Point-of-care detector bias optimization and monitoring

Abstract

In one aspect, a method for monitoring a bias voltage applied to an ion detector of a mass spectrometer is disclosed, the method comprising applying an initial bias voltage to the ion detector, at least two feasible ion detection signals corresponding to at least two different ion signal detection thresholds are acquired using an ion detector to which an initial bias voltage is applied, and the at least two feasible ion detection signals are used to determine whether the bias voltage needs to be adjusted.

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 333,898, filed on April 22, 2022, entitled “Detector Bias Optimization and Monitoring on the Fly,” which is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure generally relates to methods and systems for monitoring and / or maintaining an optimal value for a bias voltage applied to an ion detector in a mass spectrometer, such as for determining whether the detector bias voltage deviates from its optimal setting. Background Art

[0004] In mass spectrometry, a bias voltage is typically applied to an ion detector for detecting ions. The bias voltage is typically adjusted to optimize the performance of the mass spectrometer. As an example, optimization of the ion detector bias voltage traditionally involves introducing a steady flow of an analyte into a mass spectrometer and measuring the intensity of ions associated with the analyte while ramping the bias voltage. The optimal bias voltage can, for example, be selected to correspond to a bias voltage at which an increase in the bias voltage does not result in any further substantial increase in the observed ion intensity. An example of such a standard defines the optimal bias voltage as a first bias voltage that fails to result in at least a 30% increase in ion signal intensity during an increased bias voltage ramp.

[0005] Traditionally, users of mass spectrometers do not frequently check the detector bias voltage to monitor whether it has drifted from its optimal value. In fact, users often assume that the ion detector bias voltage needs to be adjusted only when a significant deterioration in ion detection intensity is observed. Summary of the invention

[0006] In one aspect, a method for monitoring a bias voltage applied to an ion detector of a mass spectrometer is disclosed, the method comprising applying an initial bias voltage to the ion detector, using the ion detector to which the initial bias voltage is applied to acquire at least two viable ion detection signals corresponding to at least two different ion signal detection thresholds, and using the at least two viable ion detection signals to determine whether the bias voltage needs to be adjusted.

[0007] In some embodiments, the ratio of the signal intensities of the two feasible ion detection signals is compared to a reference value to determine whether the ratio is within a predefined tolerance range of the reference value. When the ratio is outside the predefined range, an indication is given to adjust the bias voltage. The tolerance range can be, for example, about + / -5%, + / -10%, + / -20% of the reference value, although other ranges may also be used, for example, based on the requirements of a specific application.

[0008] In some embodiments, whether the bias voltage needs to be adjusted can be determined by calculating the degree of deviation of the bias voltage from a target value (which is typically an optimal value) using previously obtained reference data, where the degree of deviation is associated with the ratio of two feasible ion detection signal intensities corresponding to two different discriminator thresholds.

[0009] In some cases, in response to an indication that the bias voltage needs to be adjusted, the bias voltage can be adjusted so that the bias voltage is within an acceptable tolerance range of the optimal bias voltage. In some embodiments, the user can adjust the bias voltage in response to the indication that adjustment is needed. In other embodiments, such adjustment of the bias voltage can be automatically achieved, for example, via a feedback loop.

[0010] In some embodiments, the adjustment of the bias voltage can be achieved by adding the correction voltage to the bias voltage being checked or subtracting the correction voltage from the bias voltage being checked. In some implementations of such embodiments, the required correction voltage can be obtained from a lookup table containing a plurality of correction voltages corresponding to a plurality of intensity ratios associated with at least two feasible ion signal intensities.

[0011] In some embodiments, the adjusted bias voltage is checked in the above-described manner (i.e., by comparing the intensity ratio of at least two feasible ion detection signals with a reference value to determine whether the intensity ratio is within an acceptable tolerance range of the reference value). If it is found that the ion signal intensity ratio (or the deviation of the bias voltage inferred based on the ion signal intensity ratio from a target value (usually an optimal value)) is not within an acceptable tolerance range, the bias voltage is adjusted and checked iteratively until an acceptable bias voltage is obtained.

[0012] Various ion detectors may be employed in the practice of the present teachings. Some examples of such ion detectors include, but are not limited to, channel electron multipliers, discrete dynode multipliers, microchannel plate detectors, and the like. In addition, the present teachings may be practiced to adjust the bias voltage of ion detectors in various mass spectrometers employing various mass analyzers. Some examples of such mass analyzers include, but are not limited to, time-of-flight (ToF) mass analyzers, quadrupole mass analyzers, and combinations thereof.

[0013] In some embodiments, the method further comprises generating a notification when the bias voltage needs to be adjusted.Such a notification may take various forms, for example, it may be a visual notification and / or an audible notification.

[0014] In some embodiments, a process of checking the bias voltage applied to the ion detector can be triggered (i.e., initiated) at one or more times during mass spectrometry analysis of a compound. As an example, a user can initiate a check of the bias voltage at such a time, or alternatively, such a check of the bias voltage can be automatically initiated at one or more predefined times.

[0015] In some embodiments, the check of the bias voltage applied to the ion detector may be initiated after a predefined period of time has passed after the time the ion detector is triggered to begin ion detection.

[0016] In some embodiments, any one of the viable ion detection signals may be acquired by amplifying an ion detection signal generated by an ion detector in response to detecting ions incident thereon, and comparing the amplified ion detection signal relative to a discriminator threshold to accept the ion detection signal as a viable ion detection signal when the signal (i.e., the detected voltage) exceeds the discriminator threshold during a particular time portion of the signal (e.g., a duration of at least 1.3 nanoseconds or as required by the specifications of the comparator circuitry). In some embodiments in which the analog ion detection signal is digitized, various criteria may be employed to obtain a viable ion detection signal. One example of such a criterion is requiring the signal to be above a predefined threshold after smoothing and / or other processing has been performed to reduce signal noise.

[0017] In some embodiments, the acquisition of any one of the at least two possible ion detection signals can be achieved by amplifying an ion detection signal generated by an ion detector in response to detecting ions incident thereon to generate an amplified ion detection signal, and digitizing the amplified ion detection signal to generate a digital ion detection signal. The digital ion detection signal can then be processed via comparison with a plurality of discriminator thresholds to generate a plurality of ion detection intensities, each ion detection intensity corresponding to one of the discriminator thresholds. The ion detection intensities can then be used to determine whether a bias voltage needs to be adjusted.

