GB2598722A

GB2598722A - Analytical instrument circuitry

Info

Publication number: GB2598722A
Application number: GB2013867.3A
Authority: GB
Inventors: Smith Roger
Original assignee: Micromass UK Ltd
Current assignee: Micromass UK Ltd
Priority date: 2020-09-03
Filing date: 2020-09-03
Publication date: 2022-03-16
Also published as: GB202013867D0

Abstract

An analytical instrument (such as a Time of Flight Mass Spectrometer/Mass analyser or chromatographic separation device) comprises circuitry to generate an output signal 2 from an input signal 1, the circuitry comprising: a comparator 3, input circuitry (1,4) configured to provide the input signal directly or derived from the input signal to the comparator 3; and reference circuitry 5 configured to provide a reference signal to the comparator; wherein the comparator is configured to generate the output signal directly or via output circuitry (6 figure 3). The reference circuitry (e.g thermometer IC, FPGA, DAC) is configured to alter a magnitude of the reference signal depending on one or more conditions of the input circuitry, the comparator and/or the output circuitry. The input and or output circuitry may comprise an operational amplifier (op-amp/buffer 4). Thus the adaptive reference signal when applied to the comparator input may compensate for variations in the system due to variations in the conditions (e.g temperature of voltage) thus providing reduced variations in the input to output signal time delays. The input signal may for example be electrical pulses from an acceleration (pusher) electrode of a Time-of-Flight (TOF) mass analyser, whilst the output signal may be supplied to a data acquisition circuit of the analyser. Other applications in the system are disclosed. Other embodiments are disclosed including a Time of Flight mass analyser comprising the circuitry and a method of operating such a circuit.

Description

ANALYTICAL INSTRUMENT CIRCUITRY

CROSS-REFERENCE TO RELATED APPLICATION None.

FIELD OF THE INVENTION

The present invention relates generally to analytical instruments, and in particular to mass spectrometers, ion mobility spectrometers, chromatographic separation instruments, and combinations thereof.

BACKGROUND

There are a number of circumstances in analytical instruments (such as mass spectrometers, ion mobility spectrometers, chromatographic separation instruments, and combinations thereof) where an event in an input signal creates a change in an output signal.

For example, Figure 21 of W02019/229469 (Micromass) describes a pusher electrode drive unit of a Time of Flight (ToF) mass analyser in which a digital trigger signal is produced by sampling pusher pulses produced by pulsing circuitry 33. A comparator samples the pusher pulses, and receives a reference signal from an FPGA controller 32 via a DAC. ADC trigger circuitry 52 generates the digital trigger signal in response to the output from the comparator. In this arrangement, the digital trigger signal is indicative of the time at which ions are pushed into the ToF flight tube, and is used to initiate the acquisition of ion detection.

In these circumstances, it is often desirable for any time delay between the event in the input signal and the corresponding change in the output signal to remain constant during operation of the analytical instrument.

The Applicant believes that there remains scope for improvements to analytical instruments.

SUMMARY

According to an aspect, there is provided circuitry for an analytical instrument, the circuitry configured to generate an output signal from an input signal, the circuitry comprising: a comparator; input circuitry configured to provide the input signal or a signal derived from the input signal to the comparator; and reference circuitry configured to provide a reference signal to the comparator; wherein the comparator is configured to generate the output signal, or wherein the circuitry further comprises output circuitry configured to generate the output signal from an output of the comparator; and wherein the reference circuitry is configured to alter a magnitude of the reference signal depending on one or more conditions of the input circuitry, the comparator and/or the output circuitry.

According to an aspect, there is provided an analytical instrument comprising circuitry configured to generate an output signal from an input signal, the analytical instrument comprising: a comparator; input circuitry configured to provide the input signal or a signal derived from the input signal to the comparator; and reference circuitry configured to provide a reference signal to the comparator; wherein the comparator is configured to generate the output signal, or wherein the analytical instrument further comprises output circuitry configured to generate the output signal from an output of the comparator; and wherein the reference circuitry is configured to alter a magnitude of the reference signal depending on one or more conditions of the input circuitry, the comparator and/or the output circuitry.

According to an aspect, there is provided a method of operating an analytical instrument, the method comprising the analytical instrument generating an output signal from an input signal by: input circuitry of the analytical instrument providing the input signal or a signal derived from the input signal to a comparator of the analytical instrument; 3 -reference circuitry of the analytical instrument providing a reference signal to the comparator; and the comparator generating the output signal, or output circuitry of the analytical instrument generating the output signal from an output of the comparator; wherein the method further comprises the reference circuitry altering a magnitude of the reference signal depending on one or more conditions of the input circuitry, the comparator and/or the output circuitry.

Various embodiments are directed to an analytical instrument (such as a mass and/or ion mobility spectrometer, an ion mobility spectrometer, a chromatographic separation instrument, or a combination thereof), circuitry for an analytical instrument, and a method of operating an analytical instrument. The analytical instrument comprises circuitry configured to generate an output signal from an input signal, and may be configured such that a change in the magnitude of the input signal can create a change in the magnitude of the output signal.

The analytical instrument may be configured such that the output signal has a first (high) magnitude when the magnitude of the input signal provided to the comparator is larger than the magnitude of the reference signal, and such that the output signal has a second (low) magnitude when the magnitude of the input signal provided to the comparator is less than the magnitude of the reference signal (or vice versa). Thus, when the magnitude of the signal provided to the comparator changes from being lower than the magnitude of the reference signal to being higher than the magnitude of the reference signal (or vice versa), the magnitude of the output signal changes (from a low magnitude to a high magnitude (or vice versa)).

In embodiments, there may be a time delay between the time at which the magnitude of the input signal changes, and the time at which a corresponding change in the magnitude of the output signal occurs. It is generally desirable for this time delay to remain constant during operation of the analytical instrument, so as to maintain stable and consistent performance of the analytical instrument.

However, the Applicant has recognised that this time delay can vary, for example due to changes in one or more conditions (such as temperature, voltage(s), and so on) of the analytical instrument, in particular due to changes in one or more conditions of the input circuitry, and/or due to changes in one or more conditions of the comparator, and/or (optionally) due to changes in one or more conditions of the output circuitry. 4 -

The Applicant has furthermore recognised that such variations in the time delay can be reduced or avoided by altering the magnitude of the reference signal provided to the comparator in dependence upon the one or more conditions.

Thus, in various embodiments, the analytical instrument is configured to measure or determine the one or more conditions, and to alter the magnitude of the reference signal in dependence on the measured or determined one or more conditions, such that any change in the one or more conditions (that would otherwise cause a change in the time delay) results in a change in the magnitude of the reference signal, such that change in the time delay (due to the change in the one or more conditions) is prevented or reduced.

