CN104297442A - Application of endogenous small molecular substances to rapid detection of early cardiotoxicity - Google Patents
Application of endogenous small molecular substances to rapid detection of early cardiotoxicity Download PDFInfo
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Abstract
The invention discloses an application of endogenous small molecular substances to rapid detection of early cardiotoxicity, wherein the endogenous small molecular substances refers to nine early cardiotoxicity biomarkers: L-carnitine, L-tryptophan, L-palmitoyl carnitine, 19-hydroxyl deoxycorticosterone, cholic acid, lysophosphatidyl choline (14: 0), lysophosphatidyl choline (22: 6), lysophosphatidyl choline (20: 2) and lysophosphatidyl choline (16: 0), and also refers to four early cardiotoxicity exclusive biomarkers: L-carnitine, 19-hydroxyl deoxycorticosterone, lysophosphatidyl choline (14: 0) and lysophosphatidyl choline (20: 2). According to the application of the endogenous small molecular substances to the rapid detection of the early cardiotoxicity, the screened early cardiotoxicity biomarkers are capable of giving rapid alarms to the toxicity before the heart tissues suffer pathological damages, so that the toxicity discovery time is early than the conventional biochemical detection indexes, more flexible judgement is carried out on the drug toxicity and diseases, and more time is provided for the early discovery and early treatment of the clinic cardiotoxicity.
Description
Technical field
The present invention relates to and use metabonomic technology to find early stage cardiac toxic biological label, then specificity investigation is carried out to it, then use support vector machine (SVM) carry out verifying to them and optimize.That endogenous small-molecule substance is detecting the application in early stage cardiac toxicity fast in particular.
Background technology
Cardiotoxicity of medicine due to fall ill anxious, harm is large, recover difficulty is taken seriously.It is reported existing nearly 8.7% marketed drug be withdrawn owing to easily producing cardiac toxic.Therefore cardiotoxicity of medicine detection and prevention just seem particularly important.Medicine enters body and there is the regular hour to toxic exposure, how to use existing technology discovery drug toxicity to be more early the meaning of early prediction.In current clinical detection, normal employing lactic dehydrogenase (LDH), creatine kinase (CK) and creatine kinase isozyme (CK-MB) etc. are as the Testing index of cardiac toxic, but current evaluation means all needs to improve in detection sensitivity and the false positive results that easily causes etc.Metabolism group is widely used in the explanation of the diagnosis of the discovery of biomarker and disease, prevention and mechanism as the analysis means of small-molecule substance in analyzing body.Metabolism group, as the research method of metabolism terminal, in endogenous material change and the real-time Dynamic Variation Analysis of body etc. of body different phase, is compared with proteomics with genomics, can be provided better explanation in metabolin aspect.Along with the development of subject, metabolism group is more and more paid attention to by people in Drug safety assessment and toxicity prediction.Metabolism group, as the research means of function end points, in toxicity prediction, can be good at the phenotype as toxic reaction, has the feature of highly sensitive, broad covered area and favorable reproducibility.At present, UPLC/Q-TOF-MS points out its structure with features such as its high resolving power, high sensitivity, quick separating provide powerful technical support for the material that finds conspicuousness to change in numerous and jumbled endogenous small-molecule substance without target metabolic profiling analysis.In addition, new Data Management Analysis technology is also for the research of metabolism group provides more wide space.SVM, as a branch of neural network, based on the principle of empirical risk minimization, is widely used in classification and recurrence learning process.As the powerful of solution two classification problem, in the Modulation recognition, image procossing and medical diagnosis on disease etc. of pharmaceutical sanitary field, all there is good application prospect.Therefore, the combination of SVM and metabolism group, provides more wide platform by the application for metabolism group.
Summary of the invention
The present invention to be combined with SVM by metabonomic technology and finds early stage cardiac toxic biological label, quick early warning can be made to its toxicity before heart tissue is subject to pathologic damage, make toxicity discovery time early than existing biochemical detection indexes, judge drug toxicity and disease more delicately, for finding the morning of clinical heart toxicity, early treatment provides more plenty of time.
