WO2013104004A1 - Traitement exhaustif des interférences dans le cadre d'une analyse au moyen d'un spectromètre de masse à source à plasma inductif (icp-ms) - Google Patents

Traitement exhaustif des interférences dans le cadre d'une analyse au moyen d'un spectromètre de masse à source à plasma inductif (icp-ms) Download PDF

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WO2013104004A1
WO2013104004A1 PCT/US2013/020663 US2013020663W WO2013104004A1 WO 2013104004 A1 WO2013104004 A1 WO 2013104004A1 US 2013020663 W US2013020663 W US 2013020663W WO 2013104004 A1 WO2013104004 A1 WO 2013104004A1
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mass spectral
mass
peak
interferences
data
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PCT/US2013/020663
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Yongdong Wang
Ming Gu
Hongliang Xu
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Cerno Bioscience Llc
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    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/0027—Methods for using particle spectrometers
    • H01J49/0036—Step by step routines describing the handling of the data generated during a measurement

Definitions

  • the present invention relates to improvements and applications with respect to the teachings of the above referenced patent applications in the field of general mass spectrometry including inductively coupled plasma mass spectrometry (ICP-MS).
  • ICP-MS inductively coupled plasma mass spectrometry
  • an inductively coupled plasma is a plasma that contains a sufficient concentration of ions and electrons to make the gas electrically conductive.
  • the plasmas used in spectro chemical analysis are essentially electrically neutral, with each positive charge on an ion balanced by a free electron. In these plasmas the positive ions are almost all singly charged and there are few negative ions, so there are nearly equal amounts of ions and electrons in each unit volume of plasma.
  • An inductively coupled plasma (ICP) is sustained in a torch that consists of three concentric tubes, usually made of quartz.
  • This torch is placed inside an induction coil supplied with a radio -frequency electric current.
  • a flow of argon gas (usually 14 to 18 liters per minute) is introduced between the two outermost tubes of the torch and an electric spark is applied for a short time to introduce free electrons into the gas stream.
  • These electrons interact with the radio -frequency magnetic field of the induction coil and are accelerated first in one direction, then the other, as the field changes at high frequency (usually 27.12 million cycles per second).
  • the accelerated electrons collide with argon atoms, and sometimes a collision causes an argon atom to part with one of its electrons.
  • the released electron is in turn accelerated by the rapidly changing magnetic field.
  • the ICP can be retained in the quartz torch because the flow of gas between the two outermost tubes keeps the plasma away from the walls of the torch.
  • a second flow of argon (around 1 liter per minute) is usually introduced between the central tube and the intermediate tube to keep the plasma away from the end of the central tube.
  • a third flow (again usually around 1 liter per minute) of gas is introduced into the central tube of the torch. This gas flow passes through the centre of the plasma, where it forms a channel that is cooler than the surrounding plasma but still much hotter than a chemical flame. Samples to be analyzed are introduced into this central channel, usually as a mist of liquid formed by passing the liquid sample into a nebulizer.
  • nebulized sample As a droplet of nebulized sample enters the central channel of the ICP, it evaporates and any solids that were dissolved in the liquid vaporize and then break down into atoms. At the temperatures prevailing in the plasma a significant proportion of the atoms of many chemical elements are ionized, each atom losing its most loosely bound electron to form a singly charged ion.
  • the ions from the plasma are extracted through a series of cones into a mass spectrometer, usually a unit mass resolution quadrupole MS.
  • ICP-MS Due to the high energy and temperature breakdown of samples inside the ICP source, typically only ion species of smaller masses (m/z) would be observed in the mass spectrometer in the range between m/z 1 -350, which covers all known 1 18 elements in its + 1 charge state in the most recent periodic table. Combined with the high sensitivity and generality of a mass spectrometer as detector, ICP-MS has become the most versatile analytical technique in terms of its elemental coverage. On the other hand, this also means that there would be serious mass spectral interferences in samples containing multiple elements or other complex matrices as all mass spectral information would be compressed in such a narrow mass spectral range of only about 350Da.
  • One way to counter the mass spectral interference problem is to replace the lower-cost and easier-to-maintain quadrupole MS with a more expensive and higher resolution MS systems such as double focusing magnetic-electrostatic sector systems with both single and multiple collector, as well as time of flight (TOF) systems (both axial and orthogonal accelerators have been used) so as to mass spectrally separate various interferences before quantitation or identification.