[0018] In a related aspect, a method for monitoring a bias voltage applied to an ion detector of a mass spectrometer is disclosed, the method comprising: allocating an ion detection signal generated by an ion detector to which an initial bias voltage is applied among a plurality of ion signal processing channels to generate a plurality of viable ion detection signals, each ion signal processing channel being configured to process the received ion detection signal relative to a different discriminator threshold voltage, each viable ion detection signal corresponding to a respective one of the discriminator threshold voltages; and comparing the viable ion detection signal, for example relative to a reference, to determine whether the bias voltage corresponds to an optimal bias voltage.

[0019] While in some embodiments, the comparison of the digital ion detection signal acquired at different discriminator thresholds with a reference can be performed in real time (i.e., during an experimental run), in other embodiments, the comparison of the digital ion detection signal with a predefined reference can be performed after the data acquisition of the experimental run is terminated. In some implementations of the latter embodiment, data corresponding to the digital ion detection signal and the corresponding discriminator threshold can be stored in a database, which can be accessed to retrieve the data and process the data in the manner disclosed herein to determine whether the bias voltage applied to the ion detector needs to be adjusted. In some embodiments, such information can be employed in post-processing of the data to apply a correction factor (also referred to herein as a scaling factor) to the data to compensate for deviations (if any) in the bias voltage applied to the ion detector during the acquisition of the mass analysis data.

[0020] For example, in some embodiments, where analysis of detected viable ion detection signals obtained at different discriminator thresholds is performed after data acquisition is completed (e.g., after an experimental run is completed), a correction voltage (delta voltage) derived for a bias voltage based on data analysis according to the present teachings can be used to obtain a correction scaling factor for adjusting the intensity of the detected viable ion signal. In other words, the correction scaling factor can be determined based on the difference between the applied bias voltage (i.e., the bias voltage used for data acquisition) and the optimal bias voltage determined via post-processing of the data based on the present teachings.

[0021] In a related aspect, a method of monitoring a bias voltage applied to an ion detector of a mass spectrometer is disclosed, wherein for each of a reference optimal bias voltage, at least one reference bias voltage less than the optimal bias voltage, and at least one reference bias voltage greater than the optimal bias voltage, an ion signal intensity ratio of two measured ion detection signals is obtained, each measured ion detection signal being collected at a different discriminator threshold. The reference bias voltage and its corresponding ion intensity ratio are used to calculate the difference (if any) between the measured bias voltage relative to a target value (usually an optimal value), the difference corresponding to the measured ratio of the two ion detection signals, each ion detection signal being collected at one of the different discriminator thresholds. When the calculated difference between the bias voltage and the target value is not within a tolerance range, the bias voltage can be optionally adjusted to bring the bias voltage within an acceptable tolerance range.

[0022] In a related aspect, a method for monitoring, adjusting and / or maintaining a bias voltage applied to an ion detector of a mass spectrometer is disclosed, the method comprising applying a bias voltage ramp to the ion detector by the following operation: increasing the bias voltage by a plurality of discrete steps to apply a plurality of discrete bias voltages to the ion detector. At each discrete voltage value, the ion intensity at two or more discriminator threshold voltages is measured. And the ion intensity is processed (e.g., by obtaining its ratio or in other ways as disclosed herein) to obtain an intensity parameter (e.g., the intensity parameter may correspond to the ratio of two ion intensities collected at two different discriminator threshold voltages). The intensity parameter is then used as calibration data (e.g., in the form of a calibration curve), and the calibration data can then be used to determine whether the measured bias voltage is within an acceptable range of an optimal bias voltage or outside the range, and whether it is higher or lower than the optimal bias voltage.

[0023] In a related aspect, a system for monitoring the bias voltage applied to an ion detector of a mass spectrometer is disclosed, the system comprising a signal processing circuit system and a controller, the signal processing circuit system being configured to receive an ion detection signal generated by the ion detector in response to detecting ions incident thereon and amplifying the ion detection signal to generate a plurality of amplified ion detection signals, the controller communicating with the signal processing circuit system for receiving the amplified signal, wherein the controller is configured to process the amplified ion detection signal to identify a plurality of feasible ion detection signals corresponding to a plurality of different discriminator thresholds. The controller may also be configured to calculate the intensities of the feasible ion detection signals at a plurality of different discriminator thresholds, and process those ion intensities to determine whether the bias voltage needs to be adjusted. In some such embodiments, an adjustable DC voltage source communicating with the controller may be configured to supply the bias voltage to the ion detector. As an example, the controller may be configured to provide one or more control signals to the adjustable voltage source when the bias voltage needs to be adjusted so that the voltage source adjusts the bias voltage. In some such embodiments, the controller may communicate with a database to access the correction bias voltage and may be configured to provide the correction bias voltage to the adjustable voltage source via those (one or more) control signals.

[0024] In a related aspect, a mass spectrometer is disclosed, the mass spectrometer including an ion source and a mass analyzer positioned downstream of the ion source, the ion source for receiving an analyte and ionizing the analyte to generate at least one analyte ion, the mass analyzer for detecting any of the analyte ions and / or its fragments to generate one or more ion detection signals. The mass spectrometer also includes an adjustable DC voltage source for generating a bias voltage, the bias voltage being applied to the ion detector. The mass spectrometer may also include at least one circuit system for amplifying the ion detection signals, or otherwise processing those signals, and comparing each amplified ion detection signal with a discriminator threshold to generate a plurality of feasible ion detection signals. A controller communicating with the circuit system may receive the feasible ion detection signals, and compare the signals obtained at different discriminator thresholds to determine whether the bias voltage needs to be adjusted. In some embodiments, the controller may also communicate with the DC adjustable voltage source, so that when the bias voltage needs to be adjusted, one or more control signals for such adjustment are sent to the DC voltage source so that the bias voltage applied to the ion detector is within an acceptable tolerance range of the optimal value. In some embodiments, the circuitry for amplifying the ion detection signal may be integrated with the ion detector electronic circuitry, while in other embodiments the circuitry may be implemented separately from the electronic circuitry of the ion detector.

[0025] A further understanding of the various aspects of the present teachings may be obtained by reference to the following detailed description in conjunction with the associated drawings, the drawings of which are briefly described below. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 shows the variation in the intensity of the ion mass signal associated with the poly(propylene glycol) ion at m / z=906.673 as the bias voltage applied to the ion detector used to collect the mass signal increases,

[0027] Figure 2A and Figure 2B An example of an amplified signal from a capacitively coupled detection system is shown, respectively, where a graphically represented threshold level is set on the positive portion of an ion impact event, where ion events above this limit are considered viable and will be counted, and an example peak height distribution corresponding to detector pulses collected at a number of different bias voltages and at a peak detection threshold (i.e., discriminator threshold) of 15 mV,

[0028] Figure 3A A graph depicting an example of average pulse height above threshold as a function of increasing bias voltage is shown.