For achieving the above object, the invention discloses following technical scheme:
Endogenous small-molecule substance is detecting fast the application in early stage cardiac toxicity, particularly judge fast heart whether sustain damage in application.Wherein said endogenous small-molecule substance refers to early stage cardiac toxic biological label, they screen based on metabonomic technology, comprise VBT (L-carnitine), L-Trp (L-tryptophan), L-palmitoyl carnitine (L-palmitoyl carnitine), 19-hydroxyl deoxycortone (19-Hydroxydeoxycorticosterone), cholic acid (Cholic acid), lysophosphatidyl choline (14:0) [LPC (14:0)], lysophosphatidyl choline (22:6) [LPC (22:6)], lysophosphatidyl choline (20:2) [LPC (20:2)], lysophosphatidyl choline (16:0) [LPC (16:0)], they can detect cardiac toxic fast.The basis of cardiac toxic biomarker in early days refers to the exclusive biomarker of early stage cardiac toxicity through SVM checking with the endogenous small-molecule substance optimized, comprise VBT (L-carnitine), 19-hydroxyl deoxycortone (19-Hydroxydeoxycorticosterone), lysophosphatidyl choline (14:0) [LPC (14:0)], lysophosphatidyl choline (20:2) [LPC (20:2)], they can judge whether heart sustains damage fast.Because the metabolism when heart is subject to toxicity or damaging action of endogenous small-molecule substance in body changes, we show that VBT (L-carnitine), 19-hydroxyl deoxycortone (19-Hydroxydeoxycorticosterone), lysophosphatidyl choline (14:0) [LPC (14:0)], lysophosphatidyl choline (20:2) [LPC (20:2)] specificity are best at research.So be more particularly that endogenous small-molecule substance is detecting the application in early stage cardiac toxicity and heart disease fast.
The present invention further discloses based on the screening technique of metabonomic technology in conjunction with the early stage biomarker of cardiac toxic of SVM, comprise sample pre-treatments, data acquisition, data processing (multivariate statistical analysis), biomarker specificity investigate, the step such as the checking of exclusive biomarker and optimization.It is characterized in that: the condition using gradient elution in data acquisition: 0-0.5 min, A:99%-99%, 0.5-2 min, A:99%-50%, 2-9 min, A:50%-1%, 9-10 min, A:1%-1%, 10-10.5 min, A:1%-99%, 10.5-12 min, A:99%-99%, wherein mobile phase A refers to the water of 0.1% formic acid, and Mobile phase B refers to the acetonitrile of 0.1% formic acid, in the checking and optimization of exclusive biomarker, use MATLAB R2010a software (USA) to set up SVM forecast model based on the early stage biomarker of cardiac toxic, this process is as follows: using the peak area of biomarker in physiological saline group and each medicine group as input variable, Stochastic choice data set up forecast model as training set and test set, optimum punishment parameter (c) and kernel function (g) is found by optimizing, then to get rid of based on a biomarker one by one, SVM is utilized to carry out classification prediction, obtain corresponding model prediction accuracy, accuracy of analysis, whether it is distinguished with early stage cardiac toxicity is closely related.
We filter out early stage cardiac toxicity biomarker through metabonomic technology, specifically VBT (L-carnitine), L-Trp (L-tryptophan), L-palmitoyl carnitine (L-palmitoyl carnitine), 19-hydroxyl deoxycortone (19-Hydroxydeoxycorticosterone), cholic acid (Cholic acid), lysophosphatidyl choline (14:0) [LPC (14:0)], lysophosphatidyl choline (22:6) [LPC (22:6)], lysophosphatidyl choline (20:2) [LPC (20:2)], lysophosphatidyl choline (16:0) [LPC (16:0)].Early stage cardiac toxicity biomarker is through specificity investigation, checking and and obtain the exclusive biomarker of early stage cardiac toxicity after optimizing, specifically VBT (L-carnitine), 19-hydroxyl deoxycortone (19-Hydroxydeoxycorticosterone), lysophosphatidyl choline (14:0) [LPC (14:0)], lysophosphatidyl choline (20:2) [LPC (20:2)].
the more detailed technical scheme of the present invention is as follows:
1, sample pre-treatments: before sample preparation, blood plasma is at room temperature thawed.Then, 300 μ L acetonitriles are joined in 100 μ L blood plasma, and vortex mixed 1 minute.Then by potpourri in ice-water bath ultrasonic 10 minutes, then with 13000 turns at 4 DEG C centrifugal 15 minutes.Collect supernatant and be used for UPLC/Q-TOF-MS analysis.
