Computer-implemented method for detecting at least one disturbance and / or at least one artifact in at least one chromatogram

Abstract

The invention proposes a computer-implemented method for detecting at least one interference and / or at least one artifact in at least one chromatogram determined by at least one mass spectrometry device (110). The chromatogram comprises a plurality of raw data points. The method comprises the following steps: a) retrieving the at least one chromatogram by at least one processing device (126); b) applying at least one peak fitting modeling to the chromatogram by using the processing device (126); c) determining information on residuals of the raw data points by using the processing device (126); d) detecting the at least one interference and / or the at least one artifact by using the processing device (126) by comparing the determined information on residuals with at least one predetermined threshold, wherein the at least one interference and / or the at least one artifact is detected in case the determined information on residuals exceeds the predetermined threshold.

Description

Technical Field

[0001] The present invention relates to a computer-implemented method for detecting at least one interference and / or at least one artifact in at least one chromatogram, a processing system, and a mass spectrometry system. Background Technology

[0002] Peak discovery and evaluation in liquid chromatography-mass spectrometry (LC-MS) or mass spectrometry (MS) typically require user interaction or expert user correction, such as for selecting or assigning the correct peak. For years, there has been a need for automation of peak discovery and evaluation, to reduce user interaction and thus enhance the reliability of measurements.

[0003] For LC-MS assays, peak area ratios are commonly used for calculations or validation. They are part of several international guidelines for validating mass spectrometry assays, such as those developed by CLSI (Clinical and Laboratory Standards Institute), EMA (European Medicines Agency), or GTFCh (German Society for Toxicology and Forensic Chemistry). To ensure the quality of the assay, the non-extraction system suitability test of the spiked compound measured prior to the analytical run must meet acceptability requirements, such as the minimum absolute peak area or maximum retention time deviation from the target value. During the analytical run, quality control (QC) samples are subsequently tested at a set frequency, and the calculated results are checked against acceptable ranges. Furthermore, the absolute peak area of ​​retention time, peak width (given by the difference in retention time between peak boundaries), and internal standard (ISTD) is typically monitored in each sample, and should meet acceptability requirements for maximum deviation or a specific cutoff value. If single ion monitoring (SIM) is used, the peak area ratio of different analyte transitions is also typically monitored; in the case of two transitions, the so-called quantification factor / qualification factor ratio or ion ratio is monitored. This quantification factor / qualification factor ratio is often one of the main drivers for validating peak identity and eliminating interference. The principle is as follows: the peak area ratio of different analyte transitions deviates around a fixed value, which is independent of the analyte concentration. Detection artifacts or interferences in a mass transition chromatogram can cause this ratio to change and thus become detectable. However, this value can have some drawbacks, such as (i) the accuracy of the quantitative / qualitative factor ratio may be low for a particular analyte and / or assay. Furthermore, (ii) the ratio of different transitions depends on two mass transitions. Interferences in two mass transition chromatograms, to the same relative degree (as is common in the presence of isomers such as epimers), do not cause a change in the ratio of the corresponding mass transitions but can affect the final result. Therefore, interference may go undetected, and ignoring interference can lead to erroneous patient results. Additionally, (iii) some analyte assays lack a specific second transition, at least in the lower measurement range, so the quantitative / qualitative factor ratio may not be available. In these cases, guidelines typically require a higher level of review, such as by the supervisor or laboratory director. Assessments conducted through such peak reviews can be highly dependent on the operator's experience, and frequent manual peak reviews increase the workload. This may not be a satisfactory option for fully automated methods. Therefore, it is desirable to have procedures to fill the gaps mentioned above regarding interference detection and to avoid frequent manual chromatogram reviews by experts for validation.

[0004] Furthermore, known techniques typically require data from more than one m / z value to detect interference (such as isotopic patterns). This type of data is obtained through full-scan data and is not suitable for single-ion or multiple-reaction monitoring (MRM) techniques.

[0005] In "Increasing Chromatographic Resolution for Analytical Signals Using Derivative Enhancement Approach" (September 2018, Talanta 192, DOI:10.1016 / j.talanta.2018.09.048), M. Farooq Wahab et al. described a peak evaluation technique that utilizes the properties of the derivative while keeping the peak area and position constant. This technique is based on the fact that the area under the derivative of a distribution is equal to zero.

[0006] US 2019 / 0096646 A1 describes a mass spectrometry data processing apparatus comprising a data processing section and a computation section. The computation section calculates the mass difference between all peak data from a peak list, calculates the intensity ratio, which is the ratio of the intensities of two peak data used to calculate the difference, and generates difference-intensity ratio data. Furthermore, the computation section retrieves difference-intensity ratio data containing differences within a certain section, calculates the sum of the intensity ratios of the retrieved difference-intensity ratio data, and calculates difference-intensity ratio distribution data.

[0007] WO 2016 / 125059 A1 describes an intensity measurement for one or more compounds from a mixture. An intensity trace is calculated for a range of measurement dimensions known to contain product ions of a known compound. An intensity value is selected for the intensity trace. For each measurement point across this range, each intensity trace is scaled to have a minimum intensity, and a common component distribution curve is calculated as the profile of the minimum intensity across the scaled intensity traces within this range. A score is calculated for the common component distribution curve. An optimal common component distribution curve is selected, whose score, compared to the scores of other distribution curves, optimally minimizes the distance between the maximum value of the common component distribution curve and each measurement point, maximizes the area of ​​the common component distribution curve, and minimizes the area obtained by subtracting the common component distribution curve from the scaled intensity trace.

[0008] Further methods are described in CN 110320297, CN 105334279, EP 1 827 657 A2, WO 2013 / 104004A1, CN 102507814 A, US 7,904,253 B2, EP 1 879 684 A2, US 7,202,473B2, CN1292251, Meija, J., Caruso, JA “Deconvolution of isobaric interferences in mass spectro.” J Am Soc Mass Spectrom 15, 654–658 (2004). https: / / doi.org / 10.1016 / j.jasms.2003.12.016 and https: / / www.genedata.com / products / expressionist / metabolomics / .

[0009] US 2019 / 295830 A1 describes a computer-implemented method for compressing mass spectrometry data, the method comprising decomposing mass spectrometry data of a mass stream emitted from a separation device as a function of separation parameters into multiple mass traces, wherein the mass spectrometry data is generated by mass spectrometer analysis; identifying erroneous mass traces among the multiple mass traces by applying an event detection algorithm to each of the multiple mass traces; and forming a compressed version of the mass spectrometry data based on the mass traces and the mass spectrometry data corresponding to the identified erroneous mass traces.

