Patent Description:
Nuclear magnetic resonance (NMR) spectroscopy is a spectroscopic technique to observe molecular properties at atomic level. When a sample is placed in a magnetic field, local magnetic fields are induced around the atomic nuclei. These induced fields can be observed by applying radio frequency (RF) pulses to the sample and monitoring the response which is the NMR signal. This NMR signal is picked up by sensitive RF receivers. The locally induced fields are specific to the molecular environment of the atomic nuclei, thus giving access to details of the electronic structure of a molecule and its individual functional groups. For example, NMR spectroscopy is used to identify organic compounds, proteins and other complex molecules. Besides 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-<NUM> NMR spectroscopy, but it is applicable to any kind of sample that contains nuclear spins with a nuclear magnetic moment larger than zero. In this document, molecules which give rise to an NMR signal are referred to as NMR active molecules or NMR active substances.

Upon excitation of the sample with a radio frequency (typically <NUM>-<NUM>) pulse, a nuclear magnetic resonance response is obtained which is referred to as free induction decay (FID). The FID is a very weak signal and requires sensitive RF receivers to pick up. A Fourier transform can be applied to extract the frequency-domain spectrum from the raw time-domain FID. A spectrum from a single FID typically has a low signal-to-noise ratio, therefore usually multiple FIDs are acquired and averaged in order to obtain a spectrum with a better signal-to-noise ratio. Decay times of the response to the excitation, typically measured in seconds, depend on the effectiveness of relaxation, which is faster for lighter nuclei and in solids, and slower for heavier nuclei and in solutions whereas they can be very long in gases.

The evaluation of NMR spectra is typically supported by human NMR experts based on their experience with regards to how to interpret certain peaks in an NMR spectrum obtained from a real-world NMR experiment. A major task thereby is to identify which signal intervals in the obtained spectra are associated with peaks that are characteristic of the molecules in the NMR sample which is subject to evaluation. Such characteristic signal intervals may be difficult to identify because the signal of a typical NMR experiment includes signal contributions caused by sources different from the active molecule itself, such as for example, impurities, phase shifts, baseline effects, noise etc. The identification of the signal intervals is therefore an error prone procedure which depends a lot on the subjective individual experience of the supporting expert. The following prior art approaches make use of deep learning technology for NMR spectrum analysis. The document "<NPL>, discloses an example for detecting Signal Regions in 1D <NUM> on NMR Spectra using a deep neural network trained with simulated spectrum data for the detection of signal regions. The paper "<NPL>, discloses brain metabolite quantification in proton magnetic resonance spectroscopy (<NUM>-MRS) using a convolutional neural network (CNN) that maps in vivo brain spectra that are typically degraded by low SNR, line broadening, and spectral baseline into noise-free, line-narrowed, baseline-removed intact metabolite spectra. For that purpose, a CNN is trained on simulated brain spectra with wide ranges of SNR and linewidth. The paper "Magnetic Resonance Spectroscopy Quantification using Deep Learning" by Nima Hatami et al. , Medical Image Computing and Computer Assisted Intervention - MICCAI <NUM>, Springer International Publishing, discloses quantification of metabolites in MR Spectroscopic imaging using deep learning. A regression framework based on the Convolutional Neural Networks (CNN) is introduced for an accurate estimation of spectral parameters. The proposed model learns the spectral features from a large-scale simulated data set with different variations of human brain spectra and SNRs. The paper "<NPL>, discloses a method for accurate quantification of the MRSI-observed regional distribution of metabolites. To significantly shorten the processing time, an artificial neural network (ANN)-based approach was explored for quantifying the phase corrected (as opposed to magnitude) spectra. A radial basis function neural network (RBFNN) was used. The method was tested on simulated and normal human brain data. The paper "<NPL>, discloses simulating long echo time in vivo proton NMR spectra resembling human brain metabolite patterns for lineshape fitting (LF) and quantitative artificial neural network (ANN) analyses. Peak area data from ANN and LF analyses for simulated spectra yielded high correlation coefficients demonstrating that the peak areas quantified with ANN gave similar results as LF analysis. European patent application <CIT>) discloses an automated screening device that performs standardized system suitability tests and evaluations and measures components of a submitted sample to assist in the quality control screening of raw materials, ingredients, pharmaceuticals, chemicals, polymers, food products, petroleum and many other materials. After determining the performance suitability of an NMR spectrometer, the system permits samples to be submitted for screening. An NMR spectrum of a sample is acquired and a qualitative analysis unit identifies at least one reference NMR spectrum corresponding a compound present in the sample and a quantitative analysis unit integrates relative signal intensity signals of the sample spectrum in regions of peak intensity in the one reference NMR spectrum and compares integration results to a number of atoms in each region in order to confirm identification of the compound.

There is therefore a need for systems and methods that provide a more robust and objective identification of signal intervals in NMR spectra obtained from real-world NMR experiments. Further, to enable computer-implemented algorithms to automatically interpret NMR spectra, for example, to verify the structure of a molecule based on its <NUM> NMR spectrum, requires in a first step the reliable identification of signal regions.

