed and kept separate or combined.

[0066] Measurements in one histogram can be correlated with measurements in one or more other histograms.

[0067] According to one aspect, a method for mass spectrometry is created that includes: Digitizing an initial signal output by an ion detector to generate an initial digitized signal; Detecting one or more peaks in the first digitized signal and determining a first area S0 or a first intensity I0 of the one or more peaks and a first arrival time T0 of the one or more peaks, thereby forming a first list of data pairs; and Determine whether the first surface S0 or the first intensity I0 is a first threshold surface S max or a first threshold intensity I max exceeds or does not, where, if it is determined that the first area S0 or the first intensity I0 is the first threshold area S max or the first threshold intensity I max does not exceed, and the procedure further includes recording the first area S0 or the first intensity I0 and / or the first arrival time T0 or data derived from the first area S0 or the first intensity I0 and / or the first arrival time T0 in a first histogram.

[0068] According to one embodiment, the mass spectrometer may further include: (a) an ion source selected from the following group: (i) an electrospray ion source (“ESI” ion source); (ii) an atmospheric pressure photoionization ion source (“APPI ion source”), (iii) an atmospheric pressure chemical ionization ion source (“APCI ion source”), (iv) a matrix-assisted laser desorption ionization ion source (“MALDI ion source”), (v) a laser desorption ionization ion source (“LDI ion source”), (vi) an atmospheric pressure ionization ion source (“API ion source”), (vii) a desorption / ionization-on-silicon ion source (“DIOS ion source”), (viii) an electron impact ion source (“EI ion source”), (ix) a chemical ionization ion source (“CI ion source”), (x) a field ionization ion source (“FI ion source”), (xi) a field desorption ion source (“FD ion source”), (xii) a inductively coupled plasma ion source (“ICP ion source”), (xiii) a fast atom bombardment ion source (“FAB ion source”),(xiv) a liquid secondary ion mass spectrometry ion source (“LSIMS ion source”), (xv) a desorption electrospray ionization ion source (“DESI ion source”), (xvi) a radioactive nickel-63 ion source, (xvii) a matrix-assisted atmospheric pressure laser desorption ionization ion source, (xviii) a thermospray ion source, (xix) an atmospheric sampling glow discharge ionization ion source (“ASGDI ion source”), (xx) a glow discharge ion source (“GD ion source”), (xxi) an impactor ion source, (xxii) a direct analysis in real time ion source (“DART ion source”), (xxiii) a laser spray ionization ion source (LSI ion source), (xxiv) a sonic spray ionization ion source (SSI ion source), (xxv) a matrix-assisted inlet ionization ion source (MAII ion source), (xxvi) a solvent-assisted inlet ionization ion source (SAII ion source),(xxvii) a desorption electrospray ionization ion source (“DESI ion source”) and (xxviii) a laser ablation electrospray ionization ion source (“LAESI ion source”) and / or, (b) one or more continuous or pulsed ion sources and / or (c) one or more ion guides and / or (d) one or more ion mobility separation devices and / or one or more field asymmetric ion mobility spectrometer devices and / or (e) one or more ion traps or one or more ion confinement regions and / or (f) one or more collision, fragmentation or reaction cells selected from the following group: (i) a collision-induced dissociation fragmentation device (“CID fragmentation device”), (ii) a surface-induced dissociation fragmentation device (“SID fragmentation device”), (iii) an electron transfer dissociation fragmentation device (“ETD fragmentation device”), (iv) an electron capture dissociation fragmentation device (“ECD fragmentation device”), (v) an electron impact or collision dissociation fragmentation device, (vi) a photo-induced dissociation fragmentation device (“PID fragmentation device”), (vii) a laser-induced dissociation fragmentation device, (viii) an infrared radiation-induced dissociation device, (ix) an ultraviolet radiation-induced dissociation device, (x) a Nozzle-skimmer interface fragmentation device, (xi) an in-source fragmentation device, (xii) an in-source shock-induced dissociation fragmentation device,(xiii) a thermal or temperature source fragmentation device, (xiv) a device for fragmentation induced by an electric field, (xv) a device for fragmentation induced by a magnetic field, (xvi) an enzyme digestion or enzyme degradation fragmentation device, (xvii) an ion-ion reaction fragmentation device, (xviii) an ion-molecule reaction fragmentation device, (xix) an ion-atom reaction fragmentation device, (xx) an ion-metastable ion reaction fragmentation device, (xxi) an ion-metastable molecule reaction fragmentation device, (xxii) an ion-metastable atom reaction fragmentation device, (xxiii) an ion-ion reaction device for converting ions to form adducts or productions, (xxiv) an ion-molecule reaction device for converting of ions to form adducts or productions, (xxv) an ion-atom reaction device for converting ions to form adducts or productions,(xxvi) an ion-metastable ion reaction device for converting ions to form adducts or productions, (xxvii) an ion-metastable molecule reaction device for converting ions to form adducts or productions, (xxviii) an ion-metastable atom reaction device for converting ions to form adducts or productions, and (xxix) an electron ionization dissociation fragmentation device (“EID fragmentation device”) and / or, (g) a mass analyzer selected from the following group: (i) a quadrupole mass analyzer, (ii) a 2D or linear quadrupole mass analyzer, (iii) a Paul or 3D quadrupole mass analyzer, (iv) a Penning trap mass analyzer, (v) an ion trap mass analyzer, (vi) a magnetic sector mass analyzer, (vii) an ion cyclotron resonance mass analyzer (“ICR mass analyzer”), (viii) a Fourier transform ion cyclotron resonance mass analyzer (“FTICR mass analyzer”), (ix) an electrostatic mass analyzer designed to generate an electrostatic field with a quadrologarithmic potential distribution, (x) an electrostatic Fourier transform mass analyzer, (xi) a Fourier transform mass analyzer, (xii) a time-of-flight mass analyzer, (xiii) an orthogonal acceleration time-of-flight mass analyzer and (xiv) a linear acceleration time-of-flight mass analyzer and / or (h) one or more energy analyzers or electrostatic energy analyzers and / or (i) one or more ion detectors and / or (j) one or more mass filters selected from the following group: (i) a quadrupole mass filter, (ii) a 2D or linear quadrupole ion trap, (iii) a Paul or 3D quadrupole ion trap, (iv) a Penning ion trap, (v) an ion trap, (vi) a magnetic sector mass filter, (vii) a time-of-flight mass filter, and (viii) a Wien filter and / or (k) a device or ion gate for pulsing ions and / or (1) a device for converting a substantially continuous ion beam into a pulsed ion beam.