[0010] US 2011 / 246092 A1 describes a method for automatically identifying and characterizing spectral peaks of a spectrum generated by an analysis device and reporting information related to the spectral peaks to a user. The method includes the steps of: receiving a spectrum generated by the analysis device; automatically subtracting a baseline from the spectrum to generate a baseline-corrected spectrum; automatically detecting and characterizing spectral peaks in the baseline-corrected spectrum; and reporting at least one piece of information related to each detected and characterized spectral peak to a user.

[0011] Problems to be solved

[0012] Therefore, the object of the present invention is to provide methods and apparatus for detecting at least one interference and / or at least one artifact in at least one chromatogram, which avoid the disadvantages of the aforementioned known methods and apparatus. In particular, methods and apparatus for eliminating interference and artifacts are needed where common parameters such as the quantitative factor / qualitative factor ratio lack reliability. These methods and apparatus should further automate the quality assurance process of the determination and reduce manual peak review by experts. Summary of the Invention

[0013] This problem is solved by a computer-implemented method, a processing system, and a mass spectrometry system having the features of the independent claims, the method for detecting at least one interference and / or at least one artifact in at least one chromatogram determined by at least one mass spectrometry device. Advantageous embodiments that can be implemented individually or in any combination are set forth in the dependent claims and throughout the specification.

[0014] As used below, the terms “have,” “include,” or “contain,” or any of their arbitrary grammatical variations, are used in a non-exclusive manner. Thus, these terms can refer either to a situation where no other features exist in the entity described in this context besides those introduced by these terms, or to a situation where one or more other features exist. For example, the statements “A has B,” “A includes B,” and “A contains B” can refer either to a situation where no other elements exist in A besides B (i.e., where A is solely and uniquely composed of B), or to a situation where one or more other elements (such as element C, element D, or even other elements) exist in entity A besides B.

[0015] Furthermore, it should be noted that the terms "at least one," "one or more," or similar expressions indicating that a feature or element may exist once or more are generally used only once when the corresponding feature or element is introduced. In the following text, in most cases, when referring to the corresponding feature or element, the expressions "at least one" or "one or more" will not be used repeatedly, even though the corresponding feature or element may exist only once or more.

[0016] Furthermore, as used below, the terms “preferredly,” “more preferably,” “particularly,” “more particularly,” “specifically,” “more specifically,” or similar terms are used in combination with optional features without limiting the possibility of alternatives. Therefore, features introduced by these terms are optional features and are not intended to limit the scope of the claims in any way. As those skilled in the art will recognize, the invention can be carried out by using alternative features. Similarly, features introduced by “in one embodiment of the invention” or similar expressions are intended to be optional features without limiting alternative embodiments of the invention, without limiting the scope of the invention, and without limiting the possibility of combining features introduced in this way with other optional or non-optional features of the invention.

[0017] In a first aspect of the invention, a computer-implemented method is disclosed for detecting at least one interference and / or at least one artifact in at least one chromatogram determined by at least one mass spectrometry device.

[0018] As used herein, the term "computer-implemented method" is a broad term and is given a common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to, but is not limited to, methods involving at least one computer and / or at least one computer network. The computer and / or computer network may include at least one processor configured to perform at least one of the method steps according to the invention. Preferably, each method step is performed by a computer and / or computer network. The method can be performed completely automatically (specifically, without user interaction). As used herein, the term "automatically" is a broad term and is given a common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to, but is not limited to, processes performed entirely by means of at least one computer and / or at least one computer network and / or at least one machine, in particular, without the need for manual operation and / or user interaction.

[0019] As used herein, the term "chromatogram" is a broad term and is given its common and conventional meaning to those skilled in the art, and is not limited to any particular or customary meaning. Specifically, the term may refer to, but is not limited to, the visual result or outcome of a separation process for separating sample components. A chromatogram may refer to a time-varying intensity distribution generated during at least one chromatographic run. A chromatogram may be, or may include, a graph of the retention times of sample components on the x-axis and their intensities on the y-axis.

[0020] Chromatograms can be determined using at least one mass spectrometry device (e.g., at least one liquid chromatography-mass spectrometry device). As used herein, the term "liquid chromatography-mass spectrometry device" is a broad term and is given a common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. The term specifically refers to, but is not limited to, a combination of liquid chromatography and mass spectrometry. A liquid chromatography-mass spectrometry device may be or may include at least one high-performance liquid chromatography (HPLC) device or at least one microfluidic liquid chromatography (μLC) device. A liquid chromatography-mass spectrometry device may include a liquid chromatography (LC) device and a mass spectrometry (MS) device, wherein the LC device and the MS are coupled via at least one interface. As used herein, the term "liquid chromatography (LC) device" is a broad term and is given a common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. The term specifically refers to, but is not limited to, an analytical module configured to separate one or more target analytes from other components of a sample for detection of said one or more analytes using a mass spectrometry device. An LC device may include at least one LC column. For example, the LC device can be a single-column LC device or a multi-column LC device with multiple LC columns. The LC column may have a stationary phase through which a mobile phase is pumped to separate and / or elute and / or transfer the target analyte. As used herein, the term "mass spectrometry device" is a broad term and is given its common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. The term may specifically refer to, but is not limited to, a mass analyzer configured to detect at least one analyte based on its mass-to-charge ratio. The mass spectrometry device may be or may include at least one quadrupole mass spectrometer. The interface coupling the LC device and the MS may include at least one ionization source configured to generate molecular ions and to transfer the molecular ions into the gas phase.

[0021] A chromatogram may include at least one peak. As used herein, the term "peak" is a broad term and is given its common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to, but is not limited to, at least one local maximum value in a chromatogram. Specifically, a chromatogram may include at least one signal peak. The term "signal peak" may be used to represent a peak of the target analyte in a sample. As used herein, the term "sample" is a broad term and is given its common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to, but is not limited to, any sample, such as a biological sample, also known as a test sample. For example, a sample may be selected from the group consisting of: physiological fluids, including blood, serum, plasma, saliva, lens fluid, cerebrospinal fluid, sweat, urine, milk, ascites, mucus, synovial fluid, peritoneal fluid, amniotic fluid, tissue, cells, etc. Samples may be used directly when obtained from their respective sources, or may be pretreated and / or processed using a sample preparation workflow. A sample may include at least one analyte. For example, the target analytes can generally be vitamin D, abused drugs, therapeutic drugs, hormones, and metabolites.

[0022] As used herein, the term "interference" is a broad term and will be given a common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to, but is not limited to, a characteristic of a chromatogram affected by other substances (i.e., substances other than the target analyte) that can cause a signal peak to differ from its true value.

[0023] As used herein, the term "artifact" is a broad term and will be given a common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to, but is not limited to, at least one signal in a chromatogram, particularly a peak, resulting from a malfunction or failure of the mass spectrometry apparatus. Artifacts may also be referred to as "ghost peaks."

