WO2024132920A1 - Standardized sensitivity for analytical instruments - Google Patents

Abstract

A method comprises determining at least one baseline sensitivity of an analytical instrument, determining at least one sensitivity attenuation based on the at least one baseline sensitivity and at least one target sensitivity, and performing a measurement with the analytical instrument to generate a measurement result. Performing the measurement with the analytical instrument comprises using the at least one sensitivity attenuation. The method may further comprise performing the method steps for a plurality of analytical instruments with the same at least one target sensitivity.

Description

Standardized sensitivity for analytical instruments

The present invention generally relates to analytical methods and corresponding systems, particularly to methods and systems for controlling instrument sensitivity.

Generally, the sensitivity of analytical instruments is known to depend on a large number of factors and it is often impractical to keep them under perfect control during the life cycle of the instrument - or even at its start when produced in serial production. In the following, the present invention will generally be explained with reference to ICP-MS systems. However, it will be understood that the present method may also be applied to other analytical methods and systems, particularly such methods and systems that involve ion and/or light optics.

For example, the base sensitivity of inductively coupled plasma mass spectrometers (ICP- MS) may generally be subject to variations. That is, a certain lack of control can be seen in variation of instrument sensitivities achieved within an instrument's series manufacturing. Often, even a 100% check of critical components may not be sufficient to guarantee best performance in every individual case. One example for this can be given by the individual quality of the skimmer cones, which may greatly impact the overall system performance.

Such variation can often lead to difficult situations with users using more than one instrument of the same type. They might face a situation wherein for example their second instrument does achieve the guaranteed specifications, but at the same time stays significantly behind the baseline or base sensitivity of their first instrument. This may for example be disadvantageous to the comparability of measurement results on these two instruments, which may in turn impose requirements on the planning of analyses, e.g., which analysis is run on which instrument. Thus, it may for example reduce a user's flexibility in using such instruments.

In order to achieve a narrower distribution of base sensitivity, a potential path would be to identify, investigate and tighten all specifications of single instrument parts that could be responsible for sensitivity variations. However, while this may often deliver some success, it is a complex, time consuming and thus costly process, which overall may also be limited with regard to the reduction in variation that may be achieved. In particular, the effort of further reducing variations by investigating and optimizing instrument parts may oftentimes increase significantly with reducing variation. That is, it can become disproportionately more elaborate the further the variations are reduced.

In some cases, too high sensitivity of instruments or parts thereof can also be problematic since they may experience saturation effects. For such cases it is known to attenuate signals to avoid saturation effects. For example, D. Stresau and K. L. Hunter describe a pulse counting detector using conventional electronics which can handle ion count rates in excess of 10 GHz through a controllable electron attenuation to adjust the device's ion detection efficiency (D. Stresau and K. L. Hunter, "Ion Counting Beyond lOghz Using a New Detector and Conventional Electronics", presented at the European Winter Conference on Plasma Spectrochemistry, February 4-8, 2001. Lillehammer, Norway). However, by simply calibrating single instruments such that they fall within a certain range of a desired sensitivity, some of the potential of the instrument is lost and thus wasted.

Furthermore, it is known that such instruments loose sensitivity over time, which typically requires recalibration of the instrument. For example, a calibration may be triggered when the sensitivity falls under a certain sensitivity level. However, it may generally not be obvious to a user if and when a calibration is needed up until the instrument notifies the user which typically only happens when the user intends to use the instrument. This may generally be disadvantageous as the analysis may have to be postponed until after the successful calibration. Additionally, such a calibration takes valuable instrument time that may otherwise be used for running analyses. This can for example be particularly problematic in routine laboratories with a high throughput of analyses.

In light of the above, it is an object to overcome or at least alleviate the shortcomings and disadvantages of the prior art. More particularly, it is an object of the present invention to provide a predictable and stable instrument sensitivity.

These objects are met by the present invention.

In a first aspect, the present invention relates to a method. The method comprises determining at least one baseline sensitivity of an analytical instrument; determining at least one sensitivity attenuation based on the at least one baseline sensitivity and at least one target sensitivity; and performing a measurement with the analytical instrument to generate a measurement result, wherein performing the measurement with the analytical instrument comprises using the at least one sensitivity attenuation.

In other words, at least one baseline sensitivity of the analytical instrument may be established, e.g., through measurement of the current instrument sensitivity, and based on said at least one baseline sensitivity and at least one target sensitivity at least one sensitivity attenuation may be determined, e.g., calculated. The at least one baseline sensitivity may denote an instrument sensitivity available without attenuation. That is, the at least one baseline sensitivity may change, e.g., decline with usage and aging of the instrument. The at least one target sensitivity may for example be pre-defined through a user or manufacturer and may denote a desired sensitivity for the analytical instrument. In some cases, the target sensitivity may for example relate to a certain method performed by the instrument, i.e., the target sensitivity may for example be different for different methods performed by the instrument. The sensitivity attenuation may generally allow to attenuate the instrument sensitivity to provide at least one attenuated sensitivity, also referred to as at least one standardized sensitivity. The at least one attenuated sensitivity may be close to the at least one target sensitivity (e.g., within ± 10%), preferably substantially identical to the target sensitivity. The attenuation may be software- or hardware-based. Subsequently a measurement is performed with the analytical instrument to generate a respective measurement result and using the at least one sensitivity attenuation. In other words, the measurement is performed with the at least one attenuated sensitivity.

Therefore, the present method advantageously allows to artificially reduce the sensitivity of an analytical instrument, wherein reducing an instrument's sensitivity may advantageously allow to meet specified or otherwise desired intensity values more precisely with a narrow window of variance. This may for example allow to free up a so- called sensitivity reserve (or performance reserve) which can subsequently be used to quickly retune an instrument's sensitivity to the at least one target sensitivity and to thus counteract any sensitivity decline or increase that may occur during usage of the instrument. Additionally, users with two or more instruments may be enabled to tune their analytical instruments to provide a substantially identical sensitivity performance. In addition, variations in sensitivity of all instruments leaving series production may be reduced to a minimum.

Generally, it will be understood that an instrument may typically comprise a plurality of sensitivities, e.g., one sensitivity for each analyte parameter, i.e., each mass-to-charge ratio m/z in case of a mass spectrometer. Thus, it may comprise at least one baseline sensitivity, wherein each baseline sensitivity may be associated to a different analyte parameter and similarly, at least one target sensitivity may be provided and/or (predefined, wherein each target sensitivity is associated with a different analyte parameter.

Determining the at least one sensitivity attenuation based on the at least one baseline sensitivity and the at least one target sensitivity may comprise determining at least one attenuation factor based on the at least one baseline sensitivity and the at least one target sensitivity, and determining the at least one sensitivity attenuation based on the at least one attenuation factor.

That is, determining the at least one sensitivity attenuation may comprise determining at least one attenuation factor and subsequently determining the at least one sensitivity attenuation based on the at least one attenuation factor. The at least one attenuation factor may generally be defined as the ratio of the at least one target sensitivity and a respective baseline sensitivity, wherein the respective baseline sensitivity is associated with the same analyte parameter. Thus, the attenuation factor may denote the relative sensitivity.

Each of the at least one baseline sensitivity may be associated with an analyte parameter of the instrument.

In other words, each of the at least one baseline sensitivity is allocated to a respective analyte parameter of the instrument, e.g., m/z for a mass spectrometer. In this regard, an analyte parameter may denote a parameter characterizing a property of the analyte that the measuring instrument is designed to measure. Determining the at least one baseline sensitivity may comprise measuring an associated instrument sensitivity to define the respective baseline sensitivity.

That is, each baseline sensitivity may be related to a certain analyte parameter, e.g. m/z, and determining the at least one baseline sensitivity may comprise measuring an associated instrument sensitivity, i.e., an instrument sensitivity associated with the same analyte parameter, which may define the respective baseline sensitivity for that specific analyte parameter. In other words, the baseline sensitivity may correspond to the measured instrument sensitivity associated with the same analyte parameter.

A baseline reference may be used for measuring the associated instrument sensitivity.

A baseline reference may for example be a reference solution comprising a defined concentration of known analytes, such that a sensitivity may be measured for each of the comprised analytes. Thus, the baseline reference may for example define the analyte parameters for which a baseline sensitivity may be determined and thus may define or at least the number of baseline sensitivities comprised by the at least one baseline sensitivity.

The method may further comprise optimizing at least one instrument sensitivity prior to determining the baseline sensitivity.

It will be understood that the optimized at least one instrument sensitivity may be different to the associated instrument sensitivity of the at least one baseline sensitivity, in particular it may relate to different analyte parameters. For example, the at least one instrument sensitivity may be optimized based on a certain reference solution, i.e., for certain analytes in the reference solution associated with a certain analyte parameter, e.g., m/z. The at least one baseline sensitivity may in turn be determined using a different reference solution, e.g., baseline reference, and thus be related to different m/z and/or only some of the m/z of the at least one optimized instrument sensitivity.

Optimizing at least one instrument sensitivity may for example comprise using a standard optimization approach, e.g., through a software-based instrument optimization. In the case of an ICP-MS system this may be provided through a so-called autotune procedure, wherein the instrument may adjust at least a subset of the instrument's parameters in order to optimize the instrument's sensitivity. It will be understood that a subset may also only comprise a single instrument parameter. That is, the instrument may be tuned to its best (tuning) sensitivity using standard optimization methods. More specifically, it may be tuned to the best sensitivity available through tuning, i.e., without for example exchanging parts, which may allow for even better sensitivity.

Optimizing the at least one instrument sensitivity may comprise using an optimization reference.

Again, it will be understood that the baseline reference may for example be a reference solution comprising a defined concentration of known analytes, such that a sensitivity may be optimized for each of the comprised analytes. Such an optimization reference may also be referred to as tuning standard.

The optimization reference may be different to the baseline reference.

The optimization reference may be identical to the baseline reference

Optimizing the at least one instrument sensitivity may comprise employing a softwarebased instrument optimization.

Optimizing the at least one instrument sensitivity may comprise optimizing a respective instrument sensitivity for each analyte comprised in the optimization reference.

Optimizing the at least one instrument sensitivity may comprise adjusting at least a subset of parameters of the instrument.

It will be understood that a subset may also only comprise a single instrument parameter. For example, instrument parameters such as lens voltages, flow rates, ICP electronics and quadrupole voltages and/or frequencies may be adjusted.

The at least one attenuation factor may be a plurality of attenuation factors.

The at least one target sensitivity may correspond to a specified instrument sensitivity.

The specified instrument sensitivity may correspond to an instrument sensitivity that is guaranteed by the manufacturer and may thus also be referred to as guaranteed sensitivity.

The at least one target sensitivity may be provided by a user.

In other words, the user may provide and thus define the at least one target sensitivity, for example with respect to a method that the user intends to perform with the analytical instrument. That is, different methods that may be performed with the analytical instrument may have different requirements regarding the instrument's sensitivity.

The target sensitivity may amount to at least a pre-defined minimum sensitivity.

It will be understood that a pre-defined minimum sensitivity may for example correspond to a sensitivity required to ensure proper functionality of the instrument and/or to ensure reliable results for a certain method. Thus, the target sensitivity may be higher or equal to the pre-defined minimum sensitivity.

The at least one target sensitivity may be a single target sensitivity. It will be understood that such a single target sensitivity may preferably be applied over the whole measurement range of the instrument, e.g., in terms of ICP-MS for all m/z.

The at least one target sensitivity may be given as a target factor in the range of 0 to 1 with respect to the baseline sensitivity.

That is, the at least one target sensitivity may be defined relative to the baseline sensitivity. For example, the at least one target sensitivity may be given as a target factor of 0.5 of the baseline sensitivity, which corresponds to a target sensitivity of 50% of the baseline sensitivity.

The at least one attenuation factor may correspond to the target factor.

Each of the at least one attenuation factor may be associated with at least one analyte parameter of the instrument.

That is, similar to the at least one baseline sensitivity, each of the at least one attenuation factor may be related to a certain analyte parameter, e.g., m/z, which may be determined through the respective at least one baseline sensitivity and/or the respective at least one target sensitivity based on which the at least one attenuation factor is determined.

At least one, and preferably each, attenuation factor may be determined as a ratio of the respective target sensitivity and the respective baseline sensitivity associated.

That is, the at least one attenuation factor may generally correspond to a ratio of target sensitivity and baseline sensitivity. Overall, it will be understood that the at least one attenuation factor, the at least one target sensitivity and the at least one baseline sensitivity may each comprise a different number of elements, e.g. a single target sensitivity may be given and based thereon a single attenuation factor or alternatively an attenuation factor for some or each of the at least one baseline sensitivity may be determined. In particular, target sensitivity and baseline sensitivity may be associated with respective analyte parameters, e.g., each of the at least one baseline sensitivity may be associated with a specific analyte parameter. The same may be true for the target sensitivity, however, the target sensitivity may for example also be independent of a specific analyte parameter, i.e., constant, and thus associated to all analyte parameters.

The at least one attenuation factor may be determined as the ratio of the at least one target sensitivity and each of the at least one baseline sensitivity.

The at least one attenuation factor may be determined as the ratio of the single target sensitivity and a selected one of the at least one baseline sensitivity.

Thus, a constant attenuation factor may be determined. The selected one of the at least one baseline sensitivity may correspond to the lowest baseline sensitivity of the at least one baseline sensitivity.

In other words, a constant attenuation factor may be determined wherein out of the at least one baseline sensitivity, the lowest baseline sensitivity is selected to determine the attenuation factor. This may advantageously allow to avoid an attenuated sensitivity being attenuated too strongly while still using only a single attenuation factor.

The at least one target sensitivity may be at most equal to the respective at least one baseline sensitivity.

It will be understood that for example in case of a single (parameter-independent) target sensitivity all of the at least one baseline sensitivities constitute respective baseline sensitivities. On the other hand, in case of both the at least one target sensitivity and the at least one baseline sensitivity being parameter-dependent, e.g. dependent on m/z, respective values correspond to the same analyte parameter.

Furthermore, it will be understood that in case at least one of the at least one target sensitivity is higher than the respective baseline sensitivity, an optimization of the baseline sensitivity either through a standard optimization procedure, or if need be, through more elaborate maintenance, e.g., exchanging parts, may be needed. Alternatively, the at least one target sensitivity may be lowered, if possible, e.g., if still above the specified sensitivity and/or the minimum sensitivity.

Determining at least one sensitivity attenuation may comprise determining an attenuation function, wherein the at least one sensitivity attenuation comprises the attenuation function.

In other words, the at least one sensitivity attenuation may comprise an attenuation function that allows to provide the desired attenuation of the instrument sensitivity in accordance with the at least one baseline sensitivity and the at least one target sensitivity. Such an attenuation function may particularly be determined for a software-based instrument attenuation.

The attenuation function may provide an attenuation value for each analyte parameter within the instrument's measurement range.

That is, the attenuation function may provide a respective attenuation value, i.e., an amount of attenuation needed, for each analyte parameter within the measurement range. Specifically, the attenuation value may be a factor between 0 and 1 corresponding to the attenuation needed relative to the instrument sensitivity during measurement. Thus, the attenuation value may be similar to the attenuation factor.

The attenuation function may be constrained to values smaller than or equal to 1. The attenuation function may be determined through interpolation and/or extrapolation based on the plurality of attenuation factors.

For example, the attenuation function may be determined through an interpolation, e.g., using cubic spline functions, based on the plurality of attenuation factors.

The attenuation function may be determined through curve fitting to the plurality of attenuation factors.

That is, the attenuation function may be determined by fitting at least one function, e.g., a polynomial function, to the plurality of attenuation factors.

Curve fitting may comprise linear regression.

Curve fitting may comprise non-linear regression.

Curve fitting may comprise using the least squares method.

