Systems and methods for fast quantitative NMR spectrum acquisition

Abstract

To provide systems and methods for fast quantitative NMR data acquisition for multiple NMR scans performed on a sample.SOLUTION: Multiple scan batches on the sample are performed. Each batch comprises a long delay scan performed after a long delay interval ensuring near-full relaxation of the nuclei, and subsequently a set of short delay scans (SDS*) each performed after a short delay interval shorter than the long delay interval. An averaged integral loss is computed for each scan time point. For each NMR spectrum of the scan batches, an integral associated with a respective region of interest is multiplied with a corresponding correction factor. The integrals associated with the corrected NMR spectra in all the batches (B1-B3) are summed to obtain a representation of the NMR signal intensity in the region of interest for the sample.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates generally to spectroscopic measurements of samples, and more particularly to systems and methods for rapid quantitative NMR spectrum acquisition with high accuracy. [Background technology]

[0002] Nuclear magnetic resonance (NMR) is a technique used to study molecular properties by measuring the behavior of atomic nuclei in a strong magnetic field. NMR exploits the fact that certain atomic nuclei act like tiny magnets due to a property called spin. When a molecular sample is placed in a strong magnetic field, the atomic nuclei align with the field. In this equilibrium state, the nuclei have slightly different energies depending on their orientation. The sample is placed in the magnetic field and the NMR signal is generated by exciting the nuclear sample with radio frequency (RF) pulses to produce nuclear magnetic resonance, which is detected with a sensitive RF receiver. The intramolecular magnetic field around the atoms in a molecule changes the resonant frequency, so that details of the molecule's electronic structure and individual functional groups can be accessed. For example, NMR spectroscopy is used to identify single organic compounds, proteins, and other complex molecules. Beyond identification, NMR spectroscopy provides detailed information about the structure, dynamics, reaction state, and chemical environment of molecules. Common types of NMR are proton and carbon-13 NMR spectroscopy, but NMR is applicable to any type of sample that contains nuclei with spin.

[0003] Specifically, in NMR spectroscopy, the chemical shift is the resonance frequency of an atomic nucleus relative to a reference in a magnetic field. The position of the chemical shift and the intensity of the peak at said position indicate the amount of a molecule in a sample. Usually, the chemical shift δ is

number

[0004] Exciting the sample with radio frequency (typically 60-1000 MHz) that drives the nuclei to a higher energy state results in a nuclear magnetic resonance response, referred to herein as free induction decay (FID). The FID is a very weak signal and requires a sensitive RF receiver to pick it up. A Fourier transform can be applied to extract a frequency domain spectrum from the raw time domain FID. A spectrum obtained from a single FID usually has a low signal-to-noise ratio. This spectrum contains signals ("peaks") that are unique to the chemical environment around each nucleus and can be used to identify the type of component / molecule in the sample. The intensity of each peak is directly proportional to the number of respective nuclei and therefore the mass / concentration of the compound to which it belongs in the sample. For accurate quantification, especially of dilute (low concentration) samples, dozens or hundreds of these FIDs are acquired and accumulated.

[0005] The decay time of excitation, usually measured in seconds, can be very long in gases, depending on relaxation effects that are fast for light nuclei and solids, and slow for heavy nuclei and solutions. The relaxation time constants are individual for each signal in the spectrum.

[0006] Quantitative NMR acquisition is slow (time consuming) since a significant number of FIDs must be acquired in each scan to reach a high signal / noise ratio to ensure accurate results. The individual scans are then summed to the final FID. In prior art solutions, a delay between such individual scan measurements is necessary to allow the sample to relax. Advantageously, the sample is fully relaxed. Otherwise, the signal amplitude drops from scan to scan towards the equilibrium value. The delay time (also known as the relaxation delay or regeneration delay) is the period between these successive acquisitions (individual scans). This allows the spins to return to thermodynamic equilibrium. If this is set too short, the "relaxation" is incomplete and the signal intensity in successive acquisitions drops. For quantitative NMR, 5 or 7 times this relaxation time constant T1 is recommended, resulting in 99.3% or 99.9% relaxation, respectively. Relaxation of more than 99% is referred to herein as nearly complete relaxation. However, the value of T1 is not known a priori and is generally different for each signal in the spectrum. In the paper “Practical guide for selection of 1H qNMR acquisition and processing parameters confirmed by automated spectra evaluation. Magn Reson Chem. 2017 Nov;55(11):996-1005. doi:10.1002 / mrc.4622. Epub 2017 Jun 20. PMID:28561374,” authors Monakhova YB, Diehl BWK focus on the influence of acquisition and post-acquisition parameters on the developed automation routines in particular and on quantitative NMR (qNMR) in general, which have not been done before in a systematic and automated way. They provide a guide on how to select the acquisition parameters. A longest delay of 7×T1 is recommended to ensure complete relaxation of the sample.

[0007] Inappropriate choice of delay will result in quantification bias. For safety, a longer delay (e.g. 60-90 s) is usually used after each individual scan than is actually needed. Standard experiments exist to determine the TI time constant, but they require significant additional time. For example, Loening NM, Thrippleton MJ, Keeler J, Griffin RG describe fast T1 measurements in their paper “Single-scan longitudinal relaxation measurements in high-resolution NMR spectroscopy. J Magn Reson. 2003 Oct;164(2):321-8. doi:10.1016 / s1090-7807(03)00186-1. PMID:14511600.” Summary of the Invention

[0008] Therefore, it is a problem to provide a method and system for fast quantitative NMR spectrum acquisition, especially for samples with low concentrations of components of interest.For example, when using standard prior art acquisition methods, the total acquisition time can easily exceed 30 minutes when using a 60 second delay to ensure complete relaxation of low concentration samples, which is inadequate for many practical applications.The fast and accurate NMR spectrum acquisition approach disclosed herein according to the independent claims can reduce the total acquisition time to less than one third of the time required for prior art methods, while maintaining a high level of quantification accuracy.

[0009] That is, the above mentioned technical problem is solved by the embodiments of a computer implemented method, a computer program product and a computer system as set forth in the independent claims.

[0010] In one embodiment, a computer-implemented method for rapid quantitative NMR data acquisition for multiple NMR scans performed on a sample is provided, which may be performed by a computer system executing respective computer programs that implement functional modules of the computer system adapted to perform various steps of the computer-implemented method at run-time.