It will be appreciated, therefore, that various embodiments provide an improved analytical instrument.

The input circuitry may be configured to (i) amplify the input signal; (ii) reduce a voltage of the input signal; (iii) buffer the input signal; (iv) digitise the input signal; and/or (v) convert the input signal to an analogue form.

The input circuitry may comprise an operational amplifier (op-amp).

The output circuitry may be configured to (i) amplify the output of the comparator; (ii) reduce a voltage of the output of the comparator; (iii) buffer the output of the comparator; (iv) digitise the output of the comparator; and/or (v) convert the output of the comparator to an analogue form.

The output circuitry may comprise an operational amplifier (op-amp).

The comparator may be configured to compare the magnitude of the signal received from the input circuitry to the magnitude of the reference signal.

The comparator may be configured to produce an output that has a first magnitude when the magnitude of the signal received from the input circuitry is larger than the magnitude of the reference signal and that has a second different magnitude when the magnitude of the signal received from the input circuitry is less than the magnitude of the reference signal.

The one or more conditions may comprise one or more conditions that can cause variations in a time delay between a time at which a magnitude of the input signal changes, and a time at which a corresponding change in the magnitude of the output signal occurs.

The reference circuitry may be configured to alter the magnitude of the reference signal depending on the one or more conditions such that variations in the time delay are prevented or reduced.

-

The reference circuitry may be configured to alter the magnitude of the reference signal depending on one or more measured or determined conditions.

The circuitry may further comprise one or more measurement devices configured to measure or determine the one or more conditions.

The one or more conditions may comprise one or more temperatures and/or one or more voltages.

The input signal may comprise one or more electrical pulses that are supplied to an analyser of the analytical instrument; and the output signal may comprise a signal that is supplied to data acquisition circuitry of the analytical instrument, and that is used by the data acquisition circuitry to initiate data acquisition.

The input signal may comprise one or more electrical pulses that are supplied to an acceleration electrode of a Time of Flight (ToF) mass analyser; and the output signal may comprise a signal that is supplied to data acquisition circuitry of the Time of Flight (ToF) mass analyser, and that is used by the data acquisition circuitry to initiate data acquisition.

The input signal may comprise a signal that is supplied to an analyser of the analytical instrument; and the output signal may comprise a signal generated by the analyser from the input signal, and that is used by the analyser to initiate analysis.

The input signal may comprise a signal that is supplied to an acceleration electrode drive unit of a Time of Flight (ToF) mass analyser; and the output signal may comprise a signal generated by the drive unit from the input signal, and that is used by the drive unit to initiate supply of electrical pulses to an acceleration electrode of the Time of Flight (ToF) mass analyser.

The input signal may comprise one or more electrical pulses generated by a detector of the analytical instrument, and that are supplied to data acquisition circuitry of the analytical instrument; and the output signal may comprise a signal generated by the data acquisition circuitry from the input signal, and that is used by the data acquisition circuitry to determine a detection time.

The input signal may comprise one or more electrical pulses generated by a detector of the analytical instrument in response to detecting one or more ions, wherein the input signal is supplied to data acquisition circuitry of the analytical instrument; and 6 -the output signal may comprise a signal generated by the data acquisition circuitry from the input signal, and that is used by the data acquisition circuitry to determine a time of flight of the one or more ions.

According to an aspect, there is provided an analyser for an analytical instrument, the analyser comprising the circuitry described above.

The analyser may comprise a mass analyser such as a Time of Flight (ToF) mass analyser.

According to an aspect, there is provided a Time of Flight (ToF) mass analyser comprising: an acceleration electrode; a drive unit configured to supply electrical pulses to the acceleration electrode; data acquisition circuitry; and circuitry configured to generate an output signal from the electrical pulses, and to supply the output signal to the data acquisition circuitry, wherein the data acquisition circuitry is configured to use the output signal to initiate data acquisition; wherein the circuitry comprises a comparator, input circuitry configured to provide a signal derived from the electrical pulses to the comparator, reference circuitry configured to provide a reference signal to the comparator; wherein the comparator is configured to generate the output signal, or wherein the circuitry further comprises output circuitry configured to generate the output signal from an output of the comparator; and wherein the reference circuitry is configured to alter a magnitude of the reference signal depending a measured temperature of the input circuitry, the comparator and/or the output circuitry.

According to an aspect, there is provided an analytical instrument comprising the Time of Flight (ToF) mass analyser described above.

According to an aspect, there is provided an analytical instrument comprising the circuitry described above.

The analytical instrument may comprise a mass and/or ion mobility spectrometer and/or a chromatographic separation device.

BRIEF DESCRIPTION OF THE DRAWINGS 7 -

Various embodiments will now be described, by way of example only, and with reference to the accompanying drawings in which: Figure 1 shows schematically an analytical instrument in accordance with various embodiments; Figure 2 shows schematically a Time of Flight (ToF) mass analyser of an analytical instrument in accordance with various embodiments; Figure 3 show schematically circuitry of an analytical instrument configured in accordance with various embodiments; Figure 4 show schematically circuitry of an analytical instrument configured in accordance with various embodiments; Figures 5A-5D show schematically input and output signal traces in accordance with various embodiments; Figure 6 show schematically circuitry of an analytical instrument configured in accordance with various embodiments; Figure 7 show schematically circuitry of a pusher electrode drive unit of a Time of Flight (ToF) mass analyser of an analytical instrument configured in accordance with various embodiments; Figure 8A show schematically circuitry of an analytical instrument configured in accordance with various embodiments, and Figures 8B and 8C show schematically input and output signal traces in accordance with various embodiments; Figure 9 show schematically circuitry of an analytical instrument configured in accordance with various embodiments; and Figures 10A-10D show schematically input and output signal traces in accordance with various embodiments.

DETAILED DESCRIPTION

Various embodiments are directed to an analytical instrument, circuitry for an analytical instrument, and a method of operating an analytical instrument. The analytical instrument may be a mass and/or ion mobility spectrometer, a chromatographic separation instrument, or a combination thereof.

Fig. 1 shows schematically an analytical instrument in the form of a mass and/or ion mobility spectrometer in accordance with various embodiments. 8 -

As shown in Fig. 1, the analytical instrument may comprise an ion source 10, one or more functional components 20 that are arranged downstream from the ion source 10, and an analyser 30 that is arranged downstream from the ion source 10 and downstream from the one or more functional components 20.