Embodiments of the invention as claimed in the independent claims in the form of a computer-implemented method, computer system and computer program product solve this technical problem using the claimed features. It is to be noted that NMR responses are typically analyzed in the frequency domain. A signal interval, as used herein, refers to a frequency interval which is centered around the peak frequency of a respective signal peak in the NMR spectrum and characterizes a part of the spectrum which is associated with a nuclear magnetic resonance response of the NMR active molecules in response to a radio frequency pulse. Such signal intervals are sometimes also referred to as signal regions in literature. It is to be noted that in NMR spectroscopy the relative distance of the center frequency of a resonance peak from an arbitrarily chosen reference frequency (standard frequency) is called the chemical shift. A typical reference frequency which is frequently used is the frequency of the resonance peak of Tetramethylsilane (TMS). The reference frequency is thereby assigned to the chemical shift value "zero". The chemical shift is independent of the base frequency of the spectrometer and is measured in units of "ppm". In the following description and figures, the frequency values in NMR spectra are also referred to as ppm-values on a corresponding ppm scale.

In one embodiment, a computer-implemented method generates a realistic training data set for training a neural network to be used for signal analysis in NMR spectra, advantageously in liquid state <NUM> NMR spectra. Thereby, the initial hurdle for signal analysis is to identify the signal intervals (or signal regions). The data set provided by the claimed method is optimized to train the neural network to automatically identify such signal intervals in real-world NMR spectra with a high level of accuracy without any human interaction. In other words, the training data set can be considered realistic in the sense that it enables the training of the network with computed spectra that have a high similarity with NMR spectra obtained from real world experiments.

In an initial step, a plurality of computed NMR raw spectra is obtained. Each raw spectrum is thereby associated with a different NMR active molecule (also referred to as active molecule hereinafter) having a known number of protons. The plurality of computed NMR raw spectra may include exactly one raw spectrum for each active molecule. There are commercial tools available which compute a particular raw spectrum by obtaining the spin system of the associated NMR active molecule and a subsequent numerical solution of the Schroedinger equation for a given pulse sequence. An example of such a tool is the PERCH spectral simulator provided by PERCH Solutions Ltd. , Kuopio, Finland. The PERCH spectral simulator is based on quantum mechanical calculation. Large spin-systems are packed using X-approximation.

A computer system which is configured to execute the computer-implemented method may include such a tool as an integrated component or it may be communicatively coupled with such a tool and receive the plurality of computed NMR raw spectra via a corresponding interface. A molecule database may serve as a reservoir of molecule descriptions. An example of such a database is PubChem which is a database of chemical molecules and their activities against biological assays. The system is maintained by the National Center for Biotechnology Information (NCBI), a component of the National Library of Medicine, which is part of the United States National Institutes of Health (NIH). PubChem can be accessed for free through a web user interface. From such molecule descriptions the number of protons in a corresponding molecule is known. From this reservoir, a subset of NMR active molecules serves as the input for a raw spectrum generator module implemented, for example by the previously mentioned PERCH tool. The subset may include only molecules having a structure not exceeding a predefined degree of complexity. Advantageously, the molecular weight of the associated NMR active molecules is smaller or equal to <NUM> Dalton for a neural network which is used with a focus to analyze NMR spectra of active molecules used for pharmaceutical applications. Typically, in pharmaceutical applications such smaller molecules are in focus.

The output of the raw spectrum generator is a respective raw spectrum for each NMR active molecule with the peaks that are expected as nuclear magnetic resonance response of the corresponding active molecule (after having been subject to a radio frequency pulse sequence). For example, all raw spectra may be computed with the same line width parameter. The line width parameter may be chosen so that the resulting line width corresponds to the lower end of a line width range including line widths which are typically obtained in a plurality of real-world NMR measurements.

In a broadening step, peaks of the received raw spectra are broadened by convolution of each raw spectrum with one or more line shaping functions to generate a broadened spectrum as a current spectrum for each raw spectrum. This broadening step is sometimes also referred to as line broadening. Examples of typical line shaping functions are Lorentzian and/or Gaussian functions. For example, a raw spectrum may be convoluted with a Lorentzian and/or a Gaussian function. A convolution of a Lorentzian function with a Gaussian function is also known as Voigt function. A different line broadening value may be used for each raw spectrum. For example, the range of used line broadening values may be equivalent to the range from <NUM>,<NUM> to <NUM>,<NUM>. Advantageously, the different line broadening values are applied to the plurality of raw spectra in accordance with a statistical distribution, such as for example, a Gamma or Beta distribution. An advantageous example uses a Gamma distribution with shape parameter <NUM> and scale parameter <NUM> for both the Gaussian and Lorentzian line broadening parameter. Other statistical distributions may be used as well by a person skilled in the art. The broadening value is approximately the value which is added to the line width of a raw spectrum by the line broadening convolution. The line broadening values applied to the various raw spectra are thereby sampled from the statistical distribution. In other words, the effect of the Gaussian resp. the Lorentzian line broadening on the plurality of the current spectra follows the used statistical distribution. For example, when using the above described Gamma distribution, <NUM>% of current spectra would be broadened by a line broadening value between <NUM> and <NUM> (and <NUM>% between <NUM> and <NUM>, respectively). In other words, the statistical variation of the broadening values applied to the raw spectra results in a statistical variation of the line widths in the broadened spectra. There is no need to generate multiple broadened spectra with different line widths for the same active molecule. Rather, it is sufficient to have one broadened spectrum for each active molecule where the different broadened spectra as a whole cover the entire range of line widths observed in real-world NMR experiments. The line broadening step results in current spectra which already show a significantly higher similarity with NMR spectra obtained from real-world NMR experiments than the originally computed raw spectra. A typical line broadening is <NUM> and thus a typical line width is <NUM> (when using the Gamma distribution mentioned above for both the Gaussian and Lorentzian line broadening parameters) for a raw spectrum that was simulated with a line width of <NUM>.