2, data acquisition: use UPLC/Q-TOF-MS system (Waters, US) to carry out information acquisition to rat plasma sample.Chromatographic column ACQUITY UPLC HSS C18(2.1 × 100 mm, 1.7 μm, Waters, US), column temperature is 40 DEG C, and flow velocity is 0.3mL/min, and sample size is 5 μ L.UPLC piece-rate system comprises binary solvent system, by mobile phase A (water of 0.1% formic acid) and Mobile phase B (acetonitrile of 0.1% formic acid).Adopt gradient elution, concrete elution requirement: 0-0.5 min, A:99%-99%; 0.5-2 min, A:99%-50%; 2-9 min, A:50%-1%; 9-10 min, A:1%-1%; 10-10.5 min, A:1%-99%; 10.5-12 min, A:99%-99%.Mass spectrum adopts electron spray ionisation (ESI) source, carries out mass spectrophotometry at positive ion electrospray under pattern.MS parameter is as follows: dry gas flow velocity is 10mL/min, and dry gas temperature is 325 DEG C, and atomization gas air pressure is 350 psi, desolventizing airshed 600L/h, kapillary ionization voltage 3.5 kV, quadrupole rod sweep limit m/z50-1000.Boil-off gas and assist gas are high-purity nitrogens.With ([M+H] +=556.2771, [M-H]-=554.26) as the precision guaranteed with reference to ion in spectra collection process.In order to ensure the reliability of metabolism group data acquisition, the blood plasma of our draws equal amounts from each sample is mixed into QC sample, with them, the stability of instrument, method precision are monitored, until whole system could start sample message collection under a good stable state.Simultaneously within 24 hours, QC sample detects once for every 4 hours, is used for monitoring the stability of sample and system in whole gatherer process.
3, data processing:
(1) screening of early stage biomarker and qualification: the plasma sample of control group and model group adopts MarkerLynx Version 4.1(Waters Corp., Manchester, UK) carry out peak discovery, peak aligns and the peak value of raw data filters, to find out potential discrimination variable.Adopt SIMCA-P+11.5 software (Umetrics AB, Umea, Sweden) carry out multivariate data analysis, principal component analysis (PCA) (PCA) and offset minimum binary-discriminatory analysis (PLS-DA), be generally used for the data processing method of metabolism research in applying widely.PCA, for distinguishing the similarity of sample, determines outliers.PLS-DA is for determining the remarkable change plasma metabolite between different groups.Shot chart is used to the model of visual foundation.Meanwhile, SPSS 17.0 software is used to carry out independent sample T inspection to determine whether that metabolin has remarkable change from statistical angle.These materials are using as potential early stage cardiac toxic biological label, adopt Wien collection of illustrative plates (http://bioinfogp.cnb.csic.es/tools/venny/index.html) to represent that different pharmaceutical affects the correlativity of biomarker, find total early stage cardiac toxic biological label.Subsequently, we carry out identification to these biomarkers, and metabolin is analyzed and metabolin database by standard items, MS/MS, as: HMDB(http: //www.hmdb.ca/); KEGG(http: //www.genome.jp/kegg/).
(2) checking of early stage toxicity markers's thing and optimization: the present invention, in conjunction with the metabolism group data of liver, renal toxicity, carries out specificity checking for the total early stage cardiac toxic biological label filtered out.In addition, by SVM technology, the cardiac toxic potential source biomolecule label obtained is optimized.Simultaneously we are using the peak area of biomarker as the input variable of SVM, do to verify and optimize to the accuracy of potential label and specificity.SVM model adopts MATLAB(USA) set up, determine by the method for cross validation kernel function K from lower dimensional space to higher dimensional space that maps from and for determining that the error regulating study and fiducial range and empiric risk ratio proper subspace punishes parameter C.Final employing training set and test set carry out the judgement of mechanical training and predictablity rate to this model.
beneficial effect disclosed by the invention is:
In clinical at present, the detection method of normal application myocardial enzymes is as the auxiliary detection index of heart change, but this index is everlasting just there is conspicuousness change in heart tissue after there is pathologic damage, this demonstrates its toxic exposure and has relatively lagging behind property, some the azymia Sensitivity and Specificity simultaneously related to.Compare down, early stage cardiac toxic biological label can show significant difference when damage not yet appears in heart tissue, and namely toxicity discovery time is early than existing biochemical detection indexes.By screening, checking, optimizing the early stage cardiac toxic biological label obtained can at the commitment of cardiac toxic, early warning can be made to the induced cardiotoxicity of medicine, thus provide advantageously foundation reliably for the screening of cardiotoxic drugs, also for finding the morning of clinical heart toxicity, early treatment provides more plenty of time.