[0024] A chromatogram comprises multiple raw data points. As used herein, the term "raw data point" is a broad term and is given its common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to, but is not limited to, entries in a chromatogram and / or a single measurement of a mass spectrometry device. Raw data points can be preprocessed data, such as raw data with background subtraction. Specifically, peak fitting modeling can be performed on raw data points, which will be described in more detail below.

[0025] The method includes the following steps, which, as an example, can be performed in a given order. However, it should be noted that a different order is also possible. Furthermore, one or more method steps may be performed once or repeatedly. Furthermore, two or more method steps may be performed simultaneously or in a manner that overlaps as appropriate. The method may include further method steps not listed.

[0026] The method includes the following steps:

[0027] a) Retrieve at least one chromatogram using at least one processing device;

[0028] b) Apply at least one peak fitting model to the chromatogram using a processing device;

[0029] c) Determine information about the residuals of the original data points using a processing device;

[0030] d) By using a processing device, at least one interference and / or at least one artifact is detected by comparing determined information about the residual with at least one predetermined threshold, wherein at least one interference and / or at least one artifact is detected if the determined information about the residual exceeds the predetermined threshold.

[0031] Steps a) through d) of this method can be performed fully automatically, specifically using a processing device. As used herein, the term "processing device" is a broad term and is given a common and conventional meaning to those skilled in the art, and is not limited to a specific or customary meaning. The term can specifically refer to, but is not limited to, any logic circuit configured to perform basic operations of a computer or system; and / or, in general, a device configured to perform computational or logical operations. In particular, the processing device can be configured to process basic instructions that drive a computer or system. As an example, the processing device may include at least one arithmetic logic unit (ALU), at least one floating-point unit (FPU) (such as a math coprocessor or numerical coprocessor), multiple registers (specifically registers configured to provide operands to the ALU and store the results of operations), and memory (such as L1 and L2 caches). In particular, the processing device may be a multi-core processor. Specifically, the processing device may be or may include a central processing unit (CPU). Additionally or alternatively, the processing device may be or may include a microprocessor; therefore, specifically, the elements of the processing device may be contained in a single integrated circuit (IC) chip. Alternatively or concurrently, the processing device may be or may include one or more application-specific integrated circuits (ASICs) and / or one or more field-programmable gate arrays (FPGAs), etc.

[0032] As used herein, the term "retrieve at least one chromatogram" is a broad term and is given a common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to, but is not limited to, receiving, downloading, accessing, determining, measuring, detecting, and recording one or more of the at least one chromatogram. For example, a chromatogram may be retrieved by downloading and / or accessing it from at least one database (such as a database of detectors or a cloud database). For example, the method may include measuring the chromatogram using a mass spectrometry apparatus in step a). Specifically, a chromatogram may be retrieved by performing at least one chromatographic run.

[0033] As used herein, the term "peak fitting modeling" is a broad term and is given its common and conventional meaning to those skilled in the art, and is not limited to any particular or custom-defined meaning. Specifically, the term may refer to, but is not limited to, at least one fitting analysis performed on a chromatogram or at least one region of a chromatogram using at least one fitting function. Peak fitting modeling may include identifying and / or detecting peaks of a target analyte. Peak fitting modeling may include one or more of the following: peak detection, peak discovery, peak identification, determining peak onset and / or peak end, determining background, and determining baseline, etc.

[0034] Peak fitting modeling may include applying at least one curve fitting technique to the chromatogram. The original data points can be used as input values ​​for peak fitting modeling. Step b) may include fitting the original data points using at least one fitting function. Peak fitting modeling in step b) may include applying one or more of the following: at least one polynomial interpolation, at least one exponentially modified Gaussian function, at least one Gauss-Newton algorithm, and at least one Fourier transform. For example, the fitting may include using at least one fitting function, as described in "Mathematical functions for the representation of chromatographic peaks", Valerio B. Di Marco, G. Giorgio Bombi, Journal of Chromatography A, 931 (2001) 1–30. The method may include at least one optimization step, which includes determining the optimal fitting function. This so-called final peak fit can be used to determine residual information in step c).

[0035] The method may include at least one preprocessing step, particularly before applying peak fitting modeling to the chromatogram. Preprocessing may include one or more of the following: selecting at least one target region in the chromatogram; selecting at least one predefined retention time interval; at least one smoothing step, including applying one or more of a moving average filter, a Gaussian filter, discrete wavelet denoising, Savitzky-Golay smoothing, and Loess smoothing; and at least one background subtraction step, including one or more of asymmetric weighted least squares fitting regularization, applying a morphological top-hat filter, discrete or continuous wavelet basis background determination, and determining the moving average minimum.

[0036] The method according to the invention allows for the advance detection of artifacts and / or interferences by reading out the residuals between the final peak fit and the chromatogram. Based on peak fit modeling, residuals can be calculated for each raw data point. As used herein, the term "residual" is a broad term and will be given a meaning common and customary to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to, but is not limited to, the difference between the value of the raw data point at a chromatographic location and the value of the final peak fit at said location.

[0037] Information about the residuals can be one or more of the following: the residuals themselves, the mean of the residuals, the median of the residuals, the sum of the residuals, the product of the residuals, or the integral of the residuals. Determining information about the residuals can include determining the absolute value of the residuals before determining the mean, median, sum, etc. For example, the method can include determining at least one residual curve as a function of time, and information about the residuals can be the area under the residual curve. For a chromatogram without interference and / or artifacts, the area under the curve will be zero. In the presence of interference and / or artifacts, the area under the curve will be non-zero. Optionally, the resulting area value can be normalized to the peak area of ​​the fitted analyte.

[0038] This method may include comparing determined information about the residuals with at least one predetermined threshold. As used herein, the term "predetermined threshold" is a broad term and should be given its common and conventional meaning to those skilled in the art, and should not be limited to a specific or customary meaning. Specifically, the term may refer to, but is not limited to, any threshold characterizing the tolerance range of the residuals. For example, the predetermined threshold may be the maximum allowed area under the curve of the residual curve. For example, the predetermined threshold may be 15% of the information about the residuals, preferably 10%. For example, the predetermined threshold may be the maximum allowed area under the curve of the residual curve normalized to the peak area of ​​the fitted analyte. For example, the predetermined threshold may be information about the residuals <10, preferably <5.

[0039] If the determined information about the residual exceeds a predetermined threshold, at least one interference and / or at least one artifact is detected. In the event of the detection of at least one interference and / or at least one artifact, the chromatogram and / or sample may be rejected for further analysis.

[0040] In known methods, such as those described in US 2011 / 246092, it is necessary to assume a specific peak shape fit for all peaks in the chromatogram. The present invention, using information about the residuals, does not require knowledge of the peak shapes for all peaks in the chromatogram. The method may include assuming a peak shape fit for a known analyte. The method may include ignoring peak shape fits for unknown interfering peaks in the chromatogram. Therefore, it may not be necessary to assume peak shape fits for any other unknown interfering peaks.