Advantageously, for further processing, the received plurality of computed NMR raw spectra may be pre-processed so that the number of data points in each raw spectrum approximately corresponds to the number of data points of a comparable real-world NMR spectrum obtained from a real-world NMR experiment.

For each broadened spectrum signal intervals are now determined based on the computation of the indefinite integral function for a respective broadened spectrum to count the number of protons associated with peaks of the respective broadened spectrum. The computer system identifies signal intervals as such intervals in the broadened spectrum where the indefinite integral increases approximately by multiples of the value associated with a single proton. Because the broadened spectra at this stage are not disturbed by impurities, noise or any other perturbations, each peak or peak cluster in the broadened spectrum is clearly associated with an expected NMR response of the associated active molecule. The indefinite integral function is computed for the entire broadened spectrum which was scaled such that the finite integral over the whole spectrum matches the known number of protons of the associated molecule. The initially identified intervals are finally adjusted to cover at least a predefined threshold value of the corresponding known number of protons. Experiments have shown that a threshold value of at least <NUM>% of the number of protons is leading to good results. In other words, the signal interval for a particular peak cluster is adjusted so that the start and end frequencies of the interval are symmetrically set in relation to the peak maximum frequency so that the integral value between the adjusted start and end frequencies still include an integral area which covers an area equal to or larger than the predefined threshold value of the corresponding number of protons. For example, if the integral increases by <NUM> times the value associated with a single proton, the system recognizes that the increase actually should correspond to <NUM> times the value associated with a single proton. Assuming a threshold value of <NUM>%, the system would adjust the size of the signal interval to include an area corresponding to <NUM> times the value associated with a single proton.

The identified signal intervals in a particular broadened (current) spectrum represent labels associated with the respective signal intervals for the current spectrum. Once such labels have been determined for all current spectra, the current spectra are provided together with the associated labels as the training data set to the neural network to train the neural network for automatic identification of signal intervals in real-world NMR spectra.

It is to be noted that the labeling is performed completely automatically by the computer system executing said computer-implemented method without any need for human interaction. Further, the start and end frequencies of the labels are determined by the system with a very high degree of accuracy because the claimed integration method applied to the broadened spectra is not affected by any perturbations as they are found in real-world NMR spectra and therefore allows a highly accurate positioning of the start and end of the corresponding signal peak or peak clusters. Because of the statistical variation of the line widths in the plurality of current spectra, the neural network learns to generalize across all kinds of line widths occurring in real-world NMR experiments and at the same time learns to objectively identify the start and end of signal intervals with high accuracy.

In optional embodiments, the training data set may be further improved in the sense that perturbations which are present in NMR spectra obtained from real-world NMR experiment are also added to the computed broadened spectra. The term "current spectrum" as used herein always refers to the current state of a computed spectrum that is reached after the original raw spectrum has passed one or more post-processing steps. Therefore, a broadened spectrum is a current spectrum because the original raw spectrum has passed the pre-processing step of broadening. A current spectrum may then be modified by further post-processing steps.

After each post-processing step, a new (or modified) current spectrum is obtained. For the reason to keep the language simple, any new (or modified) current spectrum is also referred to as "current spectrum" herein. A person skilled in the art will recognize the state of the current spectrum based on the post-processing steps which have been applied to the original raw spectrum. After each post-processing step, a plurality of current spectra is obtained which can serve as the training data set.

In general, the post-processing steps which may be applied to the current spectra after having determined the signal intervals, apply one or more statistical modifications to each current spectrum wherein statistical parameters of a particular statistical modification are statistically distributed over the plurality of current spectra. Such statistical modifications add perturbations to the current spectra which modify the computed current spectra to become even more similar to real-world NMR spectra leading to a higher degree of recognition of signal intervals by the neural network when being trained with the perturbed current spectra.

In one embodiment, the applied perturbation is adding the effect of impurities to the current spectra. That is, a real-world NMR sample always includes impurities besides the active molecule to be analyzed. Such impurities also cause peaks in the real-world NMR spectrum obtained from such a sample. The impurities may be statistically selected from a list of known impurities. Examples of such impurities are Ethyl acetate or Cyclohexane. Impurities may also be randomly constructed impurities. Typically, known impurities are associated with known patterns in the corresponding spectrum whereas random impurities include regular and irregular patterns with a random number of lines/peaks. The spectra which will finally serve as training spectra for the neural network need to focus on the relevant signals which stem from the active molecule. There is no intention to train the network to identify impurities. Therefore, the concentration of added impurities is kept relatively low so that the impurity contribution to the integral of a particular current spectrum stays below the integral equivalent of, for example, <NUM> protons per impurity. As long as the integrated amplitude of impurity related peaks stays below the area which preferably is the equivalent of <NUM> protons, no signal regions is created because the threshold for being interpreted a multiple value associated with a single proton is not reached. Parameters characterizing the impurities comprise the number of impurities, the corresponding shift and the amplitude. Such parameters are statistically varied over the plurality of current spectra to which the impurity effect is added to. That is, similar as in the case of the statistical variation used for line broadening, each of said parameters is varied in accordance with a statistical distribution leading to current spectra with each spectrum reflecting a particular combination of parameters in accordance with said statistical parameter distributions.

In one embodiment, the applied perturbation is adding a linear phase shift to each current spectrum wherein the applied linear phase shifts are statistically distributed over the plurality of current spectra. In the model for the phase shift it is assumed that it only includes a term of zero order and a term of first order. The coefficients of the terms are again subject to a statistical distribution. For example, coefficients may be selected to result in a typical phase shift of maximal four degrees over the entire bandwidth. For each active molecule the linear phase shift is computed and applied in accordance with the given statistical distributions. Again, because of the statistical variation of the coefficients over all current spectra it is sufficient to have only one current spectrum for a given combination of coefficients in the training dataset because the neural network can already learn a generalization for the phase shift perturbation from such a training data set.