[0029] Figure 3B and Figure 3C Shows the corresponding Figure 3A The corresponding pulse height distribution and pulse height cumulative distribution of the data presented in,

[0030] Figure 3D shows an example of the frequency of a pulse height voltage associated with an ion detection signal generated by an ion detector for several bias voltages applied to the ion detector, the several bias voltages including an optimum bias of 1600 V and bias voltages of 1400 V and 1800 V that are 200 V lower and higher than the optimum bias voltage, respectively,

[0031] Figure 4A is a flow chart depicting various steps in a method for checking a bias voltage applied to an ion detector of a mass spectrometry system according to an embodiment of the present teachings,

[0032] Figure 4B is a flow chart depicting various steps in a method for monitoring a bias voltage applied to an ion detector of a mass spectrometry system according to an embodiment of the present teachings,

[0033] Figure 4C An example of an optimum bias voltage set at about 1500 volts is shown, where the dashed lines U and L indicate upper and lower error margins of about 50 volts,

[0034] Figure 5A is a flow chart depicting various steps in an implementation of a method according to an embodiment of the present teachings, wherein a plurality of ion signal intensities at different discriminator thresholds are acquired sequentially,

[0035] Figure 5B An example of a system for checking a bias voltage applied to an ion detector of a mass spectrometer according to an embodiment is depicted,

[0036] Figure 5C Describes the Figure 5B A partial schematic diagram of the discriminator circuit used in the system is shown in,

[0037] Figure 5D is a flow chart depicting various steps in an embodiment of a method according to the present teachings, wherein, for example, multiple ion signal intensity measurements at different discriminator thresholds are obtained at multiple residence times,

[0038] Fig. 6A is a flow chart depicting various steps in a method according to the present teachings, wherein an ion detection signal generated by an ion detector is digitized, and the digital signal is processed according to the present teachings to determine whether a bias voltage applied to the ion detector needs to be adjusted,

[0039] Figure 6B is a flow chart depicting various steps of an example of an implementation of a system for monitoring and optionally adjusting a bias voltage applied to an ion detector according to an embodiment of the present teachings,

[0040] Figure 6C is a flow chart depicting various steps employed in an embodiment for processing a digital signal corresponding to an ion detection event to determine whether a bias voltage applied to an ion detector needs to be adjusted,

[0041] Fig. 7A is a flow chart depicting various steps in a method for checking a bias voltage applied to an ion detector according to an embodiment,

[0042] Figure 7B Schematically depicting that in one embodiment, a controller may be initialized to begin a bias optimization process where at each loop it is determined whether a bias voltage adjustment is required, and if criteria for adjustment are met, a bias voltage change is determined from a lookup table and applied to the ion detector. A counter index is then incremented and the sequence in the loop is repeated until the bias does not require adjustment or until a predetermined number (e.g., 5) of loops have occurred in that iteration based on the counter index.

[0043] Figure 8 is a schematic diagram of a mass spectrometer according to an embodiment of the present teachings, incorporating a system for monitoring and adjusting a bias voltage applied to an ion detector according to the present teachings, and

[0044] Fig. 9are examples of implementations of controllers and / or analysis modules suitable for use in practicing the present teachings. DETAILED DESCRIPTION

[0045] It will be appreciated that, for the sake of clarity, the following discussion will illustrate various aspects of the embodiments of the present disclosure, while omitting certain specific details where it is convenient or appropriate to omit them. For example, the discussion of similar or similar features in alternative embodiments may be somewhat brief. Well-known ideas or concepts may also be discussed in less detail for the sake of brevity. Those of ordinary skill will recognize that some embodiments of the present disclosure may not require certain details of the details to be specifically described in each implementation, and these details are set forth herein only to provide a comprehensive understanding of the embodiments. Similarly, it will be clear that the described embodiments may be easily changed or varied according to common common sense without departing from the scope of the present disclosure. The following detailed description of the embodiments is not to be construed as limiting the scope of the applicant's teachings in any way.

[0046] As used herein, the terms "about" and "substantially" and "substantially equal" refer to changes in numerical quantities and / or complete states or conditions that may occur, for example, through the following situations: through measurement or processing procedures in the real world; through unintentional errors in these procedures; through differences in the manufacture, source or purity of components or reagents; etc. In general, the terms "about" and "substantially" as used herein mean 10% greater or less than the stated value or range of values ​​or complete conditions or states. For example, a concentration value of about 30% or substantially equal to 30% can mean a concentration between 27% and 33%. The term also refers to variations that would be recognized as equivalent by a person skilled in the art, as long as such variations do not cover known values ​​practiced by the prior art.

[0047] As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items and may be abbreviated as " / ".

[0048] The present disclosure generally relates to methods and systems for monitoring / adjusting and / or maintaining a bias voltage applied to an ion detector of a mass spectrometer. As discussed in more detail below, in some embodiments, systems and methods according to the present teachings can be used to set a bias voltage at an optimal value and / or determine whether a bias voltage applied to such an ion detector has varied from its optimal value by more than an acceptable tolerance margin.

[0049] As used herein, the term "actionable ion detection signal" refers to an ion detection signal having an intensity greater than a predefined discriminator threshold, for example, within a predefined time range of the ion detection signal.

[0050] The terms "discriminator threshold" or "discriminator threshold voltage," or simply "threshold voltage" or "threshold" are used interchangeably herein to refer to a reference voltage that is compared to an amplified ion detection signal to determine whether the ion detection signal is a viable ion detection signal.

[0051] Conventionally, the optimum setting of the bias voltage applied to the ion detector is determined by monitoring the intensity of the stable mass signal while ramping the bias voltage in multiple steps. Typically, a dwell time of 1 second per ramp step is required.

[0052] As an illustration, Figure 1 The change in ion mass signal intensity associated with the poly(propylene glycol) ion at m / z=906.673 is shown as a function of the increase in bias voltage applied to the ion detector used to collect the mass signal. The data were obtained using a prototype Sciex triple quadrupole 7500 mass spectrometer. The optimal bias voltage is typically selected based on the rate of increase in ion mass signal intensity. An example of a criterion for selecting an optimal bias voltage considers the optimal bias voltage to be the ion signal intensity at that bias voltage that fails to increase by 30% of the ion mass signal intensity at a bias voltage 100 volts lower than the optimal value (see, Figure 1 Another example of such a criterion defines the optimal bias voltage as the first bias voltage at which the ion signal fails to increase by at least 30% during the ramping of increasing bias voltage.