Each of the attenuation function may be a linear or polynomial function.

The attenuation function may be a piecewise-defined function comprising a plurality of subfunctions.

In other words, the attenuation function may be a function defined by multiple subfunctions, wherein each sub-function may apply to a different interval of the analyte parameter domain. Typically, the piecewise-defined function may also be a piecewise- continuous function.

Each of the sub-functions may be determined through curve fitting to a subset of the plurality of attenuation factors.

Each of the sub-functions may be determined through interpolation and/or extrapolation based on a subset of the plurality of attenuation factors.

The at least one attenuation factor may be a single attenuation factor.

The attenuation function may be a constant attenuation function equal to the attenuation factor.

In other words, the attenuation function is a linear function independent of the analyte parameter, e.g., m/z, and thus comprising a slope of zero.

The method further may comprise measuring attenuation calibration data, wherein the attenuation calibration data is indicative of a dependency of a relative signal intensity on at least one instrument parameter for at least one analyte parameter. It will be understood that the relative signal intensity is given relative to the signal intensity as measured with non-detuned, standard instrument parameters, e.g., the reference intensity corresponds to the intensity measured after sensitivity optimization. Thus, the attenuation calibration data may be indicative of the dependence of the relative signal intensity on the detuning of at least one instrument parameter. For example, attenuation calibration data may provide the relative signal intensity depending on a lens voltage.

Measuring the attenuation calibration data may comprise varying at least one instrument parameter and determining the respective relative signal intensity for the at least one analyte parameter.

In other words, measuring the attenuation calibration data may comprise detuning at least one instrument parameter and determining, e.g., measuring, the signal intensity relative to the signal intensity determined to the non-detuned instrument parameter.

Measuring the attenuation calibration data may comprise using a calibration standard.

The calibration standard may be equal to the baseline reference.

The calibration standard may define the available analyte parameters.

The attenuation calibration data may be indicative of a dependency of a relative signal intensity on at least one instrument parameter for a plurality of analyte parameters.

Determining at least one sensitivity attenuation may comprise determining at least one instrument-parameter function, wherein the at least one sensitivity attenuation comprises the at least one instrument-parameter function.

That is, at least one instrument-parameter function may be determined and comprised by the at least one sensitivity attenuation. The at least one instrument-parameter function may generally allow to determine a detuning of a respective instrument parameter which results in a desired attenuation of the instrument sensitivity and thus allows to provide at least one attenuated sensitivity.

Each of the at least one instrument-parameter function may provide a respective value of a corresponding instrument parameter value as a function of the analyte parameter.

Determining the at least one instrument-parameter function may comprise determining a plurality of instrument parameter sets based on the attenuation calibration data, wherein each of the instrument parameter sets is associated to a different analyte parameter, and wherein each instrument parameter set comprises at least one instrument parameter value chosen such that the resulting relative signal intensity corresponds to one of the at least one attenuation factor associated with the same analyte parameter. It will be understood that an instrument parameter set may comprise a single instrument parameter value or a plurality of instrument parameter values each of which corresponding to a different instrument parameter.

In other words, based on the attenuation calibration data, a plurality of instrument parameter sets may be determined, each of which associated with a different analyte parameter, and such that each instrument parameter set comprises at least one instrument parameter value for which the instrument sensitivity is attenuated in accordance with a respective attenuation factor. Thus, when setting the instrument parameters to the instrument parameter values comprised by one instrument parameter set, the respective sensitivity of the instrument for the associated analyte parameter may be attenuated, at least approximately, by the respective attenuation factor. That is, the resulting attenuated sensitivity may for example be within ± 10%, preferably ±5% of the respective target sensitivity.

An instrument parameter set may be determined for each combination of attenuation factor and respective analyte parameter comprised by the at least one attenuation factor provided that there is attenuation calibration data available for the respective analyte parameter.

In other words, each of the at least attenuation factor may be associated with at least one respective analyte parameter and for each such combination for which attenuation calibration data is available, an instrument parameter set may be determined. It will be understood that the available attenuation calibration data may be limited with respect to analyte parameters as it may only be determined, e.g., measured, for a limited number of analyte parameters, i.e., for a limited number of reference analytes.

Determining the plurality of instrument parameter sets may comprise interpolating and/or extrapolating at least part of the attenuation calibration data to determine at least one calibration curve.

For example, the attenuation calibration data may only comprise data regarding the relative signal intensity for a finite number of instrument parameter values of a respective instrument parameter, and thus a calibration curve may be determined to allow to at least approximate instrument parameter values for which no explicit calibration data is available. Such a calibration curve may be determined through interpolation/extrapolation, e.g., a using cubic spline function, but also through curve fitting.

Determining the plurality of instrument parameter sets may comprise interpolating and/or extrapolating at least part of the attenuation calibration data to determine at least one calibration curve for each analyte parameter for which the attenuation calibration data is indicative of the dependency of the relative signal intensity.

Determining the plurality of instrument parameter sets may comprise curve fitting at least part of the attenuation calibration data to determine at least one calibration curve. Determining the plurality of instrument parameter sets may comprise curve fitting at least part of the attenuation calibration data to determine a calibration curve for each analyte parameter for which the attenuation calibration data is indicative of the dependency of the relative signal intensity.

Each of the at least one calibration curve may provide the relative signal intensity as a function of a respective instrument parameter for a specific analyte parameter.

Determining the at least one instrument-parameter function may further comprise determining a respective instrument-parameter function for each instrument parameter comprised in the plurality instrument parameter sets.

Determining the at least one instrument-parameter function may comprise curve fitting instrument parameter values comprised by the instrument parameter sets which are associated with the same instrument parameter.

In other words, each instrument parameter set may comprise one or more instrument parameter values each relating to a different instrument parameter, wherein each instrument parameter set is associated to a different analyte parameter. Thus, a respective instrument-parameter function may be determined for each of these different instrument parameters by curve fitting the respective instrument parameter values of the respective different instrument parameter comprised in the instrument parameter sets. It will be understood that instead of curve fitting also interpolation and/or extrapolation may be used.

At least one of the at least one instrument-parameter function may be a piecewise-defined function comprising a plurality of sub-functions.

Each of the sub-functions may be determined through curve fitting a subset of the instrument parameter values comprised by the instrument parameter sets.

Curve fitting may comprise linear regression.

Curve fitting may comprise non-linear regression.

Curve fitting may comprise using the least squares method.

Each of the at least one instrument-parameter function may be a linear or polynomial function.

The at least one instrument-parameter function may be a single, constant instrumentparameter function and wherein determining the instrument-parameter function may comprise identifying an instrument parameter value for which the relative signal intensity corresponds to the respective attenuation factor, wherein the instrument-parameter function corresponds to the identified instrument parameter value.

In other words, based on the attenuation calibration data and potentially a respective calibration curve, an instrument parameter value may be determined for which the relative signal intensity corresponds to the respective attenuation factor. The instrumentparameter function may then be constant, i.e., analyte- para meter independent, and its value may correspond to the identified instrument parameter value.

Only a single analyte parameter may be considered.

A plurality of analyte parameters may be considered and wherein the instrument parameter value may be chosen such that the relative signal intensity for all considered analyte parameters is at most equal respective attenuation factor.

In other words, the instrument parameter value is chosen such that a resulting attenuation is at most equal to an attenuation according to the respective attenuation factor.

Using the at least one sensitivity attenuation may comprise performing the measurement with settings of the analytical instrument based on the at least one sensitivity attenuation.

In other words, during the measurement, the instrument setting may be chosen or determined based on the at least one sensitivity attenuation.

Using the at least one sensitivity attenuation may comprise scanning at least one instrument parameter of the analytical instrument according to the respective at least one instrument-parameter function synchronously with the analyzer.

That is, the instrument parameters of the analytical instrument may be set based on the at least one instrument parameter function comprised by the at least one sensitivity attenuation, which may be analyte- para meter dependent. In particular, the instrument parameters of the analytical instrument may thus be scanned synchronously with the analyzer which may generally scan through the measurement range of the analyte parameter.

Using the at least one sensitivity attenuation may comprise setting an instrument parameter of the analytical instrument to an instrument parameter value of the constant instrument-parameter function.

Performing the measurement with the analytical instrument may comprise obtaining raw data, and using the at least one sensitivity attenuation comprises attenuating the raw data to obtain resulting data. That is, during performing the measurement with the analytical instrument, raw data may be obtained and subsequently the at least one sensitivity attenuation may be used to attenuate these raw data to obtain resulting data. Attenuating raw data may generally refer to attenuation the sensitivity in the raw data in accordance with the sensitivity attenuation.

Attenuating the raw data may comprise applying the attenuation function to the raw data to obtain resulting data.

That is, the (potentially analyte-parameter dependent) attenuation function may for example be applied to the raw data by multiplying the sensitivities comprised by the raw data with an attenuation value of the attenuation function for the respective analyte parameter.

Using the at least one sensitivity attenuation may result in measuring with at least one attenuated sensitivity.

The at least one attenuated sensitivity may lie within ± 10%, preferably ±5% of the at least one target sensitivity for the analyte parameters associated with the at least one attenuation factor.

The at least one attenuated sensitivity may lie within ± 10%, preferably ±5% of the at least one target sensitivity for all analyte parameters within a measurement range of the analytical instrument.

The method may further comprise measuring at least one attenuated sensitivity.

Again, the at least one attenuated sensitivity may be the sensitivity of the analytical instrument when using the at least one sensitivity attenuation. It may also be referred to as standardized sensitivity.

Measuring the at least one attenuated sensitivity may comprise performing a measurement of the instrument sensitivity using the sensitivity attenuation and a reference solution.

The method may further comprise determining at least one sensitivity reserve.

The sensitivity reserve may also be referred to as performance reserve and may denote the renounced sensitivity of the analytical instrument. In other words, the sensitivity reserve may denote the portion of the baseline sensitivity that is renounced through attenuation. The sensitivity reserve may advantageously allow to maintain and/or recover the at least one attenuated sensitivity. In particular, the instrument's sensitivity may typically decline with usage over time and the sensitivity reserve may allow to quickly and easily re-establish the desired sensitivity through usage of the sensitivity reserve. This may advantageously be faster than known standard instrument adjustment and/or so called autotune methods and therefore for example allow to reduce the instrument's downtime.

Determining the at least one sensitivity reserve may comprise calculating the at least one sensitivity reserve based on the at least one attenuated sensitivity and the at least one baseline sensitivity.

A development of the at least one sensitivity reserve may be monitored over time.

That is, the sensitivity reserve may be tracked over time and particularly stored to allow time-resolved analysis of the sensitivity reserve.

Timing of an instrument optimization and/or other maintenance tasks may be predicted based on the time-dependent development of the at least one sensitivity reserve.

That is, timing of future instrument optimization and/or maintenance tasks may be predicted based on the monitored development of the at least one sensitivity reserve with time. This may advantageously allow to more accurately predict when optimization and/or maintenance may be needed. In particular, a time-dependent decline of the sensitivity reserve may allow to predict timing of a next instrument optimization which may typically be required once the sensitivity reserve is not sufficient to compensate for a decline in the overall instrument sensitivity. Furthermore, for example a decline of the sensitivity reserve after optimization for consecutive instrument optimizations may indicate the need to schedule additional maintenance such as manual cleaning of part and/or exchange of parts of the instrument.

The method may further comprise adjusting the at least one sensitivity attenuation to correct for a change in the at least one baseline sensitivity.

That is, the at least one sensitivity attenuation may be adjusted to account for a change, particularly a decline in the at least one baseline sensitivity, in order to correct and/or maintain the attenuated sensitivity. This may advantageously allow to account and/or correct for a decline in the at least one baseline sensitivity without the need to run a full instrument optimization procedure, e.g., an autotune procedure. In particular, such adjusting may be faster than a full instrument optimization procedure and thus allow for more efficient use of the instrument through an increasing uptime.

Furthermore, such adjusting may for example for a hardware-based sensitivity attenuation not require a new measurement of attenuation calibration data as the instrument's response to the detuning of an instrument parameter may not change significantly, e.g., the response may also decline linearly, such that the dependence of the relative signal intensity on detuning of a parameter may not change significantly.

Adjusting the sensitivity attenuation may comprise determining at least one current sensitivity of the analytical instrument. It will be understood that the current sensitivity denotes the present instrument sensitivity.

Thus, the current sensitivity may provide a measure for a potential decline of sensitivity.

Determining the at least one current sensitivity of the analytical instrument may comprise determining at least one current baseline sensitivity of the instrument.

Determining the current sensitivity of the analytical instrument may comprise determining at least one current attenuated sensitivity of the instrument.

Adjusting the at least one sensitivity attenuation may comprise updating the at least one sensitivity attenuation if at least one of the at least one current sensitivity is below a respective pre-defined at least one target sensitivity threshold.

Adjusting the at least one sensitivity attenuation may comprise maintaining the at least one sensitivity attenuation as is, if each of the at least one current sensitivity is above the respective pre-defined at least one target sensitivity threshold.

That is, the sensitivity attenuation may not be altered provided there is no substantial decline in the instrument sensitivity in that the at least one current sensitivity is above the respective pre-defined target sensitivity threshold.

The at least one target sensitivity threshold may be at least 80% of the at least one target sensitivity, preferably at least 90% of the at least one target sensitivity.

Adjusting the at least one sensitivity attenuation may comprise maintaining the at least one sensitivity attenuation and instead proceeding with optimizing the at least one instrument sensitivity to obtain a new baseline sensitivity if at least one of the at least one current sensitivity is below the respective at least one target sensitivity.

In other words, if the at least one sensitivity reserve is not sufficient for adjusting the sensitivity attenuation, the at least one instrument sensitivity is instead optimized in order to obtain a new baseline sensitivity and subsequently determine a new sensitivity attenuation, e.g., including determining new attenuation calibration data.

Additionally or alternatively, adjusting the at least one sensitivity attenuation may comprise updating the at least one sensitivity attenuation if at least one of the at least one current sensitivity is above a respective pre-defined upper target sensitivity threshold.

Adjusting the at least one sensitivity attenuation may comprise maintaining the at least one sensitivity attenuation as is if each of the at least one current sensitivity is below the respective pre-defined upper target sensitivity threshold. That is, the sensitivity attenuation may not be altered provided there is no substantial increase in the instrument sensitivity in that the at least one current sensitivity is below the respective pre-defined upper target sensitivity threshold. The upper target sensitivity threshold may be at most 130% of the target sensitivity, preferably at most 120% of the target sensitivity.

In some embodiments, adjusting the at least one sensitivity attenuation may comprise maintaining the at least one sensitivity attenuation as is if each of the at least one current sensitivity is above the respective pre-defined target sensitivity threshold, and each of the at least one current sensitivity is below the respective pre-defined upper target sensitivity threshold.

Updating the at least one sensitivity attenuation may comprise the steps of determining the at least one attenuation factor based on the at least one current sensitivity and the at least one target sensitivity; and determining the at least one sensitivity attenuation based on and the at least one attenuation factor.

It will be understood that these steps may generally be the same as described in the above embodiments.

The analytical instrument may be a mass spectrometer.

The analytical instrument may be an inductively coupled plasma mass spectrometer.

The at least one instrument parameter may comprise an RF amplitude of a multipole comprised by the analytical instrument.

The at least one instrument parameter may comprise an RF frequency of a multipole by the analytical instrument.

The at least one instrument parameter may comprise at least one lens voltage of an ion lens comprised by the analytical instrument.

The at least one lens voltage may comprise a lens voltage of an exit lens of a multipole comprised by the analytical instrument.

The at least one lens voltage may comprise a lens voltage of an entry lens of a multipole comprised by the analytical instrument.

The at least one lens voltage may comprise a lens voltage of a focus lens comprised by the analytical instrument.