In one embodiment, the applied perturbation is adding a baseline variation to each current spectrum. The baseline variation for a particular current spectrum is computed with a piece-wise polynomial interpolation function through three to twelve sampling points (so-called knots), and wherein the coordinates of the knots for the current spectra are statistically evenly distributed over the plurality of current spectra. For example, the interpolation function may be a cubic spline function. The number of the sampling points may be determined by statistically selecting the number from a uniform distribution between a minimal value of <NUM> and a maximal value of <NUM>. The x- and y-coordinates of the knots of the baseline variation are taken from a uniform distribution of the x- and y-coordinates over a predefined range. Thereby, the x-coordinate is evenly distributed over the entire spectral range of the corresponding current spectrum, and the y-coordinate is evenly distributed over a predefined range including positive and negative values. The determined knots are then fit with a cubic spline. Finally, the y-axis is scaled so that the average absolute deviation of the baseline from the zero level follows a uniform distribution.

In one embodiment, the applied perturbation is adding noise to each current spectrum wherein the noise amplitudes follow a Gaussian distribution and the standard deviation of the Gaussian distribution statistically varies over the plurality of current spectra.

Each perturbation turns the current spectrum into a spectrum which gets closer to a real-world spectrum as it can be expected from a real-world NMR experiment. It is to be noted that the added perturbations may overlay the broadened peaks of the broadened spectra. However, the labels indicating the signal intervals are still associated with the modified current spectra and, therefore, each current spectrum of the training data set provides the information about the exact locations of the signal intervals in the perturbed spectra.

In one embodiment, the provided current spectra of the training data set are now actually used for training the neural network for signal analysis in NMR spectra to enable the neural network to identify signal intervals in real-world NMR spectra obtained from real-world NMR experiments. The neural network may be part of the same computer system which is used for generation of the training data set, or it may be trained on a remote system which is communicatively coupled with this system. The neural network receives the current spectra of the generated training data set together with the labels for the identified signal intervals. A supervised learning method is used to train the neural network with the received current spectra of the training data set and with the associated label identifiers. Thereby, the received current spectra serve as inputs to the neural network and the respective signal intervals as indicated in the associated labels are used as outputs.

In one embodiment, the trained neural network is then used for signal analysis in real-world NMR spectra. The trained neural network receives a real-world NMR spectrum obtained from a real-world NMR experiment as test input. Then, the trained neural network is applied to said test input. As a result, the trained neural network provides as output one or more signal intervals as identified in the received test input.

It has been shown that the neural network which is trained with a training dataset according to any of the embodiments disclosed herein learns to generalize across the whole range of statistically varied parameters even if only a single current spectrum per active molecule is included in the training dataset. Even when all computed raw spectra were simulated at a proton resonance frequency of <NUM>, the trained neural network is able to identify signal intervals with a high level of accuracy in real-world NMR spectra obtained from NMR spectrometers which were operated at proton resonance frequencies between <NUM> and <NUM>.

In one embodiment, a computer program product is provided for generating a realistic training data set for training a neural network for signal analysis in NMR spectra. The computer program product has instructions that when loaded into a memory of a computer system and being executed by at least one processor of the computer system cause the computer system to perform the method steps according to any of the herein disclosed embodiments of the computer implemented method for generating the training data set.

In one embodiment, a computer program product is provided for training a neural network for signal analysis in NMR spectra to enable the neural network to identify signal intervals in real-world NMR spectra obtained from real-world NMR experiments. The computer program product has instructions that when loaded into a memory of a computer system and being executed by at least one processor of the computer system to receive the training data set as generated in accordance with the disclosure herein, and to train the neural network with the received current spectra of the training data set and the associated label identifiers using a supervised learning method, wherein the training input to the neural network are the current spectra of the training data set and the outputs are the respective signal intervals.

In one embodiment, a computer program product is provided for signal analysis in NMR spectra to identify signal intervals in real-world NMR spectra obtained from real-world NMR experiments. The computer program product has instructions that when loaded into a memory of a computer system and being executed by at least one processor of the computer system cause the computer system to receive a real-world NMR spectrum obtained from a real-world NMR experiment as test input for the neural network as trained in accordance with the herein disclosed training method, and to apply the trained neural network to said test input, and to provide as output of the trained neural network one or more signal intervals as identified by the trained neural network.

In one embodiment, a computer system is provided for generating a realistic training data set for training a neural network for signal analysis in NMR spectra. The system has modules adapted to perform the corresponding steps when executing the above computer program product generating a realistic training data set for training said neural network.

In one embodiment, a computer system is provided for training a neural network for signal analysis in NMR spectra to enable the neural network to identify signal intervals in real-world NMR spectra obtained from real-world NMR experiments. The system has modules adapted to perform the corresponding steps when executing the above computer program product for training said neural network.

In one embodiment, a computer system is provided for signal analysis in NMR spectra to identify signal intervals in real-world NMR spectra obtained from real-world NMR experiments. The system has modules adapted to perform the corresponding steps when executing the above computer program product for signal analysis in NMR spectra.

Further aspects of the invention will be realized and attained by means of the elements and combinations particularly depicted 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 described.