[0041] This method may include determining the location of at least one interference and / or at least one artifact in the chromatogram. To mimic manual review, a more detailed chromatogram statement may be provided. The chromatogram may be divided into more than one portion surrounding the detected and fitted peaks. For example, the method may include dividing the chromatogram into at least two portions. Information regarding the residuals, such as the area under the residual curve, may be determined individually for each portion. Optionally, the resulting area values ​​of the residual portions may be normalized to the peak area of ​​the fitted analyte. The obtained values ​​may represent additional readings to check for / monitor interferences and / or artifacts.

[0042] A chromatogram can be divided into four parts. Specifically, a chromatogram can be divided into the pre-peak portion defined between the peak start and the peak start minus the full width at half maximum (FWHM), the rising peak portion defined between the peak start and the peak maximum, the falling peak portion defined between the retention time and the peak end, and the post-peak portion defined between the peak end and the peak end plus the full width at half maximum (FWHM).

[0043] The location of at least one interference and / or at least one artifact in the chromatogram can be determined by identifying information about the residuals from the original data points and comparing this information with at least one predetermined threshold for each segment. Combinations of readings from different segments can allow for a more detailed chromatogram statement, which can supplement or replace manual chromatogram review by an expert. Furthermore, readings for each mass transition chromatogram can be individual, compared to the quantitative / qualitative factor ratio, and are therefore unaffected by the aforementioned disadvantages (i), (ii), and (iii) of known techniques.

[0044] On the other hand, a computer program is disclosed that includes computer-executable instructions for performing, when executed on a computer or computer network, specifically on a processor, any of the methods described herein, specifically method steps a) to d).

[0045] Therefore, generally speaking, this document discloses and proposes a computer program comprising computer-executable instructions for performing the method according to the invention in one or more embodiments appended herein when executed on a computer or computer network. Specifically, the computer program may be stored on a computer-readable data carrier. Therefore, specifically, one, more than one, or even all of the method steps indicated above can be performed by using a computer or computer network, preferably by using a computer program. Specifically, the computer may be wholly or partially integrated into the mass spectrometry apparatus, and the computer program may be specifically embodied as software. However, alternatively, at least a portion of the computer may also be located external to the mass spectrometry apparatus.

[0046] This document further discloses and proposes a computer program product with program code tools so that, when executed on a computer or computer network, the method according to the invention, such as one or more method steps mentioned above, can be performed in one or more embodiments appended herein. Specifically, the program code tools may be stored on a computer-readable data carrier.

[0047] This document further discloses and proposes a data carrier having a data structure stored thereon, which, after being loaded into a computer or computer network, such as into the working memory or main memory of the computer or computer network, can execute methods according to one or more embodiments disclosed herein, specifically one or more method steps mentioned above.

[0048] This document further discloses and proposes a computer program product having program code tools stored on a machine-readable medium, so that when the program is executed on a computer or computer network, it performs methods according to one or more embodiments disclosed herein, specifically one or more method steps mentioned above. As used herein, a computer program product refers to a program that is a tradable product. This product can typically exist in any format (such as in paper format) or on a computer-readable data medium. Specifically, the computer program product can be distributed on a data network.

[0049] Finally, this document discloses and proposes a modulated data signal containing instructions readable by a computer system or computer network for performing a method according to one or more embodiments disclosed herein, specifically one or more method steps mentioned above.

[0050] Specifically, this article further discloses the following:

[0051] - A computer or computer network, the computer or computer network including at least one processor, wherein the processor is adapted to perform a method according to one of the embodiments described in this specification.

[0052] - A computer-loadable data structure adapted to perform a method according to one of the embodiments described in this specification when the data structure is executed on a computer.

[0053] - A computer program, wherein the computer program is adapted, when executed on a computer, to perform a method according to one of the embodiments described in this specification.

[0054] - A computer program, comprising program tools for performing, when executed on a computer or on a computer network, one of the methods described in this specification.

[0055] - A computer program comprising program means according to the foregoing embodiments, wherein such program means are stored on a computer-readable storage medium.

[0056] - A storage medium, wherein a data structure is stored on the storage medium and wherein the data structure is adapted to be loaded into the main memory and / or working memory of a computer or computer network, and to be processed by a method according to one of the embodiments described in this specification.

[0057] - A computer program product having program code tools, wherein the program code tools can be stored or stored on a storage medium for use in performing one of the methods described in this specification when the program code tools are executed on a computer or computer network.

[0058] In another aspect of the invention, a processing system for automatically detecting at least one interference and / or at least one artifact in at least one chromatogram determined by at least one mass spectrometry device is disclosed. The chromatogram includes multiple raw data points, wherein the processing system includes:

[0059] - At least one data collector configured to retrieve chromatograms;

[0060] - At least one fitting unit configured to model the chromatogram by applying at least one peak fitting;

[0061] - At least one mathematical unit configured to determine information about the residuals of the original data points;

[0062] - At least one identification unit configured to detect at least one interference and / or at least one artifact by comparing determined information about the residual with at least one predetermined threshold, wherein the identification unit is configured to detect at least one interference and / or at least one artifact if the determined information about the residual exceeds the predetermined threshold.

[0063] As used herein, the term "system" is a broad term and is given a common and conventional meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to, but is not limited to, a device comprising at least two elements. These elements may interact functionally, for example, to perform the method according to the invention.

[0064] The processing system can be configured to perform the method according to any of the foregoing embodiments. Specifically, the processing system can be implemented in a processing apparatus configured to perform the method according to any of the foregoing embodiments. The processing system can be configured to perform method steps a) to d) fully automatically. Therefore, for the purposes of the embodiments, the terminology and possible definitions used herein can be referenced to the description of the methods described above.

[0065] A processing system can be computer-implementable and / or can be embodied in hardware. As used herein, the term "computer-implementable" is a broad term and is given a common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to, but is not limited to, the fact that a processing system includes a set (particularly sequential) of operations and / or means, such as computing devices, processors, etc., for the detection of interference and / or artifacts.

[0066] As used herein, the term "data collector" is a broad term and is given a common and conventional meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to, but is not limited to, at least one database configured to receive and / or store at least one chromatogram. A data collector may include at least one communication interface for retrieving chromatograms.

[0067] As used further herein, the term "fitting unit" generally refers to any unit suitable for performing peak fitting modeling as described above, preferably by using at least one data processing device, and more preferably by using at least one processor and / or at least one application-specific integrated circuit. Thus, as an example, at least one fitting unit may include at least one data processing device having software code stored thereon, the software code comprising a plurality of computer commands. The fitting unit may provide one or more hardware elements for performing one or more specified operations, and / or may provide software running thereon to one or more processors for applying peak fitting modeling to chromatograms.