[0053] As a further illustration, Figure 2A The raw ion detection signal is shown, where the signal with a portion of intensity exceeding the depicted threshold is considered a viable signal. In this example, the ion detection signal exhibits a derivative shape due to the capacitively coupled signal acquisition technique. Therefore, the threshold can be applied Figure 2A Both the positive and negative parts of the original signal are depicted in . Figure 2B The peak height distribution corresponding to the detector pulses extracted from such raw data is shown, which are collected at multiple different bias voltages and a peak detection threshold (i.e., discriminator threshold) of 15mV. The optimal bias voltage is determined to be 1600V based on the conventional method of ramping the bias voltage as described above.

[0054] In general, the pulse height of the voltage pulse generated by the ion detector in response to detecting one or more incident ions is the primary parameter used for bias voltage optimization. For example, in some cases, the process of bias voltage optimization can be viewed as adjusting the gain of the ion detector so that nearly 90% of the pulses in the distribution have a height above the discriminator threshold. Increasing the bias voltage shifts the peak height distribution to a higher average height and further changes the overall pulse height distribution. As an illustration, Figure 3A Shown is a graph depicting an example of average pulse height above the discriminator threshold as a function of increasing bias voltage, obtained for the poly(propylene glycol) ion at m / z = 906.673 using a prototype Sciex triple quadrupole 7500 mass spectrometer. Figure 3B and Figure 3C The corresponding pulse height distribution and pulse height cumulative distribution are shown.A clear distinction can be observed between the pulse height distributions around the optimum bias voltage of 1600V.

[0055] To examine the cumulative distribution of pulse heights at a given bias voltage, the ion detection signal can be measured using two or more discriminator thresholds. Figure 3D As schematically shown in , this approach can be viewed as moving a vertical line (see, lines A, B, and C) on the pulse height axis of the distribution to a new value and allowing only those pulses whose heights are to the right of the vertical line to contribute to the observed cumulative intensity. The present teachings are based, at least in part, on the recognition that the ratio of ion detection signals measured at different discriminator threshold voltages is related to the shape of the pulse height distribution and can therefore be used as a criterion for determining whether the bias voltage is optimized.

[0056] Generally, in many embodiments, the discriminator threshold for evaluating the bias voltage applied to the ion detector is selected in a region where the pulse height distribution exhibits the greatest sensitivity to bias voltage variations. As an example, the discriminator threshold may be in the range of about 50 mV to about 200 mV, although other ranges may be employed based on the characteristics of the instrument under examination.

[0057] As discussed in more detail below, in some embodiments, for a given bias voltage, if the decrease in ion detection signal intensity at a higher discriminator threshold relative to a lower discriminator threshold is greater than a predetermined value (i.e., if the ratio of the signal intensity at the higher discriminator threshold relative to the lower discriminator threshold is less than a reference value), then the bias voltage is less than an optimal value, and if the decrease is less than the predetermined value, then the bias voltage is greater than the optimal value.

[0058] Reference Figure 4A, an embodiment of a method for checking a bias voltage applied to an ion detector according to the present teachings includes collecting a first viable ion signal associated with an analyte ion at a first discriminator threshold and collecting a second viable ion signal associated with the analyte ion at a second discriminator threshold. The intensities of the two viable ion signals can then be used to determine whether the applied bias voltage needs to be adjusted. For example, the ratio of the two intensities can be compared to a reference value to determine whether the bias voltage deviates from an optimal value. For example, if the ratio of the two ion intensities is greater than or less than the reference value by more than a predefined error margin, the method can notify a user of a recommendation to adjust the bias voltage. In some embodiments, instead of or in addition to notifying the user, the method can include a step of automatically adjusting the bias voltage when the bias voltage needs to be adjusted so that the bias voltage is within an acceptable error margin of a predefined optimal bias voltage.

[0059] Reference Figure 4B In some embodiments, the ion signal intensities at two or more discriminator thresholds are measured for (1) an optimal reference bias voltage, (2) at a bias voltage that is a certain voltage value (e.g., 100 volts) greater than the optimal bias voltage, and (3) at a bias voltage that is a certain voltage value (e.g., 100 volts) less than the optimal bias voltage. Such a reference ion signal intensity ratio can then be used to process the measured ion signal intensity ratio corresponding to the two or more discriminator thresholds to determine the deviation (if any) from the optimal bias voltage. For example, the difference between the reference bias voltage and the optimal value can be fit to a function (e.g., a linear function) to obtain a calibration curve, which can be used to relate the measured ion intensity ratio to the deviation of the bias voltage from the optimal bias voltage. If the deviation of the bias voltage from the optimal bias voltage is determined to be outside an acceptable tolerance range, the bias voltage can be corrected (e.g., by adding or subtracting an appropriate delta voltage) to bring the bias voltage within an acceptable tolerance range.

[0060] As further illustration, consider the following case, where at the optimal bias voltage, the ionic intensities at the discriminator thresholds of 15mV and 60mV are 1e6 cps and 7e5 cps, respectively, resulting in an ionic intensity ratio of 0.7. In addition, at a bias voltage 100 volts less than the optimal value, ionic intensities corresponding to 15mV and 60mV can be measured as 9e5 cps and 3.7e5cps, and at a bias voltage 100 volts greater than the optimal value, ionic intensities corresponding to 15mV and 60mV can be measured as 1.1e6 cps and 9.24e5 cps. Such reference values ​​can then be used to monitor and adjust the bias voltage accordingly. For example, a measured intensity ratio of 0.8 would indicate (e.g., by using a linear interpolation between the reference intensity ratios corresponding to the optimal bias voltage and the bias voltage 100 volts above the optimal value) that the bias voltage is about 70 volts above the optimal value.

[0061] As an example, Figure 4C A reference optimum bias voltage is shown set at about 1500 volts. Dashed lines U and L indicate upper and lower error margins relative to the optimum bias voltage of about 50 volts. In such an implementation, correction of the bias voltage is initiated when the ratio of the ion intensities measured at different discriminator thresholds corresponding to two viable ion signals indicates that the bias voltage deviates from the optimum bias voltage by more than 50 volts.

[0062] Without being limited to any particular theory, as described above, the change in the ratio of ion signal intensities at different discriminator thresholds is traced back to a cumulative peak height distribution that is a function of the deviation of the detector bias voltage from the optimal value. The rate of change of ion intensity as the discriminator threshold increases or decreases can be used to determine whether the detector bias voltage is above or below the desired optimal bias voltage. The detector bias voltage can then be increased or decreased accordingly.

[0063] In some embodiments of the above method, in response to determining that the bias voltage has changed from an optimal value by more than an acceptable amount, a notification is issued to inform the user that it is recommended to adjust the bias voltage. Such a notification may be a visual signal and / or an audible signal.