As illustrated by Fig. 1 the analytical instrument may be configured such that ions can be provided by (sent from) the ion source 10 to the analyser 30 via the one or more functional components 20.

The ion source 10 may be configured to generate ions, for example by ionising an analyte. The ion source 10 may comprise any suitable ion source such as an ion source selected from the group consisting of: (i) an Electrospray ionisation ("ESI") ion source; (ii) an Atmospheric Pressure Photo lonisafion ("APPI") ion source; (iii) an Atmospheric Pressure Chemical Ionisation ("APCI") ion source; (iv) a Matrix Assisted Laser Desorption Ionisation ("MALDI") ion source; (v) a Laser Desorption Ionisation ("LDI") ion source; (vi) an Atmospheric Pressure Ionisation ("API") ion source; (vii) a Desorption lonisafion on Silicon ("DIOS") ion source; (viii) an Electron Impact ("El") ion source; (ix) a Chemical Ionisation ("Cl") ion source; (x) a Field Ionisation ("FI") ion source; (xi) a Field Desorption ("FD") ion source; (xii) an Inductively Coupled Plasma ("ICP") ion source; (xiii) a Fast Atom Bombardment ("FAB") ion source; (xiv) a Liquid Secondary Ion Mass Spectrometry ("LSIMS") ion source; (xv) a Desorption Electrospray lonisafion ("DESI") ion source; (xvi) a Nickel- 63 radioactive ion source; (xvii) an Atmospheric Pressure Matrix Assisted Laser Desorption Ionisation ion source; (xviii) a Thermospray ion source; (xix) an Atmospheric Sampling Glow Discharge lonisafion ("ASGDI") ion source; (xx) a Glow Discharge ("GD") ion source; (xW) an Impactor ion source; ()(xii) a Direct Analysis in Real Time ("DART") ion source; (xxiii) a Laserspray Ionisation ("LSI") ion source; (xxiv) a Sonicspray Ionisation ("SSI") ion source; (xxv) a Matrix Assisted Inlet Ionisation ("MAII") ion source; (xxvi) a Solvent Assisted Inlet Ionisation ("SAII") ion source; (orvii) a Desorption Electrospray Ionisation ("DESI") ion source; (xxviii) a Laser Ablation Electrospray Ionisation ("LAESI") ion source; (xxix) a Surface Assisted Laser Desorption Ionisation ("SALDI") ion source; (xxx) a Low Temperature Plasma ("LTP") ion source; (xxxi) a Helium Plasma Ionisation ("HePI") ion source; (xxxii) a Rapid Evaporative Ionisation Mass Spectrometry ("REIMS") ion source; and/or (xxxiii) a Laser Assisted Rapid Evaporative Ionisation Mass Spectrometry ("LA-REIMS") ion source. 9 -

The analytical instrument may comprise a chromatography or other separation device (not shown in Fig. 1) upstream of (and coupled to) the ion source 10. The chromatography separation device may comprise a liquid chromatography or gas chromatography device. Alternatively, the separation device may comprise: (i) a Capillary Electrophoresis ("CE") separation device; (ii) a Capillary Electrochromatography ("CEC") separation device; (iii) a substantially rigid ceramic-based multilayer microfluidic substrate ("ceramic tile") separation device; or (iv) a supercritical fluid chromatography separation device.

The analyser 30 may be configured to analyse ions, so as to determine (measure) one or more of their physic° chemical properties, such as their mass to charge ratio, time of flight, (ion mobility) drift time and/or collision cross section (GCS).

The analyser 30 may comprise a mass analyser (that may be configured to determine the mass to charge ratio or time of flight of ions) and/or an ion mobility analyser (that may be configured to determine the ion mobility drift time or collision cross section (CCS) of ions).

Where the analyser 30 comprises a mass analyser, the mass analyser may comprise any suitable mass analyser such as a mass analyser selected from the group consisting of: (i) a quadrupole mass analyser; (ii) a 2D or linear quadrupole mass analyser; (iii) a Paul or 3D quadrupole mass analyser; (iv) a Penning trap mass analyser; (v) an ion trap mass analyser; (vi) a magnetic sector mass analyser; (vii) Ion Cyclotron Resonance ("ICR") mass analyser; (viii) a Fourier Transform Ion Cyclotron Resonance ("FTICR") mass analyser; (ix) an electrostatic mass analyser arranged to generate an electrostatic field having a quadro-logarithmic potential distribution; (x) a Fourier Transform electrostatic mass analyser; (xi) a Fourier Transform mass analyser; (xii) a Time of Flight mass analyser; (xiii) an orthogonal acceleration Time of Flight mass analyser; and (xiv) a linear acceleration Time of Flight mass analyser.

The one or more functional components 20 may comprise any suitable such components, devices and functional elements of an analytical instrument (mass and/or ion mobility spectrometer).

For example, in various embodiments, the one or more functional components 20 comprise one or more ion guides, one or more ion traps, and/or one or more mass filters, for example which may be selected from the group consisting of: (i) a quadrupole mass filter; 00 a 2D or linear quadrupole ion trap; (iii) a Paul or -10 - 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.

The one or more functional components 20 may comprise an activation, collision, fragmentation or reaction device configured to activate, fragment or react ions.

The one or more functional components 20 may comprise an ion mobility separator configured to separate ions according to their ion mobility. The ion mobility separator may comprise a linear ion mobility separator, or a closed loop (cyclic) ion mobility separator.

The analytical instrument may be operated in various modes of operation including a mass spectrometry ("MS") mode of operation; a tandem mass spectrometry ("MS/MS") mode of operation; a mode of operation in which parent or precursor ions are alternatively fragmented or reacted so as to produce fragment or product ions, and not fragmented or reacted or fragmented or reacted to a lesser degree; a Multiple Reaction Monitoring ("MRM") mode of operation; a Data Dependent Analysis ("DDA") mode of operation; a Data Independent Analysis ("DIA") mode of operation a Quantification mode of operation or an Ion Mobility Spectrometry ("IMS") mode of operation.

It should be noted that Fig. 1 is merely schematic, and that the analytical instrument may (and in various embodiments does) include other components, devices and functional elements to those shown in Fig. 1.

As shown in Fig. 1, the analytical instrument may comprise a control system 40 that may be configured to control the operation of the analytical instrument, for example in the manner of the various embodiments described herein. The control system may comprise suitable control circuitry that is configured to cause the instrument to operate in the manner of the various embodiments described herein. The control system may comprise suitable processing circuitry configured to perform any one or more or all of the necessary processing and/or post-processing operations in respect of the various embodiments described herein. In various embodiments, the control system may comprise a suitable computing device, a microprocessor system, a programmable FPGA (field programmable gate array), and the like.

