Method for evaluating characteristics of a mass spectrometry instrument comprising at least one mass spectrometry cell

Abstract

A method is proposed for characterization of a mass spectrometry instrument (100) comprising at least one mass spectrometry cell (102, 104, 106), comprising the steps of analyzing a sample (110) containing at least one substance having a known molecular weight by the mass spectrometry instrument (100) to obtain a mass spectrum (116, 118, 144, 146) of the sample (110), determining an outer envelope and an inner envelope of the mass spectrum (116, 118, 144, 146), calculating the squared difference between the outer envelope and the inner envelope, and determining the deviation of the calculated squared difference from a theoretical mass-to-charge ratio value of the substance.

Description

Technical Field

[0001] Technical Field The present disclosure relates to a method for evaluating the characteristics of a mass spectrometry instrument comprising at least one mass spectrometry cell.

Background Art

[0002] Background Art There is an increasing interest in performing mass spectrometry. Mass spectrometry (MS) is an analytical technique used to measure the mass-to-charge ratio of ions. The results are presented as a mass spectrum, i.e., a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is used in a number of different fields and is applied to both pure samples and complex mixtures.

[0003] A mass spectrum is a plot of ion signals as a function of the mass-to-charge ratio. These spectra are used to determine the characteristics of the elements or isotopes of a sample, as well as the masses of particles and molecules, and to reveal the chemical identity or structure of molecules and other compounds.

[0004]

[0005] In a typical MS procedure, a sample, which may be a solid, liquid, or gas, is ionized, for example, by colliding it with an electron beam. This can break up some of the molecules of the sample into positively charged fragments, or simply charge them positively without fragmenting them. These ions (fragments) are then separated according to their mass-to-charge ratio, for example, by accelerating them and applying an electric or magnetic field to them: ions with the same mass-to-charge ratio undergo the same amount of deflection. The ions are detected by a mechanism capable of detecting charged particles, such as an electron multiplier tube. The results are displayed as a spectrum of the signal intensity of the detected ions as a function of the mass-to-charge ratio. Atoms or molecules in the sample can be identified by correlating them with a known mass, for example, the mass of the whole molecule that has been identified, or by a characteristic fragmentation pattern.A mass spectrometry instrument comprising at least one mass spectrometry cell has a number of different electronic potentials for guiding, filtering, and at least detecting ions. The parameters of the system should harmonize the behavior of the same ions in different systems. Mass calibration parameters correlate the weight of the ions and their resolution with the applied voltage. Due to changes in environmental conditions and system contamination over time, mass calibration can be subject to various fluctuations, shifts, and trends, which can negatively affect selectivity and sensitivity and, in the worst case, also affect patient results. Summary of the Invention Problems to be Solved by the Invention

[0006] Problems to be Solved Therefore, it is desirable to provide an automatic classification of the state of a mass spectrometry instrument, such as normal and abnormal. Means for Solving the Problems

[0007] Overview This problem is addressed by a method, a computer program, and a computer-readable storage medium for evaluating the characteristics of a mass spectrometry instrument comprising at least one mass spectrometry cell having the features of the independent claims. Advantageous embodiments, which may be implemented alone or in any combination, are set forth in the dependent claims as well as throughout the specification.

[0008] When used hereinafter, the terms "having", "comprising", or "including", or any grammatical variants thereof, are used in a non-exclusive manner. Thus, these terms can refer to both situations where there are no additional features in the entity being described in this context, in addition to the features introduced by these terms, and situations where one or more additional features are present. By way of example, the expressions "A has B", "A comprises B", and "A includes B" can refer to both situations where there are no other elements in A besides B (i.e., situations where A is exclusively composed of only B), and situations where there are one or more additional elements in entity A, such as element C, elements C and D, or yet further elements besides B.

[0009] Furthermore, note that the terms "at least one" or "one or more", or similar expressions, indicating that a feature or element may be present one or more times, are typically used only once when introducing each respective feature or element. Hereinafter, in most cases, when referring to each respective feature or element, the expressions "at least one" or "one or more" are not repeated, despite the fact that each respective feature or element may be present one or more times.

[0010] Furthermore, when used hereinafter, terms such as "preferably", "more preferably", "in particular", "even more particularly", "specifically", "more specifically", or similar terms are used with optional features without limiting the possibility of alternatives. Accordingly, the features introduced by these terms are optional features and are not intended to limit the technical scope of the claims in any way. The present invention may be practiced, as will be understood by those skilled in the art, by using alternative features. Similarly, features introduced by "in an embodiment of the present invention" or similar expressions are optional features without any limitation regarding alternative embodiments of the present invention, without any limitation regarding the technical scope of the present invention, and without any limitation regarding the possibility of combining such introduced features with other optional or non-optional features of the present invention.

[0011] Furthermore, it should be noted that when used herein, terms such as "first", "second", "third", "fourth" or similar expressions merely serve to distinguish features or structural members. It is expressly stated that these terms are not intended to define a particular order of importance or relevance.

[0012] In a first aspect, a method for evaluating the characteristics of a mass spectrometry instrument comprising at least one mass spectrometry cell is proposed.

[0013] As used herein, the term "mass spectrometry instrument" is a broad term and should be given its ordinary and common meaning to one of ordinary skill in the art and should not be limited to a special or particular meaning. Specifically, without limitation, this term may refer to a mass spectrometer used for mass spectrometry. Mass spectrometry (MS) is an analytical technique used to measure the mass-to-charge ratio of ions. The results are presented as a mass spectrum, i.e., a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is used in a number of different fields and is applicable to pure samples and complex mixtures. A mass spectrum is a plot of the ion signal as a function of the mass-to-charge ratio. These spectra are used to determine the characteristics of the elements or isotopes of a sample, as well as the masses of particles and molecules, and to reveal the chemical identity or structure of molecules and other compounds. In a typical MS procedure, a sample, which may be a solid, liquid, or gas, is ionized, for example, by colliding it with an electron beam. This can break a portion of the sample's molecules into positively charged fragments or simply charge them positively without fragmenting them. These ions (fragments) are then separated according to their mass-to-charge ratio, for example, by accelerating them and applying an electric or magnetic field to them: ions with the same mass-to-charge ratio will experience the same amount of deflection. The ions are detected by a mechanism capable of detecting charged particles, such as an electron multiplier tube. The results are displayed as a spectrum of the signal intensity of the detected ions as a function of the mass-to-charge ratio. Atoms or molecules in the sample can be identified by correlating their known mass (e.g., the whole molecule) with an identified mass or by a characteristic fragmentation pattern.

[0014] As used herein, the term "analysis cell" is a broad term and should be given its ordinary and customary meaning to one of ordinary skill in the art and should not be limited to a special or particular meaning. Specifically, without limitation, this term may refer to the part involved in mass resolution in a mass spectrometer. Thus, the analysis cell can decompose the mass of a sample or prepare or facilitate mass resolution.