[0064] In some embodiments, more than two feasible ion signal intensities associated with the analyte ion are collected, wherein each ion signal intensity is collected at a different discriminator threshold voltage. The feasible ion intensities are used to determine whether the bias voltage differs from the optimal bias voltage by more than an acceptable amount. As an example, in some embodiments, the ion signal intensities are multiplied to generate a composite ion intensity, which is then compared to a reference value.

[0065] The acquisition of ion signal intensities at different discriminator thresholds can be performed sequentially or substantially simultaneously. In some cases, the method for checking the bias voltage applied to the ion detector according to the present teachings can be performed in real time, i.e., during an experimental run, such as in the time period between elutions of different analytes from an LC column.

[0066] Figure 5A 1 is a flow chart depicting various steps in an implementation of a method according to an embodiment of the present teachings, wherein a plurality of ion signal intensities at different discriminator thresholds are sequentially acquired. In this embodiment, the method includes initiating monitoring of a bias voltage applied to an ion detector. A plurality of possible ion intensity measurements may be performed at a plurality of different discriminator thresholds (in the example, the index 'i' is used to denote the number of such measurements at the discriminator threshold voltage a). i More specifically, an ion detection signal (e.g., which may be in the form of a voltage pulse) generated by an ion detector to which a bias voltage is applied may be amplified (e.g., via a preamplifier) ​​to generate an amplified voltage pulse. The amplified voltage pulse may be input to a discriminator having a threshold value (a i mV) in a discriminator (e.g., an operational amplifier) ​​to collect the viable ion signal intensity (I i ).

[0067] As an illustration, Figure 5B and Figure 5C An example of a system 500 according to an embodiment is depicted for checking, adjusting and / or maintaining a bias voltage applied to an ion detector of a mass spectrometer by sequentially measuring a plurality of viable ion signal intensities corresponding to a plurality of different discriminator thresholds and analyzing the measured viable ion signal intensities in accordance with the present teachings.

[0068] The system 500 includes an ion detector 502 that generates ion detection signals in response to detecting ions incident thereon, and a signal processing circuit system 504 that receives the ion detection signals generated by the ion detector and processes those signals to generate a plurality of viable ion detection signals. For example, in this implementation, the signal processing circuit system 504 may include an amplifier 606 that is capable of amplifying the ion detection signals generated by the ion detector, etc. In other embodiments, the amplifier may be integrated with the ion detector rather than being part of a separate signal processing circuit system.

[0069] In this implementation, the discriminator 508 ( Figure 5C) can receive the amplified signal and compare the amplified signal to a discriminator threshold voltage to determine whether the amplified signal corresponds to a viable signal, for example, whether the amplified ion signal is greater than the discriminator threshold voltage by a predefined margin.

[0070] Specific reference Figure 5B , a DC voltage source 509 operating under the control of a controller 510 can apply an adjustable bias voltage to the ion detector. The controller 510 can be programmed to apply two or more discriminator threshold voltages sequentially to the comparator (see, Figure 5C ) to initiate and perform a check of the bias voltages to generate ion signals corresponding to those discriminator thresholds, which can be processed by the signal processing circuit system.

[0071] The controller 510 may also receive processed signals (e.g., amplified voltage pulses) from the signal processing circuit system, and may be programmed to analyze viable ion detection signals acquired at different discriminator thresholds to determine whether the bias voltage applied to the detector needs to be adjusted in accordance with the present teachings. The controller may also be configured to provide one or more control signals to the adjustable DC voltage source 509 when the bias voltage needs to be adjusted so that the DC voltage source adjusts the DC bias voltage applied to the ion detector. In some embodiments, the controller may access a lookup table (loaded on the controller itself or stored in a separate database) that provides correction voltages by which the bias voltage should be changed for various ratios of signal intensities obtained at different discriminator thresholds.

[0072] Figure 5D is a flow chart depicting various steps in an embodiment of a method according to the present teachings, wherein, for example, multiple ion signal intensity measurements at different discriminator thresholds are obtained at multiple residence times. As an illustration, the discriminator thresholds are shown as a1, ..., a n , and the measured ion signal intensity values ​​are shown as I1, ..., I n (ion counts per second).

[0073] In this embodiment, the ratio of two ion intensity measurements (e.g., b1) or the mathematical average of multiple ion intensity ratios relative to a corresponding reference (b i / b iRef The mathematical mean of the ion intensity ratios) or a subset of ion intensity ratios (i.e., b1, b2, b n-1 A subset of (a) may be employed in Condition 1 and Condition 1a, where scaling parameters c and d are used to establish a tolerance for deviations from a target value to determine whether the bias voltage needs to be adjusted. Scaling parameters c and d may be selected, for example, based on a specific application. As an example, for a deviation from a reference (target value) b iRefFor a deviation of + / - 10%, the scaling parameters c and d may be 0.9 and 1.1 respectively.

[0074] As further illustration, in another embodiment, a bias voltage ramp may be applied by increasing the bias voltage in a plurality of discrete steps to generate a plurality of discrete bias voltages (e.g., between 800 volts and 2000 volts), and the ratio of the ion detection intensity (b) relative to the corresponding ion detection intensity at each discrete bias voltage may be measured. i ) to generate multiple reference intensity ratios b 1f , b 2f ,……,b n-1f , the corresponding ion detection intensity is collected for the optimal bias voltage and for one or more bias voltages higher than the optimal bias voltage and one or more bias voltages lower than the optimal bias voltage.

[0075] A single reference value can be established as B f =w1*b 1f *w2*b 2f *...w n-1 *b n-1f , where w i are pre-established weighting factors that control the impact of each region of the peak height distribution on the optimization. As an example, these w i The values ​​may all be set to 1. In another example, the signal reference value may be obtained using: f =w1*b 1f *w2*b 2f *...w n-1 *b n-1f , where w i =1 / b if , which leads to B f =1.

[0076] A lookup table is created during the ramping at each bias voltage value, such as Table 1 below:

[0077] Table 1

[0078] (Bias - Optimal Bias) … -150 -100 -50 0 50 100 150 … Reference value … <![CDATA[B -150 ]]> <![CDATA[B -100 ]]> <![CDATA[B -50 ]]> <![CDATA[B f ]]> <![CDATA[B 50 ]]> <![CDATA[B 100 ]]> <![CDATA[B 150 ]]> …

[0079] During the bias monitoring and adjustment phase, the bias voltage corresponding to the ratio of the ion detection intensity (here denoted as B 未知 ) is calculated as B 未知 =w1*b1*w2*b2*...w n-1 *b n-1 , and compare with the values ​​in the table to determine the amount of bias voltage change.

