CN117110493A - Metabolic marker associated with neonatal pneumonia and metabolic acidosis and application thereof - Google Patents
Metabolic marker associated with neonatal pneumonia and metabolic acidosis and application thereof Download PDFInfo
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- 208000010444 Acidosis Diseases 0.000 title claims abstract description 30
- 206010027417 Metabolic acidosis Diseases 0.000 title claims abstract description 28
- 206010053584 Neonatal pneumonia Diseases 0.000 title claims abstract description 25
- 239000003550 marker Substances 0.000 title claims abstract description 14
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Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
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- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
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Abstract
The invention belongs to the technical field of biology, and particularly relates to a metabolic marker related to neonatal pneumonia and concurrent metabolic acidosis and application thereof. The metabolic markers related to the concurrent metabolic acidosis of neonatal pneumonia are one or more of 23 metabolic markers shown as ID NO. 1-23. The 23 differential metabolites show significant differences in the pneumonia concurrent metabolism acidosis group, the AUC values are above 0.7, wherein the AUC values of Farnesol and 4-Heptyloxyphenol, ramifenazone are above 0.9, and the 23 differential metabolites have high diagnosis efficacy and can be used as diagnosis markers of neonatal pneumonia concurrent metabolism acidosis.
Description
Technical Field
The invention belongs to the technical field of biology, and particularly relates to a metabolic marker related to neonatal pneumonia and concurrent metabolic acidosis and application thereof.
Background
The cause of pneumonia infection is complicated, and the symptoms of pneumonia are various, so that reasonable diagnosis is difficult. In addition, the neonate has the characteristics of low immunity, atypical clinical manifestation, urgent onset and rapid change, is more likely to cause complications such as respiratory failure and the like, and seriously threatens the life health of the neonate. Clinically, X-ray, CT examination and recently developed Lung Ultrasound (LUS) are usually used as main diagnosis means, but reliability is limited, and accurate identification of a patient suffering from pneumonia with high complication risk is a great challenge at present.
Metabonomics is a novel method for understanding diseases, and potential biomarkers of various diseases are searched for by qualitatively and quantitatively analyzing small molecular metabolites with relative molecular weights smaller than 1500 in a certain organism or cell. The metabolites and their concentration changes in the organism can directly reflect the potential metabolic states of cells, tissues and life systems, thereby obtaining detailed results of metabolic phenotypes and mining metabolic disorders hidden behind the disease.
Most of the current researches are to study abnormal metabolic pathways and metabolites of pneumonia relative to normal children, and the current research on molecular mechanisms for judging pneumonia and metabolic acidosis by using a metabonomics method is less.
Disclosure of Invention
The invention aims to provide a metabonomics method for judging neonatal pneumonia and concurrent metabolic acidosis, which is used for carrying out data analysis on a serum sample metabolic spectrum of the pneumonia and the pneumonia concurrent metabolic acidosis, screening out metabolites with obvious differences, and verifying the reliable efficacy of the different metabolites.
The invention is realized by the following technical scheme:
the invention provides metabolic markers related to neonatal pneumonia and metabolic acidosis, wherein the metabolic markers are one or more of 23 metabolic markers shown in the following ID NO. 1-23:
1)2,4-Dimethylphenol
2)Phenylpropylmethylamine
3)S-Allyl-L-cysteine
4)Methylisoeugenol
5)D-Tyrosine
6)Ferulate
7)4-Heptyloxyphenol
8)Phlorisovalerophenone
9)Farnesol
10)Ramifenazone
11)Asp-phe
12)Oleic acid
13)Sphingosine
14)Mesterolone
15)Phe-Phe
16)Quinidine
17)Benfuracarb
18)Bilirubin
19)Succinic acid
20)Dl-P-Hydroxyphenyl lactic acid
21)1-Methyluric Acid
22)LPC 17:0
23)LysoPC(18:0)。
in the above technical scheme, further, the metabolic marker is applied to the preparation of products for diagnosing neonatal pneumonia and metabolic acidosis.
In the above technical solution, further, the product comprises a reagent for detecting the content of the metabolic marker in the subject sample.
In the above technical solution, further, the detecting includes detecting by liquid chromatography-tandem mass spectrometry.
In the above technical solution, further, the product diagnoses whether neonatal pneumonia and metabolic acidosis occur or not by detecting the content level of the metabolic marker.
In the above technical scheme, the product is further used for distinguishing neonatal pneumonia from neonatal pneumonia complicated with metabolic acidosis.
In the above technical scheme, further, the product comprises a kit, a detection chip and test paper.