accompanying drawing illustrates:
Fig. 1: the overview flow chart of whole experiment;
Fig. 2: the PLS-DA shot chart of cardiac toxic each medicine group different time points multivariate statistical analysis;
Fig. 3: 39 ions relevant with early stage cardiac toxicity obtained with the Analysis and Screening of Vean diagram display integration;
Fig. 4 (comprising Fig. 4-1, Fig. 4-2): the specifying information of 39 ions relevant with early stage cardiac toxicity;
Fig. 5: the predictablity rate of supporting vector machine model;
Fig. 6: the content of cardiac toxic biochemical indicator LDH, CK and CK-MB of each group.
embodiment:
Below in conjunction with instructions and embodiment to being described further.The overview flow chart of whole experiment is shown in Fig. 1.But the present embodiment is not limited to the present invention, every employing similar change of the present invention, all should list protection scope of the present invention in.Reagent used by the present invention, medicine all have commercially available.
embodiment 1
1, reagent: acetonitrile is purchased from Oceanpak(Gothenburg, Sweden), formic acid is purchased from the ROE(U.S.), be analysis pure.Pure water is purchased from Wahaha company (Hangzhou China).Physiological saline is purchased from Qi Dou pharmaceutcal corporation, Ltd (Shandong Province of China).Adriamycin (DOX), isoprel (ISO), 5 FU 5 fluorouracil (5-FU), gentamicin, Etimicin, radix bupleuri and phenixin, purchased from Science and Technology Ltd. of Silan (Chinese Tianjin), use physiological saline solution respectively.
2, zoopery: zoopery is carried out in Inst. of Biomedicine Engineering Chinese Academy of Medicine (Chinese Tianjin).140 male Wistar rats (200 ± 20 grams) remain on SPF level laboratory.Rat buys rearmounted 12 hours day and night changes, and environment temperature is 25 ± 1 DEG C, and ambient humidity is raise under the condition that controls environment of 50 ± 5%.After the adaptation of a week, rat is divided into 14 groups at random, is respectively blank (NS) group, adriamycin 6h group, adriamycin 12h group, adriamycin 1d group, isoprel 12h group, isoprel 1d group, isoprel 3d group, 5 FU 5 fluorouracil 1d group, 5 FU 5 fluorouracil 2d group, 5 FU 5 fluorouracil 3d group, gentamicin group, Etimicin group, radix bupleuri group and phenixin group.
3, sample collection: before sample collection, all animal fasting 12 hours.Blood is collected from abdominal aorta after rat light anaesthesia.Part blood sample is put in heparinised tubes, and 3500 leave the heart 15 minutes, separated plasma, put in-80 DEG C of refrigerators and store, for metabolism group research.Another part blood sample is placed in common projectile pipe, and 500 leave the heart 15 minutes, separation of serum, put in-80 DEG C of refrigerators and store, detect for clinical biochemical.
4, above-mentioned plasma sample is analyzed and researched according to technical scheme of the present invention by we.In multivariate statistical analysis, PCA is first for rejecting outliers, adopts PLS-DA to determine the difference metabolin of different group afterwards, sees Fig. 2.We are on PLS-DA model basis, choose the biomarker of VIP>1 as having the potential biomarker of otherness between difference group.Meanwhile, p<0.05 has conspicuousness standard as metabolin is set.In order to find relatively stable and that Changing Pattern is consistent biomarker, we adopt Wien collection of illustrative plates respectively to adriamycin, ion information under the different time points of isoprel and 5 FU 5 fluorouracil is integrated, and the common ion found respectively is 106,77,69.We do integration analysis for different pharmaceutical common ion information further, see Fig. 3.Finally our preliminary screening goes out 39 the ion information relevant with early stage cardiac toxicity, and details are shown in Fig. 4.These ion information are carried out identification by us subsequently, obtain 9 metabolins determined.Meanwhile, these 39 ions are carried out specificity checking by us in liver renal toxicity group, finally filter out 10 ions with stronger cardiac toxic specificity and think the early stage biomarker that cardiac toxic is potential.SVM is finally utilized to carry out classification prediction to 10 the potential source biomolecule labels obtained.We adopt 58 metabolism group data as training set, and 30 as test set.Then based on the metabolism group data removing any one potential source biomolecule label, set up forecast model respectively, thus obtain corresponding model accuracy and predictablity rate, see Fig. 5.The model prediction accuracy rate set up with potential early stage cardiac toxic biological label is for 90%(27/30).It should be noted that its predictablity rate exists certain difference after removing any one potential source biomolecule label.Before l-cn (L-Carnitine), 19-hydroxyprogesterone (19-Hydroxydeoxycorticosterone), LPC (14:0), LPC (20:2) comparatively reject after rejecting, model predictablity rate reduces, illustrate that these biomarkers are active influence on the impact of model contribution degree, there is stronger early stage cardiac toxic specificity.
