A method and apparatus for analyzing red blood cell alloantibody specificity

Abstract

The application discloses a red blood cell alloantibody specificity analysis method, and aims at the defects in the prior art that a large amount of manual experience and subjective judgment are relied on to exclude positive antigens according to the results of non-agglutination of samples to be detected and cells, and scientific methods such as statistics are lacked to verify the reliability of detection results, and provides a red blood cell alloantibody specificity analysis method. According to the expression of red blood cell antigens of spectrum cells / anti-screen cells and the agglutination results of patient serum / plasma, the red blood cell alloantibody specificity is analyzed by using programmed analysis logic and statistical result analysis.

Description

Technical Field

[0001] This invention relates to the field of digital red blood cell antibody specificity technology, specifically to a method and equipment for red blood cell alloantibody specificity analysis. Background Technology

[0002] The analysis of red blood cell antibody specificity is generally performed using antibody identification or detection kits, such as screening cell kits or panocell / phenocell kits.

[0003] Antiscreening cells, or spectrum cells, typically consist of more than two groups of red blood cells from different independent blood donors. Each donor's red blood cell antigens are detected using molecular biology or serological methods to form a red blood cell antigen spectrum. Antiscreening cells usually consist of 3 groups of cells, but 2, 4, or 8 groups are also possible. Spectrum cells commonly consist of 10, 11, or 16 groups of cells, but combinations of 20 or 24 groups are also possible.

[0004] Common red blood cell antigen information for anti-screening cell kits / spectrum cell kits includes, but is not limited to:

[0005] RH(C,c,E,e,Cw),Kidd(Jka,Jkb),Kell(K,k,Kpa,Kpb),Duffy(Fya,Fyb),MN S(M,N,S,s,Mia,Mur),Lewis(Lea,Leb),P1,Diego(Dia,Dib,Wra,Wrb),Lutheran(Lua,Lub),Xga.

[0006] The serum or plasma to be tested agglutinates with the anti-screening cell kit / spectrum cell kit under different methodologies / media. Based on the agglutination or non-agglutination of different cells, the antigen distribution of different erythrocytes is compared to analyze the specificity of the antigen-corresponding antibodies.

[0007] The Association for the Advancement for the Blood and Biotherapy (AABB), in its technical manual, jointly published with authoritative organizations such as the Clinical Blood Use Committee of the Beijing Cancer Society, the Clinical Transfusion Management Committee of the Chinese Blood Transfusion Association, the Transfusion Medicine Branch of the Beijing Medical Association, and the Clinical Transfusion Management Committee of the Beijing Blood Transfusion Association. Expert Consensus on Red Blood Cell Antibody Identification All descriptions of the specific detection of antigen-corresponding antibodies use [the following term] Elimination methodIn other words, the core concept of antibody-specific detection of red blood cell antigens, both domestically and internationally, is to exclude positive antigens based on the result that the sample to be tested does not agglutinate with the cells.

[0008] The specific operation is briefly described below:

[0009] 1) Record the agglutination or non-agglutination results of all antibody identification reagents on the erythrocyte group and patient serum;

[0010] 2) Examine the antigen profile of the first non-reactive (non-agglutinating) red blood cell. If the antigen is present on the red blood cell and the patient specimen does not react with it, the presence of the corresponding antibody can be temporarily ruled out, and the ruled out antigen can be recorded from the list at the top of the antigen profile to speed up the detection process.

[0011] 3) After all antigens on the red blood cells have been eliminated using this reagent, repeat the test process with other non-reactive reagents on the red blood cells.

[0012] 4) Exclude other specific antibodies. In most cases, at least one group of antibodies will remain after this process is completed.

[0013] The above analytical methods rely heavily on human experience and subjective judgment. When multiple antibodies are present or when experience is lacking, there may be errors and omissions in judgment. Furthermore, they lack the ability to verify the reliability of test results using scientific methods such as statistics. Summary of the Invention

[0014] The technical problem to be solved by the present invention is to overcome the shortcomings of the prior art in which the exclusion of positive antigens based on the result of non-agglutination of the test sample and cells relies on a lot of human experience and subjective judgment, and lacks the use of scientific methods such as statistics to verify the reliability of the test results. The present invention provides a method for the specific analysis of red blood cell alloantibodies.