[0068] The processing system may also include at least one preprocessor. The preprocessor may be configured to preprocess the chromatogram by one or more of the following: selecting at least one target region in the chromatogram; selecting at least one predefined retention time interval; at least one smoothing step, including applying one or more of a moving average filter, a Gaussian filter, discrete wavelet denoising, Savitzky-Golay smoothing, and Loess smoothing; and at least one background subtraction step, including one or more of asymmetric weighted least squares fitting regularization, applying a morphological top-hat filter, discrete or continuous wavelet basis background determination, and determining the moving average minimum.

[0069] As used further herein, the term "mathematical unit" generally refers to any unit suitable for performing mathematical operations (such as determining the mean, median, sum, product, and integral of residuals, as described above) preferably by using at least one data processing device, and more preferably by using at least one processor and / or at least one application-specific integrated circuit. Thus, as an example, at least one mathematical unit may include at least one data processing device having software code stored thereon, which includes a plurality of computer commands. The mathematical unit may provide one or more hardware elements for performing one or more specified operations, and / or may provide software for mathematical operations running thereon to one or more processors.

[0070] As used herein, the term "identification unit" is a broad term and is given a common and conventional meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to, but is not limited to, at least one arbitrary unit used to detect at least one interference and / or at least one artifact by comparing determined information about the residual with at least one predetermined threshold: preferably by using at least one data processing device, more preferably by using at least one processor and / or at least one application-specific integrated circuit (ASIC). Thus, as an example, the identification unit may include at least one data processing device having software code stored thereon, the software code comprising a plurality of computer commands. The identification unit may provide one or more hardware elements for performing one or more specified operations, and / or may provide software for comparison running thereon to one or more processors.

[0071] In another aspect of the present invention, a mass spectrometry system is disclosed.

[0072] Mass spectrometry systems include

[0073] - At least one mass spectrometry device, comprising at least one mass filter and at least one detector;

[0074] - At least one processing system according to the present invention.

[0075] For the embodiments, the terms and possible definitions used herein can be referred to the description of the methods and processing systems described above.

[0076] A mass spectrometry apparatus may be or may include at least one liquid chromatography-mass spectrometry apparatus. A mass spectrometry apparatus may include at least one chromatograph. As used herein, the term "mass filter" is a broad term and is given a common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to, but is not limited to, at least one apparatus configured to separate components of a sample based on the mass of its components. As used herein, the term "detector" is a broad term and is given a common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to, but is not limited to, at least one apparatus configured to detect incoming particles and to determine at least one chromatogram.

[0077] A mass spectrometry system may also include at least one sample preparation device. As used herein, the term "sample preparation device" is a broad term and is given a common and customary meaning to those skilled in the art, and is not limited to a specific or customary meaning. Specifically, the term may refer to, but is not limited to, a device configured for preparing samples for subsequent analysis.

[0078] Compared with known methods and apparatus, the methods and apparatus according to the present invention offer numerous advantages. In particular, these methods and apparatus allow for the reliable automatic elimination of interferences and artifacts even when common parameters such as the quantitative factor / qualitative factor ratio lack reliability. These methods and apparatus further automate the quality assurance process for measurements and reduce manual peak review by experts.

[0079] In summary, and without excluding other possible embodiments, the following embodiments are conceivable:

[0080] Example 1: A computer-implemented method for detecting at least one interference and / or at least one artifact in at least one chromatogram determined by at least one mass spectrometry device, wherein the chromatogram comprises a plurality of raw data points, wherein the method includes the following steps:

[0081] a) Retrieve at least one chromatogram using at least one processing device;

[0082] b) Apply at least one peak fitting model to the chromatogram using a processing device;

[0083] c) Determine information about the residuals of the original data points using a processing device;

[0084] d) By using a processing device, at least one interference and / or at least one artifact is detected by comparing determined information about the residual with at least one predetermined threshold, wherein at least one interference and / or at least one artifact is detected if the determined information about the residual exceeds the predetermined threshold.

[0085] Example 2: The method described in the foregoing embodiments, wherein steps a) to d) are fully automatic.

[0086] It was carried out.

[0087] Example 3: The method according to Example 1, wherein the method includes using in step a)

[0088] Mass spectrometry is used to measure chromatograms.

[0089] Example 4: A method according to any of the foregoing embodiments, wherein the method includes determining at least

[0090] The location of an interference and / or at least one artifact in the chromatogram.

[0091] Example 5: The method according to the foregoing embodiments, wherein the method includes dividing the chromatogram into at least two...

[0092] Each part.

[0093] Example 6: According to the method of any one of the preceding two examples, the chromatogram is divided into four...

[0094] The chromatogram is divided into several parts, including the pre-peak portion defined between the peak start and the peak start minus the full width at half maximum (WHM), the rising peak portion defined between the peak start and the peak maximum value, the falling peak portion defined between the retention time and the peak end, and the post-peak portion defined between the peak end and the peak end plus the full width at half maximum (WHM).

[0095] Example 7: The method described according to any one of the foregoing three examples, wherein at least one dry

[0096] The location of disturbances and / or at least one artifact in the chromatogram is determined by determining information about the residuals from the original data points and comparing that information with at least one predetermined threshold for each segment.

[0097] Example 8: The method according to any of the foregoing embodiments, wherein the information regarding the residual is

[0098] One or more of the following: residual, mean of residual, median of residual, sum of residual, product of residuals, and integral of residual.

[0099] Example 9: The method according to any of the foregoing examples, wherein the peak in step b)

[0100] Fitting modeling involves applying one or more of the following: at least one polynomial interpolation, at least one exponentially modified Gaussian function, at least one Gauss-Newton algorithm, and at least one Fourier transform.

[0101] Example 10: The method according to any one of the foregoing embodiments, wherein the method includes: to

[0102] The process includes at least one preprocessing step, which includes selecting at least one target region in the chromatogram and selecting one or more of at least one predefined retention time interval; at least one smoothing step, which includes applying one or more of a moving average filter, a Gaussian filter, discrete wavelet denoising, Savitzky-Golay smoothing, and Loess smoothing; and at least one background subtraction step, which includes asymmetric weighted least squares fitting regularization, applying a morphological top-hat filter, determining discrete or continuous wavelet basis background, and determining the moving average minimum.

[0103] Example 11 A computer program comprising computer-executable instructions, wherein the computer-executable instructions are...

[0104] The instructions are used to perform the method described according to any of the foregoing embodiments, specifically method steps a) to d), when the program is executed on a computer or computer network, specifically on a processor.

[0105] Example 12: A computer program product having program code tools so that when the program is running on a computer...

[0106] When executed on a computer or computer network, the method according to any of the foregoing embodiments of the method is performed.