The mass spectrometer may comprise a differential pressure aperture upstream of an analyzer quadrupole and a focus lens configured to focus the ion beam into the pressure aperture, wherein the at least one instrument parameter preferably comprises the lens voltage of said focus lens. The analytical instrument may comprise a detector and the at least one instrument parameter comprises a voltage of a conversion dynode of the detector.

The analytical instrument may comprise a detector and the at least one instrument parameter may comprise a gate voltage configured to control a signal gain of the detector.

The analytical instrument may be an optical instrument.

The at least one instrument parameter may comprise a lens orientation.

The at least one instrument parameter may comprise a mirror orientation.

The method may further comprise performing the method steps for a plurality of analytical instruments with the same at least one target sensitivity.

The at least one target sensitivity may be at most equal to the lowest baseline sensitivity of the plurality of analytical instruments.

The at least one target sensitivity may be at most equal to the lowest baseline sensitivity of the plurality of analytical instruments after optimization of the at least one instrument sensitivity of each analytical instrument.

For example, in the context of ICP-MS each attenuation factor may be associated with at least one m/z, i.e. at least one analyte parameter. The respective analyte parameters may thus for example be limited to analytes available in the baseline reference, as each analyte corresponds to a certain m/z and thus a certain analyte parameter.

Generally, it will be understood that embodiments of the present invention relate to attenuating at least one sensitivity to arrive at at least one target sensitivity. This attenuation can be implemented software and/or hardware based. When using a hardwarebased attenuation, one or more instrument parameters may be changed and the corresponding signal attenuations may be measured to thus generate calibration data, which is subsequently used for the attenuation. Thus, also a sensitivity reserve may be provided, and this sensitivity reserve may be utilized in case the baseline sensitivity decreased subsequently. Then, the calibration data can be used to fast tap and to thus use the sensitivity reserve to again arrive at the desired target sensitivity.

The present invention also relates to a system. The system comprises an analytical instrument, and a controller, wherein the controller is configured to control the system to perform the method as discussed above.

The controller may comprise at least one processing device configured to control the system to perform the method. The analytical instrument may be a mass spectrometer.

The mass spectrometer may be an isotope ratio mass spectrometer.

The analytical instrument may be an inductively coupled plasma spectrometer.

The analytical instrument may be an optical emission spectrometer.

The present invention also relates to a use of the system as discussed above to perform the method as discussed above.

The present invention also relates to A computer program product comprising instructions which, when the program is executed by a system comprising an analytical instrument and a controller, cause the system to carry out the method discussed above.

The present invention also relates to a computer-readable data carrier having stored thereon the computer program product as discussed.

The present invention also relates to a data carrier signal carrying the computer program product as discussed.

The present invention is also defined by the following numbered embodiments.

Below, reference will be made to method embodiments. These embodiments are abbreviated by the letter "M" followed by a number. Whenever reference is herein made to "method embodiments", these embodiments are meant.

M l. A method comprising determining at least one baseline sensitivity of an analytical instrument; determining at least one sensitivity attenuation based on the at least one baseline sensitivity and at least one target sensitivity; performing a measurement with the analytical instrument to generate a measurement result, wherein performing the measurement with the analytical instrument comprises using the at least one sensitivity attenuation.

M2. The method according to the preceding method embodiment, wherein determining the at least one sensitivity attenuation based on the at least one baseline sensitivity and the at least one target sensitivity comprises determining at least one attenuation factor based on the at least one baseline sensitivity and the at least one target sensitivity, and determining the at least one sensitivity attenuation based on the at least one attenuation factor. M3. The method according to any of the preceding method embodiments, wherein each of the at least one baseline sensitivity is associated with an analyte parameter of the instrument.

M4. The method according to any of the preceding method embodiments, wherein determining the at least one baseline sensitivity comprises measuring an associated instrument sensitivity to define the respective baseline sensitivity.

That is, each baseline sensitivity may be related to a certain analyte parameter, e.g., m/z, and determining the at least one baseline sensitivity may comprise measuring an associated instrument sensitivity, i.e., an instrument sensitivity associated with the same analyte parameter, which may define the respective baseline sensitivity for that specific analyte parameter. In other words, the baseline sensitivity may correspond to the measured instrument sensitivity associated with the same analyte parameter.

M5. The method according to the preceding method embodiment, wherein a baseline reference is used for measuring the associated instrument sensitivity.

A baseline reference may for example be a reference solution comprising a defined concentration of known analytes, such that a sensitivity may be measured for each of the comprised analytes.

M6. The method according to any of the 2 preceding method embodiments, wherein the method further comprises optimizing at least one instrument sensitivity prior to determining the baseline sensitivity.

It will be understood that the optimized at least one instrument sensitivity may be different to the associated instrument sensitivity of the at least one baseline sensitivity, in particular it may relate to different analyte parameters. For example, the at least one instrument sensitivity may be optimized based on a certain reference solution, i.e., for certain analytes in the reference solution associated with a certain analyte parameter, e.g. m/z. The at least one baseline sensitivity may in turn be determined using a different reference solution, e.g., baseline reference, and thus be related to different m/z and/or only some of the m/z of the at least one optimized instrument sensitivity.

M7. The method according to the preceding method embodiment, wherein optimizing the at least one instrument sensitivity comprises using an optimization reference.

Again, it will be understood that the baseline reference may for example be a reference solution comprising a defined concentration of known analytes, such that a sensitivity may be optimized for each of the comprised analytes. Such an optimization reference may also be referred to as tuning standard. M8. The method according to the preceding method embodiment and with the features of M4, wherein the optimization reference is different to the baseline reference.

M9. The method according to embodiment M6 and with the features of M4, wherein the optimization reference is identical to the baseline reference.

M 10. The method according to any of the 4 preceding method embodiments, wherein optimizing the at least one instrument sensitivity comprises employing a software- based instrument optimization.

M il. The method according to any of the 4 preceding method embodiments, wherein optimizing the at least one instrument sensitivity comprises optimizing a respective instrument sensitivity for each analyte comprised in the optimization reference.

M 12. The method according to any of the 6 preceding method embodiments, wherein optimizing the at least one instrument sensitivity comprises adjusting at least a subset of parameters of the instrument.

It will be understood that a subset may also only comprise a single instrument parameter. For example, instrument parameters such as lens voltages, flow rates, ICP electronics and quadrupole voltages and/or frequencies may be adjusted.

M13. The method according to any of the preceding method embodiments with the features of embodiment M2, wherein the at least one attenuation factor is a plurality of attenuation factors.

M 14. The method according to any of the preceding method embodiments, wherein the at least one target sensitivity corresponds to a specified instrument sensitivity.

The specified instrument sensitivity may correspond to an instrument sensitivity that is guaranteed by the manufacturer and may thus also be referred to as guaranteed sensitivity.

M 15. The method according to any of the preceding method embodiments, wherein the at least one target sensitivity is provided by a user.

M 16. The method according to any of the preceding method embodiments, wherein the target sensitivity amounts to at least a pre-defined minimum sensitivity.

It will be understood that a pre-defined minimum sensitivity may for example correspond to a sensitivity required to ensure proper functionality of the instrument and/or to ensure reliable results for a certain method. Thus, the target sensitivity may be higher or equal to the pre-defined minimum sensitivity. M 17. The method according to any of the preceding method embodiments, wherein the at least one target sensitivity is a single target sensitivity.

It will be understood that such a single target sensitivity may preferably be applied over the whole measurement range of the instrument, e.g., in terms of ICP-MS for all m/z.

M 18. The method according to any of the preceding method embodiments, wherein the at least one target sensitivity is given as a target factor in the range of 0 to 1 with respect to the baseline sensitivity.

That is, the at least one target sensitivity may be defined relative to the baseline sensitivity. For example the at least one target sensitivity may be given as a target factor of 0.5 of the baseline sensitivity, which corresponds to a target sensitivity of 50% of the baseline sensitivity.

M19. The method according to the preceding method embodiment and with the features of embodiment M2, wherein the at least one attenuation factor corresponds to the target factor.

M20. The method according to any of the preceding method embodiments and with the features of embodiment M2, wherein each of the at least one attenuation factor is associated with at least one analyte parameter of the instrument.

M21. The method according to any of the preceding method embodiments with the features of embodiment M2, wherein at least one, and preferably each, attenuation factor is determined as a ratio of the respective target sensitivity and the respective baseline sensitivity associated.

That is, the at least one attenuation factor may generally correspond to a ratio of target sensitivity and baseline sensitivity. Overall, it will be understood that the at least one attenuation factor, the at least one target sensitivity and the at least one baseline sensitivity may each comprise a different number of elements, e.g., a single target sensitivity may be given and based on a single attenuation factor or alternatively an attenuation factor for some or each of the at least one baseline sensitivity may be determined. In particular, target sensitivity and baseline sensitivity may be associated with respective analyte parameters, e.g., each of the at least one baseline sensitivity may be associated with a specific analyte parameter. The same may be true for the target sensitivity, however, the target sensitivity may for example also be independent of a specific analyte parameter, i.e., constant, and thus associated to all analyte parameters.

M22. The method according to the preceding method embodiment, wherein the at least one attenuation factor is determined as the ratio of the at least one target sensitivity and each of the at least one baseline sensitivity. M23. The method according to the penultimate method embodiment and with the features of M17, wherein the at least one attenuation factor is determined as the ratio of the single target sensitivity and a selected one of the at least one baseline sensitivity.

Thus, a constant attenuation factor may be determined.

M24. The method according to the preceding method embodiment, wherein the selected one of the at least one baseline sensitivity corresponds to the lowest baseline sensitivity of the at least one baseline sensitivity.

M25. The method according to any of the preceding method embodiments, wherein the at least one target sensitivity is at most equal to the respective at least one baseline sensitivity.

It will be understood that for example in case of a single (parameter-independent) target sensitivity all of the at least one baseline sensitivities constitute respective baseline sensitivities. On the other hand, in case of both the at least one target sensitivity and the at least one baseline sensitivity being parameter-dependent, e.g., dependent on m/z, respective values correspond to the same analyte parameter.

M26. The method according to any of the preceding method embodiments, wherein determining at least one sensitivity attenuation comprises determining an attenuation function, wherein the at least one sensitivity attenuation comprises the attenuation function.

M27. The method according to the preceding method embodiment, wherein the attenuation function provides an attenuation value for each analyte parameter within the instrument's measurement range.

M28. The method according to any of the 2 preceding method embodiments, wherein the attenuation function is constrained to values smaller than or equal to 1.

M29. The method according to any of the 3 preceding method embodiments and with the features of M13, wherein the attenuation function is determined through interpolation and/or extrapolation based on the plurality of attenuation factors.

M30. The method according to any of M26 to M28 and with the features of M 13, wherein the attenuation function is determined through curve fitting to the plurality of attenuation factors.

M31. The method according to the preceding method embodiment, wherein curve fitting comprises linear regression. M32. The method according to any of the 2 preceding method embodiments, wherein curve fitting comprises non-linear regression.

M33. The method according to any of the 3 preceding method embodiments, wherein curve fitting comprises using the least squares method.

M34. The method according to any of the 5 preceding method embodiments, wherein each of the attenuation function is a linear or polynomial function.

M35. The method according to any the preceding method embodiments and with the features of M26, wherein the attenuation function is a piecewise-defined function comprising a plurality of sub-functions.

M36. The method according to the preceding method embodiment and with the features of M30, wherein each of the sub-functions is determined through curve fitting to a subset of the plurality of attenuation factors.

M37. The method according to the penultimate method embodiment and with the features of M2 and M29, wherein each of the sub-functions is determined through interpolation and/or extrapolation based on a subset of the plurality of attenuation factors.

M38. The method according to M26 to M28 and with the features of M2, wherein the at least one attenuation factor is a single attenuation factor.

M39. The method according to the preceding method embodiment, wherein the attenuation function is a constant attenuation function equal to the attenuation factor.

In other words, the attenuation function is a linear function independent of the analyte parameter, e.g. m/z, and thus comprising a slope of zero.

M40. The method according to any of the preceding method embodiments, wherein the method further comprises measuring attenuation calibration data, wherein the attenuation calibration data is indicative of a dependency of a relative signal intensity on at least one instrument parameter for at least one analyte parameter.

It will be understood that the relative signal intensity is given relative to the signal intensity as measured with non-detuned, standard instrument parameters, e.g., the reference intensity corresponds to the intensity measured after sensitivity optimization.

M41. The method according to the preceding method embodiment, wherein measuring the attenuation calibration data comprises varying at least one instrument parameter and determining the respective relative signal intensity for the at least one analyte parameter.

M42. The method according to any of the 2 preceding method embodiments, wherein measuring the attenuation calibration data comprises using a calibration standard. M43. The method according to the preceding method embodiment and with the features of M5, wherein the calibration standard is equal to the baseline reference.

M44. The method according to any of the 2 preceding method embodiments, wherein the calibration standard defines the available analyte parameters.

M45. The method according to any of the 5 preceding method embodiments, wherein the attenuation calibration data is indicative of a dependency of a relative signal intensity on at least one instrument parameter for a plurality of analyte parameters.

M46. The method according to any of the preceding method embodiments, wherein determining at least one sensitivity attenuation comprises determining at least one instrument-parameter function, wherein the at least one sensitivity attenuation comprises the at least one instrument-parameter function.

M47. The method according to the preceding method embodiment, wherein each of the at least one instrument-parameter function provides a respective value of a corresponding instrument parameter value as a function of the analyte parameter.

M48. The method according to any of the 2 preceding method embodiments and with the features of M45 and M2, wherein determining the at least one instrument-parameter function comprises determining a plurality of instrument parameter sets based on the attenuation calibration data, wherein each of the instrument parameter sets is associated to a different analyte parameter, and wherein each instrument parameter set comprises at least one instrument parameter value chosen such that the resulting relative signal intensity corresponds to one of the at least one attenuation factor associated with the same analyte parameter.

It will be understood that an instrument parameter set may comprise a single instrument parameter value or a plurality of instrument parameter values each of which corresponding to a different instrument parameter.

M49. The method according to the preceding method embodiment, wherein an instrument parameter set is determined for each combination of attenuation factor and respective analyte parameter comprised by the at least one attenuation factor provided that there is attenuation calibration data available for the respective analyte parameter.

M50. The method according to any of the 2 preceding method embodiments, wherein determining the plurality of instrument parameter sets comprises interpolating and/or extrapolating at least part of the attenuation calibration data to determine at least one calibration curve. M51. The method according to the preceding method embodiment, wherein determining the plurality of instrument parameter sets comprises interpolating and/or extrapolating at least part of the attenuation calibration data to determine at least one calibration curve for each analyte parameter for which the attenuation calibration data is indicative of the dependency of the relative signal intensity.

M52. The method according to any of the 4 preceding method embodiments, wherein determining the plurality of instrument parameter sets comprises curve fitting at least part of the attenuation calibration data to determine at least one calibration curve.

M53. The method according to the preceding method embodiment, wherein determining the plurality of instrument parameter sets comprises curve fitting at least part of the attenuation calibration data to determine a calibration curve for each analyte parameter for which the attenuation calibration data is indicative of the dependency of the relative signal intensity.

M54. The method according to any of the 4 preceding method embodiments, wherein each of the at least one calibration curve provides the relative signal intensity as a function of a respective instrument parameter for a specific analyte parameter.

M55. The method according to any of the 7 preceding method embodiments, wherein determining the at least one instrument-parameter function further comprises determining a respective instrument-parameter function for each instrument parameter comprised in the plurality instrument parameter sets.

M56. The method according to any of the 8 preceding method embodiments, wherein determining the at least one instrument-parameter function comprises curve fitting instrument parameter values comprised by the instrument parameter sets which are associated with the same instrument parameter.