[0069] The mass spectrometer may also contain: (i) a C-trap and a mass analyzer comprising an outer tubular electrode and a coaxial inner spindle-shaped electrode forming an electrostatic field with a quadrologarithmic potential distribution, wherein in a first operating mode ions are allowed to pass through to the C-trap and then injected into the mass analyzer, and wherein in a second operating mode ions are allowed to pass through to the C-trap and then to a collision cell or electron transfer dissociation device, fragmenting at least some ions into fragment ions, and wherein the fragment ions are then allowed to pass through to the C-trap before being injected into the mass analyzer, and / or (ii) a ring-stack ion guide comprising several electrodes, each having an opening through which ions pass during use, wherein the distance between the electrodes increases along the length of the ion path, wherein the openings in the electrodes in an upstream section of the ion guide have a first diameter, and wherein the openings in the electrodes in a downstream section of the ion guide have a second diameter which is smaller than the first diameter, and wherein opposite phases of an alternating or RF voltage are applied to successive electrodes during use.

[0070] According to one embodiment, the mass spectrometer further includes a device designed and adapted to supply an alternating or RF voltage to the electrodes. The AC or RF voltage preferably has an amplitude selected from the following group: (i) < about 50 V peak-to-peak, (ii) about 50-100 V peak-to-peak, (iii) about 100-150 V peak-to-peak, (iv) about 150-200 V peak-to-peak, (v) about 200-250 V peak-to-peak, (vi) about 250-300 V peak-to-peak, (vii) about 300-350 V peak-to-peak, (viii) about 350-400 V peak-to-peak, (ix) about 400-450 V peak-to-peak, (x) about 450-500 V peak-to-peak, and (xi) > about 500 V Peak-to-peak.