[0107] Example 13 A processing system for automatically detecting up to [value missing] determined by at least one mass spectrometer.

[0108] The processing system includes at least one interference and / or at least one artifact in a chromatogram comprising multiple raw data points, wherein the processing system comprises:

[0109] - At least one data collector configured to retrieve chromatograms;

[0110] - At least one fitting unit configured to model the chromatogram by applying at least one peak fitting;

[0111] - At least one mathematical unit configured to determine information about the residuals of the original data points;

[0112] - At least one identification unit configured to detect at least one interference and / or at least one artifact by comparing determined information about the residual with at least one predetermined threshold, wherein the identification unit is configured to detect at least one interference and / or at least one artifact if the determined information about the residual exceeds the predetermined threshold.

[0113] Example 14: The processing system according to the foregoing embodiments, wherein the processing system is implemented to...

[0114] The processing apparatus is configured to perform the method described in any of the foregoing embodiments of the method.

[0115] Example 15 A mass spectrometry system, comprising

[0116] - At least one mass spectrometry device, comprising at least one mass filter and at least one detector;

[0117] - At least one processing system according to any of the foregoing embodiments involving the processing system. Attached Figure Description

[0118] Preferably, in conjunction with the dependent claims, other optional features and embodiments will be disclosed in more detail in the following description of embodiments. These optional features, as will be recognized by those skilled in the art, can be implemented individually and in any feasible combination. The scope of the invention is not limited to the preferred embodiments. Embodiments are schematically depicted in the accompanying drawings. In these drawings, the same reference numerals refer to the same or functionally equivalent elements.

[0119] In the attached diagram:

[0120] Figure 1 An embodiment of the mass spectrometry system according to the present invention is shown;

[0121] Figures 2A to 2D The diagram shows complete separation of interference (2A), initiation of co-elution (2B), and strong co-elution.

[0122] Representative chromatograms of (2C) and complete co-elution (2D); and

[0123] Figure 3 The dependence of the average peak fitting residuals (left y-axis) and relative area ratio (right y-axis) of portions C and D on the average peak resolution (x-axis) of testosterone and epitestosterone is shown. Detailed Implementation

[0124] Figure 1 An embodiment of a mass spectrometry apparatus 110 according to the present invention is shown in a highly schematic manner. The mass spectrometry apparatus 110 includes at least one mass filter 112 and at least one detector 114. The mass spectrometry apparatus 110 may be part of a mass spectrometry system 111. The mass spectrometry system 111 also includes a processing system 116. The processing system 116 may be implemented as software and / or may be implemented in a processing device 126.

[0125] Mass spectrometry device 110 may be or may include at least one liquid chromatography-mass spectrometry device. The liquid chromatography-mass spectrometry device may be or may include at least one high-performance liquid chromatography (HPLC) device or at least one microfluidic liquid chromatography (μLC) device. The liquid chromatography-mass spectrometry device may include a liquid chromatography (LC) device and a mass spectrometry (MS) device, wherein the LC device and the MS are coupled via at least one interface. The LC device may be configured to separate one or more target analytes from other components of the sample for detection using the mass spectrometry device. The LC device may include at least one LC column. For example, the LC device may be a single-column LC device or a multi-column LC device having multiple LC columns. The LC column may have a stationary phase through which a mobile phase is pumped to separate and / or elute and / or transport the target analyte. Mass spectrometry device 110 may be or may include a mass analyzer configured to detect at least one analyte based on its mass-to-charge ratio. Mass filter 112 may be configured to separate components of the sample according to the mass of the sample's components. For example, mass spectrometry device 110 may be or may include at least one quadrupole mass spectrometer. Detector 114 may be configured to detect incoming particles and to determine at least one chromatogram. A chromatogram may be a visual result or outcome of a separation process of components of a sample. A chromatogram may refer to an intensity distribution over time generated during at least one chromatographic run. A chromatogram may be or may include a graph of the retention times of sample components on the x-axis and the intensity on the y-axis.

[0126] A chromatogram may include at least one peak. A peak may be at least one local maximum value in the chromatogram. Specifically, a chromatogram may include at least one signal peak. The signal peak may be the peak of the target analyte of the sample. The sample may be selected from the group consisting of: physiological fluids, including blood, serum, plasma, saliva, lens fluid, cerebrospinal fluid, sweat, urine, milk, ascites, mucus, synovial fluid, peritoneal fluid, amniotic fluid, tissue, cells, etc. The sample may be used directly when obtained from the appropriate source, or it may be pretreated and / or processed using a sample preparation workflow. The sample may include at least one analyte. For example, generally, the target analyte may be vitamin D, abused drugs, therapeutic drugs, hormones, and metabolites.

[0127] A chromatogram comprises multiple raw data points. Raw data points can be entries in the chromatogram and / or single measurements from a mass spectrometer. Raw data points can be preprocessed data, such as raw data with background subtraction. Specifically, peak fitting modeling can be performed on the raw data points.

[0128] Processing system 116 can be configured to detect interference and / or artifacts. Processing system 116 includes:

[0129] - At least one data collector 118 configured to retrieve chromatograms;

[0130] - At least one fitting unit 120, configured to apply at least one peak fitting modeling to the chromatogram;

[0131] - At least one mathematical unit 122, configured to determine information about the residuals of the original data points;

[0132] - At least one identification unit 124 is configured to detect at least one interference and / or at least one artifact by comparing determined information about the residual with at least one predetermined threshold, wherein the identification unit 124 is configured to detect at least one interference and / or at least one artifact if the determined information about the residual exceeds the predetermined threshold.

[0133] Retrieving at least one chromatogram may include receiving, downloading, accessing, determining, measuring, detecting, and recording one or more of the at least one chromatogram. For example, a chromatogram may be retrieved by downloading and / or accessing it from at least one database (such as the database of detector 114 or a cloud database). For example, a retrieval may include measuring the chromatogram using mass spectrometry device 110. Specifically, a chromatogram may be retrieved by performing at least one chromatographic run.

[0134] Peak fitting modeling may include at least one fitting analysis of a chromatogram using at least one fitting function or at least one region of a chromatogram. Peak fitting modeling may include identifying and / or detecting peaks of a target analyte. Peak fitting modeling may include one or more of the following: peak detection, peak discovery, peak identification, determining peak onset and / or peak end, determining background, and determining baseline, etc.

[0135] Peak fitting modeling may include applying at least one curve fitting technique to a chromatogram. The original data points can be used as input values ​​for peak fitting modeling. Peak fitting modeling may include fitting the original data points using at least one fitting function. Peak fitting modeling may include applying one or more of the following: at least one polynomial interpolation, at least one exponentially modified Gaussian function, at least one Gauss-Newton algorithm, and at least one Fourier transform. For example, the fitting may include using at least one fitting function as described in "Mathematical functions for the representation of chromatographic peaks", Valerio B. Di Marco, G. Giorgio Bombi, Journal of Chromatography A, 931 (2001) 1–30. The method may include at least one optimization step, which includes determining the optimal fitting function. This so-called final peak fit can be used to determine information about the residuals.