[0011] First, the method obtains a region of interest as an integral region of an NMR spectrum. Region of interest is a common term in NMR spectroscopy and represents an NMR spectrum portion (i.e., a wavenumber range) having relevant signal information that is characteristic of a particular molecule (i.e., the nucleus of said molecule) contained in the physical sample being analyzed. The integral value of the signal intensity in the region of interest is usually an indication of the concentration of said molecule. Thus, a point in an NMR spectrum already corresponds to a frequency range due to the nature of NMR spectroscopy. That is, the intensity value at a point in an NMR spectrum can already be considered to represent the intensity integral of the underlying frequency range. Typically, the region of interest is received from a user who is interested in a particular component. Alternatively, the region of interest can be obtained from a respective database that stores region of interest information for various components. For example, the method can be used to consecutively analyze multiple regions of interest of a measured NMR spectrum.

[0012] The approach disclosed herein uses a long delay interval and one or more short delay intervals to allow relaxation of the nuclei (i.e., relaxation of the respective spins) between individual NRM scans. In general, the delay interval used herein defines a time interval following the acquisition time interval of each NMR scan to allow further relaxation of the nuclei after each acquisition time interval. Typically, after an excitation pulse, an NMR scan is performed during the acquisition time interval to measure the decay in signal intensity caused by the relaxation of the nuclei. However, at the end of the acquisition time interval, the nuclei are not yet fully relaxed. Therefore, a delay time interval may be added after the acquisition time interval to allow further relaxation of the nuclei. Without such an additional delay time, the measurement results for low concentration components of a sample usually deteriorate with each subsequent NMR scan, resulting in a very poor signal-to-noise ratio. On the other hand, it is desirable to perform the series of NMR scans required for low concentration components as quickly as possible, especially in industrial measurement scenarios. The approach disclosed herein utilizes the surprising effect that highly accurate measurements can be performed even with a sequence of NMR scans with very short delay intervals (referred to as short delay scans), as long as an NMR scan with a long delay interval (referred to as long delay scans) is performed again after several short delay scans. The duration of the long delay interval is therefore selected to allow nearly complete relaxation of each nucleus. As used herein, nearly complete relaxation of a sample refers to a state of the sample where at least 99% of the reversed spins have returned to their original orientation. The duration of the short delay interval is shorter than the duration of the long delay interval.

[0013] For example, in one implementation, the long-term delay interval for nearly complete relaxation of the sample may be selected from the range of 30 seconds to 120 seconds to allow relaxation of more than 99% of the sample. In another implementation, the long-term delay interval is determined by experiment and may be shorter than the range mentioned above. The short-term delay interval is typically selected from the range of 0 seconds to 2 seconds. Thus, very good results with the approach disclosed herein have been achieved even with a short-term delay interval of 0 seconds (negligible delay). That is, a sequence of NMR scans may be performed without adding any short-term delay interval to the acquisition time interval of the preceding NMR scan, provided that the long-term delay scan is performed after an appropriate number of short-term delay scans. It has been found that the relaxation of the sample after the long-term delay interval is sufficient to obtain good intensity values ​​again for the subsequent short-term delay scan.

[0014] For this purpose, the method performs multiple scan batches on the sample, each batch comprising a long delay scan (performed after a long delay interval that ensures at least nearly complete relaxation of the nuclei) followed by a short delay scan (each short delay scan is performed after a short delay interval that is shorter than the long delay interval) such that the total number of NMR scans in the multiple batches is equal to or greater than the minimum required number of NMR scans for the sample. It should be noted that at the start of the measurement, the sample is usually fully relaxed, so that the first scan of the first batch is by definition a long delay scan. Each scan is associated with a corresponding scan time point relative to the time of the long delay scan of the respective scan batch. That is, each batch always starts with a long delay scan that defines a corresponding long delay scan time point LDT. It is considered that the first short delay scan in each batch is performed at a corresponding scan time point SDT1, the second short delay scan point is performed at a corresponding scan time point SDT2, and so on. All short delay scans are associated with corresponding scan time points, which indicates that the number of short delay scans in each batch is the same.

[0015] In one implementation, the short delay interval is the same for all short delay scans. In an alternative implementation, different short delay intervals may be used for the short delay scans of a batch. That is, in this implementation, at least two short delay scans of a scan batch use different short delay intervals. It should be noted that if a different short delay interval is used for a first batch, all subsequent batches must apply different delay intervals in the same order as the first batch to derive meaningful results. Advantageously, the set of short delay scans in a scan batch comprises between 3 and 9 short delay scans. The number of batches depends on the total number of NMR scans required for the sample and each low concentration component.

[0016] The method continues by determining, for each corresponding scan time, an aggregate NMR spectral portion within said region of interest by integration of the signal over said region of interest. That is, the intensity values ​​within the region of interest of all batches are summed for LDT1, SDT1, SDT2, etc. Thus, the aggregate NMR spectral portion at the LDT (after nearly complete relaxation) is highest, and the summed values ​​at the subsequent corresponding short delay scan time points show a decay over time. Note that to obtain the aggregate NMR spectral portion, it is irrelevant whether the method first applies a Fourier transform to all individual NMR scans and then aggregates the resulting individual NMR spectra, or first aggregates the individual NMR scans (for each corresponding scan time point) into aggregate NMR scans and then applies a Fourier transform to the aggregate NMR scans to obtain the aggregate NMR spectral portion. The results are the same, since the operations are commutative.

[0017] An exponential decay function is then fitted to the decay curve of the aggregate NMR spectrum portion over the corresponding scan time point. By applying the fitting function to each scan time point, an average integral loss for each scan time point is calculated. From the determined average integral loss, a correction factor is determined for each scan time point such that the integral loss is compensated.

[0018] The correction factor is then applied to all NMR spectra from the multiple scan batches by multiplying the integral value associated with each region of interest for each NMR spectrum by the corresponding correction factor. This correction also ensures that the small contribution of the short delay scans is corrected to a value as large as the long delay scans of the respective batches. Thus, if the region of interest corresponds to a point in a spectrum, the correction may be applied to only the point in the spectrum. Finally, the method sums the integral values ​​associated with the corrected NMR spectra in all the batches to obtain a representation of the NMR signal intensity in the region of interest of the sample.

[0019] In one embodiment, a correction factor may be calculated and applied to every point within the region of interest of each batch's individual NMR spectrum, and then all of the corrected individual NMR spectra may be summed into a single aggregate NMR spectrum.

[0020] The approach disclosed herein allows for fast NMR measurements of low concentration components in a sample, since most of the required scans are performed as short delay scans. Thus, the measurement time is mainly determined by a small number of long delay scans in multiple batches. The results are nearly as accurate as measurements using only a series of long delay scans, and more accurate than measurements where the long delay value is shortened to a value where the relaxation of the sample falls below a critical threshold (e.g., 99%). Details regarding the control measurements of the different approaches are given in the detailed description.