[0015] This invention aims to analyze the specificity of erythrocyte alloantibodies based on erythrocyte antigen expression in spectral / antiscreening cells and the agglutination results of patient serum / plasma, using programmed analysis logic and statistical results. It utilizes at least two cell combinations with known erythrocyte antigen expression, and analyzes the erythrocyte alloantibody specificity using the test sample and erythrocyte agglutination (antigen-antibody reaction).

[0016] A method for specific analysis of erythrocyte alloantibodies includes:

[0017] Obtain the antigen expression results and experimental reactivity results of the sample to be tested and one or more sets of identified antigen reagents for detecting red blood cell alloantibodies. Calculate the first concordance rate and the p-value of Fisher's exact test based on the antigen expression results and the experimental reactivity results. The sample refers to serum or plasma, the antigen expression results include positive and negative, and the experimental reactivity results include agglutination / non-agglutination.

[0018] The antibody is identified as the specific antibody corresponding to an antigen whose antigen expression result is positive and whose experimental reactivity result is non-agglutination, with a cell count of 0 and a p-value below a threshold. If the first consistency rate is 100%, then the antibody has the same antibody specificity.

[0019] If the first consistency rate is not 100%, the antibodies are selected based on the p-value according to the first preset standard and combined into antibody groups. The second consistency rate of each antibody group is calculated, and the antibody specificity analysis result is determined based on the second consistency rate.

[0020] The calculation of the first concordance rate and the p-value of Fisher's exact test based on the antigen expression results and the experimental reactivity results includes:

[0021] A 2x2 table is formed based on the antigen expression results and the experimental reactivity results, wherein in the 2x2 table, a represents the number of antigen expression results that are positive and the experimental reactivity results that are agglutinated, b represents the number of antigen expression results that are positive and the experimental reactivity results that are non-agglutinated, c represents the number of antigen expression results that are negative and the experimental reactivity results that are agglutinated, and d represents the number of antigen expression results that are negative and the experimental reactivity results that are non-agglutinated.

[0022] The first consistency compliance rate and the p-value of Fisher's exact test are calculated based on the 2*2 concatenation table.

[0023] The calculation of the first consistency compliance rate and the p-value of Fisher's exact test based on the 2*2 concatenation table includes:

[0024] The first consistency rate and p-value are calculated based on the following formula:

[0025]

[0026] Here, CR represents the first consistency compliance rate.

[0027] The specific antibodies corresponding to antigens that are determined to have a positive antigen expression result and a non-agglutination experimental reactivity result, with a cell count of 0 and a p-value below the threshold, include:

[0028] In the 2*2 array, the specific antibody corresponding to the antigen with cell b = 0 and p value below the threshold is determined.

[0029] The antibody is selected based on the p-value according to a first preset standard, including:

[0030] The antibody with a p-value greater than the first threshold is selected.

[0031] The calculation of the second concordance rate for each antibody group includes:

[0032] Considering only the expression of the antigen corresponding to the antibody combination in each group of cells, when all the corresponding antigens selected on a single cell are negative, the expression result of the antigen combination of that cell is negative; when any corresponding antigen selected on a single cell is positive, the expression result of the antigen combination of that cell is positive.

[0033] A second 2x2 table is generated based on the newly generated antigen combination expression results and experimental reactivity results, where a represents the number of antigens with positive expression results and agglutination results, b represents the number of antigens with positive expression results and non-agglutination results, c represents the number of antigens with negative expression results and agglutination results, and d represents the number of antigens with negative expression results and non-agglutination results.

[0034] The second consistency rate of each antibody group is calculated based on the second 2*2 concatenation table.

[0035] The determination of antibody specificity analysis results based on the second concordance rate includes:

[0036] The second antibody group with a 100% concordance rate exhibits multiple antibody specificity;

[0037] If the second concordance rate of all antibody groups is not 100%, then the antibody group with the highest second concordance rate is the highest probability antibody group.

[0038] A method for specific analysis of erythrocyte alloantibodies includes:

[0039] The calculation module is used to obtain the antigen expression results and experimental reactivity results of the sample to be tested and one or more sets of identified antigen reagent kits for detecting red blood cell alloantibodies, and to calculate the first consistency rate and the p-value of Fisher's exact test based on the antigen expression results and the experimental reactivity results. The sample refers to serum or plasma, the antigen expression results include positive and negative, and the experimental reactivity results include agglutination / non-agglutination.