[0136] The processing system 116 may further include at least one preprocessor configured for one or more of the following: selecting at least one target region in a chromatogram; selecting at least one predefined retention time interval; at least one smoothing step, which includes applying one or more of a moving average filter, a Gaussian filter, discrete wavelet denoising, Savitzky-Golay smoothing, and Loess smoothing; and at least one background subtraction step, which includes one or more of asymmetric weighted least squares fitting regularization, applying a morphological top-hat filter, discrete or continuous wavelet basis background determination, and determining a moving average minimum.

[0137] The processing system 116 can allow early detection of artifacts and / or interferences based on the residual between the final peak fit and the chromatogram. Based on peak fit modeling, a residual can be calculated for each raw data point. The residual can be calculated as the difference between the value of the raw data point at the chromatogram location and the value of the final peak fit at said location.

[0138] Information about the residuals can be one or more of the following: the residuals themselves, the mean of the residuals, the median of the residuals, the sum of the residuals, the product of the residuals, or the integral of the residuals. Determining information about the residuals can include determining the absolute value of the residuals before determining the mean, median, sum, etc. For example, mathematical unit 122 can be configured to determine at least one residual curve as a function of time, and information about the residuals can be the area under the residual curve. For a chromatogram without interference and / or artifacts, the area under the curve will be zero. In the presence of interference and / or artifacts, the area under the curve will be non-zero. Optionally, the resulting area value can be normalized to the peak area of ​​the fitted analyte.

[0139] The identification unit 124 can be configured to compare determined information about the residuals with at least one predetermined threshold. The predetermined threshold can be any threshold characterizing the tolerance range of the residuals. For example, the predetermined threshold can be the maximum allowed area under the curve of the residual curve. For example, the predetermined threshold can be 15% of the information about the residuals, preferably 10%. For example, the predetermined threshold can be the maximum allowed area under the curve of the residual curve normalized to the peak area of ​​the fitted analyte. For example, the predetermined threshold can be information about the residuals <10, preferably <5.

[0140] If the determined information about the residual exceeds a predetermined threshold, at least one interference and / or at least one artifact is detected. In the event of the detection of at least one interference and / or at least one artifact, the chromatogram and / or sample may be rejected for further analysis.

[0141] Processing system 116 can be configured to include determining the location of at least one interference and / or at least one artifact in the chromatogram. To mimic manual review, a more detailed chromatogram statement can be provided. The chromatogram can (e.g., by mathematical unit 122) be divided into more than one portion around the detected and fitted peaks. For example, the chromatogram can be divided into at least two portions. Information about the residuals, such as the area under the residual curve, can be determined individually for each portion. Optionally, the resulting area values ​​of the residual portions can be normalized to the peak area of ​​the fitted analyte. The obtained values ​​can represent additional readings to check for / monitor interference and / or artifacts.

[0142] A chromatogram can be divided into four parts. Specifically, a chromatogram can be divided into a pre-peak portion defined between the peak start and the peak start minus the full width at half maximum (FWHM), an ascending peak portion defined between the peak start and the peak maximum, a descending peak portion defined between the retention time and the peak end, and a post-peak portion defined between the peak end and the peak end plus the full width at half maximum (FWHM). For example, the outer portion can be defined as the pre-peak portion between the peak start and the peak start minus FWHM, and the post-peak portion between the peak end and the peak end plus FWHM. The pre-peak and post-peak portions can have equal ranges. Alternatively, the chromatogram can be divided into other four parts. For example, the pre-peak portion can be defined between the peak start and the absolute difference between the peak start and the peak start minus the retention time (i.e., the peak maximum) and the peak start. The post-peak portion can be defined between the peak end and the absolute difference between the peak end plus the retention time and the peak end. For perfectly symmetrical peaks, the outer portions can be identical, where the peak start and end are located at the same distance from the peak maximum. For asymmetrical peaks, the outer portions can be different.

[0143] The location of at least one interference and / or at least one artifact in the chromatogram can be determined by identifying information about the residuals from the original data points and comparing this information with at least one predetermined threshold for each segment. Combinations of readings from different segments can allow for a more detailed chromatogram statement, which can supplement or replace manual chromatogram review by an expert. Furthermore, readings for each mass transition chromatogram can be individual, compared to the quantitative / qualitative factor ratio, and are therefore unaffected by the aforementioned disadvantages (i), (ii), and (iii) of known techniques.

[0144] Figures 2A to 2DRepresentative experimental results are shown, particularly chromatograms of complete separation of interference (2A), initial co-elution (2B), strong co-elution (2C), and complete co-elution (2D). Serum samples were supplemented with a mixture of testosterone and epitestosterone, along with testosterone-d3 as an internal standard (ISTD). Samples were measured by LC-triple quadrupole (QqQ)-MS using seven different methods and six randomized analytical replicates. Each method contained the same MS settings for measuring the two transitions of testosterone and the two transitions of ISTD testosterone-d3, but with variations in the LC gradient. These variations resulted in different separation capabilities, i.e., peak resolution, between testosterone and epitestosterone, where epitestosterone represents interference because it produces signals of similar relative magnitude in both transitions of testosterone.

[0145] The original data points are integrated using an exponentially corrected Gaussian fit and peak fit, with the residuals calculated for each data point. The chromatogram around the peak is divided into four parts: AD. For example, as shown... Figure 3 As shown in the embodiment, portion A is the pre-peak portion defined between the peak start and the peak start minus the full width at half maximum (FWHM); portion B is the rising peak portion defined between the peak start and the peak maximum value (i.e., retention time); portion C is the falling peak portion defined between the retention time and the peak end; and portion D is the post-peak portion defined between the peak end and the peak end plus FWHM. The pre-peak and post-peak portions can have equal ranges. Alternatively or as an alternative, such as Figures 2A to 2D As shown in the embodiment, four other parts can be selected. Figures 2A to 2D In a peak, the pre-peak portion can be defined between the peak start and the absolute difference between the peak start minus the retention time (i.e., the peak maximum value) and the peak start. The post-peak portion can be defined between the peak end and the absolute difference between the peak end plus the retention time and the peak end. For a perfectly symmetrical peak, the outer portions can be identical, where the peak start and end are located at the same distance from the peak maximum value. For asymmetric peaks, the outer portions can be different.