[0080] In some embodiments, the ion detection signal generated by the ion detector can be digitized, and the digitized signal can be processed in the manner discussed below to determine whether the bias voltage applied to the ion detector needs to be adjusted. Fig. 6A Flowchart of, in such an embodiment, the ion detection signal generated by the ion detector can be amplified, and the amplified signal can be digitized to generate a digital ion signal. The digital ion signal can then be processed relative to each of a plurality of discriminator thresholds to generate a plurality of ion signal intensities, each ion signal intensity corresponding to one of those discriminator thresholds. The ion signal intensity can then be used to determine whether the bias voltage needs to be adjusted, i.e., whether the bias voltage deviates from the optimal value by more than an acceptable amount. For example, the calculated ion intensities can be multiplied to generate a composite ion signal intensity, and the composite ion signal intensity can be compared with a reference to determine whether the bias voltage needs to be adjusted.

[0081] Figure 6B A system 600 for implementing the above digital method of checking the bias voltage applied to an ion detector according to an embodiment is shown. The system 600 includes an ion detector 602, which can generate an ion detection signal in response to ions incident thereon, and a signal amplification circuit system 604, which receives the ion detection signal generated by the ion detector and amplifies the received ion detection signal to generate an amplified ion detection signal. As described above, in some embodiments, the amplifier can be integrated with the ion detector circuit system, while in other embodiments, the amplification circuit system can be implemented as a separate unit outside the vacuum chamber where the ion detector is located.

[0082] Analog-to-digital converter (ADC) 612 receives the amplified ion detection signal and digitizes the amplified signal to generate a digital ion detection signal. Analysis module 611 receives the digital signal and processes the digital signal according to the present teachings to determine whether the bias voltage needs to be adjusted. For example, analysis module 611 can be configured to identify the digitized ion detection voltage pulse as a viable ion detection signal when a predefined number of digitized voltage values ​​associated with the digitized ion detection voltage pulse exceeds a discriminator threshold.

[0083] As a further illustration, Figure 6C An example of processing a digitized signal generated by digitizing an ion detection signal generated by an ion detector according to an embodiment of the present teaching is shown. The digitized signal undergoes preprocessing steps, such as data smoothing, and comparing the processed digital signal to a specified discriminator threshold (a) during a dwell time. i) to identify voltage pulse events that exceed the discriminator threshold (also referred to herein as viable detection signals or viable voltage pulses). The number of viable voltage pulses is counted during the entire dwell time to calculate the intensity (I) associated with that discriminator threshold. i ). Furthermore, the calculated ion signal intensity is stored and the discriminator threshold is advanced to the next value, and the process is repeated until measurements associated with a predefined number of different discriminator thresholds have been performed.

[0084] The ion signal intensities acquired at different discriminator thresholds are then processed in the manner discussed herein (e.g., via analysis of ratios of ion signal intensities) to determine whether the bias voltage applied to the ion detector is within an acceptable tolerance range for the optimal setting for the bias voltage.

[0085] For example, the ion signal intensity can be compared to a reference to determine whether the bias voltage needs to be adjusted. For example, as described above, in some embodiments, the ion signal intensities obtained at different discriminator thresholds can be multiplied to generate a composite ion signal intensity, and the composite ion signal intensity can be compared to a reference to determine whether the bias voltage needs to be adjusted.

[0086] In some embodiments, the acquisition of multiple ion signal intensities, each at a different discriminator threshold, can be performed substantially simultaneously. As an illustration, Fig. 7A An example of an implementation of such an embodiment is schematically depicted. An ion detection signal (e.g., a signal in the form of a voltage pulse) may be amplified, and the amplified signal may be distributed among a plurality of parallel measurement channels, wherein each channel is configured to compare the received amplified signal with respect to a different discriminator threshold (referred to herein as a1, ..., a2, ..., a3, ..., a4, ..., a5, ..., a6, ..., a7, ..., a9, ..., a1, ..., a2, ..., a1, ..., a2, ..., a3, ..., a1, ..., a1, ..., a2 ... n mV) to generate a plurality of feasible ion signal intensities (referred to herein as I1, ..., I n ), each feasible ion signal intensity corresponds to a different discriminator threshold.

[0087] Similar to the previous implementation, the ion signal intensity I i Can be used to determine whether the bias voltage needs to be adjusted. For example, the ion signal intensities can be multiplied to generate a composite ion signal intensity, and the composite ion signal intensity can be compared with a reference value to determine whether the bias voltage needs to be adjusted, such as whether the deviation of the bias voltage from the optimal value is large enough to make correction of the bias voltage necessary.

[0088] like Figure 7BAs schematically shown in , upon determining that the measured bias voltage deviates from the optimal bias voltage by more than an acceptable amount, a controller can be initialized to determine a correction voltage required to adjust the bias voltage, which has been determined to deviate from the optimal value. A counter tracks the measurement by increasing the index i after each measurement at the discriminator threshold is completed. Once the counter reaches a predefined maximum number, the measurement cycle is terminated.

[0089] Ion signal intensity I i Can be used to determine whether the bias voltage needs to be adjusted. For example, the ion signal intensities can be multiplied to generate a composite ion signal intensity, and the composite ion signal intensity can be compared with a reference value to determine whether the bias voltage needs to be adjusted, such as whether the deviation of the bias voltage from the optimal value is large enough to make correction of the bias voltage necessary.

[0090] In some embodiments, methods and systems according to the present teachings can be used in real time during mass analysis of a compound to dynamically adjust the bias voltage applied to an ion detector. For example, each ion detection signal generated by the ion detector can be compared to two or more discriminator thresholds, and the ratio can be analyzed in real time to determine whether an unacceptable bias voltage drift has occurred. When such a bias voltage drift is detected, a correction voltage can be applied to the bias voltage based on the present teachings to bring the bias voltage within an acceptable range of an optimal value.

[0091] In another embodiment, the bias voltage applied to the ion detector can be periodically monitored during mass analysis of the compound to determine whether the bias voltage has drifted from its optimal setting by more than a tolerance value. In some embodiments, such periodic monitoring of the bias voltage can be performed based on a predefined schedule.

[0092] In some embodiments, instead of monitoring and adjusting the bias voltage during a sample run, the acquired ion signal intensities may be analyzed in post-processing of the acquired data to correct for deviations, if any, in the bias voltage during mass data acquisition.

[0093] As another example, in some embodiments, a bias voltage ramp can be applied (e.g., between 800 volts and 2000 volts), and intensity values ​​at a default measurement discriminator threshold can be collected at each voltage step of the ramp for establishing an intensity scaling factor value.