Where the analytical instrument is a chromatographic separation instrument, the chromatographic separation instrument may comprise a chromatography separation device. The chromatography separation device may comprise a liquid chromatography or gas chromatography device. Alternatively, the separation device may comprise: (i) a Capillary Electrophoresis ("CE") separation device; 00 a Capillary Electrochromatography ("CEC") separation device; (iii) a substantially rigid ceramic-based mulfilayer microfluidic substrate ("ceramic tile") separation device; or (iv) a supercritical fluid chromatography separation device.

The chromatographic separation instrument may also comprise a chromatography detector. The chromatography detector may comprise a destructive chromatography detector optionally selected from the group consisting of (i) a Flame Ionization Detector (FID); (ii) an aerosol-based detector or Nano Quantity Analyte Detector (NQAD); (iii) a Flame Photometric Detector (FPD); (iv) an Atomic-Emission Detector (AED); (v) a Nitrogen Phosphorus Detector (NPD) and (vi) an Evaporative Light Scattering Detector (ELSD). The chromatography detector may comprise a non-destructive chromatography detector optionally selected from the group consisting of: (i) a fixed or variable wavelength UV detector; 00 a Thermal Conductivity Detector (TCD); (iii) a fluorescence detector; (iv) an Electron Capture Detector (ECD); (v) a conductivity monitor; (vi) a Photoionization Detector (PID); (vii) a Refractive Index Detector (RID); (viii) a radio flow detector; and (ix) a chiral detector.

Figure 2 shows in more detail a Time of Flight (ToF) mass analyser 30 of an analytical instrument according to various embodiments. The analyser 30 may be connected to one or more upstream stages 20 of the instrument. Ions may be supplied to the mass analyser 30 from the one or more upstream stages 20. As illustrated in Figure 2, the mass analyser 30 may comprise an acceleration (pusher) electrode 31, an acceleration region 32, a field free or drift region 33 On the form of a "drift tube"), and an ion detector 34 arranged at the exit region of the field free or drift region 33. Figure 2 also shows a (pusher) drive unit 35, and circuitry 36 configured to supply electrical pulses generated by the drive unit 35 to the acceleration (pusher) electrode 34 of the mass analyser 30.

It should be noted here that Figure 2 is merely schematic, and that other Time of Flight (ToF) mass analyser arrangements, such as a reflectron arrangement, may be used. Thus, although not shown in Figure 2, in various embodiments the mass analyser 30 may also comprise a reflectron, in which case the detector 34 may be located adjacent the acceleration electrode 31.

Ions from the one or more upstream stages 20 may be arranged to enter the acceleration region 32 where they may be driven into the field free or drift region 33 -12 -by application of an electrical pulse generated by the (pusher) drive unit 35 to the acceleration (pusher) electrode 31.

The ions may be accelerated to a velocity determined by the energy imparted by the pulse and the mass to charge ratio (m/z) of the ions. Ions having a relatively low mass to charge ratio achieve a relatively high velocity and reach the ion detector 34 prior to ions having a relatively high mass to charge ratio.

Ions may arrive at the ion detector 34 after a time determined by their velocity and the distance travelled, which enables the mass to charge ratio of the ions to be determined. Each ion or groups of ions arriving at the detector 34 is sampled by the detector 34, and the signal from the detector 34 may be digitised, for example using an ADC (analogue to digital converter). A processor may then determine a value indicative of the time of flight and/or mass-to-charge ratio (m/z) of the ion or group of ions. Data for multiple ions may be collected and combined to generate a Time of Flight (ToF) spectrum and/or a mass spectrum.

According to various embodiments, for each ion or group of ions arriving at the detector 34, the detector 34 will produce one or more signals, which may then be digitised, e.g. by the ADC, and converted into time-intensity pairs, i.e. data values comprising a time-of-flight value together with an intensity value. In these embodiments, multiple such time-intensity pairs may be collected and combined to generate a Time of Flight (ToF) spectrum and/or a mass spectrum.

Thus, according to various embodiments the Time of Flight (ToF) mass analyser 30 is configured to cause ions to be accelerated into the field free or drift region 33 as a result of an electrical pulse being supplied to the acceleration electrode 31.

The analytical instrument of various embodiments comprises circuitry configured to generate an output signal from an input signal, and may be configured such that a change in the magnitude of the input signal can create a change in the magnitude of the output signal.

As used herein, a magnitude of a signal may refer to a voltage or a current of the signal. Thus, a change in the magnitude of a signal may be a change in a voltage or a current.

Any or all of the circuitry described herein may be implemented as a single circuit or as plural circuits. Any or all of the circuitry described herein may be implemented as standalone circuitry, and/or some of all of the circuitry may be implemented using share circuitry.

-13 -The input and output signals may be any suitable signals that are generated in an analytical instrument, where the output signal is generated from the input signal.

In embodiments, the input signal is a signal that causes one or more events to occur in the analytical instrument. For example (as will be described in more detail below), the input signal may be (or may be derived from) one or more electrical pulses (that may be generated by a (pusher) drive unit 35) that are supplied to an acceleration (pusher) electrode 31 in order to accelerate ions into a field free or drift region 33 of a Time of Flight (ToF) mass analyser 30. In this case, the input signal may be a signal that causes ions to be accelerated into the field free or drift region 33 of a Time of Flight (TOE) mass analyser 30.

In embodiments, the analytical instrument is configured such that an event-causing change in the input signal creates a change in the magnitude of the output signal. Thus, the output signal may be a signal that is indicative of the time at which the one or more events caused by the input signal occur. For example, the output signal may be indicative of the time at which ions are accelerated into the field free or drift region 33 of a Time of Flight (ToF) mass analyser 30.

The output signal may be supplied to (and used by) a component or circuitry of the analytical instrument whose operation depends on the timing of the one or more events. The output signal may be a trigger signal. For example, the output signal may be supplied to a detector 34 or to data acquisition circuitry associated with the detector 34 (for example of a Time of Flight (ToF) mass analyser 30), and may be used to initiate data acquisition using the detector 34. The analytical instrument may use the time at which an ion(s) is detected relative to the start time of the data acquisition to determine its time of flight, and therefore mass to charge ratio (m/z).

Various other embodiments are possible.

For example, the input signal may be (or may be derived from) one or more trigger signals (that may be generated by data acquisition circuitry associated with a detector 34) that may be supplied to a (pusher) drive unit 35 of a Time of Flight (ToF) mass analyser 30. The output signal may be a signal generated by the drive unit 35 from the trigger signal(s), and used by the drive unit 35 in order to initiate its supply of electrical pulse(s) to an acceleration (pusher) electrode 31.