5, the biological significance of the metabolin that we 9 of obtaining through identification are relevant to early stage cardiac toxicity:
(1) lysophosphatide has carried out lipid signal transmission [HMDB] by acting on Lysophospholipid Receptor (LPL-R).LPL-R is as one of g protein coupled receptor family member, plays courier's effect in body vital movement.After induced cardiotoxicity occurs, lysophosphatide changes, and this may affect the normal function of second messenger, further inducing cardiomyocytes apoptosis.On the other hand, lysophosphatide belongs to glycerophosphatide class metabolic product, and this kind of material, as biological membrane important component part, has important relation with cell membrane.When heart sustains damage, myocardial cell membrane changes, and phospholipase A2 is activated and affects LPC class material further, and its content is reduced.
(2) beta-oxidation of fatty acid is as the important channel of cardiac muscle cell's mitochondrial function, closely related with the apoptosis of cardiac muscle cell.When heart generation toxic reaction, myocardial consumption of oxygen can be caused to increase, further weight fat acid beta-oxidation, this kind of fatty acid component content of energy that provides of corresponding 3-hydroxyl tetradecane acid, stearic acid reduces, and raises as the VBT content of transfer tool.
(3) glycocholic acid is steroid metabolism intermediate product, can by cardiac muscle cell's lipid peroxide and endocardial endothelial cell is impaired affects the normal physiological function of heart.Amino acids material is as the important base substance of body life movement, participate in various energy and metabolism, find in this experiment, tryptophane content in cardiac toxic evolution changes, and may take part in enzyme material or intracellular signaling process in this process.
embodiment 2
The present invention further discloses based on the screening technique of metabonomic technology in conjunction with the early stage biomarker of cardiac toxic of SVM, comprise sample pre-treatments, data acquisition, data processing (multivariate statistical analysis), biomarker specificity investigate, the step such as the checking of exclusive biomarker and optimization.It is characterized in that: the condition using gradient elution in data acquisition: 0-0.5 min, A:99%-99%, 0.5-2 min, A:99%-50%, 2-9 min, A:50%-1%, 9-10 min, A:1%-1%, 10-10.5 min, A:1%-99%, 10.5-12 min, A:99%-99%, wherein mobile phase A refers to the water of 0.1% formic acid, and Mobile phase B refers to the acetonitrile of 0.1% formic acid, in the checking and optimization of exclusive biomarker, use MATLAB R2010a software (USA) to set up SVM forecast model based on the early stage biomarker of cardiac toxic, this process is as follows: using the peak area of biomarker in physiological saline group and each medicine group as input variable, Stochastic choice data set up forecast model as training set and test set, optimum punishment parameter (c) and kernel function (g) is found by optimizing, then to get rid of based on a biomarker one by one, SVM is utilized to carry out classification prediction, obtain corresponding model prediction accuracy, accuracy of analysis, whether it is distinguished with early stage cardiac toxicity is closely related.
embodiment 3
Practical application:
Collected serum at room temperature thaws by we, for detecting lactic dehydrogenase (LDH), creatine kinase (CK) and the creatine kinase isozyme (CK-MB) in serum.Result after result display DOX administration 1d, after ISO administration 3d, after 5-FU administration 3d, compared with blank group, all has conspicuousness and raise (p<0.05), and other each group does not have conspicuousness to raise, and sees Fig. 6.Analysis result we find DOX administration 1 day, ISO administration 3 days, 5-FU administration after 3 days body all expose cardiac toxic, DOX administration 6h, 12h, ISO administration 12h, 1d and 5-FU administration 1d, 2d cardiac toxic not yet exposes comparatively speaking.We think that DOX administration 1 day, ISO administration 3 days, 5-FU administration 3 days are the toxic exposure phase.In addition, as this kind of toxic action of DOX administration 6h, ISO administration 12h, 5-FU administration 1d group is occurring but existing detection means not yet can give toxic exposure situation we be defined as the commitment of cardiotoxicity.Under comparing, the early stage cardiac toxic biological label that we are found in conjunction with SVM by metabolism group assumes a marked difference, and namely toxicity discovery time is early than existing biochemical detection indexes.