[0015] As used herein, the term "characteristic evaluation" is a broad term and should be given its ordinary and customary meaning to one of ordinary skill in the art and should not be limited to a special or particular meaning. Specifically, without limitation, this term can refer to the determination or detection of the state of a mass spectrometry instrument. In a simple application, the determination or detection can clarify a normal state or an abnormal state.

[0016] The method includes the following method steps, which may be performed in a given order, in particular. However, other orders are possible. Further, it is possible to perform two or more method steps completely or partially simultaneously. Further, one or more, or all, of the method steps may be performed repeatedly, for example, repeated one or more times, or may be performed only once. Further, the method may include additional method steps not recited.

[0017] The method is the following steps, namely - Analyzing a sample containing at least one substance having a known molecular weight by a mass spectrometry instrument to provide a mass spectrum of the sample; - Determining an outer envelope and an inner envelope of the mass spectrum; - Calculating the squared difference between the outer envelope and the inner envelope; - Determining the deviation from the theoretical mass-to-charge ratio value of the substance for the calculated squared difference and includes.

[0018] As used herein, the term "analysis" and its equivalents are broad terms and should be given their ordinary and common meaning to one of ordinary skill in the art and should not be limited to a special or particular meaning. This term, without specifically limiting, may refer to an analytical technique for determining the mass-to-charge ratio of ions.

[0019] As used herein, the term "sample" refers to a biological material suspected of containing one or more analytes of interest and whose qualitative and / or quantitative detection can be correlated with a clinical condition. Samples can be derived from any biological source, such as physiological fluids including blood, saliva, aqueous humor of the eye, cerebrospinal fluid, sweat, urine, milk, ascites, mucus, synovial fluid, peritoneal fluid, amniotic fluid, tissue, cells, etc. Samples can be pretreated prior to use, such as the preparation of plasma from blood, dilution of viscous fluids, lysis, etc., and the methods of treatment can include filtration, centrifugation, distillation, concentration, inactivation of interfering components, and addition of reagents. Samples can in some cases be used directly as obtained from the source, or, for example, after pretreatment and / or a sample preparation workflow to change the nature of the sample, such as after adding an internal standard, diluting with another solution, or mixing with a reagent, to enable the performance of one or more in vitro diagnostic tests, enrich (extract / separate / concentrate) the analyte of interest, and / or remove matrix components that may interfere with the detection of the analyte of interest. While the term "sample" is often used to denote the sample prior to sample preparation, the term "prepared sample" is used to refer to the sample after sample preparation. In non-specific cases, the term "sample" may broadly denote either, or both, the sample prior to sample preparation or the sample after sample preparation. Examples of analytes of interest are generally vitamin D, addictive drugs, therapeutic drugs, hormones, and metabolites. However, this listing is not exhaustive.

[0020] As used herein, the term "envelope" is a broad term and should be given its ordinary and common meaning to one of ordinary skill in the art and should not be limited to a special or particular meaning. Specifically, but not by way of limitation, this term may refer to a curve that touches each member of a group of curves at some point, and these points of contact together form the entire envelope. Classically, a point on the envelope can be thought of as the intersection of two "nearly adjacent" curves, meaning the limit of the intersection of adjacent curves. This concept can be generalized to the envelope of a surface in space and can also be generalized to higher dimensions. In order to have an envelope, the individual members of the group of curves must be differentiable curves (otherwise the concept of contact does not apply), and there must be a smooth transition passing through the members. However, these conditions are not sufficient, and it is possible that a given group may not be able to have an envelope. A simple example of this is given by a group of concentric circles with increasing radii. Depending on whether the curve is located above or below the group of curves, the curve is called an upper envelope or a lower envelope.

[0021] For example, by closely monitoring the state during the startup process, automatic classification of the system state (normal / abnormal) is possible using the "noise limit". Identification of abnormal states can prevent incorrect patient outcomes. Additionally, proper insulation of the electrical circuit or checking the quality of the electrical components used is possible. Using the correct labeling of the state (e.g., position shift, resolution, and envelope), the correct maintenance actions can be triggered, thus reducing the system downtime and maintenance costs. From the manufacturer's perspective, this method is useful for selecting the correct quadrupole rods and can be helpful in the assembly process.

[0022] The squared difference between the outer envelope and the inner envelope can be calculated as (f o -f i ) 2 and f ois the outer envelope, f i is the inner envelope. According to this specific calculation of the squared difference, the difference between the outer envelope and the inner envelope is weighted more than the formation of a simple difference. Thus, the imbalance that may exist between both sides of the peak can be better explained or illustrated. Furthermore, this calculation facilitates a better distinction between the mass spectrum of the ions and the noise in the surrounding area of the ions.

[0023] The method may further include determining a deviation of the calculated difference along the mass-to-charge ratio axis of the mass spectrum. Thus, not only a single point of the signal is observed, but also a range along the mass-to-charge ratio axis of the mass spectrum is observed, and thus a more accurate monitoring of the state of the mass spectrometry device is possible.

[0024] The method may further include determining the deviation of the calculated difference based on positions to the left and to the right of the theoretical mass value of the substance along the mass-to-charge ratio axis of the mass spectrum. Thereby, the left and right sides of the peak of the theoretical mass value of the substance in the mass spectrum are observed. Thereby, possible asymmetric signals (which give a hint of an inappropriate state of the mass spectrometry device) can be observed.

[0025] Determining the deviation may include determining the ratio of the peak at the position to the left of the theoretical mass value of the substance along the mass-to-charge ratio axis of the mass spectrum to the peak at the position to the right. Thereby, the left and right sides of the peak of the theoretical mass value of the substance in the mass spectrum are observed. If the peak is symmetric, the ratio of the signal heights at the left and right positions should be approximately 1. In the case of an asymmetric signal peak, the ratio of the signal heights at the left and right positions is significantly different from 1 and can be 2 or 3 or even larger.

[0026] The method may further include determining that the state of the mass spectrometry device is inappropriate if the deviation determined for the calculated difference exceeds a predetermined threshold value. Thus, a clear determination regarding the state of the mass spectrometry device can be made.

[0027] This method may further include performing a wavelet transform on a mass spectrum and determining a deviation from a theoretical amplitude value of a substance at a predetermined period with respect to the amplitude of the mass spectrum after the wavelet transform. This enables a rather microscopic observation of the mass spectrum and the state of the mass spectrometer.

[0028] As used herein, the term "wavelet transform" and its equivalents are broad terms and should be given their general and ordinary meaning to those skilled in the art and should not be limited to a special or particular meaning. Specifically, but not limited thereto, this term may refer to the representation of a square-integrable (real-valued or complex-valued) function by a specific orthonormal series generated by wavelets. This paper provides a formal mathematical definition of orthonormal wavelets and integral wavelet transforms. A wavelet is a wavy oscillation that starts with an amplitude of 0, increases, and then decreases back to 0. This can typically be visualized as a "short-time oscillation" such as the vibration recorded by a seismometer or a heart monitor. Generally, wavelets are intentionally created to have specific properties that make them useful for signal processing. The basic idea of wavelet transform is that the transform should only allow changes in time dilation, not in shape. This is affected by selecting an appropriate basis function that enables this. Changes in time dilation are expected to follow the corresponding analysis frequency of the basis function. Based on the uncertainty principle of signal processing, performing a wavelet transform on a mass spectrum and determining a deviation from a theoretical amplitude value of a substance at a predetermined period with respect to the amplitude of the mass spectrum after the wavelet transform may be performed when the determined deviation of the calculated difference does not exceed a predetermined threshold value. Therefore, when a rather macroscopic observation of the envelope is less noticeable, a more detailed or microscopic observation of the mass spectrum can be performed, and it becomes possible to detect even a smaller deviation from the target state of the mass spectrometer.