[0094] If the intensity value at the default measurement discriminator threshold a1 is I1, the intensity value at the optimal bias voltage (i.e., I 1f ) divided by the intensity value I at each step of the voltage ramp 1(ΔV)to obtain the scaling factor, where ΔV is the difference between the bias voltage at a particular step and the optimal bias voltage.

[0095] A lookup table including both reference values ​​and intensity scaling factors may be created during such voltage ramping at each bias voltage value, such as Table 2 below:

[0096] Table 2

[0097] (Bias - Optimal Bias) … -150 -100 -50 0 50 100 150 … Reference value … <![CDATA[B -150 ]]> <![CDATA[B -100 ]]> <![CDATA[B -50 ]]> <![CDATA[B f ]]> <![CDATA[B 50 ]]> <![CDATA[B 100 ]]> <![CDATA[B 150 ]]> … Intensity scaling factor … <![CDATA[I 1f / I 1(-150) ]]> <![CDATA[I 1f / I 1(-100) ]]> <![CDATA[I 1f / I 1(-50) ]]> <![CDATA[I 1f / I 1f ]]> <![CDATA[I 1f / I 1(50) ]]> <![CDATA[I 1f / I 1(100) ]]> <![CDATA[I 1f / I 1(150) ]]> …

[0098] During the post-processing phase where intensity measurements at different thresholds are performed simultaneously, the unknown ion intensity parameter (e.g. the ratio of two ion detection intensities) (B 未知 ) is compared with the values ​​in the table to determine the deviation of the bias voltage from the optimal bias voltage (bias voltage change amount). An intensity correction (e.g., in the form of a scaling factor) can then be determined and applied to the measured ion intensity by multiplying the intensity scaling factor for the established bias voltage change amount by the measured intensity value. 校正的 =I 在ΔV处测量的 *(Intensity scaling factor at ΔV)

[0099] Methods and systems according to the present teachings provide significant advantages over conventional ways of monitoring and adjusting the bias voltage applied to an ion detector. As an example, in some embodiments, methods according to the present teachings can be used to automatically optimize the bias voltage applied to an ion detector of a mass spectrometer without user intervention. In addition, the practice of the present teachings does not require the injection of specific analytes for optimizing the bias voltage. In addition, in many cases, methods according to the present teachings can be essentially immune to ion beam instabilities. In addition, as discussed above, methods according to the present teachings can be used to warn the user of a mass spectrometer when the bias voltage drifts away from an optimal value by more than an acceptable amount. In some embodiments, methods according to the present teachings can be used to correct the bias voltage at a specified point during a sample run. In addition, in some embodiments, methods according to the present teachings can be used to correct measured ion intensity values ​​in real time or in a post-processing step by calculating a scaling factor based on the measured deviation of the bias voltage relative to the optimal value.

[0100] Another advantage of the method according to the present teachings is that the method can be performed faster than conventional techniques for optimizing bias voltages. For example, in many implementations, the method for optimizing bias voltages according to the present teachings can be performed in less than a few seconds.

[0101] The methods and systems according to the present teachings can be incorporated into a variety of different mass spectrometers. As an example, Figure 8Such a tandem mass spectrometer 800 is schematically depicted, which includes an ion source 802 for generating multiple ions via ionization of one or more analytes in the sample to be analyzed. Various ion sources can be adopted in the practice of this teaching. Some examples of suitable ion sources can include, but are not limited to: electrospray ionization equipment, nebulizer-assisted electrospray equipment, chemical ionization equipment, nebulizer-assisted atomization equipment, chemical ionization equipment, matrix-assisted laser desorption / ionization (MALDI) ion source, photoionization equipment, laser ionization equipment, thermal spray ionization equipment, inductively coupled plasma (ICP) ion source, sonic spray ionization equipment, glow discharge ionization source and electron impact ion source, etc.

[0102] The generated ions can be received by an ion guide that forms an ion beam that is subsequently received by a mass filter 806 that can be configured to select precursor ions with a desired m / z ratio. The mass spectrometer 800 also includes a collision chamber 808 that receives precursor ions and causes the precursor ions to fragment to generate a plurality of product ions. The product ions can be received by a downstream mass analyzer 810 that can help generate a mass spectrum of the product ions. More specifically, ions passing through the mass analyzer 810 are incident on an ion detector 812 that generates an ion detection signal in response to detecting the incident ions. The ion detection signal generated by the ion detector can be processed in a manner known in the art and as taught by the present teachings to generate a mass spectrum of the product ions.

[0103] The mass spectrometer shown includes a system 815 for monitoring and / or adjusting a bias voltage applied to an ion detector via an adjustable DC voltage source 818 in accordance with an embodiment of the present teachings. Specifically, a signal processing circuit system 814 can receive ion detection signals generated by the ion detector and can process those signals (e.g., the signal processing circuit system can amplify the signals) to generate processed signals, which in turn can be received via a controller 816. The controller 816 can operate on the received signal in accordance with the present teachings to determine whether the bias voltage needs to be adjusted. In addition, the controller 816 can be configured to apply (one or more) control signals to the adjustable DC voltage source in response to determining that the bias voltage needs to be adjusted so that the bias voltage is within an acceptable range of an optimal bias voltage value.

[0104] Systems according to the present teachings may be implemented in hardware, software, and / or firmware using techniques known in the art as taught by the present teachings. As an example, Fig. 9An example of an implementation of such a controller 900 is schematically depicted, which includes a processor 900a (e.g., a microprocessor), at least one permanent memory module 900b (e.g., a ROM), at least one transient memory module (e.g., a RAM) 900c, and a bus 900d, etc., as are generally known in the art.

[0105] The bus 900d allows communication between the processor and various other components of the controller. In this example, the controller 900 may also include a communication module 900e configured to allow sending and receiving signals.

[0106] Instructions for use by the controller 900 (e.g., for determining whether the bias voltage needs to be adjusted and for applying appropriate control signals to the adjustable DC voltage source) can be stored in the permanent memory module 900b and can be transferred to the transient memory module 900c during runtime of execution. The controller 900 can also be configured to control the operation of other components of the mass spectrometer (such as an ion guide and a mass analyzer, etc.). As an example, an analysis module, such as the above analysis module 611, can also be implemented in a similar manner.

[0107] Although some aspects have been described in the context of systems and / or devices, it is clear that these aspects also represent the description of corresponding methods, where blocks or devices correspond to method steps or features of method steps. Similarly, the aspects described in the context of method steps also represent the description of corresponding blocks or items or features of corresponding devices. Some or all of the method steps in the method steps can be performed by (or using) hardware devices, such as processors, microprocessors, programmable computers or electronic circuits. In some embodiments, one or more of the most important method steps can be performed by such devices.