[0040] The first determining module is used to determine the specific antibody corresponding to the antigen in the results of positive antigen expression and non-agglutination experimental reactivity, where the cell number is 0 and the p value is lower than the threshold. If the first consistency rate is 100%, the antibody has the same antibody specificity.

[0041] The second determining module is used to select the antibodies and combine them into antibody groups based on the p-value and a first preset standard if the first consistency rate is not 100%, calculate the second consistency rate of each antibody group, and determine the antibody specificity analysis result based on the second consistency rate.

[0042] A device for specific analysis of red blood cell alloantibodies, including a memory and a processor.

[0043] The memory is used to store computer programs;

[0044] The processor is configured to, when executing the computer program, implement the method according to any one of claims 1-7.

[0045] A computer program product includes a computer program and instructions, wherein when the computer program and instructions are executed by a processor, the above-described method is implemented.

[0046] This patent calculates the specificity p-values ​​of antibodies corresponding to various antigens based on statistical data and specific experimental results, and evaluates the results by using the consistency rate. Furthermore, based on specific results, it rearranges and combines various possible antibodies to find the most reliable result with the highest consistency rate.

[0047] The beneficial effects achieved by this invention are: traditional manual analysis involves a large amount of manual operation and sometimes fails to confirm antibody specificity. This patent confirms specificity based on statistical methods and can simultaneously perform analysis of multiple antibody sums. Attached Figure Description

[0048] The accompanying drawings are provided to further illustrate the invention and form part of the specification. They are used in conjunction with embodiments of the invention to explain the invention and do not constitute a limitation thereof. In the drawings:

[0049] Figure 1 This is an analysis chart of anti-DCE samples using existing exclusion methods;

[0050] Figure 2 The analysis results show the specific antibodies sorted from smallest to largest by p-value;

[0051] Figure 3 The results are analyzed by sorting the consistency compliance rates from high to low. Detailed Implementation

[0052] The preferred embodiments of the present invention will be described below with reference to the accompanying drawings. It should be understood that the preferred embodiments described herein are for illustration and explanation only and are not intended to limit the present invention.

[0053] Example

[0054] After testing anti-DCE samples using Panocell-16 antibody identification reagent (manufactured by Sanquin (Netherlands)), the analysis was performed using the existing exclusion method described in the expert consensus on red blood cell blood group antibody identification, which analyzes the specificity of antigen-corresponding antibody detection. The results are as follows: Figure 1 As shown.

[0055] Figure 1 The first non-agglutination result was cell number 7, which expresses the antigens c, e, K, Kpb, Jsb, Fyb, Jkb, Leb, M, S, and Lub. Therefore, the presence of antibodies against these antigens was excluded (shown as red x).

[0056] The second non-agglutination result was cell number 8, which expressed k, Kpa, Lea, P1, s, and Xga, thus ruling out the presence of antibodies against the aforementioned antigens (shown as green x).

[0057] After analysis in the above manner, the final results for this case show the antibody specificities for D, C, E, Cw, Jsa, Lua, Mia, and Dia.

[0058] This analytical method can only delete positive antigens with negative agglutination results, and cannot confirm the specificity and combination of multiple antibodies, requiring a lot of manual operation and experience analysis.

[0059] The results showed that anti-D, anti-C, anti-E, and anti-Cw could not be ruled out. This detection and analysis method has good detection power for antibody specificity when the number of unreacted antibodies is relatively large. Conversely, when the number of unreacted antibodies is small, many antibodies cannot be ruled out, and the combination of multiple antibodies cannot be effectively determined. Figure 1 For example, if only antibody 7 is unreacted, the presence of the following antibodies cannot be ruled out, and specificity cannot be effectively analyzed: anti-c, anti-e, anti-K, anti-Kpb, anti-Jsb, anti-Fyb, anti-Jkb, anti-Leb, anti-M, anti-S, and anti-Lub.

[0060] Limitation: The higher the number of non-reactive (negative) results, the higher the specificity.

[0061] In this invention, the chi-square / Fisher p value and the consistency rate of each specific antibody are calculated using the antigen expression and agglutination results of each cell.