[0021] In one embodiment, the method may provide an estimated NMR signal intensity in the region of interest of the sample after each scan batch by summing the integrals of all corrected individual NMR spectra in the already processed scan batch, i.e., the method continuously performs the above-mentioned analysis at the end of each batch and provides each intermediate result to the user.

[0022] In one embodiment, the excitation pulse that may be applied to a sample to obtain an individual NMR spectrum has a flip angle greater than 0° and less than or equal to 90°. Advantageously, the flip angle is in the range of 30° to 45°.

[0023] In one embodiment, after the delay interval of a current individual NMR scan and before a subsequent excitation pulse is applied to the sample, a trim pulse may be applied to the sample to remove residual transverse magnetization, i.e., the NMR spectrometer is instructed (e.g., by a computer system running a computer-implemented method) to apply such a trim pulse.

[0024] In one embodiment, a computer program product is provided having computer readable instructions that, when loaded into a memory of a computing device and processed by one or more processors of the computing device, cause the computing device to perform steps for rapid quantitative NMR data acquisition for multiple NMR scans performed on a sample in accordance with the computer-implemented methods disclosed herein.

[0025] In one embodiment, a computer system for rapid quantitative NMR data acquisition for multiple NMR scans performed on a sample is provided, the system having a memory storing computer readable instructions implementing a number of functional modules, and one or more processors for executing the computer readable instructions to instantiate the functional modules to perform steps according to the computer-implemented methods disclosed herein.

[0026] Additional aspects of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. [Brief description of the drawings]

[0027] [Figure 1] FIG. 1 is a block diagram illustrating a computer system for rapid quantitative NMR data acquisition, according to an embodiment. [Diagram 2] 1 is a flowchart of a computer-implemented method for rapid quantitative NMR data acquisition, according to an embodiment. [Diagram 3] 1 illustrates an example of an acquisition time interval followed by a delay time interval. [Figure 4] 4A, 4B, and 4C show example NMR spectra acquired from a sample having two regions of interest. [Diagram 5] 1 shows a sequence of NMR scans performed on a sample using a single NMR scan batch. [Figure 6A] 1 illustrates a sequence of NMR scans performed on a sample using multiple NMR scan batches separated by long delay intervals, according to an embodiment. [Figure 6B] 1 shows simulated exponential decays for subsequent NMR scans performed on samples using short delay intervals of the same length versus short delay intervals of different lengths. [Figure 7] 1 shows corrections for differences and incomplete relaxation of individual NMR scans performed on a sample, according to an embodiment. [Figure 8] 8A and 8B show examples of corrected normalized integrals obtained according to an embodiment. [Figure 9] 9A-I. Comparison of ROI integration results between different setups for scan batches applied to the same sample. [Figure 10] FIG. 1 illustrates an example of a general-purpose computing device and a general-purpose mobile computing device that can be used with the techniques described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] FIG. 1 shows a block diagram of a computer system 100 for rapid quantitative NMR data acquisition for multiple NMR scans performed on a sample 201 using an NMR spectrometer 200. The system 100 implements multiple functional modules configured to perform various data processing tasks for rapid quantitative NMR data acquisition. The functional modules described in detail herein are advantageously implemented in software, but may also be implemented by programmable hardware components or ASICs. With a software implementation, computer readable instructions of the software are loaded into the memory of the system and processed by one or more processors of the system. When the computer readable instructions are executed at run-time, run-time instances of the respective modules are instantiated to perform a computer-implemented method 1000 of an embodiment as shown in the flowchart of FIG. 2. The system 100 will be described in more detail in the context of the method 1000, and reference numbers from both figures will be used accordingly in the following description.

[0029] For NMR measurements, typically, an operator of the NMR spectrometer 200 specifies one or more regions of interest (ROI) 301 that define areas in the NMR spectrum that provide spectral information on molecules of interest in the sample. The system 100 has an interface 110 that supports an interface function (e.g., a human-machine interface) adapted to receive information from the operator and also supports an interface function that allows machine-to-machine data exchange. Depending on the NMR response properties of the molecule, a respective number of NMR scans may be required to obtain an accurate NMR measurement result. In particular, for molecules with low concentrations, a greater number of subsequent NMR scans may be required to arrive at a measurement result that allows a reliable estimate of the concentration of the molecule in the sample 201 to be derived. Alternatively, the number of required scans may be obtained from a data store (e.g., a database) that stores respective information of various molecules via the respective adapted interface 110.

[0030] The batch composer 120 may obtain 1100 the number of NMR scans 302 required for the NMR measurement of the sample 201 and create a batch schedule for the sample measurement that distributes the required number of scans into multiple scan batches, each batch starting with a long delay scan followed by a series of short delay scans. The batch composer 120 may be an optional component of the system 100 or may be an external support tool for an operator (e.g., running on a device such as the operator's smartphone or tablet computer). Alternatively, the operator of the NMR spectrometer 200 may manually provide information to the system 100 regarding the number of scans required and how they should be distributed into various scan batches with long and short delay intervals in order to instruct the spectrometer 200 accordingly.

[0031] With brief reference to FIG. 3, a graph 300 shows the FID 311 of a particular NMR scan. The delay time interval generally defines the time interval following the acquisition time interval of the respective NMR scan to allow further relaxation of the sample after the preceding acquisition time interval. In the example of FIG. 3, the acquisition time interval AT1 (decay time of FID 311) has a duration of 1.5 seconds, followed by a delay time interval DT1 having a duration of 1 second. The first scan of the first batch in a sequence of NMR scans is always considered to be a long delay scan since the sample has not been subjected to an excitation pulse for a long time and complete relaxation of the nuclear spins is assumed. In subsequent scan batches, the long delay interval is selected to allow near complete relaxation of the sample before a long delay scan is performed that starts the next scan batch. Typically, for low concentrations of molecules, the long delay interval ranges from 30 seconds to 120 seconds to allow relaxation of more than 99% of the respective nuclei. Alternatively, the long delay interval may be determined via experimentation, which may allow the long delay interval to be shorter. The short delay interval is smaller than the long delay interval, typically ranging from 0 seconds to 2 seconds. That is, if the short delay interval is 0 seconds, a series of short delay scans in a scan batch trigger each short delay scan acquisition time interval immediately after the end of the preceding acquisition time interval. Advantageously, a scan batch includes 3 to 9 short delay scans after a long delay scan. The short delay interval may have the same duration for all short delay scans in each scan batch. In another implementation, a scan batch may use different short delay values ​​for different short delay scans. Details regarding these alternative implementations are described in the context of FIG. 6B.