Concrete data are compared as follows:
--: represent content unknown significance change ↓ *: represent that content significantly declines ↑ *: represent that content significantly rises
conclusion:
The present invention attempts to find early stage cardiac toxic biological label by the method for metabolism group.We adopt UPLC/Q-TOF-MS and PLS-DA to screen early stage cardiac toxic biological label, find total early stage cardiac toxic biological label 39.Subsequently in conjunction with the method for liver renal toxicity metabolism group result by means of SVM pattern-recognition, the biomarker of primary dcreening operation is verified and optimizes, finally find wherein 10 as exclusive early stage cardiac toxic biological label, its SVM model prediction rate is 90%, and wherein the specificity of VBT (L-carnitine), 19-hydroxyl deoxycortone (19-Hydroxydeoxycorticosterone), lysophosphatidyl choline (14:0) [LPC (14:0)], lysophosphatidyl choline (20:2) [LPC (20:2)] is the strongest.The method has higher sensitivity and specificity, and the commitment that can develop at cardiac toxic, for the diagnosis and prediction of drug-induced cardiac toxic.The inspection and the drug safety evaluation that can be clinical biospecimens provide reliable foundation.
Claims (3)
1. endogenous small-molecule substance is detecting the application in early stage cardiac toxicity fast, wherein said endogenous small-molecule substance refers to 9 early stage cardiac toxic biological labels, they screen based on metabonomic technology, comprise VBT (L-carnitine), L-Trp (L-tryptophan), L-palmitoyl carnitine (L-palmitoyl carnitine), 19-hydroxyl deoxycortone (19-Hydroxydeoxycorticosterone), cholic acid (Cholic acid), lysophosphatidyl choline (14:0) [LPC (14:0)], lysophosphatidyl choline (22:6) [LPC (22:6)], lysophosphatidyl choline (20:2) [LPC (20:2)], lysophosphatidyl choline (16:0) [LPC (16:0)].
2. endogenous small-molecule substance judge fast heart whether sustain damage in application; Wherein said endogenous small-molecule substance refers to finger 4 exclusive biomarkers of early stage cardiac toxicity, they be through specificity investigate and SVM checking and with optimal screening out, comprise VBT (L-carnitine), 19-hydroxyl deoxycortone (19-Hydroxydeoxycorticosterone), lysophosphatidyl choline (14:0) [LPC (14:0)], lysophosphatidyl choline (20:2) [LPC (20:2)].
3. the application described in any one of claim 1-2, wherein based on the screening technique of metabonomic technology in conjunction with the early stage cardiac toxic biological label of SVM, comprise sample pre-treatments, data acquisition, data processing (multivariate statistical analysis), biomarker specificity investigate, the checking of exclusive biomarker and Optimization Steps, it is characterized in that: the condition using gradient elution in data acquisition: 0-0.5 min, A:99%-99%, 0.5-2 min, A:99%-50%, 2-9 min, A:50%-1%, 9-10 min, A:1%-1%, 10-10.5 min, A:1%-99%, 10.5-12 min, A:99%-99%, wherein mobile phase A refers to the water of 0.1% formic acid, and Mobile phase B refers to the acetonitrile of 0.1% formic acid, in the checking and optimization of exclusive biomarker, use MATLAB R2010a software (USA) to set up SVM forecast model based on the early stage biomarker of cardiac toxic, this process is as follows: using the peak area of biomarker in physiological saline group and each medicine group as input variable, Stochastic choice data set up forecast model as training set and test set, optimum punishment parameter (c) and kernel function (g) is found by optimizing, then to get rid of based on a biomarker one by one, SVM is utilized to carry out classification prediction, obtain corresponding model prediction accuracy, accuracy of analysis, whether it is distinguished with early stage cardiac toxicity is closely related.
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| CN109666726B (en) * | 2018-04-27 | 2022-09-27 | 首都医科大学附属北京朝阳医院 | Liver injury biomarker containing biological small molecules and genes, method and application |
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