[0071] The alternating or RF voltage can have a frequency selected from the following group: (i) < about 100 kHz, (ii) about 100-200 kHz, (iii) about 200-300 kHz, (iv) about 300-400 kHz, (v) about 400-500 kHz, (vi) about 0.5-1.0 MHz, (vii) about 1.0-1.5 MHz, (viii) about 1.5-2.0 MHz, (ix) about 2.0-2.5 MHz, (x) about 2.5-3.0 MHz, (xi) about 3.0-3.5 MHz, (xii) about 3.5-4.0 MHz, (xiii) about 4.0-4.5 MHz, (xiv) about 4.5-5.0 MHz, (xv) about 5.0-5.5 MHz, (xvi) approximately 5.5-6.0 MHz, (xvii) approximately 6.0-6.5 MHz, (xviii) approximately 6.5-7.0 MHz, (xix) approximately 7.0-7.5 MHz, (xx) approximately 7.5-8.0 MHz, (xxi) approximately 8.0-8.5 MHz, (xxii) approximately 8.5-9.0 MHz, (xxiii) approximately 9.0-9.5 MHz, (xxiv) approximately 9.5-10.0 MHz and (xxv) > approximately 10.0 MHz.

[0072] The mass spectrometer may also include a chromatography or other separation device upstream of an ion source. According to one embodiment, the chromatography separation device comprises a liquid chromatography or gas chromatography device. According to another embodiment, the separation device may include: (i) a capillary electrophoresis separation device (“CE separation device”), (ii) a capillary electrochromatography separation device (“CEC separation device”), (iii) a separation device with a substantially rigid ceramic-based multilayer microfluidic substrate (“ceramic tile”), or (iv) a supercritical fluid chromatography separation device.

[0073] The ion guidance can preferably be maintained at a pressure selected from the following group: (i) < about 0.0001 mbar, (ii) about 0.0001-0.001 mbar, (iii) about 0.001-0.01 mbar, (iv) about 0.01-0.1 mbar, (v) about 0.1-1 mbar, (vi) about 1-10 mbar, (vii) about 10-100 mbar, (viii) about 100-1000 mbar and (ix) > about 1000 mbar.

[0074] According to one embodiment, analyte ions can be subjected to electron transfer dissociation fragmentation (ETD fragmentation) in an electron transfer dissociation fragmentation device. The analyte ions can be caused to interact with ETD reagents within an ion guide or fragmentation device.

[0075] According to one embodiment, to effect electron transfer dissociation, either: (a) analyte ions are fragmented or caused to dissociate and form product or fragment ions after interacting with reagent ions, and / or (b) electrons are transferred from one or more reagent anions or negatively charged ions to one or more multiply charged analyte cations or positively charged ions, whereupon at least some of the multiply charged analyte cations or positively charged ions are caused to dissociate and form product or fragment ions, and / or (c) analyte ions are fragmented or caused to dissociate and form product or fragment ions after interacting with neutral reagent gas molecules or atoms or a non-ionic reagent gas.and / or (d) transfer electrons from one or more neutral nonionic or uncharged starting gases or vapors to one or more multiply charged analyte cations or positively charged ions, whereupon at least some of the multiply charged analyte cations or positively charged ions are caused to dissociate and form product or fragment ions, and / or (e) transfer electrons from one or more neutral nonionic or uncharged superbase reagent gases or vapors to one or more multiply charged analyte cations or positively charged ions, whereupon at least some of the multiply charged analyte cations or positively charged ions are caused to dissociate and form product or fragment ions, and / or (f) transfer electrons from one or more neutral,(a) transfer electrons from one or more non-ionic or uncharged alkali metal gases or vapors to one or more multiply charged analyte cations or positively charged ions, whereupon at least some of the multiply charged analyte cations or positively charged ions are caused to dissociate and form product or fragment ions, and / or (b) transfer electrons from one or more neutral, non-ionic or uncharged gases, vapors or atoms to one or more multiply charged analyte cations or positively charged ions, whereupon at least some of the multiply charged analyte cations or positively charged ions are caused to dissociate and form product or fragment ions, wherein the one or more neutral, non-ionic or uncharged gases, vapors or atoms are selected from the following group: (i) sodium vapor or atoms, (ii) lithium vapor or atoms, (iii) potassium vapor or atoms, (iv) rubidium vapor or atoms,(v) Cesium vapor or atoms, (vi) Francium vapor or atoms, (vii) C60 vapor or atoms and (viii) Magnesium vapor or atoms.