[0032] The computer system initiates 1200 a series of NMR scans by instructing the NMR spectrometer 200 to perform NMR scans 202-1 to 202t according to the provided scan batch schedule. With brief reference to FIG. 6A, a number of scan batches B1 to B3 (scan batch schedule 600) are performed on the sample 201. Each batch comprises a long delay scan LDS (or as the initial scan of the first batch B1) performed after a long delay interval LD ​​that ensures nearly complete relaxation of the nuclei, followed by a short delay scan SDS. * Each short delay scan SDS is followed by a set of * is performed after a short delay interval SD that is shorter than the long delay interval LD. The total number of NMR scans 202-1 to 202-t in the multiple batches B1 to B3 is equal to or greater than the minimum required number of NMR scans for the sample. Thus, each scan is associated with a corresponding scan time point t1 to t6 with respect to the long delay scan time point of the respective scan batch. In this example, t1 is the scan time point corresponding to the respective long delay scan LDS, and t2 to t5 are the scan time points corresponding to the short delay scans SDS1 to SDS5 of each scan batch. In the example of FIG. 6A, all the short delay SDs have the same length. Since all acquisition time intervals have the same length, the corresponding scan time points t1 to t6 are equidistant.

[0033] All the batches of NMR scans 201-1 to 202-t are received by the batch processor module 130 of the system 100 via the interface 110. Interfaces for exchanging data between NMR spectrometers and computer systems for the analysis of said scans are well known in the art. The batch processor 130 also receives ROI information 301 (either from an operator or a respective database). The batch processor 130 then determines 1300 aggregated NMR spectrum portions Saa to Saf (see FIG. 6A) within the region of interest 301 for each corresponding scan time t1 to t6 via integration over said region of interest. The aggregated NMR spectrum portions at the corresponding scan time points show decay over time. To aggregate the NMR spectrum portions, two equivalent implementations can be used. In a first implementation, a fast Fourier transform module 131 converts each received NMR scan into a corresponding NMR spectrum S1a to S3f. An aggregator module 132 of the batch processor 130 then aggregates the NMR spectra of the corresponding scan time points for each batch. That is, for aggregate spectrum Saa, spectra S1a, S2a, S3a of long delay scans of all batches B1-B3 are aggregated. For aggregate spectrum Sab, spectra S1b, S2b, S3b of first delay scan SDS1 of all batches B1-B3 are aggregated, and so on. The same aggregation result will be obtained if aggregator 132 first aggregates original NMR scans (FIDs) at corresponding time points, and then FFT module 131 converts the aggregated NMR scans into corresponding aggregated NMR spectra.

[0034] The fitting module 133 of the batch processor 130 fits 1400 an exponential decay function to the decay of the aggregate NMR spectrum over the corresponding time points. The exponential decay function is shown as the dotted line 610 in FIG. 6A and is fitted to the decay curve of the left peak (region of interest) of the aggregate spectrum Saa-Saf. In this example, the signal intensity within the region of interest corresponding to the left peak in the NMR spectrum shows a strong decay over the corresponding time points, while the signal intensity within the region of interest around the right peak in the spectrum is almost unaffected by the short delay scan. The interpretation is that the molecules corresponding to the left region of interest are likely to be low concentration molecules whose signal intensity deteriorates rapidly due to lack of relaxation of the respective nuclei.

[0035] Figures 4A-4B show this phenomenon in more detail. Figure 4A shows an NMR spectrum 410 of a given sample in which two regions of interest ROI1 and ROI2 have been defined. The total number of NMR scans in this example is 32, resulting in 32 spectra. The following batch schedule was applied: each batch includes a long-delay scan and seven short-delay scans with a short-delay time interval of 2 seconds. The long-delay interval was 60 seconds. Four batches were performed. Peak 411 in ROI2 is hardly affected by the short-delay scan, while the small peak to the right side of the spectrum shows a strong dependence. The signal intensity 410-y of peak 412h is obtained by the long-delay scan, while the last short-delay scan of each batch results in only a greatly reduced signal intensity as shown by peak 412l. Figures 4A and 4B show a zoomed-in view of the aggregate spectrum for the two regions of interest 410-ROI2 and 410-ROI1. For ROI2 (Figure 4B), little deviation is observed between aggregate spectra 411-1 to 411-8 at the eight corresponding time points of each batch. That is, there is almost complete relaxation of ROI2 nuclei in the sample already at the end of each acquisition time interval. For ROI1 (Figure 4C), there is a significant deviation in NMR signal intensity between aggregate spectrum 412-1 (obtained in the long-delay scan) and aggregate spectrum 412-8 (obtained in the last short-delay scan of each batch). The decay in the intensity of the remaining spectra between 412-1 and 412-8 indicates a decay of the aggregate spectrum over the corresponding time points, which is a typical behavior for low concentration molecules in the sample.

[0036] FIG. 5 shows NMR spectra 5a-5r obtained from a plurality of 18 NMR scans 50 with two regions of interest 51a, 51b. In this experiment, all scans were performed in a single batch with only the first scan 5a corresponding to a long delay scan. All subsequent scans were performed as short delay scans. In the experiment, ROI 51a (low concentration molecule) shows exponential decay. T1 relaxation is an exponential decay, where T1 is the decay constant.

number

[0037] As mentioned above, the short delay intervals of all short delay scans (as in the example of FIG. 6A) may all have the same value, resulting in equidistant corresponding time points. However, it is also possible to vary the short delay intervals within a batch. The same variation is used for all scan batches. FIG. 6B shows a simulated normalized exponential decay function 620 for equidistant scan time points 0 to 8 (indicated by x symbols). This scenario corresponds to an implementation using a single value for all short delay intervals in all scan batches (as in FIG. 6A). The black dots (individuals) in the exponential decay function indicate a scenario in which different short delay intervals are used for the short delay scans within a batch. The vertical dashed lines indicate different time intervals between scan time points of the short delay scans. Nevertheless, the shift of the corresponding scan time points due to the varying short delay intervals ensures that the measured intensity values ​​are all on the normalized exponential decay function 620. That is, even in a scenario in which the short delay intervals vary within a batch, an exponential decay function can be fitted to each aggregate spectral portion at the corresponding scan time points. If a varying delay dt(n) is used between each scan in a scan batch, a more accurate iteratively calculated modified exponential function can be used that takes into account the relaxation time constant T1, the individual delays dt(n), and the integrated intensity expected from the applied pulse angle.