M57. The method according to the preceding method embodiment, wherein at least one of the at least one instrument-parameter function is a piecewise-defined function comprising a plurality of sub-functions.

M58. The method according to the preceding method embodiment, wherein each of the sub-functions is determined through curve fitting a subset of the instrument parameter values comprised by the instrument parameter sets.

M59. The method according to any of the 3 preceding method embodiments, wherein curve fitting comprises linear regression.

M60. The method according to any of the 4 preceding method embodiments, wherein curve fitting comprises non-linear regression. M61. The method according to any of the 5 preceding method embodiments, wherein curve fitting comprises using the least squares method.

M62. The method according to any of the preceding method embodiments and with the features of M46, wherein each of the at least one instrument-parameter function is a linear or polynomial function.

M63. The method according to M46 or M47 and with the features of M2 and M40, wherein the at least one instrument-parameter function is a single, constant instrument-parameter function and wherein determining the instrument-parameter function comprises identifying an instrument parameter value for which the relative signal intensity corresponds to the respective attenuation factor, wherein the instrument-parameter function corresponds to the identified instrument parameter value.

M64. The method according to the preceding method embodiment, wherein only a single analyte parameter is considered.

M65. The method according to the penultimate method embodiment, wherein a plurality of analyte parameters is considered and wherein the instrument parameter value is chosen such that the relative signal intensity for all considered analyte parameters is at most equal respective attenuation factor.

M66. The method according to any of the preceding method embodiments, wherein using the at least one sensitivity attenuation comprises performing the measurement with settings of the analytical instrument based on the at least one sensitivity attenuation.

M67. The method according to any of the preceding method embodiments and with the features of M46, wherein using the at least one sensitivity attenuation comprises scanning at least one instrument parameter of the analytical instrument according to the respective at least one instrument-parameter function synchronously with the analyzer.

M68. The method according to any of M63 to M65, wherein using the at least one sensitivity attenuation comprises setting an instrument parameter of the analytical instrument to an instrument parameter value of the constant instrument-parameter function.

M69. The method according to any of the preceding embodiments, wherein performing the measurement with the analytical instrument comprises obtaining raw data, and using the at least one sensitivity attenuation comprises attenuating the raw data to obtain resulting data. M70. The method according to the preceding method embodiments and with the features of M26, wherein attenuating the raw data comprises applying the attenuation function to the raw data to obtain resulting data.

M71. The method according to any of the preceding method embodiments, wherein using the at least one sensitivity attenuation results in measuring with an attenuated sensitivity.

M72. The method according to the preceding method embodiment and with the features of embodiment M2, wherein the attenuated sensitivity lies within ± 10%, preferably ±5% of the at least one target sensitivity for the analyte parameters associated with the at least one attenuation factor.

M73. The method according to any of the 2 preceding method embodiments, wherein the attenuated sensitivity lies within ± 10%, preferably ±5% of the at least one target sensitivity for all analyte parameters within a measurement range of the analytical instrument.

M74. The method according to any of the preceding method embodiments, wherein the method further comprises measuring at least one attenuated sensitivity.

M75. The method according to the preceding method embodiment, wherein measuring the at least one attenuated sensitivity comprises performing a measurement of the instrument sensitivity using the sensitivity attenuation and a reference solution.

M76. The method according to any of the preceding embodiments, wherein the method further comprises determining at least one sensitivity reserve.

M77. The method according to the preceding method embodiment and with the features of M74, wherein the determining the at least one sensitivity reserve comprises calculating the at least one sensitivity reserve based on the at least one attenuated sensitivity and the at least one baseline sensitivity.

M78. The method according to any of the 2 preceding method embodiments, wherein a development of the at least one sensitivity reserve is monitored over time.

M79. The method according to the preceding method embodiment, wherein timing of an instrument optimization and/or other maintenance tasks is predicted based on the timedependent development of the at least one sensitivity reserve.

M80. The method according to any of the preceding method embodiments, wherein the method further comprises adjusting the at least one sensitivity attenuation to correct for a change in the at least one baseline sensitivity. M81. The method according to the preceding method embodiment, wherein adjusting the sensitivity attenuation comprises determining at least one current sensitivity of the analytical instrument.

M82. The method according to the preceding method embodiment, wherein determining the at least one current sensitivity of the analytical instrument comprises determining at least one current baseline sensitivity of the instrument.

M83. The method according to the preceding method embodiment, wherein determining the current sensitivity of the analytical instrument comprises determining at least one current attenuated sensitivity of the instrument.

M84. The method according to any of the 3 preceding method embodiments, wherein adjusting the at least one sensitivity attenuation comprises updating the at least one sensitivity attenuation if at least one of the at least one current sensitivity is below a respective pre-defined target sensitivity threshold.

M85. The method according to any of the 4 preceding method embodiments, wherein adjusting the at least one sensitivity attenuation comprises maintaining the at least one sensitivity attenuation as is if each of the at least one current sensitivity is above the respective pre-defined target sensitivity threshold.

M86. The method according to any of the 2 preceding method embodiments, wherein the target sensitivity threshold is at least 80% of the target sensitivity, preferably at most 90% of the target sensitivity.

M87. The method according to the preceding method embodiment, wherein adjusting the at least one sensitivity attenuation comprises maintaining the at least one sensitivity attenuation and instead proceeding with optimizing the at least one instrument sensitivity to obtain a new baseline sensitivity if at least one of the at least one current sensitivity is below the respective at least one target sensitivity.

M88. The method according to any of the 7 preceding method embodiments, wherein adjusting the at least one sensitivity attenuation comprises updating the at least one sensitivity attenuation if at least one of the at least one current sensitivity is above a respective pre-defined upper target sensitivity threshold.

M89. The method according to any of the 8 preceding method embodiments, wherein adjusting the at least one sensitivity attenuation comprises maintaining the at least one sensitivity attenuation as is if each of the at least one current sensitivity is below the respective pre-defined upper target sensitivity threshold.

M90. The method according to any of the 2 preceding method embodiments, wherein the upper target sensitivity threshold is at most 130% of the target sensitivity, preferably at most 120% of the target sensitivity. M91. The method according to any of the 3 preceding method embodiments and with the features of M84 or M85, wherein adjusting the at least one sensitivity attenuation comprises maintaining the at least one sensitivity attenuation as is if each of the at least one current sensitivity is above the respective pre-defined target sensitivity threshold, and each of the at least one current sensitivity is below the respective pre-defined upper target sensitivity threshold.

M92. The method according to any of the preceding method embodiments and with the features of M84 and/or M88, and M2, wherein updating the at least one sensitivity attenuation comprises the steps of determining the at least one attenuation factor based on the current sensitivity and the at least one target sensitivity; and determining the at least one sensitivity attenuation based on and the at least one attenuation factor.

It will be understood that these steps may generally be the same as described in the above embodiments.

M93. The method according to any of the preceding method embodiments, wherein the analytical instrument is a mass spectrometer.

M94. The method according to the preceding method embodiment, wherein the analytical instrument is an inductively coupled plasma mass spectrometer.

M95. The method according to any of the preceding method embodiments and with the features of M40, wherein the at least one instrument parameter comprises an RF amplitude of a multipole comprised by the analytical instrument.

M96. The method according to any of the preceding method embodiments and with the features of M40, wherein the at least one instrument parameter comprises an RF frequency of a multipole by the analytical instrument.

M97. The method according to any of the preceding method embodiments and with the features of M40, wherein the at least one instrument parameter comprises at least one lens voltage of an ion lens comprised by the analytical instrument.

M98. The method according to the preceding method embodiment, wherein the at least one lens voltage comprises a lens voltage of an exit lens of a multipole comprised by the analytical instrument.

M99. The method according to any of the 2 preceding method embodiments, wherein the at least one lens voltage comprises a lens voltage of an entry lens of a multipole comprised by the analytical instrument. M100. The method according to any of the 3 preceding method embodiments, wherein the at least one lens voltage comprises a lens voltage of a focus lens comprised by the analytical instrument.

M 101. The method according to any of the 8 preceding method embodiments and with the features of M40, wherein the mass spectrometer comprises a differential pressure aperture upstream of an analyzer quadrupole and a focus lens configured to focus the ion beam into the pressure aperture, wherein the at least one instrument parameter preferably comprises the lens voltage of said focus lens.

M 102. The method according to any of the preceding method embodiments and with the features of M40, wherein the analytical instrument comprises a detector and the at least one instrument parameter comprises a voltage of a conversion dynode of the detector.

M 103. The method according to any of the preceding method embodiments and with the features of M40, wherein the analytical instrument comprises a detector and the at least one instrument parameter comprises a gate voltage configured to control a signal gain of the detector.

M 104. The method according to any of the preceding method embodiments, wherein the analytical instrument is an optical instrument.

M105. The method according to the preceding method embodiment and with the features of M40, wherein the at least one instrument parameter comprises a lens orientation.

M106. The method according to the preceding method embodiment and with the features of M40, wherein the at least one instrument parameter comprises a mirror orientation.

M 107. The method according to any of the preceding method embodiments, wherein the method further comprises performing the method steps for a plurality of analytical instruments with the same at least one target sensitivity.

M108. The method according to the preceding method embodiment, wherein the at least one target sensitivity is at most equal to the lowest baseline sensitivity of the plurality of analytical instruments.

M109. The method according to any of the 2 preceding method embodiments, wherein the at least one target sensitivity is at most equal to the lowest baseline sensitivity of the plurality of analytical instruments after optimization of the at least one instrument sensitivity of each analytical instrument.

For example, in the context of ICP-MS each attenuation factor may be associated with at least one m/z, i.e., at least one analyte parameter. The respective analyte parameters may thus for example be limited to analytes available in the baseline reference, as each analyte corresponds to a certain m/z and thus a certain analyte parameter.

Below, reference will be made to system embodiments. These embodiments are abbreviated by the letter "S" followed by a number. Whenever reference is herein made to "system embodiments", these embodiments are meant.

51. A system comprising an analytical instrument, and a controller, wherein the controller is configured to control the system to perform the method according to any of the preceding method embodiments.

52. The system according to the preceding system embodiment, wherein the controller comprises at least one processing device configured to control the system to perform the method.

53. The system according to any of the 2 preceding system embodiments, wherein the analytical instrument is a mass spectrometer.

54. The system according to the preceding embodiment, wherein the mass spectrometer is an isotope ratio mass spectrometer.

55. The system according to any of the system embodiments SI to S3, wherein the analytical instrument is an inductively coupled plasma spectrometer.

56. The system according to any of the preceding system embodiments when not dependent on embodiment S3, wherein the analytical instrument is an optical emission spectrometer.

Ul. Use of the system according to any of the preceding system embodiments to perform the method according to any of the preceding method embodiments.

Cl. A computer program product comprising instructions which, when the program is executed by a system comprising an analytical instrument and a controller, cause the system to carry out the method according to any of the preceding method embodiments.

C2. A computer-readable data carrier having stored thereon the computer program product of embodiment Cl.

C3. A data carrier signal carrying the computer program product of embodiment Cl. Embodiments of the present invention will now be described with reference to the accompanying drawings. These embodiments should only exemplify, but not limit, the present invention.

Fig. 1 depicts an exemplary measurement of end-of-production instrument sensitivities;

Figs. 2a and 2b illustrate examples for attenuating instrument sensitivities;

Fig. 3 illustrates an embodiment of a method according to the present invention;

Fig. 4 illustrates an embodiment of a method according to the present invention;

Fig. 5 illustrates a software-based attenuation function;

Fig. 6 illustrates an embodiment of a method according to the present invention;

Fig. 7 illustrates exemplary components of an ICP-MS system;

Fig. 8a depicts an exemplary measurement of the relative signal intensity depending on a focus lens voltage;

Fig. 8b illustrates determining an instrument-parameter function for the focus lens voltage;

Fig. 9 depicts an exemplary measurement of the transmission of a collision/reaction cell depending on the RF amplitude of its quadrupole; and

Fig. 10 illustrates an embodiment of a method according to the present invention.

It is noted that not all the drawings carry all the reference signs. Instead, in some of the drawings, some of the reference signs have been omitted for the sake of brevity and simplicity of the illustration. Embodiments of the present invention will now be described with reference to the accompanying drawings.

Generally, determining an instruments sensitivity may be specific to the type and/or model of the respective instrument. For an ICP-MS instrument, sensitivity may be determined through measurements of at least one reference ion signal. That is, a known amount of analyte, i.e., reference ion(s), may be measured and the sensitivity may be given as registered counts per second (cps) with respect to a defined amount of analyte, e.g., cps per ppb (parts per billion). The known amount of analyte may for example be provided in the form of a reference solution, which may also be referred to as a tuning solution, standard solution or simply a standard. It will be understood that instead of cps, reference may also simply be made to Hz, wherein 1 cps = 1 Hz, and/or the count rate may be specified with respect to a different concentration, e.g., ppt (parts per trillion). In the following, when reference is made to a count rate (cps) for reference signals, this count rate is always normalized with respect to a defined amount of analyte. Figure 1 depicts exemplary end-of-production instrument sensitivities (which may also be referred to baseline sensitivities or base sensitivities) on a reference signal of several hundred ICP-MS instruments of an exemplary serial production batch. In other words, Fig. 1 depicts a signal intensity for a specific amount of reference analyte which thus corresponds to the respective instrument sensitivity to that specific reference analyte. There is a minimum sensitivity threshold of 275 kcps per ppb which is required for shipping of said units, i.e., the specified Instrument sensitivity. It can be seen that there is a significant deviation in terms of actually achieved instrument sensitivities. Particularly, it can be seen that some instruments strongly exceed the specified sensitivity, some even by a factor of 3. As can be seen, the average or mean sensitivity indicated by the dashed line a) is at about 500 kcps per ppb, which is relatively stable over the timespan of production. The asymmetry of the distribution can be attributed to the aforementioned minimum sensitivity threshold of 275 kcps per ppb. The variation corresponds to a relative standard deviation of about 20%. Thus, purely for illustrative purposes, if one would for example assume a normal distribution this would mean that the base sensitivity for 95% of the instruments is found in a range of ±40% of the mean. With regard to Fig. 1, this corresponds to the range between 300 kcps and 700 kcps per ppb. Again, due to the asymmetry of the distribution owing to the minimum sensitivity threshold, the depicted sensitivity data are naturally not well described by a normal distribution and may for example be better approximated through a log-normal distribution.

Considering the above, embodiments of the present invention aim to reduce the sensitivity experienced by a user in a reproducible and controllable manner in order to limit it to a desired target sensitivity. Thus, by renouncing part of the available sensitivity, the sensitivities of different instruments of the same type may be adjusted or even equalized to reduce the spread therebetween. In other words, a standardization method may be provided that may achieve predictable and stable sensitivities.

Thus, embodiments of the present invention provide an alternative way for achieving a narrow standardization for a batch of mass-produced instruments which may also be referred to as "calibrate the instruments to expectations". That is, the sensitivity experienced by a user may be reduced through a corresponding calibration.

While it may be apparent that such an adjustment of sensitivities may be beneficial in cases where a plurality of instruments is operated by the same user, it also provides certain advantages to users only operating a single instrument, which are further outlined herein.

For example, with reference to Fig. 2a, if three instruments each have a different baseline sensitivity S, then the target sensitivity St may be chosen to amount to (at most) the lowest baseline sensitivity of these three instruments (indicated by the solid line). Thus, the sensitivity of the other two instruments (here instruments number 2 and 3) may be adjusted to have the same, lower sensitivity, than the instrument with the lowest baseline sensitivity. While the target sensitivity St may be required to at least amount to a predefined minimum sensitivity Smin, there may typically be a difference A between Smin and the lowest baseline sensitivity of the instruments such that the target sensitivity may also be set below the lowest baseline sensitivity of the instruments. Particularly St may be chosen to be greater or equal to Smin while still being at most equal to the lowest baseline sensitivity. Thus, A may be zero in some cases.