<FIG> illustrates a block diagram of a computer system <NUM> for generating a realistic training data set <NUM> for training a neural network <NUM> for signal analysis in NMR spectra according to an embodiment. The system <NUM> of <FIG> is described in the context of the simplified flow chart of a computer-implemented spectroscopic method <NUM> for generating such a realistic training data set as illustrated in <FIG>. Therefore, the following description refers to reference numbers used in <FIG> and <FIG>. The system <NUM> is thereby configured to execute the method <NUM> when loading a respective computer program into a memory of the system and executing said program with processing means of the system.

In the example embodiment of <FIG>, an input to the computer system <NUM> is provided by a spectrum generator <NUM>. The generator <NUM> can be implemented as an integral module of the computer system <NUM> or it may be provided as a standalone tool provided on a remote computer device which is communicatively coupled with the computer system <NUM>. In both cases, standard communication means are used to provide data generated by the generator <NUM> to the computer system <NUM>. The training dataset <NUM> is provided to the neural network <NUM> which is part of an NMR spectrum analyzer <NUM>. Also the spectrum analyzer <NUM> may be an integral module of the computer system <NUM> or it may be operated on a remote computing device which is communicatively coupled with the computer system <NUM>.

The generator <NUM> is communicatively coupled with a molecule database (DB) <NUM>. This molecule DB may be part of the generator itself, or more likely, it may be a remote database which can be accessed by the generator <NUM> through respective interfaces. The molecule DB provides a reservoir of molecule descriptions. An example of such a database is the PubChem database mentioned above. From such molecule descriptions the number of protons in a corresponding molecule is known. From this reservoir, a subset of NMR active molecules <NUM> serves as the input for a raw spectrum generator module <NUM> implemented, for example by the previously mentioned PERCH spectral simulator. The subset may include only molecules having a structure not exceeding a predefined degree of complexity. Advantageously, the molecular weight of the associated NMR active molecules is smaller or equal to <NUM> Dalton. <FIG> shows an example of a structural formula <NUM> of an NMR active molecule with <NUM> hydrogen atoms (C<NUM>H<NUM>N<NUM>O<NUM>S<NUM>). This structural formula <NUM> is included in the PubChem database with the identifier CID <NUM>. To train a reliable neural network a multitude of NMR active molecules fulfilling the above conditions is selected. For example, the number of selected molecules may be in the range of <NUM> to <NUM>. <NUM> NMR active molecules.

The raw spectrum generator module <NUM> can compute a particular raw spectrum by estimating the spin system of the associated NMR active molecule and a subsequent numerical solution of the Schroedinger equation for a given pulse sequence. This allows, for example, simulation of cyclosporine A spectrum (<NUM> protons, <NUM> particles) and with X-approximation also much larger spin-networks like testosterone (<NUM> fully coupled protons). <FIG> shows an example of a computed raw spectrum <NUM> in the range from <NUM> ppm to <NUM> ppm where the computed raw spectrum <NUM> was generated under the assumption of a line width of <NUM>. Each raw spectrum is associated with a different active molecule having a known number of protons #P. The number of protons #P is known from the respective structural formulas. For example, the structural formula <NUM> (cf. <FIG>) includes <NUM> protons as evident for a person skilled in the art. The current spectra which are shown in the example figures <FIG> are actually computed for the structure formula shown in <FIG>.

The computed NMR raw spectra <NUM> together with the respective number of known protons #P are now obtained <NUM> by the computer system <NUM> serving as input to a line broadening module <NUM> of the computer system <NUM>. In one implementation, the line broadening module (or a separate pre-processing module) may perform an initial pre-processing <NUM> of the obtained raw spectra so that the number of data points in each raw spectrum approximately corresponds to the number of data points of a comparable real-world NMR spectrum obtained from a real-world NMR experiment, e.g. powers of two like <NUM>, <NUM>, <NUM>. To achieve a match between the number of data points of a test input spectrum and the number of data points of the current spectra of the training data set, the test input may be interpolated accordingly before being processed by the neural network.

The line broadening module <NUM> generates a broadened spectrum <NUM> as a current spectrum for each raw spectrum by broadening <NUM> peaks of the raw spectra by convolution of each raw spectrum <NUM> with one or more line shaping functions. The one or more line shaping functions may be a Lorentzian or Gaussian function or a combination thereof (which is equivalent to a line broadening with a Voigt function). The broadening of line widths follows a statistical distribution over the plurality of raw/current spectra. In other words, different raw spectra are broadened using different line broadening parameters where a particular line broadening parameter for the broadening of a particular raw spectrum is selected from a predefined parameter range in accordance with a statistical distribution that has a positive lower bound of the support, such as for example a gamma distribution, a beta distribution, a log-normal distribution or another suitable distribution that has a non-negative lower bound of the support. <FIG> illustrates an example where the raw spectrum <NUM> (cf. <FIG>) was convoluted with a Lorentz function (with a width of <NUM>) and a Gaussian function (with a width of <NUM>) resulting in the broadened spectrum <NUM>-<NUM> (cf. For example, in case of a raw spectrum with <NUM> linewidth, a Lorentzian function with a <NUM> linewidth and a Gaussian function with a <NUM> linewidth may be used for line broadening. The applied line broadening parameter values in this example are therefore <NUM> and <NUM>, respectively.