[0076] The multiply charged analyte cations or positively charged ions can include peptides, polypeptides, proteins, or biomolecules.

[0077] According to one embodiment, to effect electron transfer dissociation: (a) the reagent anions or negatively charged ions are derived from a polyaromatic hydrocarbon or a substituted polyaromatic hydrocarbon and / or (b) the reagent anions or negatively charged ions are derived from the following group: (i) anthracene, (ii) 9,10-diphenylanthracene, (iii) naphthalene, (iv) fluorine, (v) phenanthrene, (vi) pyrene, (vii) fluoranthene, (viii) chrysene, (ix) triphenylene, (x) perylene, (xi) acridine, (xii) 2,2'-dipyridyl, (xiii) 2,2'-biquinoline, (xiv) 9-anthracenecarbonitrile, (xv) dibenzothiophene, (xvi) 1,10'-phenanthroline, (xvii) 9'-Anthracene carbonitrile and (xviii) anthraquinone and / or (c) contain the reagents or negatively charged ions azobenzene anions or azobenzene radical anions.

[0078] According to one embodiment, the electron transfer dissociation fragmentation process includes an interaction of analyte ions with reagents, wherein the reagents include dicyanobenzene, 4-nitrotoluene or azulene. Brief description of the drawings

[0079] Various embodiments of the present invention are now described by way of example only with reference to the accompanying drawings, wherein: Fig. Figure 1 illustrates a conventional peak detection and a conventional time / intensity mapping applied to a single ion arrival event, where a digitized ion peak is converted into an arrival time and intensity value; Fig. 2 illustrates a conventional peak detection and a conventional time / intensity mapping applied to two ion arrival events within a single burst, wherein the ion arrival events are separated in time by a sufficient amount to allow the individual ion arrival events to be detected for peaks such that two ion peaks are translated into two arrival times and intensity values; Fig. Figure 3 illustrates a conventional peak detection and a conventional time / intensity mapping applied to two ion arrival events within a single burst, where the ion arrival events are close together, so that the system records a single arrival time and intensity value; Fig. 4A shows the result of a single ion counting simulation and Fig. 4B shows the result of a simulation in which ions arrive at an average arrival rate of two ions per thrust and are detected by a conventional detector system; and Fig. 5A shows the result of a single ion counting simulation and Fig. Figure 5B shows the result of a simulation according to an embodiment in which ions arrive with a mean arrival rate of two ions per thrust and are detected by a detector system according to an embodiment in which an upper ion peak area threshold is applied. Detailed description

[0080] An example of an ion detector system will first be described in more detail.

[0081] Fig. Figure 1 shows a simplified scheme illustrating the well-known peak detection and time / intensity mapping principle as described in US-8063358 B2 (Micromass).

[0082] In the conventional approach, digitized ADC values ​​are polled in bursts to determine the presence of an ion peak before the arrival time and intensity of the ion peak are calculated. The arrival time can be calculated and mapped with subclass accuracy or precision, thus improving performance compared to other conventional peak-tip or edge detection systems. In the specific, in Fig. In the example shown, the intensity assignment is arbitrary and is not intended to reflect the true ion surface area.

[0083] Fig. 2 represents the same conventional approach applied to two separate ion arrival events occurring within a single pulse. The ion arrival events are separated in time by a sufficient amount to allow the individual events to be detected by peaks.

[0084] The different intensities of the two in Fig. The two peaks shown are intended to illustrate the effects of the pulse height distribution (PHD) associated with many ion detectors, rather than relating to different numbers of ions arriving at the ion detector. It is understood that ion detectors can output ion peaks with a height that varies from one detected ion to the next.

[0085] In Fig. 1 and Fig. 2. Peak detection and time / intensity mapping effectively remove the contribution of the temporal widths of the ion response signal from the final observed mass spectral peak widths, thereby effectively improving the resolution compared to other conventional averaging analog / digital converter systems when many bursts are combined.

[0086] Fig. Figure 3 shows a schematic representation of the same two ion response signals as seen in Fig. Figure 2 shows the two ion response signals arriving much closer together. If the two signals arrive in a single burst, the displayed profile represents a combination or summation of the two individual responses to form a combined ion response profile. If the two events occur separated in time by a value comparable to the width of the ion response profile, the resulting combined profile is interpreted by the peak detection software as a single ion arrival event. Accordingly, a single time and intensity value is assigned to the two separate ion arrival events.