This may advantageously allow to not only reduce the spread of sensitivities between different instruments but to additionally free up a sensitivity reserve. Particularly, with reference to Fig. 2b, the target sensitivity St may be chosen lower than the baseline sensitivity of the least sensitive instrument in order to create the sensitivity reserve for every instrument. It will be understood that freeing up such a sensitivity reserve also applies to a single instrument.

That is, the sensitivity of at least one instrument may be attenuated to create a reserve which can for example be used to accommodate daily sensitivity changes (for example caused by material built-up on a skimmer cone or on other instrument parts) without requiring a regular re-tuning, which may be much more time-consuming. Thus, the sensitivity may be attenuated to any sensitivity between the baseline sensitivity and the minimum (required) sensitivity.

It will be understood that Figs. 2a and 2b illustrate instrument sensitivities for a specific analyte parameter, e.g., a specific m/z value corresponding to a certain reference analyte. However, the at least one instrument sensitivity and/or the at least one target sensitivity may comprise a plurality of respective sensitivities, wherein each sensitivity is associated with a certain analyte parameter of the instrument.

With reference to Fig. 1, considering for example a mean of 350 kcps of signal intensity as indicated by the dashed line b) and 95% of the instruments falling in a range of ±50 kcps, the absolute variation would be narrowed down by a factor of four, resulting in a relative standard deviation of 7% instead of the 20% above, since the mean also changes. This can be achieved by reducing the sensitivity of instruments that comprise a higher baseline sensitivity through attenuating the instruments sensitivity, which may in some cases also be referred to as recalibration process. Similarly, also other sensitivity ranges may be of interest to a user, e.g., 200 ±20 kcps (dashed line c)) or 50 ± 10 kcps (dashed line d)). Embodiments of the present invention enable to provide such standardized instrument sensitivities for analytical methods and systems.

Furthermore, according to embodiments of the present invention, the renounced sensitivity may still be utilized as a so-called sensitivity reserve, which may also be referred to as instrument performance reserve or simply performance reserve. That is, while the instrument's sensitivity may typically decline with usage over time, the sensitivity reserve may allow to quickly and easily re-establish the desired sensitivity by tapping into the instrument's sensitivity reserve. Re-establishing the desired sensitivity by using the sensitivity reserve may advantageously be faster than known standard instrument adjustment and/or so called autotune methods and therefore allow to reduce the instrument's downtime. In other words, the present invention not only allows to provide a standardized instrument sensitivity, but it also allows for a fast recovery thereof through usage of the sensitivity reserve.

More specifically and with reference to Fig. 3, the presently described method for providing a desired instrument sensitivity may comprise a first step 100, wherein at least one baseline sensitivity of the instrument is determined. This may include tuning the instrument to the best sensitivity (where it is noted that this step is optional) and measuring sensitivity of the instrument, i.e., an instrument sensitivity, to determine the at least one baseline sensitivity, and a second step 200, wherein the instrument sensitivity is adjusted to a desired level to provide a standardized sensitivity.

The first step 100 may comprise a standard optimization approach as known in the state of the art (step 120). That is, the instrument may be tuned to its best (tuning) sensitivity using standard optimization methods. That is, it may be tuned to the best sensitivity available through tuning, i.e., without for example exchanging parts, which may allow for even better sensitivity. For example, the sensitivity may be maximized by means of a multi-parametric sensitivity tuning, wherein the maximization may take into consideration certain constraints such as boundary conditions or side conditions. In other words, the instrument may be tuned to its best sensitivity by a standard optimization approach.

In terms of an ICP-MS system, this process may for example be provided through a so- called autotune procedure, which may denote a software-based instrument optimization. For such an autotune procedure, a user may provide a reference solution (i.e., tuning standard) to the ICP-MS system, i.e., a fluid with known amounts of certain reference analytes. Such a reference solution or tuning standard typically comprises a plurality of elements at different masses spreading across the entire mass range of the instrument in order to optimize sensitivity across the entire range. Throughout the autotuning procedure the instrument may then adjust at least a subset of the instrument's parameters in order to optimize the instrument's sensitivity. It will be understood that a subset may also only comprise a single parameter. For example, parameters such as lens voltages, flow rates, ICP electronics and quadrupole voltages and/or frequencies may be adjusted. The sensitivity achieved through autotuning or more generally sensitivity optimization may be used to define the at least one baseline sensitivity or inherent sensitivity of the instrument through a respective measurement. That is, the at least one baseline sensitivity may be determined through measurement of the associated current, preferably optimized, instrument sensitivity (step 140). It will be understood that an instrument may typically comprise a plurality of baseline sensitivities, e.g., one baseline sensitivity for each m/z ratio in case of a mass spectrometer. In other words, as part of step 100 the at least one baseline sensitivity is determined. As illustrated in Fig. 1, the baseline instrument sensitivity may vary significantly between instruments of the same type. It will be understood that generally the term baseline sensitivity may denote the instrument sensitivity available without attenuation. That is, the baseline sensitivity may change, e.g., decline with usage and aging of the instrument. Subsequently in the second step 200, the at least one baseline sensitivity may be attenuated to reach at least one target sensitivity, i.e., an expected or desired sensitivity, e.g., a specified instrument sensitivity or a desired instrument sensitivity. The target sensitivity may for example be set by the user and can be limited to maximally correspond to the specified instrument sensitivity, and/or can be limited to at least correspond to a specific value that is required for a certain analysis method, e.g., an analysis method to be performed with the instrument. Setting the target sensitivity below the specified instrument sensitivity may advantageously allow to free up a larger sensitivity reserve that can be used for maintaining the standardized sensitivity close to the desired target sensitivity. This very general second step 200 may comprise a number of steps as further discussed in the following with reference to Fig. 4. It will become apparent that the implementation of discussed steps may vary depending on different embodiments of the present invention, e.g., if the attenuation is software- or hardware-based.

It will be understood that upon determining the at least one baseline sensitivity (step 100), the resulting at least one baseline sensitivity may be required to at least meet and preferably surpass the target sensitivity St such that an attenuation of greater than or equal to zero can be realized. This may be achieved through optimizing the instrument sensitivity (step 120). In cases where, despite optimization of the instrument sensitivity, the baseline sensitivity is lower than the target sensitivity and particularly lower than the sensitivity specified for the instrument by the manufacturer, i.e., the specified instrument sensitivity, more elaborate recovery of sensitivity may be required, which may for example include replacing certain parts of the instrument.

Based on the at least one baseline sensitivity and the at least one target sensitivity, at least one attenuation factor may be determined (step 210). The attenuation factor /j may generally be defined as the ratio of the target sensitivity (St) and the baseline sensitivity (St>), i.e., measured sensitivity after optimization:

In the above, a single attenuation factor is described. However, this is for simplicity of description only and the skilled person will understand that embodiments of the present invention are also directed to a plurality of attenuation factors, e.g., for different analyte parameters such as different m/z ratios.

In some embodiments, the at least one target sensitivity may not be given as a specific sensitivity value but instead be given as a target factor in the range of 0 to 1 with respect to the at least one baseline sensitivity. It will be understood that in such cases the attenuation factor corresponds to the target factor. For example, a user may specify that it is desired to lower the baseline sensitivity by 50%, in other words, the user specifies a target factor of 0.5, i.e., St = 0.5 Sb. Thus, in such a case /J=0.5. Generally, it will be understood that the baseline sensitivity and potentially also the target sensitivity may depend on an analyte parameter, e.g., in the case of mass spectrometry the sensitivity may typically depend on the mass-to-charge ratio (m/z). That is, for example in the case of an ICP-MS system the at least one baseline sensitivity may be a list of sensitivities comprising an entry for each of the analytes, i.e., reference ions, comprised by the reference solution used for optimizing, i.e., a baseline reference, and determining the instrument sensitivity. That is, if the reference solution for example comprises 6 reference ions, the at least one baseline sensitivity may be a list of 6 sensitivities each of which is associated to one of the reference ions, more specifically associated to the mass- to-charge ratio of the respective reference ion, i.e., a respective analyte parameter. Thus, generally different attenuation factors may be determined for different reference ions, depending on the respective parameter-dependent baseline sensitivity and the desired target sensitivity (which may also be parameter dependent). That is, p(m/z) =

However, in some embodiments, also a constant attenuation factor may be determined independent of any parameter dependence of the at least one baseline sensitivity and/or the at least one target sensitivity. Again, it will be understood that such attenuation factors cannot be greater than 1 as this would imply artificially creating additional sensitivity. In such a case, the baseline sensitivity needs to be optimized, e.g., a standard optimization (step 120) or if need be, through more elaborate calibration and/or instrument maintenance, or the target sensitivity needs to be lowered.

In a next step 230, a corresponding sensitivity attenuation may be determined based on the at least one attenuation factor. The sensitivity attenuation may for example comprise an attenuation function f_a(p) and/or at least one instrument-parameter function. The attenuation function f_a(p) may provide an attenuation for measured signals and thus may allow for a software-based attenuation of the signals, while the at least one instrumentparameter function may provide a function for setting at least one instrument parameter in order to achieve a desired, preferably analyte- para meter dependent, attenuation of the sensitivity. That is, the at least one instrument-parameter function may allow for controlled detuning of the at least one instrument parameter.

Subsequently, in step 250, a measurement may be performed with the analytical instrument to generate a measurement result, wherein performing the measurement with the analytical instrument comprises using the at least one sensitivity attenuation. For example, the measurement may be performed with settings of the analytical instrument based on the at least one instrument-parameter function and thus based on the at least one sensitivity attenuation which comprises said at least one instrument-parameter function. Alternatively or additionally, raw data obtained through the measurement may be attenuated using the attenuation function f_a to obtain resulting data.

Thus, the measurement may be performed with an attenuated sensitivity, wherein the attenuation is hardware and/or software based. In other words, to determine a respective attenuation factor and consequently a respective sensitivity attenuation, at least one sensitivity measurement is performed (step 140) as part of determining the at least one baseline sensitivity (step 100) - e.g., including optimization of the instrument's sensitivity (step 120), wherein a sensitivity measurement comprises measuring a known amount of analyte and determining the measured sensitivity, e.g., cps per ppb for a mass-spectrometric measurement. That is, for example, at least one reference ion may be measured to determine the respective sensitivity. For an analyte-parameter-dependent sensitivity attenuation a plurality of sensitivity values may be measured, each corresponding to different analyte parameters. Subsequently at least one sensitivity attenuation may be determined. For example, an attenuation function may be determined through curve fitting, interpolation and potentially also extrapolation, e.g., with a polynomial function. In some embodiments, the attenuation function may also be a piecewise-defined function, e.g., a piecewise-continuous function composed of a plurality of continuous, e.g., polynomial functions.

Once the sensitivity attenuation is determined, the baseline sensitivity Sb of the instrument may be attenuated accordingly during measurement to provide a standardized instrument sensitivity S_s. That is, the sensitivity attenuation may be used accordingly in order to attenuate (i.e., reduce) the sensitivity of the instrument below its baseline sensitivity (step 250). Put differently, by using the attenuation function, the sensitivity of the instrument is artificially limited to the standardized sensitivity S_s. Thus, a standardized sensitivity may be provided for the instrument, which may fall within ± 10%, preferably ±5% of the target sensitivity for at least one of the reference ion (i.e., analytes) provided for determining the baseline sensitivity, preferably for all of the reference ions provided for determining the baseline sensitivity.

Generally, attenuation of the baseline sensitivity may be achieved either software-based or hardware-based or through a combination thereof. Thus, the step 230 of determining the sensitivity attenuation may generally depend on the chosen approach.

For example, with reference to Fig. 5, a software- based attenuation for an ICP-MS system is discussed. Here, 5 attenuation factors /J are determined as indicated by the dots. Each attenuation factor corresponds to a specific, different analyte mass, i.e., different m/z or more generally analyte parameter. Once the attenuation factors have been determined a respective attenuation function f_a(m/z) (dotted line) may be determined through curve fitting to the attenuation factors. Generally, curve fitting in the context of the present application may comprise linear regression and/or non-linear regression. Additionally or alternatively, curve fitting may comprise using the least squares method or a maximum likelihood estimation. The attenuation function may be a linear or polynomial function. Alternatively, a polynomial interpolation may be applied to determine a respective attenuation function f_a(m/z), e.g., using a cubic spline function. Again, it will be understood that a boundary condition for curve fitting, interpolating and/or extrapolating is that the attenuation function cannot be greater than 1. Furthermore, it will also be understood that such a curve fitting and/or interpolation may be improved by determining even more individual attenuation factors. In other words, the instrument may be tuned to its best sensitivity by a standard optimization approach (step 120). To determine at least one attenuation factor, the result of this optimization may then be set into relation to a sensitivity expectation (also referred to as target sensitivity), i.e., an expected sensitivity, such as the specified instrument sensitivity, or a desired sensitivity sufficient for a certain measurement (step 210). Subsequently, a sensitivity attenuation comprising a respective attenuation function may be determined (step 230).

It will be understood that the attenuation function and thus each attenuation factor must be < 1 as sensitivity cannot be artificially created. In other words, the attenuation factor and/or attenuation function must not exceed the value of 1 anywhere, because this would suggest that there are higher sensitivities than the real (measured) ones. Thus, if the attenuation factor is determined, e.g., measured, to be greater than one, the instrument may need a full optimization and new re-calibration tune to get back into the specified sensitivity range. Other maintenance activities by the user might be required and advised as well.

A successful tuning may typically result in over-achieving a sensitivity check, such that a percentage can be calculated which quantifies the excess sensitivity (or sensitivity reserve) that is available, e.g., for a given m/z. In the case of mass spectrometry, this percentage may generally be mass-dependent, but the attenuation can also be determined as a constant value over the mass range and thus the resulting sensitivity reserve may generally also be constant with respect to m/z. Subsequently, a measurement may be performed using the determined attenuation function f_a to attenuate measured raw data in order to obtain resulting data based on an attenuated sensitivity (step 250). In other words, the optimization may be followed by a re-calibration procedure, which is able to reduce the instrument sensitivity to the required (or desired) value, e.g., through applying the software-based attenuation function.

For a software- based attenuation, each measured signal may simply be multiplied with the respective attenuation function during post processing. That is, firstly an attenuation function may be determined based on the measurement of reference analytes such as reference ions for which respective attenuation factors are determined and then curve fitted or interpolated (and optionally extrapolated) to determine a respective analyteparameter-dependent attenuation function. Subsequently, for each measured signal, the attenuation function may be applied for the analyte parameter corresponding to the measured signal, which can also be seen as determining a respective attenuation factor based on the attenuation function that corresponds to the analyte- para meter value of the signal and the measured signal may be multiplied with said factor. More generally, the attenuation function will be applied across all measured signals. In other words, after the calibration measurement is completed and curve fitting, or inter- and/or extrapolation is done (e.g., as in Fig. 5), all measured instrument signals I(m/z) may be multiplied with the respective attenuation function: I_s m/z) = I (m/z) * f_a (m/z),

Wherein it will be understood that attenuation function f_a and measured signal I, and thus also the standardized signal Is may be parameter dependent, e.g., dependent on m/z. That is, in the context of a sensitivity measurement based on a reference solution, I(m/z) may correspond to the baseline sensitivity Sb and the standardized signal would then correspond to the standardized sensitivity S_s. That is, the raw data comprising measured instrument signals I is attenuated by applying the attenuation function to said raw data, thereby obtaining resulting data comprising the standardized signal Is.