[0062] The detection and analysis steps of this invention are as follows:

[0063] Step 1: Calculate the antibody specificity for each antigen using a 2x2 concatenation table based on the data in the table above.

[0064] The 2x2 join table for example, C, is as follows:

[0065]

[0066] Taking C as an example: the analysis results of the 2*2 table are as follows:

[0067] Cells expressing the C antigen were cells 1, 2, 5, and 11-15, all of which were agglutination results, totaling 8 groups a.

[0068] Cells that do not express the C antigen are cells 3, 4, 6-10, and 16.

[0069] The three groups of cells represent agglutination results, specifically cells 3, 4, and 6 (c).

[0070] Five groups of cells showed no agglutination, namely cells 7-10 and 16 (days).

[0071] Step 2: Then use a 2x2 table to calculate the chi-square value (Fisher extract test) and the corresponding p-value;

[0072] The formula for the consistency compliance rate is as follows:

[0073] The first consistency rate and p-value are calculated based on the following formula:

[0074]

[0075] Here, CR represents the first consistency compliance rate.

[0076] In the above formula, a, b, c, d correspond to a, b, c, d in the 2*2 linked list with C as an example.

[0077] Step 3: Select antigens with a spectrum + result of -0 corresponding to antibody specificity (b cell = 0).

[0078] Step 4: Sort the antigens by their corresponding antibody specificity p-values ​​from smallest to largest.

[0079] Step 5: 100% consistency is defined as: antigen-to-antibody specificity (isoantibody specificity).

[0080] Step 6: When the consistency rate is not 0, the selected antibodies are arranged and the consistency rate is recalculated, and the results are sorted from high to low according to the consistency rate.

[0081] The anti-DCE samples were analyzed using the detection method of this invention, and the specificity results for each antibody are shown in Table 1.

[0082] Table 1: Reactivity analysis of erythrocyte-specific antibodies with cell antigens

[0083] result Spectrum + Fruit + Spectrum + Fruit - Spectrum-Fruit+ Spectrum-Result- Consistency compliance rate P value Anti-D 9 0 2 5 87.5％ 0.0048 Anti-C 8 0 3 5 81.3％ 0.0128 Anti-c 5 5 6 0 31.3％ 0.0577 Anti-E 5 0 6 5 62.5％ 0.1058 Anti-e 8 5 3 0 50.0％ 0.2946 Anti-Cw 1 0 10 5 37.5％ 0.6875 Anti-K 3 3 8 2 31.3％ 0.2060 Anti-k 11 4 0 1 75.0％ 0.3125 Anti-Kpa 1 1 10 4 31.3％ 0.4583 Anti-Kpb 11 5 0 0 68.8％ 1.0000 Anti-Jsa 0 0 11 5 31.3％ 1.0000 Anti-Jsb 11 5 0 0 68.8％ 1.0000 Anti-Fya 9 1 2 4 81.3％ 0.0343 Anti-Fyb 6 4 5 1 43.8％ 0.2885 Anti-Jka 9 4 2 1 62.5％ 0.4911 Anti-Jkb 6 3 5 2 50.0％ 0.4038 Anti-Lea 3 4 8 1 25.0％ 0.0721 Anti-Leb 8 1 3 4 75.0％ 0.0721 Anti-P1 8 4 3 1 56.3％ 0.4533 Anti-M 10 3 1 2 75.0％ 0.1964 Anti-N 7 4 4 1 50.0％ 0.3777 Anti-S 6 2 5 3 56.3％ 0.3590 Anti-s 8 4 3 1 56.3％ 0.4533 Anti-Lua 1 0 10 5 37.5％ 0.6875 Anti-Lub 11 5 0 0 68.8％ 1.0000 Anti-Xga 6 4 5 1 43.8％ 0.2885 Anti-Mia 0 0 11 5 31.3％ 1.0000 Anti-Dia 0 0 11 5 31.3％ 1.0000 Anti-Bg(a) 1 1 10 4 31.3％ 0.4583 Anti-Lwa 0 0 11 5 31.3％ 1.0000 Anti-V 0 0 11 5 31.3％ 1.0000 Anti-VS 0 0 11 5 31.3％ 1.0000 Anti-f 2 5 9 0 12.5％ 0.0048

[0084] Specific antibodies that were positive for cell antigens but showed negative agglutination results (0 in total) were selected as candidates from Table 1. The selected antibodies were then ranked from smallest to largest using the chi-square test / Fisher extract testing value. The analysis results are as follows: Figure 2 As shown.