[0087] When multiple bursts are combined, this effect leads to a merging of closely spaced mass or time peaks, resulting in a detrimental loss of mass / time resolution and accuracy. This effect is further described below with reference to Fig. 4A and Fig. 4B explained.

[0088] Fig. 4A and Fig. Figure 4B shows the results of two simulations. Fig. Figure 4A shows data simulated in a single-ion counting experiment, where only one ion arrival event can occur per burst at the ion detector. Ignoring digitization effects and combining thousands of bursts, the following results... Fig. 4a represents the true arrival time distribution (“ATD”) of the analyzer for two species / components that are closely related in mass-to-charge ratio.

[0089] In the second simulation, the results of which were presented in Fig. As shown in Figure 4B, the same two components with similar mass-to-charge ratios arrive at the ion detector according to a Poisson probability distribution with a mean arrival rate of two ions per thrust (“2IPP”). According to this simulation, some thrusts exhibit only one event per thrust, while other thrusts exhibit two, three, or more events per thrust due to the Poisson distribution governing the ion arrival rates.

[0090] The measurement of single-event pulses is accurate, while the measurement of multi-event pulses suffers from the disadvantages mentioned above, since in the simulation the individual ion response widths are comparable to the separation of the two components.

[0091] When thousands of thrusts are combined or histogramed, the arrival time distributions (“ATDs”) appear to merge and reduce the resolution, as can be seen from comparing the mass spectrum obtained in Fig. 4B shows the (ideal) mass spectrum as shown in Fig. As shown in 4A, it is evident.

[0092] This problem can be partially addressed by unfolding overlapping ion responses thrust by thrust, as described in WO 2011 / 098834 A1 (Micromass), or based on data from combined thrusts. However, such an approach can be time-consuming and lead to spectral artifacts.

[0093] One embodiment will now be described.

[0094] The embodiment relates to an improved method for histogramling ADC data, wherein only events within a selected ion area range are histogramled, i.e., wherein only ion peaks with an ion area or intensity greater than (or equal to) a minimum threshold and less than (or equal to) a maximum threshold are recorded or histogramled. In particular, if a detected ion peak has an ion area exceeding an (upper) threshold, this can indicate that the ion peak actually corresponds to the near-simultaneous arrival of two ions that the ion detector cannot resolve.

[0095] This embodiment offers an improvement over the conventional approach by utilizing the strong correlation between the measured area of ​​an ion peak and the number of ion arrival events per thrust. This correlation allows for the definition of thresholds corresponding to a limited range of ion areas and, consequently, a limited range of ions per thrust. According to this embodiment, only ion peaks with an ion peak area below a certain threshold are assumed to relate to a single ion arrival event, and therefore the corresponding intensity and arrival time values ​​are further processed or histogramed. Ion peaks with an ion peak area above the (upper) threshold are assumed to relate to multiple ion arrival events, and the corresponding intensity and arrival time values ​​are not further processed or histogramed.

[0096] The correlation is not perfect because the pulse height distribution (“PHD”) of the ion detector and digitization quantization effects can mean that individual ions exhibit a range of measured ion areas. The approach according to the embodiment will therefore benefit from new generations of ion detectors being developed that feature improved pulse height distribution and digitization. Nevertheless, the application of an ion peak area threshold according to the embodiment leads to a significant improvement in the shape of the resulting arrival time distribution for ions and thus represents a significant advance in the technology.

[0097] Fig. Figure 5B shows the advantage of the approach according to the embodiment in which an upper ion peak area threshold is applied, so that only ions or ion peaks with an area corresponding to a single ion arrival event are histogramled.

[0098] As from Fig. As can be seen in Figure 5B, the approach according to the embodiment leads to an arrival time distribution (“ATD”) that corresponds to the arrival time distribution of a true single-ion counting arrival time distribution, as described in Fig. The embodiment shown in 5A comes very close. Advantageously, the practical dynamic range for resolution and mass accuracy is extended according to the embodiment.

[0099] The approach according to the embodiment can be extended to generate multiple histogramed areas. Values ​​calculated from one histogram, such as mass accuracy, can be mapped to values ​​calculated in other histograms, such as intensity.