[0029] The method may further include determining that the state of the mass spectrometry instrument is inappropriate when the deviation determined for the amplitude exceeds a predetermined amplitude threshold. Thus, a clear determination regarding the state of the mass spectrometry instrument can be made.

[0030] In a second aspect, a method for evaluating the characteristics of a mass spectrometry instrument comprising at least one mass spectrometry cell is proposed.

[0031] The method includes the following method steps, which may be performed, in particular, in a given order. However, other orders are possible. Furthermore, it is possible to perform two or more method steps completely or partially simultaneously. Furthermore, one or more, or all, of the method steps may be performed only once or may be repeatedly performed, for example, repeated one or more times. Furthermore, the method may include additional method steps not listed.

[0032] The method includes the following steps, namely - Analyzing a sample containing at least one substance having a known molecular weight by a mass spectrometry instrument to provide a mass spectrum of the sample; - Performing a wavelet transform of the mass spectrum; - Determining, for the amplitude of the mass spectrum after wavelet transform, the deviation from the theoretical amplitude value of the substance in a predetermined period and includes.

[0033] It is clearly stated here that the method of the second aspect may be combined with the method of the first aspect. In particular, the method of the second aspect may be performed, for example, after the method of the first aspect when, in the method of the first aspect, it is not necessary to determine the deviation from the theoretical mass-to-charge ratio value of the substance for the calculated squared difference. Thus, the method of the second aspect enables a more detailed observation of the state of the mass spectrometer.

[0034] The method may further include generating a heat map of the mass spectrum after wavelet transform and determining the deviation of the amplitude at a predetermined period in the heat map. Such a heat map enables observation of highly affected regions of the mass spectrum after wavelet transform.

[0035] As used herein, the term "heat map" is a broad term and should be given its general and ordinary meaning to one of ordinary skill in the art and should not be limited to a special or particular meaning. Specifically, without limitation, this term may refer to a data visualization technique that shows the magnitude of a phenomenon as color in two dimensions. The change in color may be due to hue or intensity and gives the reader a clear visual cue as to how the phenomenon is clustered or varies in space. There are two fundamentally different categories of heat maps, namely cluster heat maps and spatial heat maps. In a cluster heat map, the magnitudes are laid out in a matrix of fixed cell sizes, where the rows and columns of the matrix are discrete phenomena and categories, and the sorting of the rows and columns is intentional and somewhat arbitrary for the purpose of suggesting clusters or depicting clusters as discovered by statistical analysis. The cell size is arbitrary but large enough to be clearly visible. In contrast, the position of the magnitude in a spatial heat map is forced by the position of the magnitude in that space, there is no concept of a cell, and the phenomenon is considered to vary continuously.

[0036] When using a wavelet, the heat map is also known as a scalogram. In a scalogram, the result of the wavelet transform is visualized as a three-dimensional graph. The first spatial dimension is the defined range of the signal, which is the mass-to-charge ratio m / z on the x-axis used herein. The second spatial dimension is the frequency or period of the signal on the y-axis. The third spatial dimension represents the amplitude, i.e., the wavelet power, of a specific period associated with a specific position within the defined range, i.e., m / z. The latter is represented in a colored manner rather than a spatial manner, specifically, gray for lower amplitudes and white for higher amplitudes.

[0037] As used herein, the term "period" is a broad term and should be given its ordinary and common meaning to one of ordinary skill in the art and should not be limited to a special or particular meaning. Specifically, without limitation, this term can refer to a periodic signal portion located within the frequency range and defined range of the signal. Thus, it can indicate potential variations in frequency within the frequency range and clearly associate prominent frequencies with specific portions of the defined range.

[0038] The method may further include determining the deviation of the amplitude at a predetermined period according to the wavelet power.

[0039] As used herein, the term "wavelet power" is a broad term and should be given its ordinary and common meaning to one of ordinary skill in the art and should not be limited to a special or particular meaning. Specifically, without limitation, this term can refer to the amplitude of a specific period associated with a specific position within the defined range of the mass spectrum after wavelet transform. Thus, the amount of a specific periodic signal portion may be visualized when compared to all other periodic signal portions. Thus, a relative description is possible that enables derivation of the amount of a specific frequency within the signal.

[0040] The method may further include determining that the state of the mass spectrometry device is inappropriate when the deviation determined for the amplitude exceeds a predetermined amplitude threshold. Accordingly, a clear determination regarding the state of the mass spectrometry device can be made.

[0041] The mass analysis cell may be a quadrupole. Accordingly, the mass spectrometry device may be a so-called quadrupole mass spectrometer. Accordingly, the sample can be analyzed with high resolution.

[0042] As used herein, the term "quadrupole mass analyzer" is a broad term and should be given its ordinary and customary meaning to one of ordinary skill in the art and should not be limited to a special or particular meaning. Specifically, without limitation, this term may refer to a type of mass analyzer used in mass spectrometry. A quadrupole mass spectrometer (QMS) is also known as a transmission quadrupole mass spectrometer, a quadrupole mass filter, or a quadrupole mass. As the name suggests, this consists of four cylindrical rods set parallel to each other. In a quadrupole mass spectrometer, the quadrupole is a mass analyzer and is a component of the instrument that serves to select sample ions based on their mass-to-charge ratio (m / z). Ions are separated in the quadrupole based on the stability of their trajectories in an oscillating electric field applied to the rods. The quadrupole consists of four parallel metal rods. Each pair of opposing rods is electrically connected to each other, and a radio frequency (RF) voltage with a DC offset voltage is applied between one pair of rods and the other pair of rods. Ions flow down through the quadrupole between the rods. At a given voltage ratio, only ions of a specific mass-to-charge ratio reach the detector, and the trajectories of other ions become unstable and they collide with the rods. This enables the selection of ions having a specific m / z or enables the operator to scan a range of m / z values by continuously varying the applied voltage. Mathematically, this can be modeled with the aid of the Mathieu differential equation. Ideally, the rods are hyperbolic, but cylindrical rods having a specific ratio of rod diameter to spacing provide an adequate approximation that is easier to manufacture than hyperbolic rods. Small variations in the ratio have a large impact on the resolution and peak shape. Different manufacturers select slightly different ratios to fine-tune the operating characteristics in the context of the expected application requirements.

[0043] The mass spectrometry instrument may comprise two or more mass spectrometry cells, and the method may be performed for each mass spectrometry cell.