The input signal may alternatively be (or may be derived from) one or more electrical pulses that may be generated by a detector 34 in response to an ion or -14 -ions being detected by the detector, and that may be supplied to data acquisition circuitry. The output signal may be a signal generated by the data acquisition circuitry from the detector signal(s), and used by the data acquisition circuitry to determine a time at which an ion(s) is detected.

Although examples of the input and output signals have been given above primarily in the context of a Time of Flight (ToF) mass analyser 30, the skilled person will understand that analogous signals are used in other forms of analytical instrument (as described above), and that various embodiments are intended to encompass such arrangements.

The analytical instrument circuitry of various embodiments comprises a comparator, input circuitry configured to provide the input signal or a signal derived from the input signal to the comparator, and reference circuitry configured to provide a reference signal to the comparator.

The comparator may have two input terminals, and may have one output.

The comparator may be configured to receive a signal from the input circuitry (namely, the input signal or the signal derived from the input signal) at one of its input terminals, and to receive the reference signal from the reference circuitry at its other input terminal. The comparator may be configured to compare the magnitude of the signal received from the input circuitry (namely, the magnitude of the input signal or the magnitude of the signal derived from the input signal) to the magnitude of the reference signal, and may be configured to produce an output indicative of which of the signal magnitudes is larger.

In particular, the comparator may be configured to produce an output that has a first magnitude when the magnitude of the signal received from the input circuitry is larger than the magnitude of the reference signal, and that has a second different magnitude when the magnitude of the signal received from the input circuitry is less than the magnitude of the reference signal. The first magnitude may be a high magnitude, and the second different magnitude may be a low magnitude (or alternatively, the first magnitude may be a low magnitude, and the second different magnitude may be a high magnitude).

Thus, the comparator may be configured such that when the magnitude of the signal received from the input circuitry (namely, the input signal or the signal derived from the input signal) changes from being lower than the magnitude of the reference signal to being higher than the magnitude of the reference signal, the magnitude of the comparator output changes (from the second (low) magnitude to -15 -the first (high) magnitude). The comparator may also be configured such that when the magnitude of the signal received from the input circuitry changes from being greater than the magnitude of the reference signal to being less than the magnitude of the reference signal, the magnitude of the comparator output changes (from the first (high) magnitude to the second (low) magnitude).

The input circuitry may comprise any suitable input circuitry that is configured to receive the input signal. The input circuitry may be configured to provide the input signal (directly) to the comparator or may be configured to provide a signal derived from the input signal to the comparator. In this latter case, the input circuitry may be configured to produce the derived signal from the input signal.

For example, the input circuitry may be configured to amplify or reduce a voltage of the input signal (and the derived signal may be an amplified or reduced voltage version of the input signal). The input circuitry may also or instead be configured to buffer the input signal (and the derived signal may be a buffered version of the input signal). The input circuitry may also or instead be configured to digitise the input signal or to convert the input signal to an analogue form (and the derived signal may be a digitised or analogue version of the input signal). Many other arrangements would be possible.

The comparator may be configured to generate the output signal, or the analytical instrument may further comprise output circuitry configured to generate the output signal from an output of the comparator.

Where the analytical instrument further comprises output circuitry configured to generate the output signal from the output of the comparator, the output circuitry may comprise any suitable such circuitry. For example, the output circuitry may be configured to amplify or reduce a voltage of the output of the comparator, and/or the output circuitry may be configured to buffer the output of the comparator, and/or the output circuitry may be configured to digitise the output of the comparator or convert the output signal to an analogue form, and so on.

It will be appreciated from the above that the analytical instrument may be configured such that the output signal has a first magnitude when the magnitude of the input signal provided to the comparator is larger than the magnitude of the reference signal, and such that the output signal has a second different magnitude when the magnitude of the input signal provided to the comparator is less than the magnitude of the reference signal. The first magnitude may be a high magnitude, and the second different magnitude may be a low magnitude (or alternatively, the -16 -first magnitude may be a low magnitude, and the second different magnitude may be a high magnitude).

Thus, the analytical instrument may be configured such that when the magnitude of the signal provided to the comparator changes from being lower than the magnitude of the reference signal to being higher than the magnitude of the reference signal, the magnitude of the output signal changes (from the second (low) magnitude to the first (high) magnitude). The analytical instrument may also be configured such that when the magnitude of the signal provided to the comparator changes from being greater than the magnitude of the reference signal to being lower than the magnitude of the reference signal, the magnitude of the output signal changes (from the second (high) magnitude to the first (low) magnitude).

In embodiments, there may be a time delay between the time at which the magnitude of the input signal changes, and the time at which a corresponding change in the magnitude of the output signal occurs. It is generally desirable for this time delay to remain constant during operation of the analytical instrument, so as to maintain stable and consistent performance of the analytical instrument. However, the Applicant has recognised that this time delay can vary, for example due to changes in one or more conditions (such as temperature, voltage(s), and so on) of the analytical instrument, in particular due to changes in one or more conditions of the input circuitry, and/or due to changes in one or more conditions of the comparator, and/or due to changes in one or more conditions of the output circuitry.

Thus, the reference circuitry is configured to alter a magnitude of the reference signal depending on one or more conditions of the input circuitry, the comparator and/or the output circuitry.

The analytical instrument may be configured to measure or determine the one or more conditions, and the reference circuitry may be configured to alter the magnitude of the reference signal in dependence on the measured or determined one or more conditions. This may be done such that any change in the one or more conditions (that would otherwise cause a change in the time delay) results in a change in the magnitude of the reference signal, wherein the change in the -17 -magnitude of the reference signal is configured such that a change in the time delay (due to the change in the one or more conditions) is prevented or reduced.

Thus, the reference circuitry may be configured to alter the magnitude of the reference signal depending on the one or more conditions such that variation(s) in the time delay (due to changes in the one or more conditions) are prevented or reduced. To do this, the reference circuitry may be configured to alter the magnitude of the reference signal using a function or functions that depend(s) on the one or more (measured or determined) conditions. The particular form that the function(s) may take will depend on the nature of the particular analytical instrument. The function(s) may be determined in any suitable manner, for example by empirical observation and/or using theoretical considerations.

The one or more conditions may comprise any condition or conditions that causes a variation in the (above-described) time delay. The condition(s) may have the (direct) effect of causing a variation in the time delay between the time at which the magnitude of the input signal changes, and the time at which a corresponding change in the magnitude of the output signal occurs. Additionally or alternatively, the condition(s) may have some other effect that effectively causes a variation in this time delay. For example, the condition may have the (direct) effect of causing one or more or each of a variation in an offset between the input and output signals, an amplitude variation between the input and output signals, a variation in a slope of the input and output signals, and so on.