[0100] In particular, the approach according to this embodiment is especially advantageous when implemented with ion detector systems where a single-ion response width provided by the ion detector is comparable to or greater than the arrival time distributions obtained from a time-of-flight analyzer. The event area can be correlated with the number of ions in the event. The arrival time distribution of single-ion arrival event bursts, double-ion arrival event bursts, triple-ion arrival event bursts, etc., is the same, meaning that the arrival time distribution of any subset accurately represents the true arrival time distribution. In practice, the pulse height distribution may limit this approach.

[0101] Multiple histograms of different areas or combined areas can be retained, and the relative values ​​can be used in further analysis.

[0102] The mass spectral data can be rescaled based on the number of events or non-events and the number of thrusts using the Poisson distribution or other suitable probability distributions.

[0103] Other embodiments are being considered in which histogramming can be performed using heights and which employ systems where the analog peak width is smaller than the arrival time distribution, but which use the arrival time distribution width to group events. In the latter alternative, the histogramed response regions can vary with the mass-to-charge ratio and / or the charge state and can be computed in real time.

Claims

[1] Time-of-flight mass spectrometry methods, which include: Digitizing an initial signal output by an ion detector to generate an initial digitized signal; Detecting one or more peaks in the first digitized signal and determining a first area S0 of the one or more peaks and a first arrival time T0 of the one or more peaks, thereby forming a first list of data pairs; and Determine whether the first surface S0 is a first threshold surface S max exceeds or does not exceed the first threshold area S max a peak area that indicates an essentially simultaneous arrival of two ions which the ion detector cannot resolve, and where, when it is determined that the first area S0 is the first threshold area S maxdoes not exceed, the procedure further comprises recording the first area S0 and the first arrival time T0 or data derived from the first area S0 and the first arrival time T0 in a first histogram, and wherein, if it is determined that the first area S0 is the first threshold area S max The procedure includes not including the first area S0 and the first arrival time T0, or data derived from the first area S0 and the first arrival time T0, in the first histogram. [2] Method according to claim 1, wherein the step of determining whether the first surface S0 is the first threshold surface S max Whether or not the time of flight is exceeded is determined for each pulse of a time-of-flight mass analyzer performing time-of-flight mass spectrometry. [3] Method according to claim 1 or 2, wherein the step of determining whether the first surface S0 is the first threshold surface S maxWhether or not this is exceeded, before histograming of data pairs from arrival time and area. [4] Method according to claim 1, 2 or 3, wherein the step of determining whether the first surface S0 is the first threshold surface S max Whether or not the limit is exceeded, prior to histograming mass spectral data from separate acquisitions to form or create a composite mass spectrum. [5] A method according to any of the preceding claims, further comprising filtering out, attenuating or otherwise discarding one or more data pairs from the first list, thereby forming a second reduced list, wherein a data pair is filtered out, attenuated or otherwise discarded from the first list if it is determined that the first area S0 of a peak in a data pair in the first list is smaller than a second threshold area S min is. [6] Method according to any one of the preceding claims, wherein: (i) the first signal comprises an output signal, a voltage signal, an ion signal, an ion current, a voltage pulse or an electron current pulse; and / or (ii) the ion detector comprises a microchannel plate, a photomultiplier or an electron multiplier device; and / or (iii) the ion detector includes a current / voltage converter or amplifier for generating a voltage pulse in response to the arrival of one or more ions at the ion detector. [7] Method according to any of the preceding claims, further comprising applying an amplitude threshold to the first digitized signal prior to determining the first area S0 of the one or more peaks and the first arrival time T0 of the one or more peaks in order to filter out at least some noise peaks from the first digitized signal. [8] Method according to any of the preceding claims, further comprising smoothing the first digitized signal using a moving average, a boxcar integrator, a Savitsky-Golay or Hites-Biemann algorithm prior to determining the first area S0 of the one or more peaks and the first arrival time T0 of the one or more peaks. [9] Method according to any of the preceding claims, further comprising the use of an analog-to-digital converter or transient recorder for digitizing the first signal. [10] Method according to any of the preceding claims, further comprising subtracting a constant value from the first digitized signal, wherein, if a section of the first digitized signal falls below zero after the subtraction of a constant value from the first digitized