[0038] Returning to Figure 1, the correction module 134 of the batch processor 130 is used to calculate 1500 the average integral loss for each scan time point by applying a fitting function to each scan time point, and to determine 1600 from the average integral loss a correction factor for each scan time point such that the integral loss is compensated for. For example, the following formula may be applied: CorrectionFactor(t)=Integral(timepoint0) / fit(t) Then, for each NMR spectrum of the multiple scan batch, the integral value associated with each region of interest is multiplied 1700 by a corresponding correction factor. Figure 7 illustrates the concept of this correction mechanism for a region of interest ROI 7. A zoom-in 701 of the acquired NMR spectrum shows the decay of signal intensity over each scan time point. Fitting and correction steps 1400, 1500, 1600, and 1700 are applied. As a result, all corrected spectra in the zoomed-in portion 702 show approximately the same signal intensity.

[0039] 8A and 8B show in more detail an example of the correction of the spectrum obtained in the example of FIG. 4A and FIG. 4B. FIG. 8A shows the normalized integrals 810-ROI1 and 810-ROI2 of the aggregate spectrum for two regions of interest ROI1 and ROI2 over the corresponding scan time points 1 to 8. It can be seen that the peak of ROI2 remains unaffected by the short delay scan, since the integrals are substantially the same for all corresponding scan time points. However, the peak of ROI1 shows an exponential decay over the corresponding scan time points. The effect that the normalized integral of 810-ROI1 is larger at the corresponding scan time point 8 than at the corresponding scan time point 7 is due to the fact that the signal-to-noise ratio for the respective low concentration molecules is already very low when the seventh short delay scan in the respective scan batch is performed. Nevertheless, after the fitting and correction steps, the corrected normalized integral 820-ROI1 shows good coherence with an ideal value of "1". After correction, the spread of all corrected integral values ​​for ROI1 is 0.97-1.03, which is almost as good as the spread of ROI2 (region of interest not affected by short-delay scans) which has corrected integral values ​​of 0.98-1.02. In principle, the correction mechanism described above derives a correction factor for each corresponding scan time point as the ratio of the respective attenuation function value to the corresponding intensity value at the first corresponding scan time point (i.e., the aggregate spectrum associated with the long-delay scans of all the batches).

[0040] Finally, the batch integrator 140 of the system 100 sums up 1800 integral values ​​associated with the corrected NMR spectra in all batches B1-B3. Note that after the fitting and correction steps, each corrected spectrum of each short delay scan of each batch has similar intensity values ​​as the corrected spectrum obtained from the respective long delay scan. As a result, after the last scan batch is completed, the batch aggregator 140 obtains a very accurate representation 202-sf of the NMR signal intensity in the region of interest of the sample 201, even for low concentration molecules, in a relatively short acquisition time compared to the typical measurement time using only long delay scans for low concentration molecules.

[0041] In one embodiment, the batch integrator 140 may provide an estimated NMR signal intensity 202-si in the region of interest of the sample after each scan batch by summing the integrals of all the corrected individual NMR spectra in the already processed scan batch. In some scenarios, it may be advantageous for the operator to already know the estimate 202-si after the first batch and not wait for the final result 202-sf after the completion of all batches.

[0042] Table 1 shows the experimental data of different NMR measurements on the same sample. [Table 1]

[0043] In the first row of Table 1, data on the NMR measurement of a standard acquisition are shown. In the standard acquisition setup, only a series of 32 long-delay scans with a long-delay time interval of 60 seconds were performed. The total measurement time amounted to 33 minutes and 18 seconds (including acquisition and delay time intervals). The ratio of the two integral values ​​related to the two respective ROIs was determined to be 1.6421. This ratio, determined by a series of NMR scans after almost complete relaxation of the nuclei before each scan, can be seen as a kind of ground truth for the ratios to be determined.

[0044] In the second row of Table 1, an additional "long-delay scan only" measurement was performed on 32 long-delay scans. However, to reduce the total measurement time, the long-delay interval was shortened to 30 seconds, resulting in a total measurement time of 17 minutes and 30 seconds. The ratio was determined to be 1.6548, indicating a deviation of 0.8% from the ground truth.

[0045] In the third row of Table 1, a "short delay scan only" measurement was performed by using 32 short delay scans with a short delay interval of 2 seconds. The total measurement time was significantly reduced to 2 minutes and 25 seconds. Correction was applied according to the single batch scheme described in the context of Figure 5 by fitting an exponential decay function to each region of interest in each NMR spectrum and using the first NMR scan for normalization of the spectra. However, the ratio was determined to be 1.5418, showing a large deviation of 6% from the ground truth. Results with such deviations are not precise enough to obtain signal intensities / integrals relevant to low concentration molecules.

[0046] In line 4, the batchwise NMR measurement described in FIG. 6A according to the scheme described in claim 1 was performed in 5 scan batches, each batch starting with a long delay scan after a 60 second long delay interval, followed by 7 short delay scans with a short delay interval of 2 seconds. The total number of scans in this measurement was 40, and the measurement time was 6 minutes 30 seconds, which is approximately one third of the less accurate measurement in line 2. The ratio was determined to be 1.6493, showing only a 0.4% deviation from the ground truth. That is, even though the measurement time was reduced to about one third of the measurement time in line 2, the determined ratio was twice as accurate as in the case of the shortened long delay scan in line 2.

[0047] 9A-9I show a comparison of ROI integration results between different setups for a batch of scans applied to the same sample. FIG. 9A shows an NMR spectrum 90 obtained from the sample. Spectrum 90 shows the results of two ROI integrations for two different molecules contained in the sample. * , B* In this example, ROIA * The molecule related to ROIB is a known aromatic compound that exhibits three multiple peaks A1, A2, and A3 in the NMR spectrum. * The molecule related to corresponds to dimethyl sulfoxide (DMSO) and results in peak B1 in the NMR spectrum. In experiments, it has been shown that the integral value related to A3 is not affected by the short delay interval in the sense that the nuclear relaxation resulting in A3 is so fast that it shows almost complete relaxation even after the short delay scan A3. However, there is a significant effect of a series of short delay scans on the respective peak integrals of A1, A2, and B1, in the form of an exponential decay over the corresponding scan time points. As shown in the enlarged graph A1, and in the further enlarged zoom area A1z, for peak A1, 32 NMR scans in four scan batches with seven short delay scans after a long delay scan result in eight aggregate spectra A1_1 to A1_8. The aggregate spectra A1_1 to A1_8 show significant deviations. The same is true for the aggregate spectra A2_1 to A2_8 of peak A2 and the aggregate spectra B1_1 to B1_8 of peak B1.