In the entire spectrum it appears, as if the original raw spectrum <NUM>-<NUM> is identical to the broadened spectrum <NUM>-<NUM> because the differences between the two spectra are too small to be recognized by the human eye in a black and white representation without applying zooming. In the upper part of <FIG>, a zoomed part of the spectra is illustrated in the range from <NUM> ppm to <NUM> ppm where the spectra have been shifted apart in the vertical axis for better visibility. In the zoomed view, the effect of the broadening step becomes clearly visible. The raw spectrum <NUM>-<NUM> has - especially when looking at peaks with low amplitudes <NUM>-1a, <NUM>-1b - significantly sharper peaks which almost disappear in the broadened spectrum <NUM>-<NUM>. Due to line broadening the peak to valley ratio decreases. The broadened spectra <NUM> are already much more comparable with a real-world NMR spectrum than the originally computed raw spectra <NUM>.

Of course, as the number of protons #P is known for the raw spectrum, this number is also known for the derived broadened spectrum. The broadened spectra <NUM> together with their respective number of protons #P serve as input for a signal interval (SI) identifier module <NUM>. The SI identifier <NUM> computes <NUM> for each broadened spectrum <NUM> its integral function to count the number of protons associated with peaks of the respective broadened spectrum. <FIG> illustrates the integral function <NUM> which is computed for the broadened spectrum <NUM>-<NUM>. The SI identifier <NUM> now analyses the integral function <NUM> and detects intervals in the broadened spectrum where the integral function <NUM> increases approximately by multiples of the value associated with a single proton. The dashes on the ppm-axis (e.g., <NUM>-1a, <NUM>-1b, <NUM>-2a, <NUM>-2b) represent the count for the number of protons associated with the respective peaks (e.g., <NUM>-<NUM>, <NUM>-<NUM>). In other words, the peak integral for peak <NUM>-<NUM> corresponds to the equivalent of two protons. Also the peak integral for peak <NUM>-<NUM> corresponds to the equivalent of two protons. The integral function <NUM> is scaled over the entire spectrum to lead to a total number of counted protons which matches the known number of protons #P of the associated molecule. Signal intervals are now identified <NUM> as such intervals in the broadened spectrum <NUM> where the integral function increases approximately by multiples of the value associated with a single proton. Thereby, the identified intervals <NUM> are adjusted to cover at least a predefined threshold value of corresponding peak integrals. For example, the predefined threshold value may be defined so that <NUM>% of the respective peak integral are covered. Higher coverage values may also be used.

<FIG>, illustrates a schematic view of an integral function <NUM> computed for a broadened spectrum for an active molecule with <NUM> protons. The y-axis shows the value of the indefinite integral in equivalents of protons (#P). In this example embodiment, the signal intervals are determined using a three-step computation. In a first step, the broadened spectrum is convoluted with a rectangular window function having a width of <NUM>. Intervals which exceed a predefined threshold value in the convoluted (further broadened) spectrum <NUM> define intermediate signal intervals. Such intermediate signal intervals are illustrated for the two peaks on the left (with intermediate intervals A1, A2), the next two peaks (intermediate interval B), followed by four peaks (intermediate intervals C1, C2), each associated with one proton, and one peak (intermediate interval D) on the right of the spectrum associated with <NUM> protons. It is to be noted, that multiple peaks associated with a single proton are typical characteristics of liquid state <NUM> NMR spectra making the identification of signal intervals a difficult and error prone task in NMR spectrum analysis prior art solutions. In a second step, neighboring intervals are merged in case that the indefinite integral does not get close to a multiple of a single proton anywhere between the intermediate signal intervals. In the example of <FIG>, this is the case for the two intermediate intervals A1 and A2 on the left (merged into A) and the two intermediate signal intervals C1 and C2 (merged into C). In a third step, these modified intermediate signal intervals are adjusted to cover, for example, <NUM>% of the integral area for the respective peaks. This embodiment allows a reliable identification of single intervals even in cases where a signal peak does not come back to the zero line because of overlaps with neighboring peaks. It is to be noted that the computed signal peaks never come back to the zero line but actually have an infinite tail. As a consequence, the determined integral values do not show the full multiples of proton equivalents but only come close to those multiples. For example, for the interval D the computed integral value in the corresponding initially determined intermediate interval sections may only sum up to <NUM>. As this value corresponds to approximately two protons, the merged interval is then adjusted to cover, for example, <NUM>% of the area corresponding to two proton equivalents (i.e. to <NUM> proton equivalents).

It is to be noted that the signal intervals <NUM> are determined without any further perturbations of the broadened spectra. The identified signal intervals <NUM> which are associated with the respective broadened spectra <NUM> are represented by corresponding labels. <FIG> illustrates an example of a broadened spectrum <NUM> and its associated labels <NUM>-<NUM> to <NUM>-n. Thereby, each label includes the information about the respective start and end ppm-value of the signal region associated with the corresponding peak.

The broadened spectra <NUM>, being the current spectra at this point in time, are then provided <NUM> together with the associated labels for the identified signal intervals <NUM> as the training data set <NUM> to the neural network <NUM>.

In one embodiment, the computer system <NUM> further includes a statistical modifier module <NUM> providing one or more statistical modifier functions. Each modifier function relates to a modification which is typically observed in a real-world NMR spectrum as a perturbation of the respective spectrum (e.g., noise, baseline, etc.). Once the signal intervals have been determined for the broadened spectra, the resulting current spectra can be transformed into even more realistic spectra by applying <NUM> computed perturbations which correspond to such perturbations that occur in real-world NMR experiments. For this purpose, the statistical modifier <NUM> applies <NUM> statistical modifications to each current spectrum. Thereby, the statistical parameter of a particular statistical modification which relates to a corresponding characteristics of a real-world NMR spectrum is statistically distributed over the plurality of current spectra. Typical distributions which can be used for the statistical distribution used for line broadening are Gamma and Beta distributions. Possible choices for distributions of the line broadening parameters are shown in <FIG>. For other types of modifications other statistical distributions may be advantageously used, such as for example uniform distributions in the cases of base line or phase shift modification. In other words, a particular current spectrum is modified by adding the computed impact of the respective perturbation to that current spectrum. To generate a training data set from which the neural network <NUM> can generalize, the modification for a particular parameter applied to the various current spectra is varied over all spectra in accordance with a predefined statistical distribution that is appropriate to reflect the entire range of parameter values which may be expected in real-world NMR experiments obtained with a variety of different NMR spectrometers.