signal, the method further comprises resetting the section of the first digitized signal to zero. [11] A method according to any of the preceding claims, further comprising: Digitizing one or more additional signals output by the ion detector to generate one or more additional digitized signals; Detecting one or more peaks in the one or more further digitized signals and determining a first area S0 of the one or more peaks and a first arrival time T0 of the one or more peaks, thereby forming a first list of data pairs; and Determine whether the first surface S0 is a first threshold surface S max exceeds or does not, where it is determined that the first surface S0 is the first threshold surface S max does not exceed, and the procedure further includes recording the first area S0 and the first arrival time T0, or data derived from the first area S0 and the first arrival time T0, in the first histogram. [12] Method according to claim 11, wherein one or more further signals contain at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000 or 10000 signals from the ion detector, each signal corresponding to a separate trial run or a separate acquisition. [13] Control system for a time-of-flight mass spectrometer, wherein the control system is designed and adapted to: (i) Digitizing a first signal output by an ion detector to generate a first digitized signal; (ii) Detecting one or more peaks in the first digitized signal and determining a first area S0 of the one or more peaks and a first arrival time T0 of the one or more peaks, thereby forming a first list of data pairs; and (iii) Determine whether the first surface S0 is a first threshold surface S max exceeds or does not exceed the first threshold area S max a peak area that indicates an essentially simultaneous arrival of two ions which the ion detector cannot resolve, and where, when it is determined that the first area S0 is the first threshold area S maxdoes not exceed, the control system is further designed and adapted to: record the first area S0 and the first arrival time T0 or data derived from the first area S0 and the first arrival time T0 in a first histogram, and wherein, if it is determined that the first area S0 is the first threshold area S max exceeding, the control system is further designed and adapted to: not include the first area S0 and the first arrival time T0 or data derived from the first area S0 and the first arrival time T0 in the first histogram. [14] Mass spectrometer comprising a control system according to claim 13. [15] Mass spectrometer according to claim 14, further comprising an analog / digital converter or transient recorder for digitizing the first signal. [16] Time-of-flight mass spectrometry methods, which include: Digitizing an initial signal output by an ion detector to generate an initial digitized signal; Detecting one or more peaks in the first digitized signal and determining a first area S0 of the one or more peaks and a first mass or mass-to-charge ratio M0 of the one or more peaks, thereby forming a first list of data pairs; and Determine whether the first surface S0 is a first threshold surface S max or a first threshold intensity I max exceeds or does not exceed the first threshold area S max a peak area that indicates an essentially simultaneous arrival of two ions which the ion detector cannot resolve, and where, when it is determined that the first area S0 is the first threshold area S maxdoes not exceed, the method further comprises recording the first area S0 and the first mass or the first mass-to-load ratio M0 or data derived from the first area S0 and the first mass or the first mass-to-load ratio M0 in a first histogram, and wherein, if it is determined that the first area S0 is the first threshold area S max The procedure further includes not including the first area S0 and the first mass or the first mass-to-charge ratio M0, or data derived from the first area S0 and the first mass or the first mass-to-charge ratio M0, in the first histogram. [17] Control system for a time-of-flight mass spectrometer, wherein the control system is designed and adapted to: (i) Digitizing a first signal output by an ion detector to generate a first digitized signal; (ii) Detecting one or more peaks in the first digitized signal and determining a first area S0 of the one or more peaks and a first mass or mass-to-charge ratio M0 of the one or more peaks, thereby forming a first list of data pairs; and (iii) Determine whether the first surface S0 is a first threshold surface S max exceeds or does not exceed the first threshold area S max a peak area that indicates an essentially simultaneous arrival of two ions which the ion detector cannot resolve, and where, when it is determined that the first area S0 is the first threshold area S maxdoes not exceed, the control system is further designed and adapted to: record the first area S0 and the first mass or the first mass-to-load ratio M0 or data derived from the first area S0 and the first mass or the first mass-to-load ratio M0 in a first histogram, and wherein, if it is determined that the first area S0 is the first threshold area S max exceeds, the control system is further designed and adapted to: not include the first area S0 and the first mass or the first mass-to-charge ratio M0 or data derived from the first area S0 and the first mass or the first mass-to-charge ratio M0 in the first histogram.

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