  • TOF time of flight
  • these higher resolution MS systems come with reduced sensitivity due to the loss of ion signals through higher resolution ion optics (in the case of magnetic sector instrument) or much increased maintenance and/or capital budget (in the case of TOF)
  • the use of higher resolution MS in ICP-MS has been quite limited.
  • another lower-cost and easier-to- maintain alternative approach has been developed and widely adopted commercially, which helps to eliminate or reduce mass spectral interferences through the use of a collision or reaction cell with an otherwise conventional and lower cost quadrupole MS.
  • Dynamic reaction cell The collision reaction cell known by the trade name dynamic reaction cell was introduced by Perkin-Elmer on their Elan DRC (followed by Elan DRC II and Elan DRC-e) instrument.
  • the dynamic reaction cell is a chamber placed before the traditional quadrupole chamber of an ICP-MS device, for eliminating isobaric interferences.
  • the chamber has a quadrupole and can be filled-up with reaction (or collision) gases (ammonia, methane, oxygen or hydrogen), with one gas type at a time or a mixture of two of them, which reacts with the introduced sample, eliminating some of the interference.
  • the DRC is characterized by the following paramters, that can be modified: RPq (the corresponding q parameter from the Mathieu equation), RPa (the corresponding a parameter from the Mathieu equation), which refer to the voltage applied to the quadrupole rods and the gas flow of the reaction gas.
  • Axial field technology is a patented improvement of DRC made by Perkin-Elmer, which consists in two supplementary rods placed in the DRC cell, smaller than normal quadrupole's rods, with the purpose of "pushing" the ions faster to the exit by generating a supplementary electric potential, minimizing the time needed for the gas to be in the DRC and improving analysis speed.
  • the supplementary potential of the AFT rods does not contribute significantly to the global energy, but drastically improve ion passage time.
  • Thermo Scientific's XSeries2 instrument utilizes a collision/reaction cell for interference removal, consisting of a non-consumable hexapole and chicane ion deflector, which takes the ion beam off-axis and leads to low instrument backgrounds of ⁇ 0.5 integrated counts per second (icps) at vacant masses such as 5 and 220.
  • This hexapole is inherently part of the Thermo lens system and is present in the ion path, regardless of the use of the collision cell.
  • the collision/reaction gas mixtures can be 1 % NH3 in He, 7% H2 in He and 100% H2, where the NH3 and H2 are reactive gasses and the He is a collisional gas.
  • the 3rd generation cell utilizes kinetic energy discrimination, which employes running the quadrupole bias slightly less negative (more positive) than the hexopole bias.
  • Polyatomic ions generated within the plasma can have larger atomic radii than analyte ions of similar mass, i.e. the interferent NaAr+ (mass 63) is larger than the analyte Cu+ (mass 63).
  • Octopole reaction system Another implementation of this type of interference removal is an octopole (instead of a quadrupole) collision cell, implemented by Agilent's 7500 series.
  • the octopole reaction system uses only helium or hydrogen and the volume of the cell is smaller than that of a DRC.
  • the small molecules of helium and hydrogen collide with the large, unwanted polyatomic ions formed in the plasma and break them up into other ions that can be separated in the quadrupole mass analyzer.
  • the ORS system is based only on collision reactions and not on chemical reactions.
  • reaction or collision may not reach 100% completion and therefore there would always be residual interferences even with the use of a cell.
  • the present disclosure is directed to the following improvements, which are applied to inductively coupled plasma mass spectrometry (ICP-MS) where the ionization source is the inductively coupled plasma (ICP):
  • the method in accordance with the invention allows for the highly accurate quantitation of a mixture of ions where their monoisotopic masses differ by as little as a small fraction of IDa with a conventional mass spectrometer of unit mass resolution.
  • Fig. 1 is a block diagram of an analysis system in accordance with the invention, including a mass spectrometer.
  • Fig. 2A is a table of exact isotope distribution for a polyatom CSi.
  • Fig. 2B is the simulated mass spectral profile mode data for CSi on a unit mass resolution system.
  • Fig. 2C is the simulated mass spectral profile mode data for CSi M+l isotope cluster on very high resolution system.
  • Fig. 2D is the simulated mass spectral profile mode data for CSi M+2 isotope cluster on the same high resolution system.
  • Fig. 3 is the theoretical isotope profile mode data at unit mass resolution for two candidate matches of As and adjacent interference whose isotope profile overlaps the isotope profile of As.