[0044] For example, the mass spectrometry instrument may be a so-called triple quadrupole mass spectrometer (TQMS). As used herein, the term "triple quadrupole mass spectrometer" is a broad term and should be given its general and ordinary meaning to those skilled in the art and should not be limited to a special or particular meaning. Specifically, without limitation, this term may refer to a tandem mass spectrometer consisting of two serial quadrupole mass analyzers with a (non-mass resolving) high-frequency (RF) only quadrupole that functions as a cell for collision-induced dissociation between them. This configuration is often abbreviated as QqQ and herein as Q1q2Q3. Essentially, the triple quadrupole mass spectrometer operates on the same principle as a single quadrupole mass analyzer. Each of the two mass filters (Q1 and Q3) includes four parallel cylindrical metal rods. While both Q1 and Q3 are controlled by a direct current (dc) and a radio frequency (rf) potential, the collision cell q receives only the RF potential. The RF potential associated with the collision cell (q) allows the passage of all selected ions. In some instruments, the normal quadrupole collision cell has been replaced by a hexapole or octapole collision cell to improve efficiency.

[0045] Unlike traditional MS techniques, MS / MS techniques allow mass spectrometry to be performed continuously in different regions of the instrument. Since ionization, primary mass selection, collision-induced dissociation (CID), mass analysis of the fragments generated in CID, and detection occur in separate segments of the instrument, TQMS follows an in-space tandem arrangement. Sector instruments tend to outperform TQMS in mass resolution and mass range. However, triple quadrupoles have the advantages of being less expensive, easier to operate, and extremely efficient. Also, when operating in the selected reaction monitoring mode, TQMS has excellent detection sensitivity and quantification. Triple quadrupoles enable the study of low-energy low-molecular-weight reactions, which is useful when small molecules are being analyzed.

[0046] This method may be executed at a predetermined time point. In particular, those time points may include at least the startup time of the mass spectrometry instrument. Therefore, the state can be checked at regular intervals or the like.

[0047] This method may further include executing this method as a predictive maintenance strategy. Therefore, any defective component of the mass spectrometry instrument can be replaced before the entire mass spectrometry instrument becomes defective.

[0048] This method may be computer-implemented. As used herein, the term "computer-implemented" is a broad term and should be given its general and ordinary meaning to those skilled in the art and should not be limited to a special or particular meaning. Specifically, without limitation, this term may refer to a process that is fully or partially implemented by using data processing means, such as data processing means comprising at least one processing unit of a focus electronics and a control system. Therefore, the term "computer" can generally refer to a device having at least one data processing means, such as at least one processing unit, or a combination of devices or a network. The computer may further comprise one or more additional components, such as at least one of a data storage device, an electronic interface, or a human-machine interface.

[0049] In a further aspect, a computer program comprising instructions is proposed, the instructions causing a mass spectrometry instrument comprising at least one mass spectrometry cell to execute the method according to any one of the preceding claims when the program is executed by the mass spectrometry instrument.

[0050] In a further aspect, a computer-readable storage medium comprising instructions is proposed, the instructions causing a mass spectrometry instrument comprising at least one mass spectrometry cell to execute the method according to any one of the preceding claims when the program is executed by the mass spectrometry instrument.

[0051] As used herein, the term "moving average" is a broad term and should be given its ordinary and common meaning to one of ordinary skill in the art and should not be limited to a special or particular meaning. Specifically, without limitation, this term can refer to a calculation for analyzing data points by creating a series of averages of different subsets of an entire data set. Also known as a moving mean (MM) or rolling average, it is a type of finite impulse response filter. Variations include simple form, cumulative form, or weighted form. Given a series of numbers and a fixed subset size, the first element of the moving average is obtained by taking the average of the first fixed subset of the series of numbers. The subset is then changed by a "forward shift", i.e., by excluding the first number in the series of numbers and including the next number in the subset. Moving averages are commonly used in time series data to smooth out short-term fluctuations and emphasize long-term trends or cycles. The threshold between short-term and long-term depends on the application, and the parameters of the moving average are set accordingly. For example, it is often used in the technical analysis of financial data such as stock prices, returns, or trading volumes. It is also used in economics to examine gross domestic product, employment, or other macroeconomic time series. Mathematically, since the moving average is a type of convolution, it can be considered an example of a low-pass filter used in signal processing. When used in non-time series data, the moving average removes high-frequency components regardless of time, but typically some kind of ordering is implied. Simply put, it can be considered data smoothing.

[0052] A computer program comprising computer-executable instructions for performing the method according to the present invention in one or more of the embodiments included herein when the program is executed on a computer or computer network is further disclosed and proposed herein. Specifically, the computer program may be stored on a computer-readable data carrier and / or a computer-readable storage medium.

[0053] As used herein, the terms "computer-readable data carrier" and "computer-readable storage medium" may specifically refer to non-transitory data storage means such as a hardware storage medium storing computer-executable instructions. The computer-readable data carrier or storage medium may specifically be a storage medium such as random access memory (RAM) and / or read-only memory (ROM), or may comprise such a storage medium.

[0054] Thus, specifically, one, two or more, or all of the method steps a) to d) as described above may be performed using a computer or computer network, preferably using a computer program.

[0055] A computer program product is further disclosed and proposed herein, and the computer program product has program code means for performing the method according to the present invention in one or more of the embodiments included herein when the program is executed on a computer or computer network. Specifically, the program code means may be stored on a computer-readable data carrier and / or a computer-readable storage medium.

[0056] A data carrier storing a data structure capable of executing a method according to one or more of the embodiments disclosed herein after being loaded into a computer or computer network, such as the working memory or main memory of a computer or computer network, is further disclosed and proposed herein.

[0057] A computer program product storing program code means on a machine-readable carrier is further disclosed and proposed herein for executing a method according to one or more of the embodiments disclosed herein when the program is executed on a computer or computer network. As used herein, a computer program product refers to a program as a tradable product. The product can generally exist in any format, such as a paper format, or on a computer-readable data carrier and / or a computer-readable storage medium. Specifically, the computer program product may be distributed on a data network.

[0058] Finally, a modulated data signal containing instructions readable by a computer system or computer network for executing a method according to one or more of the embodiments disclosed herein is disclosed and proposed herein.

[0059] Regarding the computer-implemented aspects of the present invention, one or more or all of the method steps of the method according to one or more of the embodiments disclosed herein may be executed by using a computer or computer network. Thus, generally, any method step may be included, typically excluding method steps that require manual work, such as specific ways of providing samples and / or performing actual measurements.

[0060] Specifically, in this specification, - a computer or computer network comprising at least one processor, the processor being configured to execute a method according to one of the embodiments described herein, - a computer loadable data structure configured to execute a method according to one of the embodiments described herein when executed on a computer, - a computer program configured to execute a method according to one of the embodiments described herein when executed on a computer, - a computer program comprising program means for executing a method according to one of the embodiments described herein when executed on a computer or computer network, - a computer program comprising program means according to a previous embodiment, the program means being a computer program stored on a computer-readable storage medium, - a storage medium storing a data structure, the data structure being configured to execute a method according to one of the embodiments described herein after being loaded into the main memory and / or working memory of a computer or computer network, and - a computer program product having program code means storable or stored on a storage medium, wherein when the program code means is executed on a computer or computer network, a method according to one of the embodiments described herein is executed is further disclosed.