The computed perturbations may include the adding <NUM> of the effect of impurities <NUM> to each current spectrum, applying <NUM> a linear phase shift <NUM> to each current spectrum, adding <NUM> a baseline variation to each current spectrum, and adding <NUM> noise <NUM> to each current spectrum.

<FIG> shows an example illustrating the impact of impurities on a current spectrum according to an embodiment. The current spectrum <NUM> is the spectrum which is obtained after the computed effect of impurities was added. The effect is basically not visible for the human eye at the resolution used in <FIG>. For this reason, the computed effect is illustrated in a magnified difference spectrum <NUM>-<NUM> underneath the modified current spectrum <NUM>. The difference spectrum <NUM>-<NUM> thereby shows the difference between the original broadened spectrum and the current spectrum <NUM> which results from adding the impurity perturbations. The impurities may be statistically selected from a list of known impurities and from unknown/constructed impurities. In the example, Tetramethylsilan (TMS) with the structural formula Si(CH3)<NUM> in addition to <NUM> random multiplets were used as impurities. In case of known impurities the NMR response of such impurities is well known and can be retrieved from corresponding databases. In case of random impurities, clusters of small perturbation signal lines are inserted into the current spectrum where the positions (frequencies) in the spectrum are randomly chosen. For computing the effect of impurities to the current spectra, the corresponding shift and the amplitude of the perturbation signals are statistically varied over the plurality of current spectra. For each particular current spectrum <NUM>' the impurity contribution to the integral stays below the integral equivalent of <NUM> protons. This way it is avoided that the addition of the impurity effect could lead to new signal intervals.

<FIG> illustrates the impact of a phase shift perturbation on a current spectrum <NUM> according to an embodiment. The current spectrum <NUM> is the spectrum which is obtained after the effect of the phase shift was added. The effect is hardly visible for the human eye at the resolution used in <FIG>. For this reason, the effect of the phase shifting is illustrated in a magnified difference spectrum <NUM>-<NUM> underneath the modified current spectrum <NUM> which illustrates the difference between the current spectrum before the application of the phase shift perturbation and the current spectrum <NUM> resulting from adding the phase shift perturbation.

In the applied phase shift model it is assumed I that it only includes a term of zero order and a term of first order. The coefficients of the terms are again subject to a statistical distribution which typically results in a phase shift of maximal four degrees over the entire range of the spectrum. The real part of the phased NMR signal can be described by: <MAT> with A being the absorption spectrum (i.e., the real part of the spectrum before the phase shift is applied) and D being the dispersion spectrum (i.e., the imaginary part, respectively). The phase α depends linearly on the chemical shift δ: α = a +b * δ, with a and b being the phase shift parameters which are sampled from said uniform distributions.

For each active molecule, and therefore for each associated current spectrum, the linear phase shift is computed and applied in accordance with a given statistical distribution (e.g., a uniform distribution). Because of the statistical variation of the coefficients over all current spectra it is sufficient to have only one current spectrum for a given combination of coefficients in the training dataset because the neural network can already learn a generalization for the phase shift perturbation from such a training data set. This avoids an exponential growth of the number training spectra. The statistical variance results from the distribution of the phase shift over the plurality current spectra.

For example, for the statistical variation may be based on a uniform distribution with a zero order phase shift of [-<NUM>,+<NUM>] degrees/ppm and a first order phase shift of [-<NUM>/<NUM>,+<NUM>/<NUM>] degrees/ppm. That is, in the extreme case when the zero order phase shift equals +<NUM> degrees/ppm and the second order phase shift is +<NUM>/<NUM> degrees/ppm, the phase is <NUM> degrees at <NUM> ppm (chosen pivot point) and <NUM>+(<NUM>-<NUM>)*<NUM>/<NUM>=<NUM> degrees at <NUM> ppm. In other words the maximal possible phase shift which can occur in the spectrum is <NUM> degrees in this example.

<FIG> illustrates the impact of a baseline variation on a current spectrum <NUM> according to an embodiment. The current spectrum <NUM> is the spectrum which is obtained after the effect of the baseline variation was added <NUM>. The effect is hardly visible for the human eye at the resolution used in <FIG>. For this reason, the computed effect is illustrated in a magnified baseline spectrum <NUM>-<NUM> underneath the modified current spectrum <NUM>. The baseline spectrum corresponds to the difference between the current spectrum before applying the modification and the modified current spectrum <NUM> after the modification. In the example, the baseline variation for the current spectrum <NUM> was computed with a spline function having four sampling points. The coordinates of the sampling points of the spline functions for all current spectra are statistically evenly distributed over the plurality of current spectra. Thereby, the x-coordinate is distributed over the entire spectral range and the y-coordinates are distributed over a predefined range with positive and negative values. A cubic spline, as an example of a piece-wise polynomial function, is then used for interpolation through the sampling points assigned to the respective current spectrum in accordance with the distribution.