In various embodiments, the one or more conditions comprise a temperature and/or a voltage. Thus, the one or more conditions may comprise a temperature and/or a voltage of the input circuitry, a temperature and/or a voltage of the comparator, and/or a temperature and/or a voltage of the output circuitry.

The (reference circuitry of the) analytical instrument may further comprise one or more measurement devices configured to measure or determine the one or more conditions. One or more or each measurement device may be configured to (continuously or non-continuously) monitor or determine a condition.

One or more or each measurement device may be configured to directly measure or determine a condition. For example, a measurement device may be configured to directly measure a condition (such as temperature and/or voltage) of the input circuitry, the comparator and/or the output circuitry.

Additionally or alternatively, one or more or each measurement device may be configured to indirectly measure or determine a condition. For example, a -18 -measurement device may be configured to indirectly measure a condition (such as temperature and/or voltage) of the input circuitry, the comparator and/or the output circuitry, by (directly) measuring or determining a condition of another part of the analytical instrument (where the condition of the other part of the analytical instrument is indicative of the condition of the input circuitry, the comparator and/or the output circuitry).

Where a condition comprises a temperature, the analytical instrument may comprise a temperature measurement device (such as a thermistor, a resistance temperature detector (RID), and so on) configured to measure or determine a temperature. The temperature measurement device may be configured to directly measure or determine the temperature of the input circuitry, the comparator and/or the output circuitry. Additionally or alternatively, the temperature measurement device may be configured to indirectly measure or determine the temperature of the input circuitry, the comparator and/or the output circuitry by (directly) measuring or determining a temperature of other circuitry or another part of the analytical instrument (where the temperature of the other circuitry or other part of the analytical instrument is indicative of the temperature of the input circuitry, the comparator and/or the output circuitry).

Where a condition comprises a voltage, the circuitry may further comprise a voltage determination device or circuitry configured to measure or determine a voltage. The voltage determination device may be configured to directly measure or determine the (relevant) voltage of the input circuitry, the comparator and/or the output circuitry. Additionally or alternatively, the voltage determination device may be configured to indirectly measure or determine the voltage of the input circuitry, the comparator and/or the output circuitry by (directly) measuring or determining a voltage of other circuitry or another part of the analytical instrument (where the voltage of the other circuitry or other part of the analytical instrument is indicative of the relevant voltage of the input circuitry, the comparator and/or the output circuitry).

Other arrangements would be possible.

Figure 3 shows schematically circuitry of an analytical instrument configured in accordance with various embodiments.

As shown in Figure 3, the circuitry is configured to generate an output signal 2 from an input signal 1. The circuitry comprises a comparator 3, input circuitry 4 configured to provide the input signal 1 or a signal derived from the input signal 1 to -19 -the comparator 3, reference circuitry 5 configured to provide a reference signal to the comparator 3, and output circuitry 6 configured to generate the output signal 2 from an output of the comparator 3.

The circuitry may be configured such that an event in the input signal 1 creates a change in the output signal 2. The circuitry may be configured such that a time delay between the input signal 1 event and the output signal 2 changing can vary due to delays in the input circuit 4, the output circuit 6, or both the input circuit 4 and the output circuit 6. These delays may in turn be due to variations in one or more conditions of the input 4 and/or output circuitry 6, such as temperature variations, voltage variations, or other conditions.

In accordance with various embodiments, the reference input signal to the comparator 3 is varied in response to the condition(s) causing the delay(s). This is done in such a way as to compensate for variation in the delay(s), so as to therefore maintain a constant delay.

Figure 4 shows schematically circuitry of an analytical instrument configured in accordance with various embodiments. In these embodiments, the variable delays may be in the input circuit 4 only, and the output signal 2 may be directly from the comparator 3 output.

As shown in Figure 4, the circuitry is configured to generate an output signal 2 from an input signal 1. The circuitry comprises a comparator 3, input circuitry 4 configured to provide the input signal 1 or a signal derived from the input signal 1 to the comparator 3, and reference circuitry 5 configured to provide a reference signal to the comparator 3. The comparator 3 is configured to generate the output signal 2.

Figure 5 illustrates input and output signal magnitudes for a system configured in accordance with various embodiments.

As illustrated by Figure 5B, when the voltage level of the input 7 to the comparator (which is derived from the input signal 1 as shown in Figure 5A) crosses the threshold voltage 8 provided by the reference circuit 5, then the output of the comparator 3 changes state, providing the output signal 2.

As also illustrated by Figure 5B, there is a delay time between the change in the input signal 1, and a corresponding change in the input 7 to the comparator. There is therefore a delay time between the change in the input signal 1, and the corresponding change in the output signal 2. As described above, this delay time may be due to a delay in the input circuit 4.

-20 -As illustrated by Figure 5C, when a condition (such as temperature) changes which causes the delay in the input circuit 4 to change, then without any compensation the time delay between the change in the input signal 1 and the change in the output signal 2 is similarly altered.

As illustrated by Figure 5D, where the reference signal to the comparator 3 is altered, then the change in delay can be compensated for.

Figure 6 shows schematically a more detailed example of circuitry of an analytical instrument configured in accordance with various embodiments.

As illustrated by Figure 6, the input circuit 4 may comprise an op-amp (operational amplifier) configured as a voltage follower. The Applicant has recognised, in particular, that such an op-amp may have a characteristic that causes a temperature related delay. Thus, the op-amp may be (predominantly) responsible for the temperature related time delay changes described above.

In these embodiments, the reference circuit 5 may comprise a DAC (digital to analog converter) controlled by a controller such as an FPGA (field programmable gate array). As shown in Figure 6, the controller (FPGA) may be configured to monitor the temperature of the analytical instrument (of the circuitry, such as of the op-amp), which may be measured by a temperature measurement device (integrated circuit (IC)). The controller (FPGA) may use the temperature measurement to control the value of the signal sent to the DAC, to thereby control the magnitude of the reference signal for the comparator 3.

Circuitry such as the circuitry illustrated in Figure 6 may, for example, form part of an acceleration (pusher) electrode drive unit of a Time of Flight (ToF) mass analyser, such as the pusher electrode drive unit described in W02019/229469 (Micromass). The entire content of this application is incorporated herein by reference.

Figure 7 shows schematically circuitry of an acceleration (pusher) electrode drive unit of a Time of Flight (ToF) mass analyser configured in accordance with these embodiments.