In other words, the sensitivity attenuation may comprise an attenuation function f_a that may be determined. The attenuation function may generally serve to implement the attenuation of measured signals and is based on the determined attenuation factors. Preferably, the attenuation function may also provide for respective attenuation of signals corresponding to analyte parameters for which no attenuation factor p has been explicitly determined, e.g., for m/z for which no reference ion has been measured. Again, such an attenuation function f_a(p) may depend on an analyte parameter p of the measured analytes, e.g., f_a(m/z). However, in some embodiments, the attenuation function may also be constant and thus independent of any analyte parameter (f_a=f_a(p)). It will be understood that also the attenuation function is constrained to values smaller than or equal to one (fa<l). That is, also the attenuation function cannot give values greater than 1.

However, as explained above, the attenuation function f_a may also be constant. Again, it will further be understood that p denotes an analyte parameter on which the baseline sensitivity and/or the target sensitivity and consequently potentially also the attenuation function and the sensitivity reserve may depend, e.g., p=m/z.

Thus, the sensitivity may be adjusted during post-processing in a software-based manner. This may be advantageous as it is independent of any specific hardware characteristics and instead directly re-calibrates the measured signal using an analyte-parameter-dependent "attenuation factor" function. Furthermore, it may advantageously be readily applied to existing instruments, e.g., through a software update or plugin.

In other words, in contrast to a hardware-based attenuation specific analyte-parameter- dependent (e.g., mass-dependent) properties of hardware attenuators may be omitted. Nevertheless, sensitivities of a defined set of reference analytes may be measured, related to the target sensitivities for all reference analytes, and a curve fitted function or an inter- /extrapolation function may be calculated in order to estimate the desired attenuation across the complete range of analytes.

Alternatively, the attenuation of the inherent sensitivity may be hardware-based. In such a case, particularities of the respective system may need to be considered. In general, a hardware-based attenuation may be achieved by manipulating at least one parameter of the instrument such that the sensitivity is lowered to reach the target sensitivity. That is, one or more instrument parameter may be manipulated such that the instrument is operated in a non-optimal state. In other words, at least one parameter of the instrument may be detuned. However, such a detuning or manipulation may be done in such a controlled and well-defined way that the target sensitivity can be reached.

That is, instead of multiplying a measured signal with the respective (mathematical) attenuation function, the beam attenuation may be created - and can be measured - by setting at least one or more instrument parameters away from the optimum in such a well- defined way that the sensitivity performance is reduced (close) to the specified values, I . e. , the at least one target sensitivity. For example, the attenuated sensitivity, also referred to as standardized sensitivity may be within ± 10%, preferably ±5% of the at least one target sensitivity. These parameters may be determined in a "standardized sensitivity" calibration procedure and provided through at least one instrument-parameter function which may be comprised by the sensitivity attenuation. Thus, also the hardware-based attenuation may be considered to provide a hardware-controlled attenuation function equivalent to that shown in Fig. 5. If the attenuation factor > 1, the instrument needs a full optimization and new recalibration tune to get back into the specified sensitivity range. Other maintenance activities by the user might be required and advised as well.

Both when the attenuation is achieved by means of software and hardware, a sensitivity attenuation is used, either to directly attenuate measured intensities by means of an attenuation function f_a or to set system parameters accordingly by means of an instrumentparameter function.

It will be understood that the instrument-parameter function may be a function for setting at least one instrument parameter depending on an analyte parameter in such a way that a analyte-parameter-dependent attenuation of the baseline sensitivity is achieved.

With reference to Fig. 6, step 230 of determining at least one sensitivity attenuation may generally comprise the step 232 of determining at least one instrument-parameter function, which is comprised by the at least one sensitivity attenuation. Each of the at least one instrument-parameter function may provide a respective value of a corresponding instrument parameter value as a function of the analyte parameter. For example, the instrument-parameter function may specify a lens voltage as a function of the mass-to- charge ratio m/z.

In order to determine the instrument-parameter function, information on a behavior of the analytic instrument with respect to detuning a certain parameter may be needed. Thus, the method may further comprise the step 220 of measuring attenuation calibration data, which may be indicative of a dependency of a relative signal intensity on at least one instrument parameter for at least one analyte parameter. Thus, the attenuation calibration data may indicate how the signal intensity depends on the detuning of at least one instrument parameter with respect to the signal intensity measured for the non-detuned parameters. In other words, it will be understood that the relative signal intensity is given relative to the signal intensity as measured with non-detuned, standard instrument parameters, e.g., the reference intensity corresponds to the intensity measured after sensitivity optimization.

Said attenuation calibration data may be measured for at least one analyte parameter, i.e., for at least one reference analyte, preferably for a plurality of reference analytes.

Based on the detuning behavior of at least one parameter that can be derived from the attenuation calibration data, the at least one instrument-parameter function may be determined such that it results in the desired attenuation of the instrument sensitivity. Preferably, only a single instrument-parameter function is determined. However, if detuning a single parameter may for example not provide the desired attenuation, a combination of parameters may be detuned and thus more than one instrument-parameter function may be determined.

For the hardware-based attenuation, the step 250 of performing a measurement using the at least one sensitivity attenuation may thus comprise the step 252 of scanning at least one instrument-parameter of the analytical instrument according to the respective at least one instrument-parameter function synchronously with the analyzer.

It is noted that an instrument-parameter function may preferably depend on the analyte parameter, e.g., m/z, however, it may also be constant. Thus, scanning at least one instrument parameter according to the respective at least one instrument parameter function may simply comprise setting the respective instrument parameter to a constant value.

In the following, hardware-based attenuation is mainly described with respect to an ICP- MS system. A schematic illustration an exemplary system is depicted in Fig. 7. Generally, the ICP-MS system 1 (in the following also simply the system 1) may comprise an atmospheric plasma source 10 for ionizing a sample. Subsequently, a resulting ion beam may pass through a vacuum interface 15, which may for example comprise a sampling cone and a skimmer cone. The ion beam may then pass through an assembly 20 designated to ion extraction and transport, which may for example comprise at least one ion lens, e.g., an entry lens for a subsequent pre-selector 25, e.g., a multipole 25. Here, ion extraction may be related to separating positive from negative charges, which enter the instrument as a fraction of the plasma generated by the source. Furthermore, during transport, e.g., by means of a lens or a lens stack, separate neutrals may be separated from ions and (positive) ions may be focused on to an aperture of the pre-selector 25. Plasma source 10, vacuum interface 15 and assembly 20 may generally be used to create and shape the ion beam.

Furthermore, downstream of the assembly 20 the ion beam may pass through a preselector 25, which may comprise a multipole, which may be configured to pre-select certain ions by mass. Subsequently the ion beam may pass through an ion transport assembly 30, which may for example comprise at least one ion lens, such as an exit lens of the preselector 25 and/or an entry lens for a subsequent multipole. Downstream of the ion transport assembly 30 the ion beam may pass through a multipole device 35, which may for example be a collision/reaction cell 35, and subsequently be guided through another ion transport assembly 40, which may again comprise at least one ion lens. Particularly, the ion transport assembly 40 may comprise a differential pressure aperture and a focus lens configured to focus the ion beam into the differential pressure aperture. Downstream of the ion transport assembly 40 the ion beam may pass through an analyzer 45, which may again comprise a multipole, e.g., a quadrupole. Subsequently the ion beam may pass a further ion transport assembly 50, which may again comprise at least one ion lens and then be detected in a detector 55.

Thus, an entry stage of the ICP-MS system 1 may comprise the atmospheric plasma source 10, the vacuum interface 15 and the ion extraction & transport assembly 20. This entry stage may be followed by plurality of multipoles 25, 35, 45 each followed by an ion transport assembly 30, 40, 50, wherein the ion transport assemblies may for example comprise focus lenses configured to focus the ion beam and entry and/or exit lenses for the respective multipoles 25, 35, 45. Generally, the ion transport assemblies 30, 40, 50 may comprise a single lens and/or a defined aperture held at a defined electrical potential. In some embodiments, one or more of the ion transport assemblies 30, 40, 50 may comprise a plurality of lenses, e.g., a stack of lenses. Furthermore, they may additionally provide means to separate two vacuum regimes such as a differential pressure aperture. Additionally or alternatively, one or more of the ion transport assemblies 30, 40, 50 may comprise a multipole element configured for guiding ions, e.g., along a certain distance to an aperture of a next analytical device.

For hardware-based attenuation at least one instrument parameter may be detuned from its optimal value in order to provide the desired target sensitivity. Generally, an instrument parameter of an element comprised in any of pre-selector 25 to detector 55 (Fig. 7) may preferably be used to achieve attenuation. In particular, the lens voltage of the focus lens into the differential pressure aperture upstream of the analyzer multipole may be preferred.

Generally, hardware-based attenuation may be achieved through various embodiments, e.g., dependent on user requirements and system capabilities.

A first, very basic embodiment would be to monitor only a single reference ion signal and to use a single instrument parameter for detuning the instrument such that the sensitivity for measuring the monitored reference ion signal meets with the specified target sensitivity value. In other words, only a single exemplary ion signal (i.e., reference ion signal) may be monitored to determine a required attenuation factor and consequently a corresponding instrument-parameter function. That is, a constant instrument-parameter function may be employed based on the sensitivity for measurement of a single reference ion.

Put differently, determining the instrument-parameter function may comprise identifying an instrument parameter value for which the relative signal intensity corresponds to the respective attenuation factor while considering only a single analyte parameter, i.e., a single reference analyte. The instrument-parameter function may then correspond to the identified instrument parameter value and may thus be constant.

Alternatively, a plurality of reference ion signals may be monitored and a single instrument parameter may be used for detuning until one of the ion signals reaches the desired target sensitivity value. In other words, a plurality of reference ion signals may be monitored in such a way that the attenuation factor is determined by a single reference ion reaching the desired sensitivity value. Again, this corresponds to a single attenuation factor based on the sensitivity measurement for a plurality of reference ions and consequently a constant attenuation function.

Put differently, determining the instrument-parameter function may comprise identifying an instrument parameter value for which the relative signal intensity corresponds to the respective attenuation factor while considering a plurality of analyte parameters, i.e., a plurality of reference analytes, wherein the instrument parameter value may be chosen such that the relative signal intensity for all considered analyte parameters is at most equal to the respective attenuation factor. The instrument-parameter function may then correspond to the identified instrument parameter value and may thus be constant.

Based on the above-described embodiments appropriate instrument parameter values may be determined that only need to be set statically during data acquisition. This renders such a modification of the sensitivity relatively straight forward to implement and no particular requirements are imposed upon the instrument parameter that is to be modified.

A more elaborate method would be an instrument specific detuning, wherein a plurality of reference ion signals may be monitored and a single instrument parameter may be used for detuning. In an initial calibration measurement, the instrument parameter may be detuned while monitoring the sensitivity of the plurality of reference ion signals. Generally, some data points may be saved indicating the detuning behavior of the signal intensity. For example, whenever one of said monitored sensitivities reaches the target sensitivity, the corresponding parameter value may be saved, such that a list is generated that comprises a respective instrument parameter value for each of the plurality of reference ions, or more generally based on an analyte parameter. Based on this list, an instrumentparameter function for varying the respective instrument parameter may be determined through curve fitting, interpolation and/or extrapolation.

In other words, a plurality of reference ion signals may be monitored and only one instrument parameter may be used for detuning. While the detuning process progresses, all those parameter values may be saved, where one of the reference signals reaches the required value. The result is a table of discrete parameter values that are associated with a specific analyte. If the parameter is then scanned with the analyte to be measured, this may result in the instrument achieving substantially (or even exactly) the expected signal intensity on all of the reference ion signals. All analytes that are not included in the data acquisition for the detuning procedure may be approximated, e.g., interpolated/extrapolated, by an appropriate fitting function. It may be determined from the table of discrete parameter values and their respective analyte, e.g., characterized by its m/z value.

For example, in an ICP-MS, the attenuation behavior of the focus lens comprised by transport device 40 into the differential pressure aperture before the analyzer quadrupole 45 may be measured for a plurality of reference ions, wherein the focus lens voltage serves as the instrument parameter that is varied to alter the respective attenuation behavior. Such an example is depicted in Fig. 8a, wherein for 4 different reference ions the signal intensity has been determined for 5 different lens voltages. These data may constitute or be comprised by the attenuation calibration data. The ordinate of the graph shown in Fig. 8a denotes the signal intensity relative to the highest intensity at a lens voltage of 20 V. Thus, such attenuation calibration data is indicative of a dependency of the relative signal intensity on the lens voltage, i.e., an instrument parameter, for a plurality of mass-to- charge ratios m/z, i.e., a plurality of analyte parameters. For each of the respective reference ions a 4^th order polynomial is fitted to the data in order to estimate the relative signal intensity for other (non-measured) lens voltages as indicated by the dotted lines. The order of the polynomial fit may be chosen for example based on the number of available data points, the complexity of the response to varying the parameter and available resources. Based on these data, the required lens voltage depending on the mass to charge ratio m/z may be determined. For example, if an attenuation of 50% across all mass-to-charge ratios m/z is desired (as indicated by the dashed horizontal line), the voltage of the focus lens needs to be set individually for each m/z to a value between 2 and 8 V. That is, the graph depicted in Fig. 8a shows the attenuation factor AP as a function of the lens voltage V, i.e., A_P(V) for different analyte parameters p. It will be understood that these functions can also be inverted. That is, instead of understanding the attenuation factor AP to depend on the lens voltage V, one can also understand that the lens voltage V is a function of the attenuation factor A_p. Thus, depending on which attenuation one wishes to achieve, one can set the lens voltage V accordingly.

Thus, based on the determined attenuation behavior of the focus lens for each of the reference ions, i.e., the determined dependency of the relative signal intensity on the lens voltage, a respective voltage can be determined to achieve the desired attenuation. These values provide data points for determining the focus lens voltage depending on the mass- to-charge ratio as depicted in Fig. 8b, i.e., for determining the m/z-dependent instrumentparameter function. In other words, each of the data points depicted in Fig. 8b corresponds to the intersection of the polynomial describing the respective attenuation behavior for the corresponding reference ion with the dashed line indicating a 50% attenuation (i.e., a relative signal intensity of 0.5). In that regard it is noted that for clarity, Fig. 8a does not depict measurements for all reference analytes for which a data point is shown in Fig. 8b, but merely comprises measurements for 4 exemplary reference analytes. That is, each data point corresponds to a lens voltage value chosen such that the resulting relative signal intensity corresponds to the desired attenuation factor of 0.5. These data points may again be fitted with one or more polynomial functions through curve fitting, interpolation and/or extrapolation to determine the instrument-parameter function. In the depicted example a piecewise-defined and thus piecewise-continuous instrument-parameter function is determined, which comprises 2 sub-functions Vi(m/z) and V2(m/z). A first sub-function for the low mass-to-charge ratios up to about 50 u/e (using the values indicated as Vp_l(Ap)), and a second sub-function for the higher mass-to-charge ratios between 55 and 238 u/e (using the values indicated as Vp_2(Ap)). This piecewise-defined instrument parameter function allows to scan the focus lens voltage synchronously with the analyzer. When assessing Figure 8b and particularly considering the low-mass range, the skilled person will understand that further measurements for reference ions below 50 u/e may further improve the accuracy.

That is, in Figs. 8a and 8b, it is assumed that overall (i.e., over the complete m/z range) a 50% sensitivity attenuation should be achieved, i.e., an analyte-parameter independent attenuation factor of 0.5 is assumed. Fig. 8b depicts how to set the focus lens voltage to achieve this sensitivity attenuation for different m/z values. While the dots depict actual lens voltages determined from the attenuation calibration data, the dotted lines depict polynomials best fitting the dots. While in this exemplary Figure, it was assumed that the same attenuation of 50% should be achieved for all m/z values, the skilled person will understand that this is merely exemplary and that embodiments of the present technology also allow for different attenuations for different m/z values.