[0061] In summary, without excluding the possibility of further embodiments, the following embodiments may be envisaged.

[0062] Embodiment 1: A method for evaluating the characteristics of a mass spectrometry instrument comprising at least one mass spectrometry cell, - analyzing a sample containing at least one substance having a known molecular weight by a mass spectrometry instrument to provide a mass spectrum of the sample, - Determining the outer envelope and the inner envelope of the mass spectrum, and - Calculating the squared difference between the outer envelope and the inner envelope, and - Determining, for the calculated squared difference, the deviation from the theoretical mass-to-charge ratio value of the substance A method comprising.

[0063] Embodiment 2: The squared difference between the outer envelope and the inner envelope is calculated as (f o - f i ) 2 , where f o is the outer envelope and f i is the inner envelope, the method according to the preceding claim.

[0064] Embodiment 3: The method according to any one of the preceding claims, further comprising determining the deviation of the calculated difference along the mass-to-charge ratio axis of the mass spectrum.

[0065] Embodiment 4: The method according to the preceding claim, further comprising determining the deviation of the calculated difference based on the positions on the left and right sides of the theoretical mass value of the substance along the mass-to-charge ratio axis of the mass spectrum.

[0066] Embodiment 5: Determining the deviation comprises determining the ratio of the peak at the position on the left side of the theoretical mass value of the substance along the mass-to-charge ratio axis of the mass spectrum to the peak at the position on the right side, the method according to the preceding claim.

[0067] Embodiment 6: The method according to any one of the preceding claims, further comprising determining that the state of the mass spectrometry instrument is inappropriate when the determined deviation of the calculated difference exceeds a predetermined threshold difference.

[0068] Embodiment 7: The method according to the preceding claim, further comprising performing a wavelet transform on the mass spectrum and determining the deviation of the amplitude of the mass spectrum after the wavelet transform from the theoretical amplitude value of the substance at a predetermined period.

[0069] Embodiment 8: A method according to the preceding claims, wherein wavelet transformation of a mass spectrum is performed, and a deviation from a theoretical amplitude value of a substance in a predetermined period is determined for the amplitude of the mass spectrum after wavelet transformation, which is executed when the determined deviation of the calculated difference does not exceed a predetermined difference threshold value.

[0070] Embodiment 9: A method according to the preceding claims, further comprising determining that the state of the mass spectrometry device is inappropriate when the determined deviation of the amplitude exceeds a predetermined amplitude threshold value.

[0071] Embodiment 10: A method for evaluating the characteristics of a mass spectrometry device comprising at least one mass analysis cell, - analyzing a sample containing at least one substance having a known molecular weight by a mass spectrometry device to provide a mass spectrum of the sample; - performing wavelet transformation of the mass spectrum; - determining a deviation from a theoretical amplitude value of a substance in a predetermined period for the amplitude of the mass spectrum after wavelet transformation and a method comprising.

[0072] Embodiment 11: A method according to the preceding claims, further comprising generating a heat map of the mass spectrum after wavelet transformation and determining a deviation of the amplitude in a predetermined period in the heat map.

[0073] Embodiment 12: A method according to any one of the preceding two claims, further comprising determining a deviation of the amplitude in a predetermined period depending on the wavelet power.

[0074] Embodiment 13: A method according to any one of the preceding claims, further comprising determining that the state of the mass spectrometry device is inappropriate when the determined deviation of the amplitude exceeds a predetermined amplitude threshold value.

[0075] Embodiment 14: The mass spectrometry instrument includes two or more mass spectrometry cells, and the method is the method according to any one of the preceding claims, which is executed for each mass spectrometry cell.

[0076] Embodiment 15: The method according to the preceding claims, wherein the mass spectrometry cell is a quadrupole.

[0077] Embodiment 16: The method according to any one of the preceding claims, which is executed at a predetermined time point.

[0078] Embodiment 17: The method according to the preceding claims, wherein the time point includes at least the start time of the mass spectrometry instrument.

[0079] Embodiment 18: The method according to any one of the preceding claims, further including executing the present method as a predictive maintenance measure.

[0080] Embodiment 19: The method according to any one of the preceding method claims, which is computer-implemented.

[0081] Embodiment 20: A computer program including instructions, which, when the program is executed by a mass spectrometry instrument including at least one mass spectrometry cell, causes the mass spectrometry instrument to execute the method according to any one of the preceding claims regarding the method.

[0082] Embodiment 21: A computer-readable storage medium including instructions, which, when the program is executed by a mass spectrometry instrument including at least one mass spectrometry cell, causes the mass spectrometry instrument to execute the method according to any one of the preceding claims regarding the method.

Brief Description of the Drawings

[0083] Further optional features and embodiments are preferably disclosed in more detail in the following description of the embodiments in conjunction with the dependent claims. Among them, each optional feature may be implemented in an independent manner and in any feasible combination, as can be understood by those skilled in the art. The scope of the present invention is not limited by the preferred embodiments. The embodiments are schematically shown in the figures. Here, the same reference numerals in these figures refer to the same or functionally equivalent elements. In the figures,

[0084]

Figure 1

Figure 2

Figure 3A

Figure 3B

Figure 4A

Figure 4B

Figure 5A

Figure 5B

Figure 6

Figure 7A

Figure 7B

Figure 8A

Figure 8B

Figure 9A

Figure 9B

Figure 10A

Figure 10B

[0085] Detailed description of the embodiments FIG. 1 shows a schematic diagram of a mass spectrometer 100. The mass spectrometer 100 includes at least one mass analysis cell 102. In this exemplary embodiment, the mass spectrometer 100 is a triple quadrupole mass spectrometer including three analysis cells 102, 104, and 106. Thus, each of the analysis cells 102, 104, and 106 is a quadrupole. In particular, the mass spectrometer 100 includes a first analysis cell 102, a second analysis cell 104, and a third analysis cell 106, which are arranged to construct a tandem mass spectrometer consisting of two quadrupole mass filters 102 and 106 in series, and a (non-mass resolving) high-frequency (RF) only quadrupole serving as a cell 104 for collision-induced dissociation is located between them. The mass spectrometer 100 further includes an ionization source 108 such as an electrospray ionization (ESI) source or an atmospheric pressure chemical ionization (APCI) source arranged adjacent to the first analysis cell 102, and a sample 110 may be input to the ionization source 108. The mass spectrometer 100 further includes a particle multiplier 112 arranged adjacent to the third analysis cell 106 and configured to provide an output signal 114. In this configuration, the sample 110 is ionized in the ionization source. The first analysis cell 102 performs mass-to-charge selection (m / z selection) of the sample ions. The second analysis cell 104 cleaves the sample ions. The third analysis cell 106 performs mass-to-charge selection (m / z selection) of the sample ions after cleavage. Since the basic operating principle of such a mass spectrometer is known to those skilled in the art from the prior art as described above, for example, a further description of its operating principle is omitted. Some conventional mass spectrometers have a rather low resolution of 20 points / Da. The determination of the maximum signal intensity (accuracy of mass calibration) and the full width at half maximum of the maximum signal intensity (separation efficiency to adjacent ions) can be performed very easily. However, signal shifts or other changes are not accurate enough to monitor. In the present embodiment, the mass spectrometer 100 has a higher resolution suppressed to 0.0076 Da, enabling a higher accuracy data evaluation of 1000 points / Da.