[0085] When the consistency rate is not 0, the selected antibodies are reordered and the consistency rate is recalculated. The results are then sorted from highest to lowest consistency rate, as shown below. Figure 3 As shown.

[0086] Example 2:

[0087] The 185 reports were analyzed using both existing manual exclusion methods and the method of this invention. The results are compared below:

[0088] In existing manual exclusion methods, 110 cases showed a single specific antibody, and 75 cases showed two or more specific antibodies. However, using the analytical method of this invention, the consistency rate of the 110 cases with single specific antibodies was 100%, with kappa < 0.001. But in this patent, 73 out of the 110 cases indicated the presence of antibodies that could not be excluded, and further experimental analysis of 32 cases revealed the presence of other low-frequency specific antibodies in 14 samples.

[0089] The existing manual exclusion method identified 75 cases with two or more specific antibodies. Compared with the analysis in this patent, the consistency rate was 86% (65 / 75). The 10 inconsistent results were mainly due to the manual exclusion method not considering the antibody dose effect. Among the 65 consistent results, 35 indicated the presence of additional antibodies that could not be excluded; further experimental analysis of 15 cases revealed the presence of unidentified low-frequency antibodies in 9 cases.

[0090] Therefore, the analytical method of this invention can not only confirm antibody specificity but also simultaneously perform analysis of multiple antibody sums. Furthermore, it overcomes the shortcomings of traditional methods that rely heavily on human experience and subjective judgment, leading to errors and omissions in judgment. The analytical method of this invention can scientifically evaluate and verify the reliability of test results.

[0091] Finally, it should be noted that the above descriptions are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for analyzing red blood cell alloantibody specificity, characterized by, The method comprises the following steps: acquiring antigen expression results and experimental reactivity results of a sample to be detected and a single set or multiple sets of antigen reagent red blood cell reagent kits for detecting red blood cell alloantibodies, calculating a first consistency coincidence rate and a p value of Fisher's exact test based on the antigen expression results and the experimental reactivity results, wherein the sample is serum or plasma, the antigen expression results include positive and negative, and the experimental reactivity results include agglutination / non-agglutination; determining an antibody specific to an antigen corresponding to a result in which the number of cells is 0 and the p value is lower than a threshold value in a result in which the antigen expression result is positive and the experimental reactivity result is non-agglutination, and if the first consistency coincidence rate is 100%, the antibody has alloantibody specificity; if the first consistency coincidence rate is not 100%, selecting the antibody based on the p value according to a first preset standard and combining the antibody into an antibody group, calculating a second consistency coincidence rate of each antibody group, and determining an antibody specificity analysis result based on the second consistency coincidence rate; wherein the generation rule of the antibody group is: only considering the expression of the antigen corresponding to the antibody combination in each group of cells, when the corresponding antigens selected in a single cell are all negative, the expression result of the antigen combination of the cell is negative, and when any corresponding antigen selected in a single cell is positive, the expression result of the antigen combination of the cell is positive; the calculation of the first consistency coincidence rate and the p value of Fisher's exact test based on the antigen expression results and the experimental reactivity results comprises: forming a 2*2 contingency table based on the antigen expression results and the experimental reactivity results, wherein in the 2*2 contingency table, a is the number of results in which the antigen expression result is positive and the experimental reactivity result is agglutination, b is the number of results in which the antigen expression result is positive and the experimental reactivity result is non-agglutination, c is the number of results in which the antigen expression result is negative and the experimental reactivity result is agglutination, and d is the number of results in which the antigen expression result is negative and the experimental reactivity result is non-agglutination; calculating the first consistency coincidence rate and the p value of Fisher's exact test based on the 2*2 contingency table, wherein the calculation formula is: ， wherein CR is the first consistency coincidence rate; the determination of the antibody specificity analysis result based on the second consistency coincidence rate comprises: if the second consistency coincidence rate is 100%, it is determined that the antibody has multiple antibody specificity; if the second consistency coincidence rate of all antibody groups is not 100%, the antibody group with the highest second consistency coincidence rate is taken as the highest probability antibody group.