The data set (p,V_P), or (m/z , V_P), which describes how the attenuator is to be operated, so that all target sensitivities St,_P are reached, may be approximated by a continuous function defined across the analyte range, or mass range m/z. In Figure 8b, this is exemplary done by using two functions Vi(p) and F2( ) on separate definition ranges and piecewise curve fitting. According to this function (these functions), the hardware parameter will be scanned together with the analyzer of the instrument.

It will be understood that the embodiments discussed in conjunction with Figs. 8a and 8b relate to a hardware-based attenuation, as a hardware parameter and more particularly a lens voltage is used to attenuate the sensitivity. For the calibration of a hardware attenuator, the baseline sensitivity Sb,_P,vt may be measured for a sequence of i different hardware parameter settings (voltages) Vi and for each calibration analyte p. Using the normalized signals from one calibrant p, a curve fit V_P(A) is determined to approximate the attenuation behaviour of the hardware. The plurality of all curve fits V_P (A) are saved as the hardware calibration functions. An example for such calibration functions is shown in Fig. 8a. In fact, the graph shows the inverse function A_P(V) , but both are created from the same set of calibration data (Fi , Sb,_P,vi).

Having determined them once, it is possible to calculate the voltages for an arbitrary attenuation for all calibrated analytes p. An example is shown in Fig. 8b. The figure shows the voltages necessary to reduce the signals of 8 calibration analytes to 50 % of their baseline signal Sb,_P. Four of these values can also be read from Fig. 8a as the crossing points between the attenuation curves A_P(V) with the horizontal line (relative intensity 0,5). In Fig. 8b, the voltages are approximated with two separate functions Vi(p) and Vzf ). It will depend on the individual hardware attenuator, which approach is best to fit the required voltages V_P across the mass range m/z (analyte parameter p) and different approaches, e.g., different fitting functions and different number of fitting functions may be used.

For each analyte p, the curve fit V_P(A) approximates the voltage that needs to be set to achieve an individual attenuation A_P, as discussed in conjunction with Fig. 8a. Other than in Fig. 8a and 8b, where the attenuation A_P is fixed to 50%, the values A_P,_new may typically individually deviate, when more than one target sensitivity St is to be recovered. For example, while it might be desirable to have an attenuation of 65% for 9BE, 55% for 59Co and 45% for 209BL The plurality of all A_{p new} = ( \ —5_rne -_M —_Z/p+l/ ), inserted into V_P (A), will create a new set of data (p, V_P or (m/z , V_P), which describes how the attenuator is to be operated so that all target sensitivities St,_P are reached.

Of course, also other instrument parameters may be used. For example, in the case of an ICP-MS system also the RF amplitude of a multipole, such as the pre-selector 25, the multipole device 35, e.g., collision/reaction cell, may be varied. For example, a collision/reaction cell may comprise a quadrupole whose q-factor and thus transmission is dependent on the RF amplitude and also on the m/z. Figure 9 depicts exemplary measurements of the transmission of a collision/reaction cell depending on the RF amplitude of its quadrupole for different reference ions. Here, the RF amplitude set by means of a digital-to-analog converter (DAC) is varied and the respective signal is shown relative to the standard DAC setting for each of the respective reference ions. Again, such data may constitute or be comprised by attenuation calibration data. It can be seen that the transmission of the collision/reaction cell strongly depends on the RF amplitude and that it also strongly depends on the mass-to-charge ration m/z. Thus, instead of setting the RF amplitude to maximum transmission, it can be used to control beam attenuation as a function of m/z. The process for choosing the RF amplitude to be applied to certain m/z may be similar to the process described above with respect to the voltage of the focus lens. That is, in some embodiments, the RF amplitude of the collision/reaction cell may be varied (instead of the focus lens voltage) to attenuate the measured signal and thus controllably decrease the instruments sensitivity to the target sensitivity.

Generally, the ratio of analyte signals measured with and without the hardware-based attenuation quantifies the attenuation provided through the instrument-parameter function and reproduces a curve as shown in Fig. 5 for the software- based attenuation function.

However, it will be understood that also a multi-parameter instrument detuning may be feasible. That is, it may also be possible to vary a plurality of instrument parameters based on monitoring a plurality of reference ions. Similar as discussed before, an initial calibration may be performed, wherein the desired instrument parameters are detuned and parameter value combinations for which a reference ion signal reaches a value that corresponds to the desired attenuation down to the target sensitivity may be stored to subsequently determine required parameter variations for m/z-dependent detuning of the instruments parameters for achieving the desired target sensitivity.

In other words, a multi-parameter instrument detuning may be provided, wherein a plurality of reference ion signals may be monitored and two or more instrument parameters may be used for detuning. While the detuning process progresses, instrument parameter sets may be saved, wherein each instrument parameter set may in such a case comprise a plurality of instrument parameter values each of which corresponding to a different instrument parameter. For example, all those n-tuples of parameter values (i.e., instrument parameter sets) may be saved, where one of the reference analyte signals reaches the expected value (wherein n may denote the number of parameters varied). The result may be a table of n discrete parameter values that are associated with a specific analyte, e.g., characterized by its m/z value. If the n parameters are then scanned with the measured analyte, this may result in the instrument achieving substantially (or even exactly) the desired sensitivity for all of the reference ion signals. All analytes that are not included in the data acquisition for the detuning procedure may be interpolated/extrapolated by at least n appropriate fitting functions. They may be determined from n tables of discrete parameter values and their respective analyte, e.g., characterized by its m/z value. Thus, in such a case a plurality of instrument parameter functions are generated, each relating to a different instrument parameter and the combination of the plurality of instrument parameter functions may in total provide the desired sensitivity attenuation.

Using a plurality of instrument parameter functions and thus varying a plurality of instrument parameters may be advantageous if a single parameter cannot provide the desired attenuation or if usability is problematic. The latter may for example be the case for the RF-amplitude depicted in Fig. 9 for low m/z, as the transmission curves are very steep and may be prone to drift effects. Thus, a second instrument parameter could help to attenuate the low m/z range, while the higher m/z range is attenuated using RF- amplitude detuning. That is, it may generally allow to overcome limitations of some of the hardware attenuators, i.e., elements of the instrument whose parameters are tuned.

The above embodiments, wherein at least one instrument parameter is detuned to account for an analyte parameter dependence of the sensitivity may require instrument parameters that can be switched quickly enough that signals are stable within the typical settling time of the instrument (between two data acquisitions), e.g., within microseconds. Thus, the number of suitable instrument parameters may be restricted.

More generally, in the context of an ICP-MS instrument a number of different instrument parameters may be suitable for a hardware-based attenuation, partly depending on further conditions, e.g., in which mode the instrument is operated.

When choosing suitable instrument parameters, it may be desirable to maintain certain instrument parameters in order to avoid adversely effecting desired instrument properties. In other words, important instrument properties may not be sacrificed, for example the matrix robustness of the instrument. Here matrix may denote all components of a sample that are not analyte (i.e., not the specific component(s) to be analyzed) or the solvent, e.g., dissolved solids or salts. Thus, matrix robustness refers to the robustness to so-called matrix effects, which are measurement effects caused by components of the sample that are not analyte or solvent. In the case of an ICP-MS instrument, the parameters in the entry stage of the instrument 10, 15, 20 (e.g., extraction and beam shaping entry lens voltages which may be comprised by the ion extraction & transport assembly 20) may not be an ideal choice for the sensitivity control recalibration as these are paramount to the matrix robustness of such instruments.

Generally, hardware parameters of elements that are located behind the first entry lens of the first RF multipole of an ICP-MS may be good options for a hardware-based attenuation, i.e., elements downstream of the ion extraction and transport assembly 20 which includes the entry lens for the pre-selector 25. For example, the voltage applied to an exit lens of a first or second multipole, e.g., comprised by pre-selector 25, multipole device 35, may be a suitable instrument parameter. Additionally or alternatively, the RF amplitude and/or frequency of the first and/or second multipole, e.g., comprised by pre-selector 25, multipole device 35, may be a suitable instrument parameter provided the respective multipole is not designated for mass selection.

Other potential instrument parameters relate to the voltages of the entry lens before the analyzer quadrupole, or an entry lens of the detector assembly, as well as any other additional lens that is capable of detuning the intensity intentionally and fast enough during a scan as long as it is downstream of the entry stage of the instrument.

A preferred instrument parameter would be the voltage of the focus lens into the differential pressure aperture before the analyzer quadrupole. As discussed above and indicated in Fig. 8a, lens voltages can have a very strong mass-dependent effect when used for detuning. This can be compensated with mass-dependent voltage settings, as shown in Figs. 8a and 8b.

With regard to multipole devices, particularly quadrupole devices, the RF amplitude determines the q-factor of such multipole devices for a certain m/z. In elemental analysis, the RF is scanned with m/z.

In no-gas modes, i.e., wherein the multipole is not filled with a collision/reaction gas, individual transmission characteristics can be achieved by adjusting the RF(m/z) function - and therewith the q-factor - according to the attenuation for a certain m/z setting. When operating in such a mode, RF amplitude may be a preferred instrument parameter.

When a multipole is operated in gas mode, i.e., the multipole is filled with a collision/reaction gas, the q-factor of the multipole further depends on the type of gas, the specific gas flow, and on the type of operation, i.e., with or without kinetic energy discrimination. Additional delay times for the ions to penetrate the gas cell may also play a role. A RF(m/z)-function may therefore need to be determine at a fixed gas flow. Another option for controlling an instruments sensitivity may be the detection efficiency of the detector, ultimately also in an analyte-dependent way. Possible parameters on a secondary electron multiplier are the voltage on the conversion dynode to control the ion detection probability either as a function of position on the conversion surface (consisting of different materials) or as a function of ion momentum. A preferred parameter for controlling the detection efficiency may be a gate voltage downstream of the conversion dynode, before the first ("analog") signal port of the ("dual-mode") detector used as a variable gate voltage to control signal gain.

In summary, preferred detuning parameters on ICP-MS instruments may be the voltage of the focus lens located behind the collision/reaction cell exit aperture or the collision/reaction cell RF amplitude, whose standard RF(m/z)-function can be modified to tailor collision/reaction cell transmission. Both options may allow for a mass-dependent transmission due to fast voltage/amplitude switching, which stabilizes within 1 ms, the typical time delay needed for analyzer stabilization.

As mentioned above, in addition to providing at least one standardized/attenuated sensitivity, at least one sensitivity reserve Sr may be determined (step 240). The at least one sensitivity reserve Sr may denote the portion of the at least one baseline sensitivity Sb that is renounced through attenuation. For example, if the baseline sensitivity Sb corresponds to 150% of the standardized (i.e., attenuated) sensitivity Ss, the corresponding sensitivity reserve Sr would amount to 50% of the standardized sensitivity S_s. In other words, the at least one sensitivity reserve denotes the excess sensitivity available after attenuating the at least one baseline sensitivity. That is, the sensitivity reserve Sr in % relates to the standardized sensitivity as

It will be understood that the at least one sensitivity reserve may be determined based on the at least one sensitivity attenuation and thus may for example be determined prior to step 250 (i.e., as separate step 240) or also be determined as part of step 250. That is, at least one standardized sensitivity Ss may be measured by performing a measurement using the at least one sensitivity attenuation and a reference solution, e.g., the baseline reference. Subsequently the at least one sensitivity reserve can be calculated based on the at least one baseline sensitivity and the at least one standardized sensitivity according to the above formula.

That is, as long as the at least one standardized sensitivity Ss is smaller than the respective at least one baseline sensitivity Sb, there is a sensitivity reserve for the instrument that can be activated, e.g., in order to maintain or restore the standardized sensitivity to the target sensitivity. As described above, it is known that the sensitivity of an instrument may decline with time and/or usage. Thus, the baseline sensitivity may change, e.g., between consecutive days of measurements. The present invention may allow to utilize an available sensitivity reserve to correct for such a decline in a fast and reliable manner. That is, as long as sufficient sensitivity reserve is present, the sensitivity attenuation may be adjusted in order to account for a change in the current instrument sensitivity. In other words, the present method may allow for adjusting the at least one sensitivity attenuation to maintain the standardized sensitivity, i.e., the attenuated sensitivity.

With reference to Fig. 4, once a sensitivity attenuation has been determined and at least one measurement using said sensitivity attenuation may be performed (step 250), the method may further allow to adjust the at least one sensitivity attenuation to correct for a decline in baseline sensitivity (step 300). In other words, the at least one attenuated sensitivity, i.e., the standardized sensitivity may thus be maintained. That is, the sensitivity may be kept above at least one target sensitivity threshold. Such at least one target sensitivity threshold may for example be defined relative to the at least one target sensitivity. For example, a target sensitivity threshold may correspond to anything between 50% to 90% of the target sensitivity, e.g., 70%, 75%, 80%, 85%, or 90% of the target sensitivity, wherein 80%, 85% and/or 90% may be preferred. The at least one sensitivity threshold may also be defined as a factor of the accuracy of the at least one attenuated sensitivity. That is, if the at least one attenuated sensitivity lies within ± 10%, preferably ±5% of the target sensitivity, the target sensitivity threshold may for example correspond to a factor thereof, e.g., a factor 2, 3, or 4.

Similarly, adjusting the at least one sensitivity attenuation (step 300) may comprise correcting for an increase in baseline sensitivity. That is, the sensitivity may be kept below at least one upper target sensitivity threshold. Such at least one upper target sensitivity threshold may for example be defined relative to the at least one target sensitivity. For example, an upper target sensitivity threshold may correspond to anything between 110% to 150% of the target sensitivity, e.g., 110%, 115%, 125%, 130%, 135%, 140%, 145% or 150% of the target sensitivity, wherein 110%, 115% and/or 120% may be preferred. The at least one upper sensitivity threshold may also be defined as a factor of the accuracy of the at least one attenuated sensitivity. That is, if the at least one attenuated sensitivity lies within ± 10%, preferably ±5% of the target sensitivity, the upper target sensitivity threshold may for example correspond to a factor thereof, e.g., a factor 2, 3, or 4.

With reference to Fig. 10, maintaining the at least one attenuated sensitivity may comprise the step 310 of determining at least one current sensitivity of the instrument. That is, either the current baseline sensitivity, i.e., the current sensitivity without attenuation, or the current attenuated sensitivity, i.e., the current sensitivity determined for at least one analyte parameter while using the at least one sensitivity attenuation, or both is determined through measurement thereof.

Once the at least one current sensitivity has been determined, it is checked whether there is a decline in sensitivity and particularly whether the resulting at least one attenuated sensitivity is lower than the respective at least one target sensitivity threshold (step 320). That is, in case for example the at least one current baseline sensitivity is measured, the resulting at least one current attenuated sensitivity may be estimated based thereon, wherein when the at least one current attenuated sensitivity is measured it may directly be compared to the at least one target sensitivity threshold. Again, additionally or alternatively, it may also be checked whether there is an increase in sensitivity and particularly whether the resulting at least one attenuated sensitivity is higher than the respective at least one upper target sensitivity threshold (not shown). That is, if for example the at least one current baseline sensitivity is measured, the resulting at least one current attenuated sensitivity may be estimated based thereon. Further, if the at least one current attenuated sensitivity is measured, it may directly be compared to the at least one upper target sensitivity threshold.

Thus, the at least one current sensitivity of the analytical instrument may be determined and checked in view of the desired attenuated sensitivity. Such checks may for example be performed based on schedule (e.g., in regular intervals), upon user request (i.e., manually triggered), and/or triggered by certain events (e.g., prior to each measurement). For such a check, the at least one current sensitivity may be determined again using a reference solution comprising at least one reference ion, preferably the baseline reference may be used. This check of sensitivity is performed without performing an optimization of the baseline sensitivity, e.g., without an running an autotune procedure.