[0086] FIG. 2 shows a flowchart of a method for the characterization of a mass spectrometry instrument 100 comprising at least one mass spectrometry cell 102 according to a first embodiment of the present disclosure. The method of the present disclosure begins at step S10 of analyzing a sample 110 containing at least one substance having a known molecular weight by a mass spectrometry instrument 100, resulting in a mass spectrum of the sample 110. Subsequently, the method further proceeds to step S12 of determining the outer envelope and the inner envelope of the mass spectrum. Subsequently, the method further proceeds to step S14 of calculating the squared difference between the outer envelope and the inner envelope. Subsequently, the method further proceeds to step S16 of determining, for the calculated squared difference, the deviation from the theoretical mass-to-charge ratio value of the substance. Subsequently, the method further proceeds to step S18 of determining whether the deviation from the theoretical mass-to-charge ratio value of the substance determined for the calculated difference exceeds a predetermined difference threshold. If the determined deviation for the calculated difference exceeds the predetermined difference threshold, the method further proceeds to step S20 of determining that the state of the mass spectrometry instrument is inappropriate. Conversely, if the determined deviation for the calculated difference does not exceed the predetermined difference threshold, the method further proceeds to step S22 of determining that the state of the mass spectrometry instrument is appropriate. The method may be implemented for each of the mass spectrometry cells 102, 104, 106.

[0087] The method and its optional modifications are described in further detail below.

[0088] FIG. 3A shows an exemplary first mass spectrum 116 of test testosterone and its internal standard analyzed by the mass spectrometer 100 of the present embodiment in the first analysis cell 102. FIG. 3B shows an exemplary second mass spectrum 118 of test testosterone and its internal standard analyzed by the mass spectrometer 100 of the present embodiment in the third analysis cell 106. In FIGS. 3A and 3B, the mass-to-charge ratio (m / z ratio) is given as the x-axis 120. The signal intensity (unit: %) is given as the y-axis 122. The graph 124 shows the signal intensity according to the mass-to-charge ratio. As can be seen from FIG. 3A, a relatively unremarkable front shoulder 126 can be observed, and there are multiple maxima 128 in the higher region. Therefore, higher resolution and data evaluation with more data points can bring better calibration efficiency. As can be seen from FIG. 3B, the difference in the quadrupoles can be observed. For example, the upward flank 130 on the left side has more noise than the downward flank 132 on the right side. Therefore, the method according to the present disclosure is based on the discovery that it is possible to evaluate the fingerprint characteristics of the quadrupole based on the behavior of the mass spectrum, such as monitoring system-specific or long-term effects.

[0089] FIG. 4A shows an exemplary first mass spectrum 116 of test testosterone and its internal standard analyzed by the mass spectrometer 100 of the present embodiment in the first analysis cell 102. FIG. 4B shows an exemplary second mass spectrum 118 of test testosterone and its internal standard analyzed by the mass spectrometer 100 of the present embodiment in the third analysis cell 106. Hereinafter, only the differences from FIGS. 3A and 3B will be described, and the same features are indicated by the same reference numerals. As shown in FIGS. 4A and 4B, the method according to the present disclosure further includes the step of determining the outer envelope f o and the inner envelope f i of the mass spectra 116, 118. The y-axis 122 shows the signal intensity of the mass spectra 116, 118, the outer envelope f o , and the inner envelope f i . The outer envelope f o and the inner envelope fi The difference from this results in a left relative spectrum that can further characterize the quadrupole state. Variations in environmental conditions such as humidity, temperature, and pressure, or contamination of the matrix provided by the sample 110, can be visualized by evaluating the characteristics of this “macroscopic” fingerprint. As can be seen from the comparison between FIGS. 4A and 4B, the envelope f of the first mass spectrum 116 of the first analysis cell 102 o and f i is more symmetric than the second mass spectrum 118 of the third analysis cell 106 where the outer envelope f o shows a bulge 134 on the left side.

[0090] The method according to the present disclosure further includes the step of calculating the squared difference between the outer envelope f o and the inner envelope f i . The squared difference between the outer envelope and the inner envelope is calculated as (f o -f i ), where f 2 is the outer envelope and f o is the inner envelope. i is the inner envelope.

[0091] FIG. 5A shows an exemplary diagram of the squared difference calculated in this way according to the mass-to-charge ratio (m / z ratio) of the first analysis cell 102. FIG. 5B shows an exemplary diagram of the squared difference calculated in this way according to the mass-to-charge ratio (m / z ratio) of the third analysis cell 106. Hereinafter, only the differences from FIGS. 3A and 3B will be described, and similar features are denoted by the same reference numerals. In FIGS. 5A and 5B, the mass-to-charge ratio (m / z ratio) is given as the x-axis 120. The calculated squared difference between the outer envelope f o and the inner envelope f i is given as the y-axis 122. The graph 136 shows the squared difference calculated according to the mass-to-charge ratio (m / z ratio) to the left of the theoretical value. The graph 138 shows the squared difference calculated according to the mass-to-charge ratio (m / z ratio) to the right of the theoretical value. As can be seen from the comparison between FIGS. 5A and 5B, the envelopes f o , fi The squared difference between them is much larger for the third analysis cell 106.

[0092] The method according to the present disclosure further includes determining a deviation from the theoretical mass-to-charge ratio value of the substance for the calculated squared difference. The deviation of the calculated difference is determined along the mass-to-charge ratio axis of the mass spectrum. In particular, the deviation of the calculated difference is determined based on positions to the left and right of the theoretical mass value of the substance along the mass-to-charge ratio axis of the mass spectrum. Determining the deviation includes determining the ratio of the peak at the position to the left of the theoretical mass value of the substance along the mass-to-charge ratio axis of the mass spectrum to the peak at the position to the right. The ratio of the peak heights of the calculated squared difference is approximately equal to 1 for both the left and right sides in the case of symmetry, as shown by line 140 in FIG. 5A. In the case of asymmetry, this is not the case, and the difference in height can be determined, as shown by line 142 in FIG. 5B. Thus, for example, as shown by approximately the same peak height in FIG. 5A, when the deviation determined for the calculated difference does not exceed a predetermined difference threshold, it is determined that the state of the mass spectrometry device 100 is appropriate. Conversely, thus, for example, as shown by different peak heights in FIG. 5B, when the deviation determined for the calculated difference exceeds a predetermined difference threshold, it is determined that the state of the mass spectrometry device 100 is inappropriate.