[0048] FIG. 9B shows the results obtained from the above sample with 32 NMR scans including only long-delay scans with a long-delay interval of 60 seconds. The total measurement time for the 32 long-delay scans was 33 minutes and 22 seconds. Table 91-1 shows the ROIA * and B. *91-1 shows the ratios of integrals associated with the four peaks in the NMR spectrum. Note that peaks A1 and A2 contain several relatively broad sub-peaks, whereas peak A3 contains several very narrow sub-peaks. For this reason, the integral of A3 is approximately the same size as the integral of A2, while the integral of A1 is approximately twice as large as the integrals of A2 and A3. In this example, the theoretical integral ratio of the known aromatic compounds is A1:A2:A3=2:1:1. This is confirmed by the long delay scan measurements summarized in Table 91-1, where the integral ratio of A1 to A2 is 2.001 and the integral ratio of A1 to A3 is 2.014. The integral ratio of A1 to B1 is 0.832. The ratio of A2 to A3, which is 1.0057, is close to the theoretical ratio of 1. The ratio of A1 to B1 is derived from the measurements as 0.832. Table 91-2 shows the respective relative errors for the derived integral ratios. For the "long delay scan only" scans, all relative errors are less than 1%.

[0049] Figure 9C shows the results obtained from the above sample by 32 NMR scans including only short-delay scans with a short-delay interval of 2 seconds. The total measurement time of the 32 short-delay scans was 2 minutes and 30 seconds. The deviation of the A1:A2:A3 integral ratios from the theoretical ratio in Table 92-1 is significantly larger than the long-delay scan setup in Figure 9B. However, the deviation between the ratios of A* to B1 is very large in the "short-delay scan only" setup. Looking at Table 92-2, the respective relative errors are on the order of 12% to 18%. Usually, the ratio between the integrals of the two regions of interest is the relevant information derived from the spectrum. Therefore, the results obtained from the "short-delay scan only" setup are very inaccurate and not useful for the analytical purpose of determining the DMSO concentration from the NMR scan results.

[0050] Table 93 in FIG. 9D shows the deviation of the measurement of the "short delay scan only" in FIG. 9C with respect to the measurement of the "long delay scan only" in FIG. 9B. In particular for A3, there is practically no deviation since A3 has a short relaxation time that is not affected by the short delay scan. However, for A1 and A2, the integrals of the "short delay scan only" reach only 94% and 93% of the integrals of the "long delay scan only", respectively. The highest deviation is seen for the integral of B1, which is of most interest. The integral value of the "short delay scan only" is only 83% of the integral value of the "long delay scan only". That is, the high loss of NMR signal intensity caused by the measurement on the not yet relaxed nuclei reduces the accuracy of these integrals determined with the "short delay scan only" setup.

[0051] 9E-9G show the decay in the integral of the aggregate spectrum over the corresponding scan time points for A1, A2, and B1, respectively, as well as the corresponding correction values. Graph 94 is for A1, where the curve defined by the aggregate spectrum integrals (represented by circles) is fitted with an exponential decay function resulting in curve 94-2. The correction values ​​are represented by x icons, and the resulting correction curve 94-2 is approximately constant over the corresponding scan time points. The same is true for A2 and B1, as can be seen in graphs 95 and 96, respectively, with exponential decay fit curves 95-2, 96-2 and resulting correction value curves 95-1 and 96-1.

[0052] 9H, 9I show the results obtained from the above sample by using a scan batch according to the approach disclosed herein. In FIG. 9H, the long-term delay interval before the long-term delay scan of the scan batch was 60 seconds. The short-term delay interval used for all seven short-term delay scans in the scan batch was 1 second. The total measurement time for all four scan batches was 6 minutes. Table 97-1 shows the ROIA derived from the corrected spectra. * and B. * The integral ratio between the peaks of A *The ratios of known molecules related to are nearly identical to the theoretical ratios with a relative error of less than 0.5%, as shown in Relative Error Table 97-2. Also, the integral ratios derived from the spectra corrected for B1 show a very small relative error of only about 1% or less.

[0053] FIG. 9I shows the results obtained with a slightly different setup. To verify whether an extended short-delay interval would result in even higher accuracy, the short-delay interval used for all seven short-delay scans was 2 seconds. The total measurement time for all four scan batches in this setup was 7 minutes and 20 seconds. The integral ratio results derived from the corrected spectra in Table 98-1 show an accuracy nearly equal to that of the results obtained with the shorter short-delay interval of 1 second in FIG. 9H. The relative errors in Table 98-2 are again on the order of 1%. After evaluation, it was realized that the difference in relative errors between the ratios A2 / B1 (0.42) and A3 / B1 (0.42) is due to differences in the unshown digits of the ratios. For visualization in Table 98-1, the ratios were rounded to two decimal places.

[0054] The approach disclosed herein results in a significant reduction in the total measurement time of NMR scans of samples with low concentrations of substances by achieving comparable high accuracy results in terms of corrected integral values ​​at much shorter "short delay intervals."

[0055] FIG. 10 illustrates an example of a general-purpose computing device 900 and a general-purpose mobile computing device 950 that may be used with the techniques described herein. In some embodiments, the computing device 900 may be associated with the system 100 (see FIG. 1). The computing device 950 is intended to represent various forms of mobile devices, such as, for example, personal digital assistants, mobile phones, smartphones, and other similar computing devices. In the context of the present disclosure, the computing device 950 may provide I / O means for a user to interact with the computing device 900 (e.g., to display to the user a preview image provided). The illustrated components, their connections and relationships, and their functions are intended to be merely exemplary and are not intended to limit the implementation of the invention described and / or claimed herein.

[0056] The computing device 900 includes a processor 902, a memory 904, a storage device 906, a high-speed interface 908 connecting to the memory 904 and a high-speed expansion port 910, and a low-speed interface 912 connecting to a low-speed bus 914 and the storage device 906. Each of the components 902, 904, 906, 908, 910, and 912 may be interconnected using various buses and mounted on a common motherboard or in other manners as appropriate. The processor 902 may process instructions for execution within the computing device 900, including instructions stored in the memory 904 or the storage device 906, for example to display graphical information for a GUI on an external input / output device such as a display 916 coupled to the high-speed interface 908. In other implementations, multiple processors and / or multiple buses may be used, along with multiple memories and multiple types of memories, as appropriate. Multiple computing devices 900 may also be connected, with each device providing a portion of the required operations (e.g., as a bank of servers, a group of blade servers, or a multiprocessor system).

[0057] The memory 904 stores information within the computing device 900. In one implementation, the memory 904 is one or more volatile memory units. In another implementation, the memory 904 is one or more non-volatile memory units. The memory 904 may also be another form of computer-readable medium, such as, for example, a magnetic disk or optical disk.