  • Fig. 4 is a flow chart for the highly selective compound identification process disclosed herein.
  • Fig. 5A is a simulated raw mass spectral profile mode data for the As.
  • Fig. 5B is an externally calibrated version of mass spectral profile mode data for
  • Figs. 6A, 6C, and 6E are calibrated data measured on a unit mass resolution system and the fitted version with AS, As+Ar2, and As+Ar2+ArCl, respectively.
  • Figs. 6B, 6D, and 6F are the corresponding fitting residuals of FIG. 6 A, 6C, and
  • Fig. 7 is a flow chart for the unbiased quantitative analysis process disclosed herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • FIG. 1 there is shown a block diagram of an analysis system 10, that may be used to analyze atoms or polyatoms, as noted above, incorporating features of the present invention.
  • an analysis system 10 that may be used to analyze atoms or polyatoms, as noted above, incorporating features of the present invention.
  • Analysis system 10 has a sample preparation portion 12, a mass spectrometer portion 14, a data analysis system 16, and a computer system 18.
  • the sample preparation portion 12 may include a sample introduction unit 20, of the type that introduces a sample containing metal elements of interest to system 10, such as the iCAP Q ICP- MS, manufactured by Thermo Electron Corporation of Waltham, MA, USA.
  • the sample preparation portion 12 may optionally also include an analyte separation unit 22, which is used to perform a preliminary separation of analytes, such as the metal elements to be analyzed by system 10.
  • Analyte separation unit 22 may be any one of a liquid chromatography system.
  • the mass spectrometer portion 14 may be a conventional mass spectrometer and may be any one available, but is preferably one of MALDI-TOF, quadrupole MS, ion trap
  • mass spectrometer portion 14 may include an ion source 24, a mass analyzer 26 for separating ions generated by ion source 24 by mass to charge ratio, an ion detector portion 28 for detecting the ions from mass analyzer 26, and a vacuum system 30 for maintaining a sufficient vacuum for mass spectrometer portion 14 to operate efficiently. If mass spectrometer portion 14 is an ion mobility spectrometer, generally no vacuum system is needed.
  • the data analysis system 16 includes a data acquisition portion 32, which may include one or a series of analog to digital converters (not shown) for converting signals from ion detector portion 28 into digital data
  • This digital data is provided to a real time data processing portion 34, which process the digital data through operations such as summing and/or averaging.
  • a post processing portion 36 may be used to do additional processing of the data from real time data processing portion 34, including library searches, data storage and data reporting.
  • Computer system 18 provides control of sample preparation portion 12, mass spectrometer portion 14, and data analysis system 16, in the manner described below.
  • Computer system 18 may have a conventional computer monitor 40 to allow for the entry of data on appropriate screen displays, and for the display of the results of the analyses performed.
  • Computer system 18 may be based on any appropriate personal computer, operating for example with a Windows® or UNIX® operating system, or any other appropriate operating system.
  • Computer system 18 will typically have a hard drive 42, on which the operating system and the program for performing the data analysis described below is stored.
  • a drive 44 for accepting a CD or floppy disk is used to load the program in accordance with the invention on to computer system 18.
  • the program for controlling sample preparation portion 12 and mass spectrometer portion 14 will typically be downloaded as firmware for these portions of system 10.
  • Data analysis system 16 may be a program written to implement the processing steps discussed below, in any of several programming languages such as C++, JAVA or Visual Basic. Mass Spectral Fitting for Molecular Search
  • Mass spectrometry with highly accurate ion mass measurement offers a quick and unique way for the determination of elemental compositions or molecular formulae, which can offer great insights for the ions under the measurement, ranging from unknown metabolite identification to DNA or protein identification or sequencing.
  • the conventional approach for molecular formula determination starts with high mass accuracy determination of a mass spectral peak of interest and searches for all possible formula within a given mass error window (typically measured as parts per million or ppm), for example, +/-5ppm from the determined mass. Since all elements in the periodic table have their exact masses carefully measured for the lowest isotope, the elemental composition or molecular search algorithm amounts to the following optimization:
  • n t is the number of elements for the i-th element
  • m,- is the lowest exact mass among all isotopes of this i-th element.
  • This optimization problem can typically be solved through integer programming, which can be drastically sped-up through the introduction of such constraints as the lowest possible and the highest possible number of each element n and the maximal number of elements p.