The invention provides a screening method of the metabolic markers, which comprises the following steps:
s1, selecting a sample, and selecting a serum sample of neonatal pneumonia complicated with metabolic acidosis, wherein the neonatal pneumonia serum sample is used for comparison;
s2, preprocessing a serum sample;
s3, based on a liquid chromatography-tandem mass spectrometer, acquiring metabolic characteristic information of a serum sample of neonatal pneumonia and pneumonia concurrent metabolic acidosis;
s4, preprocessing data;
s5, screening out metabolites with significant differences through univariate and multivariate statistical analysis;
in the step S4, based on software One-MAP/PTO software, the collected LC-MS original data is converted into mzML format, and peak extraction, peak alignment, peak matching, peak intensity correction and the like are carried out to obtain an excel format file containing compound retention time and mass-to-charge ratio information;
in step S5, the processed data matrix is imported into One-MAP statistical software for qualitative and statistical analysis, qualitative results are checked based on an HMDB library, metabolites with obvious differences are screened out through comprehensive univariate and multivariate analysis according to the identified metabolites, and the reliability of the screened differences is verified through an ROC curve.
Compared with the prior art, the invention has the beneficial effects that: according to the invention, 23 differential metabolites are screened out to show significant differences in the pneumonia concurrent metabolic acidosis group through metabonomics research, the AUC values are all above 0.7, the AUC values of Farnesol and 4-Heptyloxyphenol, ramifenazone are all above 0.9, the diagnosis efficiency is very high, the method can be used as a diagnosis marker of neonatal pneumonia concurrent metabolic acidosis, and a new research thought and a new method are provided for judging the disease.
Drawings
FIG. 1 is a sample metabolic profile analysis: (A) is a TIC diagram of QC in positive ion mode; (B) is a TIC diagram of QC in negative mode ion;
FIG. 2 is a graph of metabolic profile analysis of pneumonic concurrent metabolic acid groups and pneumonic groups in positive ion mode: (A) is a PLS-DA score map; (B) is a volcanic plot; (C) is a displacement check chart; wherein, (PN) represents a pneumonia group and (PN & MA) represents a pneumonia and metabolic acidosis group.
FIG. 3 is a graph of metabolic profile analysis of pneumonia concurrent metabolic acid groups and pneumonia groups in negative ion mode: (A) is a PLS-DA score map; (B) is a volcanic plot; (C) is a displacement check chart; wherein, (PN) represents a pneumonia group and (PN & MA) represents a pneumonia and metabolic acidosis group.
FIG. 4 is a ROC verification graph of the difference between the pneumonia and the metabolic acid group and the pneumonia group.
Detailed Description
The invention is further illustrated below in connection with specific examples, but is not limited in any way.
Example 1
1. The method for judging the neonatal pneumonia and the concurrent metabolic acidosis based on the non-targeted metabonomics comprises the following steps:
s1, selecting a sample
20 cases of neonatal pneumonia complicated with metabolic acidosis serum samples were collected as an experimental group, and 20 cases of neonatal pneumonia (without complications) serum samples were collected as a control group. Blood samples were collected from Changzhou urban women and child healthcare institute (approval number: 2019017), serum was prepared by a standardized procedure, and neonatal parents signed informed consent.
S2, pretreating a serum sample and standing at low temperature
On ice, 50ul of serum samples were removed in a 1.5ml EP tube; 200ul of cold methanol (containing mixed standard) is added respectively, vortex 1500r is oscillated for 4min, and low temperature is stopped for 10min; centrifuging at 14000rpm for 15min at 4deg.C; 200ul of supernatant was aspirated into a new EP tube and the remaining supernatant from each sample was aspirated to prepare QC sample solutions; and (3) centrifuging and concentrating the sample at low temperature, and then placing the sample in a refrigerator at-40 ℃ for standby.
S3, based on a liquid chromatography-tandem mass spectrometer, acquiring metabolic characteristic information of a serum sample of neonatal pneumonia and pneumonia concurrent metabolic acidosis.
Before on-machine analysis, the samples were lyophilized again with 100ul of 20% methanol/water solution until completely dissolved, and after shaking centrifugation, the supernatant was taken for positive and negative ion pattern analysis. And carrying QC samples at each sample injection analysis treatment.
Liquid chromatography conditions: in positive ion mode, the following 15min gradient was used on a BEH C8 column (1.7 um,2.1 x 100 mm) at a flow rate of 0.35 mL/min: 0-1min,5% solvent B (mobile phase A:0.1% formic acid/water; mobile phase B:0.1% methanol/acetonitrile); 1.1-11min,5% -100% of solvent B;11.1-13min,100% solvent B;13.1-15min,5% solvent B; the column temperature was set at 50 ℃. In negative ion mode, on HSS T3 column (1.8 um,2.1 x 100 mm), the rest conditions are the same as in positive ion mode.
Mass spectrometry conditions: in positive ion mode, spray voltage +3.8kV, capillary temperature 320 ℃, and no target scan was performed on all samples from 70 to 1050m/z at 70000 resolution. The sheath gas flow rate is 35, the extracted mass spectrum characteristics are divided into a plurality of target lists, and the target lists are imported into an MS2 method for target MS/MS analysis; the resolution of the MS/MS fragment acquisition was 17500. In negative ion mode, the spraying voltage is-3.0 kV, and the rest conditions are the same as those in positive ion mode.