[0058] The storage device 906 can provide mass storage for the computing device 900. In one implementation, the storage device 906 can be or include a computer-readable medium, such as, for example, a floppy disk device, a hard disk device, an optical disk device, or a tape device, a flash memory, or other similar solid-state memory device, or an array of devices including devices in a storage area network or other configuration. The computer program product can be tangibly embodied in an information carrier. The computer program product can also include instructions that, when executed, perform one or more methods, such as those described above. The information carrier is a computer-readable or machine-readable medium, such as, for example, the memory 904, the storage device 906, or a memory on the processor 902.

[0059] The high-speed controller 908 manages bandwidth-intensive operations for the computing device 900, and the low-speed controller 912 manages low-bandwidth-intensive operations. Such an allocation of functions is merely exemplary. In one implementation, the high-speed controller 908 is coupled to the memory 904, a display 916 (e.g., via a graphics processor or accelerator), and a high-speed expansion port 910 that may accept various expansion cards (not shown). In this implementation, the low-speed controller 912 is coupled to the storage device 906 and the low-speed expansion port 914. The low-speed expansion port, which may include various communication ports (e.g., USB, Bluetooth, Ethernet, wireless Ethernet), may be coupled to one or more input / output devices, such as, for example, a keyboard, a pointing device, a scanner, or a networking device, such as, for example, a switch or a router, via a network adapter.

[0060] The computing device 900 may be implemented in many different forms as shown. For example, the computing device 900 may be implemented as a standard server 920 or multiple in a group of such servers, or may be implemented as part of a rack server system 924. In addition, the computing device 900 may be implemented in a personal computer, such as, for example, a laptop computer 922. Alternatively, the components of the computing device 900 may be combined with other components in a mobile device (not shown), such as, for example, device 950. Each such device, the computing device 900, 950, and the entire system may be comprised of multiple computing devices 900, 950 in communication with each other.

[0061] Computing device 950 includes, among other components, a processor 952, a memory 964, an input / output device such as a display 954, a communication interface 966, and a transceiver 968. Device 950 may also be provided with a storage device such as a microdrive or other device to provide additional storage. Each of the components 950, 952, 964, 954, 966, and 968, etc., are interconnected using various buses, and some of the components may be mounted on a common motherboard or in other manners as appropriate.

[0062] The processor 952 can execute instructions in the computing device 950, including instructions stored in the memory 964. The processor may be implemented as a chipset of chips including multiple individual analog and digital processors. The processor may provide coordination of other components of the device 950, such as, for example, control of a user interface, applications executed by the device 950, and wireless communication by the device 950.

[0063] The processor 952 may communicate with a user via a control interface 958 and a display interface 956 coupled to a display 954. The display 954 may be, for example, a TFT LCD (thin film transistor liquid crystal display) or an OLED (organic light emitting diode) display, or other suitable display technology. The display interface 956 may comprise suitable circuitry for driving the display 954 to present graphical and other information to the user. The control interface 958 may receive commands from the user and translate them for presentation to the processor 952. An external interface 962 may also be provided in communication with the processor 952 to enable short-range communication between the device 950 and other devices. The external interface 962 may provide, for example, wired communication in some implementations and wireless communication in other implementations, and multiple interfaces may be used.

[0064] The memory 964 stores information within the computing device 950. The memory 964 may be implemented as one or more of one or more computer-readable media, one or more volatile memory units, or one or more non-volatile memory units. An expansion memory 984 may also be provided and connected to the device 950 via an expansion interface 982, which may include, for example, a SIMM (single in-line memory module) card interface. Such expansion memory 984 may provide extra storage space for the device 950 or may store applications or other information of the device 950. In particular, the expansion memory 984 may include instructions that perform or supplement the processes described above and may also include secure information. Thus, for example, the expansion memory 984 may function as a security module for the device 950 and may be programmed with instructions that enable secure use of the device 950. Also, secure applications may be provided via a SIMM card along with additional information, for example, providing identification information on the SIMM card in an unhackable manner.

[0065] The memory may include, for example, flash memory and / or NVRAM memory, as described below. In one implementation, a computer program product is tangibly embodied on an information carrier. The computer program product includes instructions that, when executed, perform one or more methods, for example, as described above. The information carrier is a computer-readable or machine-readable medium, such as, for example, memory 964, expansion memory 984, or memory on processor 952, which may be received, for example, via transceiver 968 or external interface 962.

[0066] The device 950 may communicate wirelessly via a communication interface 966, which may include digital signal processing circuitry as necessary. The communication interface 966 may provide communications under various modes or protocols, such as, for example, GSM voice calls, SMS, EMS, or MMS messaging, CDMA, TDMA, PDC, WCDMA, CDMA2000, or GPRS, among others. Such communications may occur, for example, via a radio frequency transceiver 968. Short-range communications may also occur, for example, using Bluetooth, WiFi, or other such transceivers (not shown). A GPS (Global Positioning System) receiver module 980 may also provide additional navigation and location related wireless data to the device 950, which may be used as appropriate by applications running on the device 950.

[0067] Device 950 may communicate verbally using audio codec 960, which may receive voice information from a user and convert it into usable digital information. Audio codec 960 may similarly generate audible sounds for the user, for example through a speaker in a headset of device 950. Such sounds may include sounds from voice calls, may include recorded sounds (e.g., voice messages, music files, etc.), and may include sounds generated by applications running on device 950.

[0068] Computing device 950 may be implemented in many different forms, as shown, For example, computing device 950 may be implemented as a mobile phone 980, or as part of a smartphone 982, personal digital assistant, or other similar mobile device.

[0069] Various implementations of the systems and techniques described herein may be realized in digital electronic circuitry, integrated circuits, specially designed ASICs (application-specific integrated circuits), computer hardware, firmware, software, and / or combinations thereof. These various implementations may include implementation in one or more computer programs executable and / or interpretable on a programmable system including at least one programmable processor, which may be special purpose or general purpose, coupled to receive data and instructions from and transmit data and instructions to a storage system, at least one input device, and at least one output device.

[0070] These computer programs (also known as programs, software, software applications or code) include machine instructions for a programmable processor and may be implemented in a high level procedural and / or object-oriented programming language and / or in assembly / machine language. As used herein, the term "machine-readable medium" and "computer-readable medium" refers to any computer program product, apparatus, and / or device (e.g., magnetic disk, optical disk, memory, programmable logic device (PLD)) used to provide machine instructions and / or data to a programmable processor, including a machine-readable medium that receives machine instructions as a machine-readable signal. The term "machine-readable signal" refers to any signal used to provide machine instructions and / or data to a programmable processor.