  • Other constraints may include the existence of rings, double bonds, or a limited selection of possible elements (for example, a typical small molecule drug may contain only C, H, N, O, S, P, CI etc.).
  • the mass spectrometer is of high resolution, typically a quadruple time-of- flight (qTOF) system or FTMS, allowing for the monoisotopic peak of an ion to be baseline-resolved from its other isotopes in order to achieve high mass accuracy and facilitate the compound identification.
  • qTOF quadruple time-of- flight
  • the monoisotopic peak is pure and free from any interfering ions or isobaric interferences.
  • the molecule being searched is generally a small molecule with molecular weight less than lOOODa where the only pure isotope peak is the monoisotopic peak which is typically the most abundant peak.
  • Fig. 2A shows the theoretical isotope distribution for a polyatom CSi, where the monoisotope (39.9764Da) is the most abundant and composed of a single isotope. All other isotope peaks are weaker and composed of multiple individual isotopes that are about IDa from the monoisotope and easily separated from the monoisotope on a unit mass resolution system as shown in Fig. 2B.
  • the separation of the 2 most abundant isotopes (41.9732 and 41.9793 Da) under the M+2 peak would have required high resolving power, a feature only available on the high resolution systems where some sensitivity may have to be compromised.
  • Fig. 2A shows the theoretical isotope distribution for a polyatom CSi, where the monoisotope (39.9764Da) is the most abundant and composed of a single isotope. All other isotope peaks are weaker and composed of multiple individual isotopes that are about IDa from
  • FIG. 2D shows the simulated mass spectrum for the M+2 isotopes at such high resolving power that the two most abundant isotopes can be visually observed.
  • the two isotopes at 40.9759 and 40.9797Da are no longer separated even at the same high resolution, resulting in some ambiguity in peak picking or centroiding which can adversely impact quantitative ICP-MS analysis based on peak picking results alone.
  • the profile data in Fig. 2C contains all relevant information about the M+l isotope cluster of this polyatom and provides a unique signature on which a quantitative mixture analysis may be based.
  • the peak analysis can still be performed on peaks with unresolved isobaric interferences to arrive at a unique accurate mass for the isotope clusters. Since the peak shape function has been converted into a symmetrical function after the calibration transformation, this unique accurate mass is in fact a weighted average of all the isotopes included in the cluster with their relative abundances as weights, i. e., a mathematically defined centroid. With the centroids for all isotope clusters clearly defined and calculated, one can in theory perform a molecular formula search based on the actual observed centroids and the theoretical centroids calculated from the corresponding isotope distributions given the elemental compositions. One may even incorporate the apparent peak areas for the identified peaks as weights into the subsequent searches and scoring based on centroid masses to reflect the relative abundances of these isotope clusters.
  • centroid and theoretical centroid masses can be performed through a weighted least squares regression which will automatically provide some measurement for the goodness-of-fit or probability for the molecular formula assignment or library hit.
  • the statistics and assignment of probabilities become less rigorous or elegant or diagnostic due to the loss in information content during the peak analysis process where all unresolved isotopes are effectively binned together.
  • Fig. 3 shows the mass spectra of one ion with its monoisotopic mass within 10 mDa of that of the ion of interest, but with very dissimilar spectral patterns due to the differences in their elemental compositions.
  • This comprehensive mass spectral calibration enables interference correction without use of high resolution mass spectrometers or collision cells on even unit mass resolution mass spectrometers, a unique feature generally thought of as being reserved for higher resolution systems.
  • Quantitative ICP-MS analysis can now be performed without identifying the monoisotope peak, which may be quite weak or even un-observable. Furthermore, this analysis can also be performed using any section of the isotope clusters that may contain many individual isotopes without physically separating them. It may even be possible to use a single isotope cluster, for example, the M+2 cluster from Fig. 2B, for a quantitative ICP- MS analysis, especially when other clusters have poor signal to noise, encounters nonlinearity, or have significant overlaps from interferences.
  • Fig. 5A shows a section of such a simulated raw mass spectral data corresponding to As. This step is shown as 410 in the flowchart of Fig. 4.
  • Fig. 5B shows the same section in Fig.
  • a peak picking process preferably one disclosed in the section starting from line 8 on page 32 of United States Patent Application Serial No. 10/689,313 or PCT/US2004/034618 filed on 20 October, 2004 (section starting from line 14 of page 34), to generate a peak list containing peak mass locations as well as integrated peak areas.