If the resulting at least one attenuated sensitivity is not lower than the respective at least one target sensitivity threshold, no measures may need to be taken as the current sensitivity is still within the specified limits and one or more further measurements may be performed using the at least one sensitivity attenuation (step 250). If, however, the sensitivity experienced a decline such that the at least one attenuated sensitivity based on the at least one current sensitivity attenuation is below the respective at least one target sensitivity threshold, it may be checked whether the at least one current sensitivity still is above the at least one target sensitivity (step 340). It will be understood that steps 320 and 340 may also be carried out in reverse order. Alternatively, or additionally, it may be checked whether there is still a sensitivity reserve available and whether the available sensitivity reserve is sufficient for adjusting the at least one sensitivity attenuation without needing to optimize the instrument sensitivity (step 120).

In case the at least one current sensitivity is below the respective at least one target sensitivity, the method may revert back to step 120, i.e., optimizing the at least one instrument sensitivity for example based on an autotune procedure, and subsequently follow the procedure as described above with reference to Figs. 3, 4 and 6.

In case the at least one current sensitivity is above the respective at least one target sensitivity, the at least one sensitivity attenuation is updated (step 360). Updating the at least one sensitivity attenuation may for example comprise steps 210 and 230 as described above, particularly if the at least one current sensitivity comprises the at least one current baseline sensitivity. That is, at least one (updated or new) attenuation factor may be determined (being equivalent to step 210) and based thereon at least one (updated or new) sensitivity attenuation may be determined (being equivalent to step 230). That is, the at least one current sensitivity may constitute the new at least one baseline sensitivity and based thereon at least one attenuation factor and consequently at least one sensitivity attenuation may be determined.

Again, in some embodiments, the at least one sensitivity attenuation may also be updated in cases where none of the at least one attenuated sensitivity is lower than the respective at least one target sensitivity threshold. In particular, if the resulting at least one attenuated sensitivity is for example higher than the respective at least one upper target sensitivity threshold, the at least one sensitivity attenuation may nonetheless be updated to correct for such an increase.

In cases where the at least one current sensitivity only comprises the current at least one attenuated sensitivity, the at least one previous and current baseline sensitivity may be determined based on the last determined sensitivity reserve using the relation 100.

For example, a scenario is considered where the sensitivity reserve is initially 50% for a certain analyte parameter (e.g., in case of a mass spectrometer for a certain m/z value). That is, for this analyte parameter, the initial attenuated sensitivity is 2/3 of the baseline sensitivity. As a mere example, a certain amount of analyte results in a reading of 1,500 V as a baseline result, and the attenuated result thus is 1,000 V, thus resulting in a reserve of 500 V and a sensitivity reserve of 50%. This initially corresponds to an attenuation Amitiai of

Herein, p is the analyte parameter and Sr, initial is the initial sensitivity reserve. Thus, in the above example, the attenuation or attenuation factor is 2/3.

Over time, the baseline sensitivity may decrease, e.g., due to unintended misalignments in the system. This can be detected by the certain amount of analyte initially resulting in an attenuated result of 1,000 V now only resulting in an attenuated result of 800 V.

This can be accounted for by re-setting the attenuation factor accordingly. In the above example, the attenuation factor would be changed by a factor of 1.25. That is, in the above example, instead of applying the initial attenuation factor of 2/3 = 0.67, an attenuation factor of 2/3 x 1.25 = 0.83 would be applied to thus result in a new attenuated result of 1,000 V. This means that in the described example, the initial baseline result would be 1,500 V (initial attenuated result / initial attenuation factor) and the later baseline result would be 1,200 V (later attenuated result / later attenuation factor).

Generally, what is known is the target sensitivity (yielding the target result, e.g., 1,000 V for a certain amount of analyte), and the attenuation factor is set accordingly to yield the target sensitivity.

By means of the target sensitivity and the attenuation factor, the baseline sensitivity SB can be determined at any point of time by:

Here, A is the attenuation factor (which depends on the analyte parameter and time) and ST is the target sensitivity.

This may advantageously allow to provide a fast readjustment/recalibration of the attenuated sensitivity based on the available sensitivity reserve and thus without the need to run a general, typically more elaborate, optimization procedure for the instrument sensitivity.

In particular, in case of a hardware-based attenuation the attenuation calibration data does not need to be redetermined in case the at least one current baseline sensitivity is still above the respective at least one target sensitivity as the instrument sensitivity is not optimized and the attenuation calibration data is thus still valid. Therefore, particularly when utilizing hardware-based sensitivity attenuation, additional time may be saved when updating the at least one sensitivity attenuation as only steps 210 and 230 but not step 220 are needed to update the at least one sensitivity attenuation. Generally, a sensitivity loss may be calculated from comparing previous (or target) and actual sensitivity data. That can be done using baseline levels or identically measured attenuated sensitivities.

When maintaining the at least one standardized sensitivity close to the at least one target sensitivity by using the available sensitivity reserve, the decline of the at least one sensitivity reserve may be monitored and can for example advantageously allow to predict desirable instrument optimizations, e.g., autotune procedures, or other maintenance tasks such that a user may be able to better judge required instrument downtime and particularly the timing thereof. That is, a user may be able to better plan usage of the instrument and schedule potentially required optimization procedures and/or maintenance for times where the instrument may not be needed.

In other words, embodiments of the present invention generally speaking provide a method that allows to artificially reduce the sensitivity of an instrument, e.g., an over-performer (i.e., instrument whose sensitivity surpasses the instrument's specification), so that the specified - or otherwise desired - intensity values are more precisely met with a narrow window of variance. For example, by using an adaptive tuning approach (based on an attenuation function or an instrument-parameter function) sensitivity outliers may be clipped, but their potential may be shifted to a "performance reserve".

This "performance reserve" may be used during the life cycle of the instrument to stabilize its performance over time and can be characterized by a percentage, e.g., 90% (at 190% of the specified - or otherwise expected - sensitivity). By frequent and fast re-calibration, sensitivity under-performance can be compensated by releasing a part of the performance reserve. For example, when sensitivity is lost at the next day of operation a "fast adjust" or "quick re-calibration" step may be performed, wherein the "reserve" drops e.g., to 70% (at 170% of the expected sensitivity), and the desired performance is regained.

Advantages of using the present method can also be seen in Fig. 11, wherein the instrument performance and particularly the instrument sensitivity is depicted with respect to the operating time. The graph indicates three maintenance and tuning slots wherein the instruments sensitivity is optimized through elaborate optimization procedures. After each such maintenance and tuning slot, the baseline sensitivity Sb depicted as light gray line steadily declines up until the consecutive maintenance and tuning slot. The attenuated sensitivity is illustrated as the black graph. That is, the baseline sensitivity Sb is attenuated using the at least one sensitivity attenuation to provide the attenuated sensitivity. It can be seen that the attenuated sensitivity is held above a target sensitivity threshold Smin for most of the time and thus within a certain target sensitivity range between Smin und St. This is possible through usage of the available sensitivity reserve Sr (area between the baseline sensitivity Sb and upper and of the target sensitivity range as indicated by St) for a fast adjust of the attenuated sensitivity through adjusting the at least one sensitivity attenuation (step 300). This illustrates that embodiments of the present invention allow to operate the instrument within a much narrower sensitivity window while using the renounce sensitivity, i.e., the sensitivity reserve Sr, to maintain the current sensitivity above the respective target sensitivity threshold. This way time consuming and complex maintenance and tuning slots which may otherwise be needed once the attenuated sensitivity falls below the target sensitivity threshold, can be reduced to increase the instruments running time. As outlined above, the present method may also allow to maintain the current sensitivity below a respective upper target sensitivity threshold.

For example, Fig. 11 may depict an application of sensitivity-fast-adjust capability during instrument operation. Using a calibration standard solution, any loss of standardized sensitivity & below the amount of sensitivity reserve S_r can quickly be recovered by "fastadjust" and will not need maintenance and prior-art tuning.

Overall, the present invention thus provides a tuning approach which does not only provide sensitivity optimization but also intelligent attenuation of the ion beam. Furthermore, it allows for fast automatic restoration of a target sensitivity (e.g., standardized sensitivity) on analytical instruments.

Therefore, it may advantageously allow for a better reproducibility of instrument sensitivity throughout the lifetime of the instrument, wherein performance is stabilized based on the initial sensitivity specifications. Further, users with two or more instruments may experience identical sensitivity performance on identical systems (similar to an equalizer or speedometer) and variations in sensitivity of all instruments leaving series production may be reduced to a minimum. Overall, utilizing the disclosed method may require a lower number of retuning of the instrument.

Additionally, the present method may also allow to better predict when instrument maintenance is desirable as sensitivity becomes a predictable parameter for instrument health monitoring.

Whenever a relative term, such as "about", "substantially" or "approximately" is used in this specification, such a term should also be construed to also include the exact term. That is, e.g., "substantially straight" should be construed to also include "(exactly) straight".

Whenever steps were recited in the above or also in the appended claims, it should be noted that the order in which the steps are recited in this text may be accidental. That is, unless otherwise specified or unless clear to the skilled person, the order in which steps are recited may be accidental. That is, when the present document states, e.g., that a method comprises steps (A) and (B), this does not necessarily mean that step (A) precedes step (B), but it is also possible that step (A) is performed (at least partly) simultaneously with step (B) or that step (B) precedes step (A). Furthermore, when a step (X) is said to precede another step (Z), this does not imply that there is no step between steps (X) and (Z). That is, step (X) preceding step (Z) encompasses the situation that step (X) is performed directly before step (Z), but also the situation that (X) is performed before one or more steps (Yl), ..., followed by step (Z). Corresponding considerations apply when terms like "after" or "before" are used.

While in the above, a preferred embodiment has been described with reference to the accompanying drawings, the skilled person will understand that this embodiment was provided for illustrative purpose only and should by no means be construed to limit the scope of the present invention, which is defined by the claims.

Claims

Claims

1. A method comprising determining at least one baseline sensitivity of an analytical instrument; determining at least one sensitivity attenuation based on the at least one baseline sensitivity and at least one target sensitivity; and performing a measurement with the analytical instrument to generate a measurement result, wherein performing the measurement with the analytical instrument comprises using the at least one sensitivity attenuation; wherein the method further comprises performing the method steps for a plurality of analytical instruments with the same at least one target sensitivity.

2. A method comprising determining at least one baseline sensitivity of an analytical instrument; determining at least one sensitivity attenuation based on the at least one baseline sensitivity and at least one target sensitivity; and performing a measurement with the analytical instrument to generate a measurement result, wherein performing the measurement with the analytical instrument comprises using the at least one sensitivity attenuation; wherein performing the measurement with the analytical instrument comprises obtaining raw data, and using the at least one sensitivity attenuation comprises attenuating the raw data to obtain resulting data.

3. The method according to any of claims 1 and 2, wherein determining the at least one sensitivity attenuation based on the at least one baseline sensitivity and the at least one target sensitivity comprises determining at least one attenuation factor based on the at least one baseline sensitivity and the at least one target sensitivity, and determining the at least one sensitivity attenuation based on the at least one attenuation factor.

4. The method according to any of the preceding claims, wherein determining the at least one baseline sensitivity comprises measuring an associated instrument sensitivity to define the respective baseline sensitivity.

5. The method according to claim 4, wherein the method further comprises optimizing at least one instrument sensitivity prior to determining the baseline sensitivity.

6. The method according to any of the preceding claims, wherein determining at least one sensitivity attenuation comprises determining an attenuation function, wherein the at least one sensitivity attenuation comprises the attenuation function

7. The method according to claim 6, wherein the attenuation function provides an attenuation value for each analyte parameter within the instrument's measurement range.

8. The method according to any of the claims 6 and 7 and with the features of claim 3, wherein the at least one attenuation factor is a plurality of attenuation factors, and wherein the attenuation function is determined through interpolation and/or extrapolation based on the plurality of attenuation factors, or wherein the attenuation function is determined through curve fitting to the plurality of attenuation factors.

9. The method according to any of claims 6 to 8 and with the features of claim 2, wherein attenuating the raw data comprises applying the attenuation function to the raw data to obtain resulting data.

10. The method according to any of the preceding claims, wherein using the at least one sensitivity attenuation results in measuring with an attenuated sensitivity.

11. The method according to claim 10 and with the features of claim 3, wherein the attenuated sensitivity lies within ± 10%, preferably ±5% of the at least one target sensitivity for the analyte parameters associated with the at least one attenuation factor.

12. The method according to any of the preceding claims, wherein the method further comprises measuring at least one attenuated sensitivity, and determining at least one sensitivity reserve, wherein the determining the at least one sensitivity reserve comprises calculating the at least one sensitivity reserve based on the at least one attenuated sensitivity and the at least one baseline sensitivity.

13. The method according to claim 12, wherein a development of the at least one sensitivity reserve is monitored over time.

14. The method according to any of the preceding claims, wherein the method further comprises adjusting the at least one sensitivity attenuation to correct for a change in the at least one baseline sensitivity.

15. The method according to claim 14, wherein adjusting the at least one sensitivity attenuation comprises determining at least one current sensitivity of the analytical instrument, and updating the at least one sensitivity attenuation if at least one of the at least one current sensitivity is below a respective pre-defined target sensitivity threshold.

16. The method according to claim 14 or 15, wherein adjusting the at least one sensitivity attenuation comprises determining at least one current sensitivity of the analytical instrument, and updating the at least one sensitivity attenuation if at least one of the at least one current sensitivity is above a respective pre-defined upper target sensitivity threshold.

17. The method according to claim 15 or 16, and with the features of claim 3, wherein updating the at least one sensitivity attenuation comprises the steps of determining the at least one attenuation factor based on the current sensitivity and the at least one target sensitivity; and determining the at least one sensitivity attenuation based on and the at least one attenuation factor.

18. The method according to any of the preceding claims, wherein the method further comprises measuring attenuation calibration data, wherein the attenuation calibration data is indicative of a dependency of a relative signal intensity on at least one instrument parameter for at least one analyte parameter.

19. The method according to any of the preceding claims, wherein determining at least one sensitivity attenuation comprises determining at least one instrument-parameter function, wherein the at least one sensitivity attenuation comprises the at least one instrument-parameter function.

20. The method according to claim 19 and with the features of claims 3 and 18, wherein the attenuation calibration data is indicative of a dependency of a relative signal intensity on at least one instrument parameter for a plurality of analyte parameters, and wherein determining the at least one instrument-parameter function comprises determining a plurality of instrument parameter sets based on the attenuation calibration data, wherein each of the instrument parameter sets is associated to a different analyte parameter, and wherein each instrument parameter set comprises at least one instrument parameter value chosen such that the resulting relative signal intensity corresponds to one of the at least one attenuation factor associated with the same analyte parameter.

21. The method according to claim 20, wherein determining the plurality of instrument parameter sets comprises interpolating and/or extrapolating at least part of the attenuation calibration data to determine at least one calibration curve.

22. The method according to any of the claims 20 and 21, wherein determining the plurality of instrument parameter sets comprises curve fitting at least part of the attenuation calibration data to determine at least one calibration curve.

23. The method according to any of the claims 21 and 22, wherein each of the at least one calibration curve provides the relative signal intensity as a function of a respective instrument parameter for a specific analyte parameter.

24. The method according to any of the claims 20 to 23, wherein determining the at least one instrument-parameter function comprises curve fitting instrument parameter values comprised by the instrument parameter sets which are associated with the same instrument parameter.

25. The method according to any of the preceding claims, wherein using the at least one sensitivity attenuation comprises performing the measurement with settings of the analytical instrument based on the at least one sensitivity attenuation.

26. A system comprising an analytical instrument, and a controller, wherein the controller is configured to control the system to perform the method according to any of the preceding claims.

27. A computer program product comprising instructions which, when the program is executed by a system comprising an analytical instrument and a controller, cause the system to carry out the method according to any of claims 1 to 25.