[0093] FIG. 6 shows a flowchart of a method for characterizing a mass spectrometry instrument 100 comprising at least one mass spectrometry cell 102 according to a second embodiment of the present disclosure. It should be clearly stated that the method of the second embodiment may be combined with the method of the first embodiment, for example, when the calculated difference does not exceed a predetermined difference threshold. Needless to say, the method of the second embodiment may be implemented independently of the method of the first embodiment. The method of the present disclosure begins at step S30 of analyzing a sample 110 containing at least one substance having a known molecular weight by a mass spectrometry instrument 100 to provide a mass spectrum of the sample 110. Subsequently, the method further proceeds to step S32 of performing a wavelet transform on the mass spectrum. Subsequently, the method further proceeds to step S34 of determining the deviation of the amplitude of the mass spectrum after wavelet transform from the theoretical amplitude value of the substance at a predetermined period. Subsequently, the method further proceeds to step S36 of determining whether the deviation of the amplitude of the mass spectrum after wavelet transform from the theoretical amplitude value of the substance at a predetermined period exceeds a predetermined amplitude threshold. If the deviation of the amplitude of the mass spectrum after wavelet transform from the theoretical amplitude value of the substance at a predetermined period exceeds the predetermined amplitude threshold, the method further proceeds to step S38 of determining that the mass spectrometry instrument is in an inappropriate state. Conversely, if the deviation of the amplitude of the mass spectrum after wavelet transform from the theoretical amplitude value of the substance at a predetermined period does not exceed the predetermined amplitude threshold, the method further proceeds to step S40 of determining that the mass spectrometry instrument is in an appropriate state. The method may be implemented for each of the mass spectrometry cells 102, 104, 106.

[0094] The method and its optional modifications will be described in more detail below.

[0095] FIG. 7A shows an exemplary third mass spectrum 144 of the first analysis cell 102 for test testosterone analyzed by the mass spectrometer 100 of the present embodiment. FIG. 7B shows an exemplary fourth mass spectrum 146 of the third analysis cell 106 for test testosterone analyzed by the mass spectrometer 100 of the present embodiment. In FIGS. 7A and 7B, the mass-to-charge ratio (m / z ratio) is given as the x-axis 120. The signal intensity and the moving average of the signal intensity are given as the y-axis 122. The graph 148 shown at the top of FIGS. 7A and 7B shows the signal intensity according to the mass-to-charge ratio. The graph 150 shown at the bottom of FIGS. 7A and 7B shows the moving average of the signal intensity according to the mass-to-charge ratio.

[0096] The method of the second embodiment is based, inter alia, on the discovery that an alternative method of characterizing the mass spectrum is to examine the wavelet transform of the signal "microscopically". At the frequency of the noise, it can be predicted that the amplitude of the fourth mass spectrum 146 of the third analysis cell 106 will be larger compared to the third mass spectrum 144 of the first analysis cell 102.

[0097] The method further includes generating a heat map of the mass spectrum after wavelet transform and determining the deviation of the amplitude at a predetermined period in the heat map. In particular, the deviation of the amplitude at a predetermined period is determined according to the wavelet power.

[0098] FIG. 8A shows an exemplary first heat map 152 of the first analysis cell 102 for test testosterone analyzed by the mass spectrometer 100 of the present embodiment. FIG. 8B shows an exemplary second heat map 154 of the third analysis cell 106 for test testosterone analyzed by the mass spectrometer 100 of the present embodiment. In FIGS. 8A and 8B, the mass-to-charge ratio (m / z ratio) is given as the x-axis 120. The period (mz) is given as the left y-axis 156. The wavelet power level is shown as the right y-axis 158, with a high wavelet power level shown in white and a low or even lower wavelet power level shown in gray or black for simplicity. As indicated by the circle 160 in the second heat map 154 of the third analysis cell 106, a region with the largest amplitude at a predetermined period can be observed within the second heat map 154 of the third analysis cell 106.

[0099] FIG. 9A shows an exemplary first wavelet transform diagram 162 of the first analysis cell 102 for test testosterone analyzed by the mass spectrometer 100 of the present embodiment. FIG. 9B shows an exemplary second wavelet transform diagram 164 of the third analysis cell 106 for test testosterone analyzed by the mass spectrometer 100 of the present embodiment. In FIGS. 9A and 9B, the average wavelet power is given as the x-axis 120. The period (mz) is given as the y-axis 122. The graph 166 shown in FIG. 9A shows the third mass spectrum 144 after wavelet transform of the first analysis cell 102. The graph 168 shown in FIG. 9B shows the fourth mass spectrum 146 after wavelet transform of the third analysis cell 106. As shown by the graph 166, there is no significant signal less than one period in the first wavelet transform diagram 162 of the first analysis cell 102. As indicated by the circle 170, at a predetermined period marked in this way, a larger amplitude can be observed only for the third analysis cell 106 by a significant signal of 0.02 cycles / 5 kHz.

[0100] FIG. 10A shows an exemplary first wavelet amplitude diagram 172 of the first analysis cell 102 for test testosterone analyzed by the mass spectrometer 100 of the present embodiment. FIG. 10B shows an exemplary second wavelet amplitude diagram 174 of the third analysis cell 106 for test testosterone analyzed by the mass spectrometer 100 of the present embodiment. In FIGS. 10A and 10B, the mass-to-charge ratio m / z is given as the x-axis 120. The wavelet amplitude is given as the y-axis 122. The graph 176 shown in FIG. 10A shows the wavelet amplitude of the third mass spectrum 144 of the first analysis cell 102 according to the mass-to-charge ratio m / z. The graph 178 shown in FIG. 10B shows the wavelet amplitude of the fourth mass spectrum 146 of the third analysis cell 106 according to the mass-to-charge ratio m / z. As shown by the graph 176, the wavelet amplitude does not show a significant signal at 0.02 cycles / 5 kHz. As shown by the circle 180, there is a large wavelet amplitude at approximately 0.02 cycles / 5 kHz because the signal is highest at the position of the mass spectrum peak.

[0101] Therefore, for example, as indicated by the absence of a peak or amplitude in FIG. 9A, when the deviation determined for the amplitude does not exceed a predetermined amplitude threshold, the state of the mass spectrometer 100 is determined to be appropriate. Conversely, for example, as indicated by the peak or amplitude in FIG. 9B, when the deviation determined for the amplitude exceeds a predetermined amplitude threshold, the state of the mass spectrometer 100 is determined to be inappropriate.

[0102] The method according to each embodiment described herein can use the following exemplary parameters to classify the state of the mass spectrometer 100 as appropriate / normal or inappropriate / abnormal.