[0071] To provide interaction with a user, the systems and techniques described herein may be implemented in a computer having a display device (e.g., a CRT (cathode ray tube) or LCD (liquid crystal display) monitor) for displaying information to the user, and a keyboard and pointing device (e.g., a mouse or trackball) that allows the user to provide input to the computer. Other types of devices may be used to provide interaction with the user as well, e.g., feedback provided to the user may be any form of sensory feedback (e.g., visual feedback, auditory feedback, or tactile feedback), and input from the user may be received in any form, including acoustic, speech, or tactile input.

[0072] The systems and techniques described herein may be implemented in a computing device that includes back-end components (e.g., as a data server), or that includes middleware components (e.g., an application server), or that includes front-end components (e.g., a client computer having a graphical user interface or a web browser that allows a user to interact with an implementation of the systems and techniques described herein), or any combination of such back-end, middleware, or front-end components. The components of the system may be interconnected by any form or medium of digital data communication (e.g., a communications network). Examples of communications networks include a local area network ("LAN"), a wide area network ("WAN"), and the Internet.

[0073] Computing devices may include clients and servers. Clients and servers are generally remote from each other and typically interact through a communication network. The relationship of client and server arises by virtue of computer programs running on the respective computers and having a client-server relationship to each other.

Claims

1. A computer-implemented method (1000) for high-speed quantitative NMR data acquisition for a plurality of NMR scans performed on a sample (201), the method comprising: Obtaining a region of interest (ROI1) as an integration region of the NMR spectrum (1100), the region of interest corresponding to each nucleus of the sample; Initiating a plurality of scan batches (B1 to B3) on the sample (1200), each batch having a long-delay scan (LDS) performed after a long-delay interval ensuring substantially complete relaxation of the nuclei such that the total number of NMR scans (202-1 to 202-t) in the plurality of batches is greater than or equal to the minimum required number of NMR scans for the sample, and a set of short-delay scans (SDS*) each performed after a short-delay interval shorter than the long-delay interval, each scan being associated with a corresponding scan time point (t1 to t6) related to the time point of the long-delay scan of each scan batch; For each corresponding scan time point, determining an aggregated NMR spectrum portion (Saa to Saf) within the region of interest via integration across the region of interest (1300), the aggregated NMR spectrum portion at the corresponding scan time point exhibiting decay over time; Fitting an exponential decay function (610) to the decay (1400); Calculating an average integration loss for each scan time point by applying the fitted function to each scan time point (1500), and determining a correction factor for each scan time point from the average integration loss such that the average integration loss is compensated (1600); Multiplying each NMR spectrum of the plurality of scan batches by the correction factor corresponding to the integration value associated with each region of interest (1700); Summing the integration values associated with the corrected NMR spectra in all batches (B1 to B3) to obtain an expression (202-sf) of the NMR signal intensity in the region of interest for the sample (201) (1800); A method comprising the above steps.

2. The long delay interval (LD) for substantially complete relaxation of the sample is selected from the range of 30 seconds to 120 seconds to enable relaxation of more than 99% of the sample, and one or more short delay intervals (SD) are selected from the range of 0 seconds to 2 seconds, the method according to claim 1.

3. Obtaining the long delay interval comprises determining the long delay interval via an experiment, and one or more short delay intervals are selected from the range of 0 seconds to 2 seconds, the method according to claim 1.

4. The short delay interval has a single short delay value used for all short delay scans of each scan batch, the method according to any one of claims 1 to 3.

5. At least two corresponding short delay intervals for each batch use different delay values, the method according to any one of claims 1 to 3.

6. The set of short delay scans within a scan batch comprises 3 to 9 short delay scans, the method according to any one of claims 1 to 5.

7. After each scan batch, by summing the integrated values of all corrected individual NMR spectra in the already processed scan batch, providing the estimated NMR signal intensity (202 - si) in the region of interest for the sample The method according to any one of claims 1 to 6, further comprising.

8. The excitation pulse applied to the sample to obtain an individual NMR spectrum has a flip angle less than or equal to 90° and greater than 0°, the method according to any one of claims 1 to 7.

9. The flip angle is in the range from 30° to 45°, the method according to claim 8.

10. The correction factor is calculated for and applied to all points within the region of interest of each individual NMR spectrum of each batch, the method according to any one of claims 1 to 9.

11. The correction factor is calculated for and applied to all points of each individual NMR spectrum of each batch, and all corrected individual NMR spectra are summed into a single aggregated NMR spectrum, the method according to any one of claims 1 to 10.

12. Starting to apply a trim pulse to the sample to remove residual transverse magnetization after the delay interval of the current individual NMR scan and before the subsequent excitation pulse is applied to the sample The method according to any one of claims 1 to 11, further comprising

13. The determining (1600) comprises For each scan time point, applying a Fourier transform to each individual NMR scan to obtain corresponding individual NMR spectra (S1a to S1f, S2a to S2f, S3a to S3f), and aggregating corresponding portions of the individual NMR spectra related to the corresponding scan time points (t1 to t6) within the plurality of scan batches into an aggregated NMR spectrum portion (Saa to Saf) within the region of interest, or Aggregating the individual NMR scans at corresponding scan time points into respective aggregated NMR scans, applying a Fourier transform to the aggregated NMR scans, and obtaining the aggregated NMR spectrum portions (Saa to Saf) for the corresponding scan time points within the region of interest The method according to any one of claims 1 to 12, comprising

14. A computer program product comprising computer-readable instructions, which when loaded into the memory of a computing device and processed by one or more processors of the computing device, cause the computing device to perform steps for high-speed quantitative NMR data acquisition for a plurality of NMR scans performed on a sample according to the method according to any one of claims 1 to 13, and starting (1200) further comprises starting a plurality of scan batches by instructing an NMR spectrometer (200) to perform each NMR scan, and performing the determining (1300) step comprises receiving the NMR scans of the scan batches by the computing device from the NMR spectrometer, a computer program product.

15. A computer system for high-speed quantitative NMR data acquisition for a plurality of NMR scans performed on a sample, the computer system comprising: a memory storing computer-readable instructions implementing a plurality of functional modules; and one or more processors of the computer system for executing the computer-readable instructions to instantiate the functional modules to perform steps according to the method of any one of claims 1 to 13, the starting step (1200) further comprising starting a plurality of scan batches by instructing an NMR spectrometer (200) to perform each NMR scan, the NMR scans of the scan batches being received by the computer system from the NMR spectrometer prior to the step of determining (1300), computer system.

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