As shown in Figure 7, in these embodiments, the input signal 1 may be the high voltage pusher output pulse which is used to push a packet of ions into the flight tube of the mass analyser. The output signal 2 may be the ADC trigger pulse, which may be used to initiate the acquisition of ion detection.

In Time of Flight mass spectrometry (ToF-MS), it is important that the delay between ions entering the flight tube and the start of the acquisition of ion detection -21 -remains constant during operation of the instrument. This is because the mass to charge ratio (m/z) of ions is determined based on their time of flight between entering the flight tube and being detected. Changes in the delay between ions entering the flight tube and the start of the acquisition of ion detection can accordingly result in inaccurate mass to charge ratio (m/z) measurements.

As shown in Figure 7, the ADC acquisition trigger pulse may be derived from an analog circuit and a comparator 3 to create a digital trigger pulse.

In particular, the HV pulse (used to push ions into the flight tube) may be divided down to a low voltage pulse. This may be done using a capacitive divider.

This low voltage pulse may be buffered using an op-amp. The pulse signal may then be provided to one input of a comparator 3. The other input (the switching threshold reference) may be from a DAC controlled by a controller such as an FPGA. As the signal level crosses the threshold, the comparator 3 output switches to produce a trigger signal which is used (directly or indirectly) to trigger the ADC acquisition system.

Temperature dependent variations in the characteristics of the electronic components mean that as the temperature changes, the time delay between a fixed point on the edge of the high voltage pusher pulse and the generated trigger signal varies. In these embodiments, it may be the op-amp which is the source of most of the (undesired) temperature dependence, due to a change in gain, offset or delay of the signal. Fluctuations in ambient temperature of the analytical instrument can cause drift in the temperature of the electronic components (particularly op-amps).

This variation may be compensated for by varying the reference input to the comparator 3 according to the measured temperature (as described above).

In order to do this in these embodiments, the controller (FPGA) may be configured to control the DAC which generates the reference voltage. The controller (FPGA) may receive an input from a temperature measuring device. The controller (FPGA) may use the temperature measurement to adjust the DAC output being used as the comparator reference. Such adjustments to the DAC threshold can be used to compensate for the temperature induced shift in the signal path.

The op-amp may not necessarily be the source of the temperature dependent effect. Any element may be the source of a temperature dependence, including (but not limited to) one or more of the divider circuit, the op-amp, the DAC or the comparator 3.

-22 -It should be noted that embodiments are not only applicable to the particular acceleration (pusher) electrode drive unit depicted in Figure 7, but to all instances in an analytical instrument where temperature dependent time delays or voltage variations can be compensated for by altering voltage references, which may for example be generated by a DAC (digital to analog converter).

For example, embodiments are not restricted to control by an FPGA. Any digital system (including, but not limited to, a microcontroller or microprocessor) could be used.

Embodiments are not restricted to dividing the HV to low voltage through use of a capacitive divider. Any method (including, but not limited to, a resistive divider or a pulse transformer) could be used.

Embodiments are also not restricted to triggering signals derived from a divided down HV pulse. The technique according to various embodiments can be applied to any instance where the threshold for a comparator 3 is being adjusted.

In embodiments, the op-amp described above could be replaced with a unity gain buffer, a circuit with gain (positive or negative, greater or less than 1), any other circuit, or there may be no additional circuitry between the input (pulse) signal 1 and the comparator 3.

In embodiments, rather than using an FPGA (or other digital device) to measure the temperature and control a DAC, a temperature dependent device (such as a thermistor or resistance temperature detector (RTD)) could be used in the comparator reference circuit (with or without a DAC contributing to the reference voltage).

Figures 8A-8C illustrate an embodiment in which the input 7 to the comparator 3 comprises a trigger pulse from an acceleration (pusher) electrode drive unit into an ion acquisition system. The input 7 to the comparator 3 may be the trigger signal from the acceleration (pusher) electrode drive unit indicating the pusher pulse has pushed the ions into the flight tube.

As shown in Figures 8A-8C, the pusher unit generates a low voltage trigger signal 7 from the high voltage pusher pulse 1 using a pulse transformer. The high voltage pusher pulse 1 may be positive (as shown in Figure 83) or negative (as shown in Figure 8C). The trigger signal 7 is provided to the acquisition system.

In the ADC (analog to digital converter) or TDC (time to digital converter) acquisition system, this trigger pulse 7 is converted to a digital pulse by a comparator 3 and is used to start the timing for the flight time of the ions.

-23 -In these embodiments, by altering the threshold voltage into the comparator 3, the delay can be altered to correct for delays caused by changes in temperature or other factors.

Figure 9 shows an embodiment in which the acquisition system (ADC or TOO) sends a signal to the pusher unit to start the high voltage pusher pulse initiating the flight time of the ions in the flight tube. In these embodiments, the input signal 1 may be the trigger signal from the acquisition system (ADC or TOO).

As shown in Figure 9, the ADO/TOO generates a trigger signal 1 which the pusher unit uses to initiate the high voltage pulse. By altering the threshold voltage into the comparator 3, the delay can be altered to correct for delays caused by changes in temperature or other factors.

It should also be noted that embodiments are not only applicable to circuitry of an acceleration (pusher) electrode drive unit.

For example, further embodiments relate to a TDC (time to digital converter) acquisition system. In these embodiments, the input signal 1 may be a signal from a detector indicating the arrival of ions into the acquisition system. The output signal 2 may be a signal indicating the arrival of one or more ions. The TOO system may record the time from the start of acquisition to the arrival of one or more ions.

In these embodiments, a delay may be within the sensor (which may be a photomultiplier, electron multiplier or other ion detector). The delay may be within the circuit processing the signal from the sensor before it is converted into a digital signal. The delay may be due to a change in conditions in the pusher, the flight tube, or with other voltages in the system. The delay may be elsewhere in the system.

In these embodiments, the method of adjusting the delay by altering the comparator 3 reference in response to one or more factors (temperature, voltage, and so on) may be used to minimise changes in the delay between the start of a push of a packet of ions and the signal indicating the arrival of those ions.

Although, the primary cause of the variations described above are temperature effects that cause changes in delay times, various embodiments are applicable to other arrangements.

As illustrated by Figures 10A-100, in general, changes in a delay of an input signal (or output signal) (Figure 10A), changes in an offset of the input signal (Figure 9B), changes in an amplitude of the input signal (Figure 100), and changes -24 -in the slope of the input signal (Figure 10D), can be compensated for by altering the threshold voltage to the comparator 3 in response to the factor causing the effect. As well as temperature effects causing changes in the input or output circuits, other factors may include (but are not limited to): variations in supply voltage(s) (low voltage) to the electronics, variations in pusher voltage(s) (high voltage) affecting the time or speed at which ions enter the flight tube, variations in other high voltages (flight tube, reflectron, and so on).