[0103] Regarding the resolution in Da, an appropriate state can be defined as 0.8 ± 0.1, and an inappropriate state can be defined as < 0.7 and > 0.9. Regarding the accuracy, i.e., the position of the mass axis (unit: Da), an appropriate state can be defined as the tolerance range regarding the shift of ±0.1, and an inappropriate state can be defined as the shift > 0.1. Regarding the high-precision characteristic evaluation, i.e., multiple systems with machine learning, an appropriate state can be defined as comparable to other systems and without shift over time or environmental changes, and an inappropriate state can be defined as the quadrupole not being comparable to other systems and having shift over time or environmental changes. Regarding the envelope characteristic evaluation, an appropriate state can be defined as the symmetric arrangement of the outer envelope and the inner envelope, and an inappropriate state can be defined as the asymmetric arrangement of the outer envelope and the inner envelope. Regarding the wavelet or Fourier transform, an appropriate state can be defined as the absence of characteristic frequencies, and an inappropriate state can be defined as the interference between the signal and the noise frequency.

[0104] The method according to each embodiment described herein is executed at a predetermined time point. In particular, those time points include at least the startup time of the mass spectrometer 100. For example, the method is executed as a predictive maintenance measure. The method according to each embodiment described herein may be computer-implemented. For example, the method may be automatically executed under the control of a computer or a computer system. Instead of the wavelet transform, a Fourier transform may be executable.

Explanation of Signs

[0105] List of reference numerals 100 Mass spectrometer 102 First analysis cell 104 Second analysis cell 106 Third analysis cell 108 Ionization source 110 Sample 112 Particle multiplier 114 Signal 116 The first mass spectrum of the first analysis cell 118 The second mass spectrum of the third analysis cell 120 x-axis 122 y-axis 124 Signal intensity according to the mass-to-charge ratio 126 Front shoulder 128 Maximum value 130 Left rising flank 132 Right falling flank 134 Bulge 136 Squared difference calculated according to the mass-to-charge ratio on the left from the theoretical value 138 Squared difference calculated according to the mass-to-charge ratio on the right from the theoretical value 140 Ratio of symmetric peak heights 142 Ratio of asymmetric peak heights 144 The third mass spectrum of the first analysis cell 146 The fourth mass spectrum of the third analysis cell 148 Signal intensity according to the mass-to-charge ratio 150 Moving average of signal intensity according to the mass-to-charge ratio 152 Exemplary first heat map of the first analysis cell 154 Exemplary second heat map of the third analysis cell 156 Left y-axis 158 Right y-axis 160 Region of maximum amplitude in a predetermined period 162 First wavelet transform diagram of the first analysis cell 164 Second wavelet transform diagram of the third analysis cell 166 Third mass spectrum after wavelet transform of the first analysis cell 168 Fourth mass spectrum after wavelet transform of the third analysis cell 170 Predetermined period 172 First wavelet amplitude diagram of the first analysis cell 174 Second wavelet amplitude diagram of the third analysis cell The wavelet amplitude of the third mass spectrum of the first analysis cell according to the mass-to-charge ratio m / z of 176 The wavelet amplitude of the fourth mass spectrum of the third analysis cell Large wavelet amplitude S10 Analyze the sample S12 Determine the outer envelope and the inner envelope of the mass spectrum S14 Calculate the squared difference between the outer envelope and the inner envelope S16 Determine the deviation from the theoretical mass-to-charge ratio value of the substance for the calculated squared difference S18 Determine whether the deviation from the theoretical mass-to-charge ratio value of the substance determined for the calculated difference exceeds a predetermined difference threshold S20 Determine that the mass spectrometer is in an inappropriate state S22 Determine that the mass spectrometer is in an appropriate state S30 Analyze a sample containing at least one substance having a known molecular weight S32 Perform wavelet transform of the mass spectrum S34 Determine the deviation from the theoretical amplitude value of the substance at a predetermined period for the amplitude of the mass spectrum after wavelet transform S36 Determine whether the deviation from the theoretical amplitude value of the substance at a predetermined period determined for the amplitude of the mass spectrum after wavelet transform exceeds a predetermined amplitude threshold S38 Determine that the mass spectrometer is in an inappropriate state S40 Determine that the mass spectrometer is in an appropriate state

Claims

1. A method for evaluating the characteristics of a mass spectrometer (100) comprising at least one mass analysis cell (102, 104, 106), comprising: - Analyzing the sample (110) by the mass spectrometer (100) to provide a mass spectrum (116, 118, 144, 146) of the sample (110) containing at least one substance having a known molecular weight; - Determining an outer envelope and an inner envelope of the mass spectrum (116, 118, 144, 146); - Calculating the squared difference between the outer envelope and the inner envelope; - Determining the deviation of the calculated squared difference from the theoretical mass-to-charge ratio value of the substance; A method comprising the steps of:

2. The square difference between the outer envelope and the inner envelope is (f ｏ − f ｉ ), ２ which is calculated as, where f ｏ is the outer envelope and f ｉ is the inner envelope, the method according to claim 1.

3. The method according to claim 1, further comprising the step of determining the deviation of the calculated squared difference along the mass-to-charge ratio axis of the mass spectrum (116, 118, 144, 146).

4. The method according to claim 3, further comprising the step of determining the deviation of the calculated squared difference based on positions on the left and right sides of the theoretical mass-to-charge ratio value of the substance along the mass-to-charge ratio axis of the mass spectrum (116, 118, 144, 146).

5. The method according to claim 4, wherein the step of determining the deviation comprises determining the ratio of the peak at the position on the left side of the theoretical mass-to-charge ratio value of the substance along the mass-to-charge ratio axis of the mass spectrum (116, 118, 144, 146) to the peak at the position on the right side.

6. The method according to claim 1, further comprising the step of determining that the state of the mass spectrometer (100) is inappropriate when the determined deviation of the calculated squared difference exceeds a predetermined threshold difference.

7. The method according to claim 6, further comprising performing a wavelet transform on the mass spectrum (116, 118, 144, 146) and determining the deviation of the amplitude of the mass spectrum (116, 118, 144, 146) after the wavelet transform from the theoretical amplitude value of the substance at a predetermined period.

8. Performing the wavelet transform on the mass spectra (116, 118, 144, 146), and determining the deviation from the theoretical amplitude value of the substance at a predetermined period for the amplitude of the mass spectra (116, 118, 144, 146) after the wavelet transform, the step is executed when the determined deviation for the calculated squared difference does not exceed the predetermined threshold value. The method according to claim 7.

9. The method according to claim 8, further comprising the step of determining that the state of the mass spectrometer (100) is inappropriate when the determined deviation for the amplitude exceeds a predetermined amplitude threshold value.

10. The method according to any one of claims 7 to 9, further comprising the step of determining that the state of the mass spectrometer (100) is inappropriate when the determined deviation for the amplitude exceeds a predetermined amplitude threshold value.

11. The mass spectrometer (100) includes two or more mass analysis cells (102, 104, 106), and the method is executed for each mass analysis cell (102, 104, 106). The method according to any one of claims 1 to 9.

12. The method is executed at a predetermined time point, and the time point includes at least the startup of the mass spectrometer (100). The method according to any one of claims 1 to 9.

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