  • Either target peak shape functions or actual peak shape functions may be used for peak analysis, depending on whether a calibration step 410B in Fig. 4 has been performed.
  • the monoisotopic peak mass thus calculated from the data trace in Fig. 5B is 74.931 IDa. .
  • this aspect of the invention calculates the theoretical mass spectral isotope profile for each of the candidate atom or polyatom identified and compare its theoretical mass spectral profile with that of the actual isotope profile as acquired or after the calibration (external and/or internal calibration, step 410B in Fig. 4).
  • This calculation involves calculating the theoretical isotope distribution followed by convolution with either the target peak shape functions or actual peak shape functions, all defined in the comprehensive calibration process disclosed in the United States Patent Application Serial No. 10/689,313 or PCT/US2004/034618 filed on 20 October, 2004.
  • the actual mass spectral peak shape after calibration where applicable will be transformed to the target peak shape function.
  • a Weighted Multiple Linear Regression (WMLR, equation 6 on page 34 of United States Patent Application Serial No. 10/689,313 and equation 6 on page 35 of PCT/US2004/034618 filed on 20 October, 2004) is now performed between the acquired raw or calibrated isotope profile (for example, Fig. 5B) and each peak component matrix using the inverse of the peak intensity variance w (page 34 of United States Patent Application Serial No. 10/689,313 and page 35 in PCT/US2004/034618 filed on 20 October, 2004) as weights.
  • a fitting error (Root-Mean Squared Error or RMSE) or t-value is calculated from each regression (pages 35 and 39 of United States Patent Application Serial No. 10/689,313 and on pages 36 and 39 in PCT/US2004/034618 filed on 20 October, 2004). This step is illustrated as 410J in Fig. 4.
  • This aspect of the invention eliminates intermediate and error-prone steps for quantitative analysis of mixture of ions, yielding more reliable results by taking into consideration of all the isotopes available, their relative abundances, and their differing masses.
  • this profile-based quanitative analysis offers significant advantages even though the monoisotopic peak is likely to be the most abundant for these atoms or polyatoms.
  • FWHM instrument resolution width
  • mass spectrometers such as TOF or FTMS
  • Fig. 6A shows a simulated mass spectral isotope profile measured on a unit mass resolution instrument after the comprehensive calibration (solid line) and the fitted As (exact monoisotopic mass 74.921 ODa) theoretical profile (dashed) with residual given in Fig. 6B.
  • Fig. 6C shows the fit with both As and Ar 2 + (fitting residual shown in Fig. 6D).
  • Fig. 6E shows the fitting with As, Ar 2 + , and ArCl
  • the fitting is much improved (Fig. 6E) with the residual much reduced (Fig. 6F).
  • the regression coefficients represent the relative contribution of each ion into the combined mass spectral profile data, providing quantitative information about the ions involved in addition to qualitative identification information.
  • the decision to add components into the peak component matrix P is made at step 410L in Fig. 4, typically based on statistical measures from the regression such as F-test or t-test.
  • the step of adding one or more components into the peak component matrix for mixture analysis and identification in a mixture is illustrated as 410M in Fig. 4.
  • a decision can be made to remove one or more components at step 410N based on similar significance test such as F-test or t-test.
  • the step of deleting one or more components from the peak component matrix is illustrated as 410O in Fig. 4.
  • the added or removed components mentioned above may also include baseline component or components or the 1 st derivative terms mentioned above.
  • isobaric tags used in iTRAQTM (WO 20004/070352 A2) where digested peptides from different samples may be labeled with a different reporter tag (with mass of 114.1, 115.1, 116.1 , or 117.1), which is attached to a corresponding balance tag of 31 , 30, 29, or 28 such that the combined tag has the same nominal mass, allowing for peptides from different samples to be tagged differently with the same combined mass.
  • the same peptide from different samples would be tagged with tags of the same combined mass, giving the peptide of different tags the same apparent mass in MS analysis where one MS/MS will be performed to break apart the differently tagged peptide ion into a reporter tag, balance tag, peptide and its fragments during the MS/MS fragmentation.
  • Each reporter tag would now have different mass of 114.1, 115.1 , 116.1, or 117.1, the signal intensity of each corresponding to the amount of this peptide in a particular sample before the mixing and combining.
  • Another example involves drug metabolism resulting from the dehydrogenation of the parent drug or its fragment where a combined isotope profile from the ion before and after dehydrogenation will be observed.