<FIG> illustrates the impact of noise on a current spectrum <NUM> according to an embodiment. In the example, the noise spectrum <NUM>-<NUM> is added <NUM> to the current spectrum and results in the modified current spectrum <NUM>. The noise amplitudes follow a Gaussian distribution over all current spectra, and the standard deviation of the Gaussian distribution statistically varies over the plurality of current spectra.

It is to be noted, that the accuracy of the neural network <NUM> for the correct identification of signal intervals in real-world NMR spectra significantly improves when applying at least the noise perturbation to the broadened spectra. A further significant improvement can be achieved by adding the baseline perturbation.

<FIG> illustrates examples of probability density functions which may be used as statistical distributions by embodiments of the invention (e.g., for sampling of the line broadening parameters). The gamma distribution example is shown with a bold line and uses shape parameter <NUM> and scale parameter <NUM>. The beta distribution example uses shape parameter <NUM> and scale parameter <NUM>. When using such distributions for the statistical variations applied by the statistical modifier functions as described (for adding perturbations), the neural network learns from this training data set to generalize in such a way that signal intervals can be reliably recognized in NMR spectra obtained from real-world NMR experiment with a high degree of accuracy. However, other shape and scale parameters may be used, too.

Turning back to <FIG> and <FIG>, the computer-implemented method for generating the training dataset <NUM> can be continued by a further computer-implemented method <NUM> for training the neural network <NUM> for signal analysis in NMR spectra. The trained neural network <NUM> is thereby enabled to identify signal intervals in real-world NMR spectra obtained from real-world NMR experiments. For this purpose, the spectrum analyzer <NUM>, which includes the neural network <NUM> to be trained, receives <NUM> the training data set <NUM> with the labels <NUM> for the identified signal intervals. The neural network is then trained <NUM> with the received training data set and the associated label identifiers <NUM> using a supervised learning method. Thereby, the training input to the neural network <NUM> are the received current spectra <NUM>' of the training data set <NUM> and the outputs are the respective signal intervals. The outputs can be compared to the received labels <NUM> and the weights in the neural network are adjusted accordingly.

Once the neural network has been trained <NUM>, it can be used by the spectrum analyzer <NUM> for executing a further computer implemented method <NUM> for signal analysis in NMR spectra. Initially, the spectrum analyzer <NUM> receives <NUM> a real-world NMR spectrum <NUM> obtained from a real-world NMR experiment as test input for the trained neural network <NUM>. The spectrum analyzer <NUM> applies <NUM> the trained neural network <NUM> to said test input <NUM>. The output of the trained neural network <NUM> includes one or more signal intervals <NUM> as identified by the trained neural network <NUM>. This output is then provided <NUM> by the signal analyzer <NUM> to a user or to another analysis module for further evaluation.

<FIG> is a diagram that shows an example of a generic computer device <NUM> and a generic mobile computer device <NUM>, which may be used with the techniques described here. In some embodiments, computing device <NUM> may relate to the system <NUM> (cf. Computing device <NUM> is intended to represent various forms of mobile devices, such as personal digital assistants, cellular telephones, smart phones, and other similar computing devices. In the context of this disclosure the computing device <NUM> may provide I/O means for a user to interact with the computing device <NUM>. In other embodiments, the entire system <NUM> may be implemented on the mobile device <NUM>.

Thus, for example, expansion memory <NUM> may act as a security module for device <NUM>, and may be programmed with instructions that permit secure use of device <NUM>. In addition, secure applications may be provided via the SIMM cards, along with additional information, such as placing the identifying information on the SIMM card in a non-hackable manner.

The systems and techniques described here can be implemented in a computing device that includes a back end component (e.g., as a data server), or that includes a middleware component (e.g., an application server), or that includes a front end component (e.g., a client computer having a graphical user interface or a Web browser through which a user can interact with an implementation of the systems and techniques described here), or any combination of such back end, middleware, or front end components.

Claim 1:
A computer-implemented method (<NUM>) for generating a training data set (<NUM>) for training a neural network (<NUM>) for signal analysis in NMR spectra, comprising:
obtaining (<NUM>) a plurality of computed NMR raw spectra (<NUM>), each raw spectrum being associated with a different NMR active molecule (<NUM>) having a known number of protons (#P);
characterized in that the method further comprises
broadening (<NUM>) line widths of the raw spectra by convolution of each raw spectrum (<NUM>) with one or more line shaping functions to generate a broadened spectrum (<NUM>) as a current spectrum for each raw spectrum, wherein the broadening of line widths follows a statistical distribution over the plurality of current spectra by sampling respective broadening values for the various raw spectra from the statistical distribution;
computing (<NUM>) for each broadened spectrum (<NUM>) its integral function to count the number of protons associated with peaks of the respective broadened spectrum;
identifying (<NUM>) signal intervals as intervals in the broadened spectrum (<NUM>) where the integral function increases approximately by multiples of the value associated with a single proton so that the total number of counted protons matches the known number of protons (#P) of the associated molecule, the total number of protons being counted by computing an indefinite integral function for the entire broadened spectrum which is scaled such that the finite integral over the whole spectrum matches the known number of protons of the associated molecule, wherein the identified intervals (<NUM>) are adjusted to cover at least a predefined threshold value of the corresponding known number of protons, with a signal interval being defined as a frequency interval which is centered around the peak frequency of a respective signal peak in an NMR spectrum and characterizes a part of the NMR spectrum which is associated with a nuclear magnetic resonance response of NMR active molecules in response to a radio frequency pulse;
providing (<NUM>) the current spectra (<NUM>, <NUM>') with associated labels (<NUM>) for the identified signal intervals as the training data set (<NUM>) to the neural network.