[0108] Depending on certain implementation requirements, embodiments of the present invention may be implemented in hardware and / or in software. The implementation may be performed using a non-transitory storage medium, such as a digital storage medium, for example a floppy disk, DVD, Blu-ray, CD, ROM, PROM, EPROM, EEPROM or FLASH memory, on which is stored an electrically readable control signal that cooperates (or is capable of cooperating) with a programmable computer system in order to perform the corresponding method. Thus, the digital storage medium may be computer readable.

[0109] Those of ordinary skill in the art will appreciate that various changes may be made to the above-described embodiments without departing from the scope of the present teachings.

Claims

1. A method for checking a bias voltage applied to an ion detector of a mass spectrometer, comprising: acquiring, using the ion detector, at least two viable ion detection signals corresponding to at least two different discriminator thresholds, and The at least two viable ion detection signals are used to determine whether a bias voltage applied to the ion detector needs to be adjusted.

2. The method according to claim 1, wherein: The step of using the at least two viable ion detection signals to determine whether the bias voltage needs to be adjusted includes comparing a ratio of the intensities of the at least two viable ion detection signals to a reference value to determine whether the ratio is within a predefined tolerance range about the reference value.

3. The method according to claim 2, wherein: When the ratio is outside the predefined tolerance range, the bias voltage needs to be adjusted.

4. The method according to any one of claims 2 to 3, wherein: The tolerance range has a value in the range of about 5% to about 50% of the reference value.

5. According to the method described in any one of the above claims, the method also includes adjusting the bias voltage by increasing or decreasing the bias voltage to generate an adjusted bias voltage when the bias voltage needs to be adjusted, and applying the adjusted bias voltage to the ion detector, and the method also optionally includes obtaining the correction voltage from a lookup table, the lookup table containing multiple correction voltages corresponding to multiple ratios of the intensities of the at least two feasible ion detection signals.

6. The method according to any one of the above claims further includes performing steps (1)-(2) using the adjusted bias voltage as the bias voltage applied to the ion detector to determine whether additional adjustment of the adjusted bias voltage is required.

7. A method according to any one of the preceding claims, wherein: The ion detector comprises any one of a channel electron multiplier, a discrete dynode multiplier, a microchannel plate detector, and a hybrid ion detector, and wherein the mass spectrometer comprises any one of a time-of-flight mass analyzer, a quadrupole mass analyzer, or a combination thereof.

8. The method of any of the preceding claims, further comprising generating a notification when the bias voltage needs to be adjusted, and wherein, Optionally, the notification comprises any of a visual notification, an auditory notification or a combination thereof.

9. A method according to any one of the preceding claims, wherein: The step of acquiring at least two viable ion detection signals using the ion detector is initiated at one or more times during mass spectrometry analysis of at least one compound, and wherein, optionally, the one or more times are defined by a user.

10. The method according to any one of claims 1 to 8, wherein: The step of acquiring at least two viable ion detection signals using the ion detector is initiated after a predefined cumulative number of ions are detected by the ion detector or after a predefined time has passed after the ion detector is triggered to start detecting ions.

11. A method according to any one of the preceding claims, wherein: The step of acquiring any one of the at least two viable ion detection signals comprises: amplifying an ion detection signal generated by the ion detector in response to detecting ions incident thereon, and The amplified signal is compared relative to a discriminator threshold and the ion signal is identified as a viable ion signal when at least a predefined portion of the ion signal exceeds the discriminator threshold.

12. The method according to any one of claims 1 to 11, wherein: The step of acquiring any one of the at least two viable ion detection signals comprises: amplifying an ion detection signal generated by the ion detector in response to detecting ions incident thereon to generate an amplified signal, digitizing the amplified signal to generate a digital ion detection signal, When the digital ion detection signal meets a predefined criterion, characterizing the digital ion detection signal as a feasible ion detection signal, and For each discriminator threshold of the plurality of discriminator thresholds, viable ion detection signals obtained at the discriminator threshold are counted to calculate an ion intensity associated with the discriminator threshold.

13. The method according to claim 12, wherein: The predefined criteria require that the digital ion detection signal exhibit an amplitude above a corresponding discriminator threshold for at least a predefined portion of the digital ion detection signal in order to be identified as a viable ion detection signal, and wherein, optionally, the predefined portion of the digital ion detection signal is collected during a time period in the range of about 0.1 nanoseconds to about 10 nanoseconds.

14. A method according to any one of the preceding claims, wherein: The at least one compound includes a plurality of compounds introduced into the mass spectrometer in a batch processing mode.

15. A system for monitoring a bias voltage applied to an ion detector of a mass spectrometer, comprising: signal processing circuitry configured to receive an ion detection signal generated by the ion detector in response to detecting ions incident thereon, and to amplify the ion detection signal to generate a plurality of amplified ion detection signals, and a controller in communication with the signal processing circuitry, the controller for receiving the amplified signal, the controller being configured to process the amplified ion detection signal to identify a plurality of viable ion detection signals corresponding to a plurality of different discriminator thresholds, The controller is further configured to calculate intensities of the viable ion detection signals at the plurality of different discriminator thresholds, and process the ion intensities to determine whether the bias voltage needs to be adjusted.

16. The system of claim 15, further comprising an adjustable DC voltage source in communication with the controller and configured to supply the bias voltage to the ion detector.

17. The system of claim 16, wherein: The controller is configured to provide a control signal to the adjustable voltage source when the bias voltage needs to be adjusted so that the voltage source adjusts the bias voltage, and wherein, optionally, the controller communicates with a database to access a correction bias voltage, and the controller is configured to provide the correction bias voltage to the adjustable voltage source via the control signal.

18. A system for monitoring a bias voltage applied to an ion detector of a mass spectrometer, comprising: a signal processing circuit system configured to receive an ion detection signal generated by the ion detector in response to detecting ions incident thereon, and to amplify the ion detection signal to generate a plurality of amplified ion detection signals, an analog-to-digital converter ADC configured to receive the amplified ion detection signal and digitize the received signal to generate a plurality of digital ion detection signals, and An analysis module in communication with the ADC, the analysis module being configured to receive the digital ion detection signal and process the digital ion detection signal to determine whether the bias voltage needs to be adjusted.

19. The system of claim 18, wherein: The analysis module is configured to compare the digital ion detection signal to a plurality of different discriminator thresholds to generate a plurality of viable ion detection signals.

20. The system of claim 19, wherein: The analysis module is also configured to calculate an intensity of the viable ion detection signal and process the intensity relative to a reference to determine whether the bias voltage needs to be adjusted.

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