  • the combined isotope profile is a linear combination of two individual isotope profiles only 2Da apart from each other with significant overlaps. It is desirable to measure the relative concentration of the dehydrogenated metabolite to that of the parent drug or drug fragment in order to assess the extent of this particular metabolic process.
  • Another example involves mass spectral measurement of a mixture of "cold” and “hot” samples where the "cold” sample refers to an unlabeled sample and "hot” sample refers to a (radio) labeled sample such as C 14 -labeled sample, resulting in an observed mass spectral response composed of two mutually overlapping isotope profiles. Due to the high chemical and ionization similarity between the unlabeled and labeled ion, they each serve as a great internal reference to the other when quantitative information is sought after in an analysis. It is therefore highly desirable to quantify the relative concentrations of the unlabeled and labeled ion with overlapping isotope profiles.
  • step 2 When no calibration is available, one may omit steps 2 & 3 and consider a generally accepted peak shape function, either mathematically defined or numerically derived from the measurement of standard ions, as the peak shape function for the convolution operation in step 5.
  • peak shape function for the convolution operation in step 5.
  • These insignificant components may include baseline components or 1 st derivative components mentioned above.
  • centroiding is a very typical approach according to prior art from commercially available systems. As mentioned above, the centroiding process prone to error due to the deconvolution nature of the operation.
  • This profile mode analysis when performed in the preferred embodiment with the comprehensive mass spectral calibration, can further enhance the analytical capacity from 4 ions to possibly 100-400 co-existing ions in such a narrow mass window due to the high mass accuracy (down to 5-10mDa mass error) achievable on even unit mass resolution systems.
  • ICP-MS Inductively Coupled Plasma Mass Spectrometry
  • the regression coefficients c can be numerically calculated using any of the available matrix or non-matrix computational routines well established in the art, along with the fitting residual e, which can be used to compute relevant fitting statistics for statistical inference on the significance or the lack thereof for any of the components included in the peak component matrix K. Components can be either added or removed according to Fig. 7, using any relevant statistic metric thus derived or other user input parameters. The construction of the peak component matrix K will now be described.
  • a baseline component in the peak component matrix can be measured experimentally in a separate data acquisition using the matrix-matched blank sample, in which case the baseline component (a mass spectral data array the same dimension as the r) would be arranged as a column in the peak component matrix K in above equation 1 and the corresponding regression coefficient (an element in c) would represent the relative change in mass spectral intensities between the blank when the baseline component is measured and unknown sample when the mass spectral data r is acquired. It should be noted that more than one baseline components can be accommodated into the peak component matrix K resulting in more than one regression coefficients.
  • some or all of the baseline columns in K can be calculated, e.g., as a flat line (zeroth order) or a tilted line (1 st order) or any nonlinear form such as quadratic or exponential.
  • a flat line zero order
  • a tilted line 1 st order
  • any nonlinear form such as quadratic or exponential.
  • IRMS isotope ration mass spectrometry
  • the typical interferences from the ICP source can also be added, including possible polyatomic ions such as Ar 2 + , ArO + , each element with one oxygen added etc. These polyatomic ions can even have a range of charges even though singly charged positive ion is most likely the case for ICP-MS. Though it is in theory possible to measure these possible interferences to be arranged into columns in K matrix, some of these interferences may not be stable at all to be isolated and measured alone, making theoretical calculations of them more desirable and preferred. The user may optionally elect to consider some but not other forms of the interference based on the experimental conditions such as the type of sample, sample matrix, ICP source condition such as power level, carrier gas or collision or reaction gas involved.
  • rj (n x 1) refers to the net mass spectral signal for component i
  • Q refers to the regression coefficients or relative concentration for this same component
  • k; (n x 1) is taken from the ith column from the peak component matrix K.
  • the separated mass spectral signal r; or its corresponding regression coefficient c can be used along with similar terms obtained after the same processing via Equation2 1 and 2 of other concentration standard samples to establish a calibration curve which relates the separated mass spectral signal or its regression coefficient to the known/given concentration.
  • This calibration curve could then be applied to determine the unknown concentrations of an unknown sample through its separated mass spectral signal or corresponding regression coefficient, after a similar processing of the unknown sample through Equations 1 and 2.