[0146] Then, the area under the residual curve was calculated separately for each part and normalized to the peak area. Furthermore, to estimate the impact on the results, the area ratio of the analyte to the ISTD was calculated and set in relation to the area ratio calculated in the method with the highest peak resolution (i.e., separating power). For illustration, Figure 2 shows representative chromatograms exhibiting specific separating power, where... Figure 2A It completely isolates interference. Figure 2B It's the start of co-washing. Figure 2C It is strong CCP debunking, and Figure 2D It is a complete co-elution. In addition, the individual components of AD are given, along with rough visual estimates of their changes ("-" = no change; "↑" = slight increase; "↑↑" = high increase).

[0147] Figure 3 The dependence of the average peak fit residuals (left y-axis) and relative area ratios (right y-axis) of portions C and D on the average peak resolution (x-axis) of testosterone and interfering epitestosterone is shown. The area ratio (right y-axis), representing the results, is affected when the peak resolution is below 1.0. This information is often unknown when measuring samples with unknown concentrations. Peak residual portion D begins to be affected when the peak resolution is below 1.2, shows its maximum at 0.6, and ends at 0.4. The parallel peak residual portion C begins to be affected when the peak resolution is below 1.0, shows its maximum at 0.4, and ends between 0.4 and 0.0. All methods, as well as the quantitative / qualitative factor ratio (data not shown), have no effect on peak residual portions A and B. For specific maximum thresholds for these peak residual portion values, such as for portion D < 10 and for portion C < 5 (left y-axis), samples with affected area ratios (right y-axis) can be detected until the peak resolution between the analyte testosterone and interfering epitestosterone is below 0.4. These interfered samples may be overlooked by monitoring the quantitative / qualitative factor ratio alone, and are usually only detectable by manual chromatogram review by experts.

[0148] Using the process described here, the location of interference and / or artifacts, such as right-side or left-side interference, can be estimated by combining information from parts A and B relative to parts C and D, and / or the peak resolution between the analyte and the interference can be estimated by combining information from parts A relative to parts B or parts C relative to parts D.

[0149] List of reference numerals

[0150] 110 Mass spectrometry apparatus

[0151] 111 Mass Spectrometry System

[0152] 112 Filter

[0153] 114 detectors

[0154] 116 Processing System

[0155] 118 Data Collector

[0156] 120 fitting units

[0157] Unit 122 Mathematics

[0158] 124 Identification Units

[0159] 126 Processing Unit

Claims

1. A computer-implemented method for detecting at least one interference and / or at least one artifact in at least one chromatogram determined by at least one mass spectrometry device (110), wherein the chromatogram comprises a plurality of raw data points, wherein the method comprises the following steps: a) Retrieve the at least one chromatogram using at least one processing device (126); b) Apply at least one peak fitting model to the chromatogram using the processing device (126); c) Using the processing device (126), determine information about the residuals of the original data points; d) By using the processing device (126), the at least one interference and / or the at least one artifact is detected by comparing determined information about the residual with at least one predetermined threshold, wherein the at least one interference and / or the at least one artifact is detected if the determined information about the residual exceeds the predetermined threshold. The method includes determining the position of the at least one interference and / or the at least one artifact in the chromatogram, wherein the chromatogram is divided into four parts: a pre-peak portion defined between the peak start and the peak start minus the full width at half maximum (FWHM); a rising peak portion defined between the peak start and the peak maximum; a falling peak portion defined between the retention time and the peak end; and a post-peak portion defined between the peak end and the peak end plus the FWHM. The position of the at least one interference and / or the at least one artifact in the chromatogram is determined by determining the residual information of the original data points and comparing the residual information with at least one predetermined threshold for each of the portions.

2. The method according to claim 1, wherein steps a) to d) are performed automatically.

3. The method of claim 1, wherein the method includes measuring the chromatogram using the mass spectrometer in step a).

4. The method of claim 1, wherein the method comprises dividing the chromatogram into at least two parts.

5. The method according to any one of claims 1-4, wherein the information about the residuals is one or more of the residuals, the mean of the residuals, the median of the residuals, the sum of the residuals, the product of the residuals, and the integral of the residuals.

6. The method according to any one of claims 1-4, wherein the peak fitting modeling in step b) comprises applying one or more of the following: at least one polynomial interpolation, at least one exponentially modified Gaussian function, at least one Gauss-Newton algorithm, and at least one Fourier transform.

7. The method according to any one of claims 1-4, wherein the method comprises: At least one preprocessing step, comprising selecting at least one target region in the chromatogram and selecting one or more of at least one predefined retention time interval; at least one smoothing step, comprising applying one or more of a moving average filter, a Gaussian filter, discrete wavelet denoising, Savitzky-Golay smoothing, and Loess smoothing; and at least one background subtraction step, comprising one or more of asymmetric weighted least squares fitting regularization, applying a morphological top-hat filter, determining discrete or continuous wavelet basis background, and determining the moving average minimum.

8. A computationally readable medium having a computer program stored thereon, the computer program comprising computer-executable instructions configured to, when the program is executed on a computer or computer network, specifically on a processor, perform the method according to any one of claims 1-7, specifically method steps a) to d).

9. A computer program product having program code tools for performing the method of any one of claims 1-7 when the program is executed on a computer or a computer network.

10. A processing system (116) for automatically detecting at least one interference and / or at least one artifact in at least one chromatogram determined by at least one mass spectrometry device (110), wherein the chromatogram comprises a plurality of raw data points, wherein the processing system comprises: - At least one data collector (118) configured to retrieve the chromatogram; - At least one fitting unit (120) configured to apply at least one peak fitting modeling to the chromatogram; - At least one mathematical unit (122) configured to determine information about the residuals of the original data points; - At least one identification unit (124) configured to detect the at least one interference and / or the at least one artifact by comparing determined information about the residual with at least one predetermined threshold, wherein the identification unit (124) is configured to detect the at least one interference and / or the at least one artifact if the determined information about the residual exceeds the predetermined threshold. The processing system (116) is configured to determine the position of the at least one interference and / or the at least one artifact in the chromatogram, wherein the chromatogram is divided into four parts, wherein the chromatogram is divided into a pre-peak portion defined between the peak start and the peak start minus the full width at half maximum (FWHM), a rising peak portion defined between the peak start and the peak maximum (VWHM), a falling peak portion defined between the retention time and the peak end (VWHM), and a post-peak portion defined between the peak end and the peak end plus the full width at half maximum (FWHM), wherein the position of the at least one interference and / or the at least one artifact in the chromatogram is determined by determining the information about the residuals of the original data points and comparing the information about the residuals with at least one predetermined threshold for each of the portions.

11. The processing system (116) according to claim 10, wherein the processing system (116) is implemented in a processing apparatus (126) configured to perform the method according to any one of claims 1-7.

12. A mass spectrometry system (111), comprising: - At least one mass spectrometry device (110) comprising at least one mass filter (112) and at least one detector (114); At least one processing system (116) according to any one of claims 10-11.

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