2. The method of claim 1, wherein, the determination of the antibody specific to the antigen corresponding to the result in which the number of cells is 0 and the p value is lower than the threshold value in the result in which the antigen expression result is positive and the experimental reactivity result is non-agglutination comprises: in the 2*2 contingency table, determining the antibody specific to the antigen corresponding to the result in which the b cell is 0 and the p value is lower than the threshold value.

3. The method of claim 1, wherein, the selection of the antibody based on the p value according to the first preset standard comprises: selecting the antibody with the p value greater than the first threshold value.

4. The method of claim 1, wherein, the calculation of the second consistency coincidence rate of each antibody group comprises: Only considering the expression of corresponding antigens of the antibody combination in each group of cells, when the corresponding antigens selected in a single cell are all negative, the cell antigen combination expression result is negative, and when any of the corresponding antigens selected in a single cell is positive, the cell antigen combination expression result is positive; based on the newly generated antigen combination expression result and the experimental reactivity result, a second 2*2 contingency table is generated, wherein a is the number of antigen expression results being positive and the experimental reactivity result being agglutination, b is the number of antigen expression results being positive and the experimental reactivity result being non-agglutination, c is the number of antigen expression results being negative and the experimental reactivity result being agglutination, and d is the number of antigen expression results being negative and the experimental reactivity result being non-agglutination; Based on the second 2*2 contingency table, the second consistency coincidence rate of each of the antibody groups is calculated.

5. An apparatus for analyzing red blood cell alloantibody specificity, comprising: It comprises: A calculation module is configured to obtain antigen expression results and experimental reactivity results of a sample to be detected and a single group or multiple groups of antigen reagent red blood cell kits for detecting red blood cell alloantibodies, and calculate a first consistency coincidence rate and a p value of Fisher's exact test based on the antigen expression results and the experimental reactivity results, wherein the sample refers to serum or plasma, the antigen expression results include positive and negative, and the experimental reactivity results include agglutination / non-agglutination; A first determination module is configured to determine specific antibodies corresponding to antigens with 0 cell number in the results of antigen expression results being positive and experimental reactivity results being non-agglutination and a p value lower than a threshold value, and if the first consistency coincidence rate is 100%, the antibodies have alloantibody specificity; A second determination module is configured to select the antibodies based on a first preset standard according to the p value if the first consistency coincidence rate is not 100%, combine the antibodies into antibody groups, calculate a second consistency coincidence rate of each of the antibody groups, and determine an antibody specificity analysis result based on the second consistency coincidence rate; The generation rule of the antibody groups is: Only considering the expression of corresponding antigens of the antibody combination in each group of cells, when the corresponding antigens selected in a single cell are all negative, the cell antigen combination expression result is negative, and when any of the corresponding antigens selected in a single cell is positive, the cell antigen combination expression result is positive; The calculation of the first consistency coincidence rate and the p value of Fisher's exact test based on the antigen expression results and the experimental reactivity results comprises: Based on the antigen expression results and the experimental reactivity results, a 2*2 contingency table is formed, wherein in the 2*2 contingency table, a is the number of antigen expression results being positive and the experimental reactivity result being agglutination, b is the number of antigen expression results being positive and the experimental reactivity result being non-agglutination, c is the number of antigen expression results being negative and the experimental reactivity result being agglutination, and d is the number of antigen expression results being negative and the experimental reactivity result being non-agglutination; Based on the 2*2 contingency table, the first consistency coincidence rate and the p value of Fisher's exact test are calculated, and the calculation formula is: ， Wherein, CR is the first consistency coincidence rate; The determination of the antibody specificity analysis result based on the second consistency coincidence rate comprises: wherein if the second concordance rate is 100%, it is determined that the antibody has multiplex antibody specificity; If the second concordance rate of all antibody groups is not 100%, the antibody group with the highest second concordance rate is determined as the highest probability antibody group.

6. An apparatus for analyzing red blood cell alloantibody specificity, comprising: The computer program product comprises a memory and a processor, wherein the memory is configured to store a computer program, and the processor is configured to implement the method according to any one of claims 1-4 when the computer program is executed.

7. A computer program product comprising a computer program, instructions, which, when executed by a processor, implement the method according to any one of claims 1-4.

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