  • ICP-MS analysis there are typically internal concentration standards of fixed or known concentrations at various m/z values added to or co-introduced along with each concentration standard or unknown sample so as to monitor and compensate for any mass spectral intensity variations such as those from the ICP source fluctuation. Proper interpolation is typically carried out to arrive at a compensation or normalization factor for any given m/z value of interest.
  • the separated mass spectral signal r; or its corresponding regression coefficient c can be used instead so as to eliminate any contamination of internal standard signals by interferences or even the analyte of interest, making the selection of suitable internal standards much more easier.
  • the regression coefficients obtained from Equation 1 can be used in any statistical significance test to determine if and how much of a particular element exists, thus leading to an ultimate elemental analysis system capable of delivering on-the-spot qualitative and quantitative analysis for any sample without any method development.
  • the mass spectral data r from Equation 1 does not have to be continuously sampled or even equally spaced profile mode data from the mass spectrometer covering the complete mass spectral range (m/z values). It can have holes or gaps to avoid very intense signals (from Ar 2 in the ICP source, for example) that are saturating the detector. It can also just be a segment of mass spectral range or a combination of a few segments, e.g., set up to monitor and analyze a particular set of analytes of interest for given applications.
  • the calibration of mass spectral data can be carried out using mass spectral calibration standards typically involving a few pure elements located across the mass spectral range of interest, e.g., a calibration mixture of Be (m/z 9)/Rh (m/z 103), Tb (m/z 159), and Bi (m/z 209), measured under the same ICP-MS conditions as the concentration standard or unknown sample (including internal standard), i.e., under the same ICP source power, temperature, carrier gas flow rate, mass spectrometer scan range/rate, settle/dwell time etc.
  • uncalibrated mass spectral data can also be used to some effect, the error term from Equation 1 above would be larger due to the error in m/z calibration or peak shape mismatch between r and those components in K, leading to sub-optimal results.
  • This new software based approach of interference treatment addresses all the issues associated with the hardware based reaction or collision cell approaches without the loss of ion signal and thus preserving the high sensitivity of ICP-MS.
  • the description above contains many specifics, these should not be construed as limiting the scope of the invention but as merely providing illustrations of some feasible embodiments of this invention.
  • linear equations and linear regressions are used for illustrative purpose but the same approach can be utilized to nonlinear equations with the nonlinear regressions for cases where such nonlinear relationship is preferred.
  • the calibrated profile mode mass spectral data are preferred, it is possible to use the same methodology for un-calibrated data or centroid data with typically inferior results.
  • a different form of ionization source is capable of turning elemental species into ions for mass spectral analysis, the same approach can be applied to the same or similar effects.

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Abstract

La présente invention concerne un procédé permettant d'expliquer les données spectrales ou de compenser les interférences dans le cadre de l'analyse de données de spectre de masse. Ledit procédé comprend les étapes consistant à acquérir des données de spectre de masse en mode profil ; à étudier les formes possibles des analytes et/ou des interférences au sein du domaine spectral ; à calculer une réponse théorique du spectre de masse ou à mesurer une réponse effective du spectre de masse pour une forme correspondante de l'analyte et/ou de l'interférence ; à former une matrice à base des composants à l'origine des pics comprenant une réponse du spectre de masse pour chaque forme correspondante des analytes et/ou des interférences ; à réaliser une analyse de régression impliquant la matrice à base des composants à l'origine des pics et les données de spectre de masse acquises ; et à rapporter les coefficients de régression ou les signaux de spectre de masse associés comme représentant les concentrations ou les signaux de spectre de masse des formes correspondantes d'analytes et/ou d'interférences. L'invention concerne également un système de spectromètre de masse (fig.7) fonctionnant conformément audit procédé et un support informatique utilisable avec un ordinateur et le spectromètre de masse et qui va actionner ce dernier.
PCT/US2013/020663 2012-01-08 2013-01-08 Traitement exhaustif des interférences dans le cadre d'une analyse au moyen d'un spectromètre de masse à source à plasma inductif (icp-ms) WO2013104004A1 (fr)

Applications Claiming Priority (2)

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CN112033951A (zh) * 2020-08-20 2020-12-04 中航金属材料理化检测科技有限公司 一种基于icp-aes法测定铁基样品中铈含量的方法
WO2022063816A1 (fr) 2020-09-23 2022-03-31 Roche Diagnostics Gmbh Procédé mis en œuvre par ordinateur de détection d'au moins une interférence et/ou d'au moins un artefact dans au moins un chromatogramme
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