Although the present invention has been described with reference to preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made without departing from the scope of the invention as set forth in the accompanying claims.

Claims

-25 -Claims 1. Circuitry for an analytical instrument, the circuitry configured to generate an output signal from an input signal, the circuitry comprising: a comparator; input circuitry configured to provide the input signal or a signal derived from the input signal to the comparator; and reference circuitry configured to provide a reference signal to the comparator; wherein the comparator is configured to generate the output signal, or wherein the circuitry further comprises output circuitry configured to generate the output signal from an output of the comparator; and wherein the reference circuitry is configured to alter a magnitude of the reference signal depending on one or more conditions of the input circuitry, the comparator and/or the output circuitry.
2. The circuitry of claim 1, wherein: the input circuitry is configured to (i) amplify the input signal; (ii) reduce a voltage of the input signal; (H) buffer the input signal; (iv) digitise the input signal; and/or (v) convert the input signal to an analogue form; and/or the output circuitry is configured to (i) amplify the output of the comparator; (ii) reduce a voltage of the output of the comparator; (iii) buffer the output of the comparator; (iv) digitise the output of the comparator; and/or (v) convert the output of the comparator to an analogue form.
3. The circuitry of claim 1 or 2, wherein the input circuitry and/or the output circuitry comprises an operational amplifier (op-amp).
4. The circuitry of any one of the preceding claims, wherein the comparator is configured: to compare the magnitude of the signal received from the input circuitry to the magnitude of the reference signal; and -26 -to produce an output that has a first magnitude when the magnitude of the signal received from the input circuitry is larger than the magnitude of the reference signal and that has a second different magnitude when the magnitude of the signal received from the input circuitry is less than the magnitude of the reference signal.
5. The circuitry of any one of the preceding claims, wherein the one or more conditions comprise one or more conditions that can cause variations in a time delay between a time at which a magnitude of the input signal changes, and a time at which a corresponding change in the magnitude of the output signal occurs.
6. The circuitry of claim 5, wherein the reference circuitry is configured to alter the magnitude of the reference signal depending on the one or more conditions such that variations in the time delay are prevented or reduced.
7. The circuitry of any one of the preceding claims, wherein the reference circuitry is configured to alter the magnitude of the reference signal depending on one or more measured or determined conditions.
8. The circuitry of any one of the preceding claims, further comprising one or more measurement devices configured to measure or determine the one or more conditions.
9. The circuitry of any one of the preceding claims, wherein the one or more conditions comprise one or more temperatures and/or one or more voltages. 25
10. The circuitry of any one of the preceding claims, wherein: the input signal comprises one or more electrical pulses that are supplied to an analyser of the analytical instrument; and the output signal comprises a signal that is supplied to data acquisition circuitry of the analytical instrument, and that is used by the data acquisition circuitry to initiate data acquisition.
11. The circuitry of any one of the preceding claims, wherein: the input signal comprises one or more electrical pulses that are supplied to an acceleration electrode of a Time of Flight (ToF) mass analyser; and -27 -the output signal comprises a signal that is supplied to data acquisition circuitry of the Time of Flight (ToF) mass analyser, and that is used by the data acquisition circuitry to initiate data acquisition.
12. The circuitry of any one of claims 1 to 9, wherein: the input signal comprises a signal that is supplied to an analyser of the analytical instrument; and the output signal comprises a signal generated by the analyser from the input signal, and that is used by the analyser to initiate analysis.
13. The circuitry of any one of claims 1 to 9 or 12, wherein: the input signal comprises a signal that is supplied to an acceleration electrode drive unit of a Time of Flight (ToF) mass analyser; and the output signal comprises a signal generated by the drive unit from the input signal, and that is used by the drive unit to initiate supply of electrical pulses to an acceleration electrode of the Time of Flight (ToF) mass analyser.
14. The circuitry of any one of claims 1 to 9, wherein: the input signal comprises one or more electrical pulses generated by a detector of the analytical instrument, and that are supplied to data acquisition circuitry of the analytical instrument; and the output signal is a signal generated by the data acquisition circuitry from the input signal, and that is used by the data acquisition circuitry to determine a detection time.
15. The circuitry of any one of claims 1 to 9 or 14, wherein: the input signal comprises one or more electrical pulses generated by a detector of the analytical instrument in response to detecting one or more ions, wherein the input signal is supplied to data acquisition circuitry of the analytical instrument; and the output signal is a signal generated by the data acquisition circuitry from the input signal, and that is used by the data acquisition circuitry to determine a time of flight of the one or more ions.-28 -
16. An analyser for an analytical instrument, the analyser comprising the circuitry of any one of the preceding claims, optionally wherein the analyser comprises a mass analyser such as a Time of Flight (ToF) mass analyser.
17. An analytical instrument comprising the circuitry of any one of claims 1 to 15.
18. The analytical instrument of claim 17, wherein the analytical instrument comprises a mass and/or ion mobility spectrometer and/or a chromatographic separation device.
19. A Time of Flight (ToF) mass analyser comprising: an acceleration electrode; a drive unit configured to supply electrical pulses to the acceleration electrode; data acquisition circuitry; and circuitry configured to generate an output signal from the electrical pulses, and to supply the output signal to the data acquisition circuitry, wherein the data acquisition circuitry is configured to use the output signal to initiate data acquisition; wherein the circuitry comprises a comparator, input circuitry configured to provide a signal derived from the electrical pulses to the comparator, reference circuitry configured to provide a reference signal to the comparator; wherein the comparator is configured to generate the output signal, or wherein the circuitry further comprises output circuitry configured to generate the output signal from an output of the comparator; and wherein the reference circuitry is configured to alter a magnitude of the reference signal depending a measured temperature of the input circuitry, the comparator and/or the output circuitry.
20. A method of operating an analytical instrument, the method comprising the analytical instrument generating an output signal from an input signal by: input circuitry of the analytical instrument providing the input signal or a signal derived from the input signal to a comparator of the analytical instrument; reference circuitry of the analytical instrument providing a reference signal to the comparator; and -29 -the comparator generating the output signal, or output circuitry of the analytical instrument generating the output signal from an output of the comparator; wherein the method further comprises the reference circuitry altering a magnitude of the reference signal depending on one or more conditions of the input circuitry, the comparator and/or the output circuitry.