S4, data preprocessing.
And converting the collected LC-MS original data into mzML format based on software One-MAP/PTO, and carrying out peak extraction, peak alignment, peak matching, peak intensity correction and the like to obtain an excel format file containing the information of the retention time and the mass-to-charge ratio of the compound.
S5, screening out metabolites with significant differences through univariate and multivariate statistical analysis, and verifying the metabolites with differences through an ROC curve.
Importing the processed data matrix into One-MAP statistical software for qualitative determination, and checking qualitative results based on an HMDB library; screening differential metabolites by univariate volcanic mapping (FC >1.5, p < 0.05) and multivariate partial least squares discriminant analysis (VIP >1, p < 0.05); the screened differential metabolites were validated by ROC survival curves.
2. Results
Sample metabolic profile analysis: the overlapping of QC samples in positive and negative ion mode was good (fig. 1A, 1B), indicating that data quality can be used for analysis.
Pneumonic concurrent metabolic acidosis group and pneumonic group metabolic profile analysis: PLS-DA modeling was performed based on metabonomics data from infants suffering from pneumonia and pneumonia-associated metabolic acidosis, with good separation in positive ion mode (FIG. 2A) and also with a tendency to separate in negative ion mode (FIG. 3A). The univariate volcanic diagrams in the positive and negative ion modes intuitively identify metabolites with large variation range and statistical significance (fig. 2B and 3B). Substitution test in positive and negative ion mode (FIGS. 2C, 3C) R 2 Greater than Q 2 The establishment model is proved to be good and stable.
Poor foreign matter ROC analysis: ROC curves are useful for characterizing performance of a particular feature when distinguishing between two populations, "AUC" refers to the area under the curve of a subject's working feature (ROC) curve for ROC curve validation of screened differential metabolites, and the diagnostic efficacy of a metabolite marker is assessed using "AUC" values, the higher the AUC, the higher the accuracy of the metabolite classification for between different groups.
By ROC analysis on 23 significantly altered metabolites, the AUC values were all greater than 0.7, with Farnesol, AUC values of 4-Heptyloxyphenol, ramifenazone above 0.9.
According to the invention, 23 differential metabolites are obviously changed in a pneumonia concurrent metabolic acidosis group, and the substances are taken as detection variables to judge the diagnosis efficacy, so that the results show that AUC values of 23 differential substances 2,4-Dimethylphenol, phenylpropylmethylamine, S-all-L-cysteine, methylisoeugenol, D-Tyrosine, ferulate, 4-Heptyloxyphenol, phlorisovalerophenone, farnesol, ramifenazone, asp-phe, oleic Acid, sphingosine, mesterolone, phe-Phe, quinidine, benfuracarb, bilirubin, succinic Acid, dl-P-Hydroxyphenyl lactic Acid, 1-methyl Acid, LPC 17:0 and Lysopc (18:0) are all above 0.7, wherein AUC values of Farnesol and 4-Heptyloxyphenol, ramifenazone are above 0.9, and the invention has higher sensitivity, specificity and accuracy.
Claims (7)
1. A metabolic marker associated with neonatal pneumonia and metabolic acidosis, characterized in that the metabolic marker is one or more of 23 metabolic markers as shown in the following ID NOs 1-23:
1)2,4-Dimethylphenol
2)Phenylpropylmethylamine
3)S-Allyl-L-cysteine
4)Methylisoeugenol
5)D-Tyrosine
6)Ferulate
7)4-Heptyloxyphenol
8)Phlorisovalerophenone
9)Farnesol
10)Ramifenazone
11)Asp-phe
12)Oleic acid
13)Sphingosine
14)Mesterolone
15)Phe-Phe
16)Quinidine
17)Benfuracarb
18)Bilirubin
19)Succinic acid
20)Dl-P-Hydroxyphenyl lactic acid
21)1-Methyluric Acid
22)LPC 17:0
23)LysoPC(18:0)。
2. use of the metabolic marker of claim 1 in the manufacture of a product for diagnosing neonatal pneumonia and metabolic acidosis.
3. The use according to claim 2, wherein the product comprises reagents for detecting the level of the metabolic marker in a sample from the subject.
4. The use according to claim 3, wherein the detection comprises detection by liquid chromatography-tandem mass spectrometry.
5. The use according to claim 2, wherein the product is used for diagnosing the occurrence of neonatal pneumonia and metabolic acidosis by detecting the level of the metabolic marker.
6. The use according to claim 2, wherein the product is for distinguishing neonatal pneumonia from neonatal pneumonia complicated with metabolic acidosis.
7. The use according to claim 2, wherein the product comprises a kit, a detection chip, a test paper.
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