CN116500280B - Group of markers for diagnosing carotid aneurysm and application thereof - Google Patents
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Abstract
The application belongs to the field of biomedicine, and particularly relates to a group of markers for diagnosing carotid aneurysms and application thereof. The blood metabolites of the application comprise itaconic acid, phosphoethanolamine, gamma-carboxyl-L-glutamic acid and phosphorylcholine; preferably, the combination of the three metabolites itaconic acid, phosphoethanolamine and phosphorylcholine provides a better diagnostic effect on the diagnosis of carotid aneurysms.
Description
Technical Field
The application belongs to the field of biomedicine, and particularly relates to a group of markers for diagnosing carotid aneurysms and application thereof.
Background
Carotid Body Tumor (CBT) is a rare tumor located at the carotid bifurcation, which can invade cranial nerves and carotid arteries, and even cause cerebral ischemia and stroke, with serious consequences. Carotid aneurysms have a disease incidence of about 30,000 percent, are rare in clinic, and have limited clinical experience.
Carotid aneurysms are often manifested as slow growing, pain-free cervical bumps, often delayed diagnosis due to subtle clinical symptoms, and most patients experience symptomatic visits due to local findings of the bumps or compression of adjacent blood vessels, nerves. Carotid aneurysms should be diagnosed with differences from other cervical tumors such as lymphadenitis, carotid aneurysms, salivary gland tumors, gill cyst and lymph node metastasis, vascular malformations, ectopic thyroid, ewing's sarcoma.
The etiology of carotid aneurysms is not known. It is believed that non-hereditary or sporadic carotid aneurysms are associated with chronic hypoxia, long-term occupancy in plateau areas, and genetic factors. The chronic hypoxia stimulates the compensatory hyperplasia of carotid body tissue in the population in the plateau area, and is an important factor for the pathogenesis of carotid aneurysm. Carotid aneurysms are insensitive to radiotherapy and chemotherapy, surgical excision is the only effective treatment method at present, but because tumors are rich in blood supply and have complex local anatomy, the operation difficulty is high, the risk of bleeding and neurovascular injury in the operation is high, and even stroke and death occur. So far, no medicine can treat carotid aneurysm clinically, and the identification of carotid aneurysm biomarkers helps to reveal possible pathophysiological mechanisms of carotid aneurysm and find potential therapeutic targets.
Metabonomics is an emerging field of research downstream of genomics, proteomics and transcriptomics. There are more than 40,000 metabolites in the human body at concentrations that provide a snapshot of the individual's current health status. Metabolome is a quantitative collection of low molecular weight compounds produced by metabolism, such as metabolic substrates and products, lipids, small peptides, vitamins and other protein cofactors. The metabolome is downstream of the transcriptome and proteome, so any changes from normal are amplified and easier to handle in value.
Disclosure of Invention
The application determines novel preoperative screening and diagnosis biomarkers for carotid aneurysms by performing targeted metabolic mass spectrometry analysis on plasma from carotid aneurysms patients and healthy controls.
Specifically, the application provides the following technical scheme:
the application provides a method for constructing a carotid aneurysm (CBT) diagnosis model, which comprises the following steps:
1) Collecting a concentration measurement of blood metabolites of carotid aneurysmal patients and healthy controls, the blood metabolites comprising 1, 2, 3, or 4 of: itaconic acid, phosphoethanolamine, gamma-carboxy-L-glutamic acid, phosphorylcholine;
2) Constructing a diagnostic model according to the information collected in the step 1);
alternatively, the method comprises the steps of:
1) Collecting blood or plasma from a subject, and detecting the concentration of a blood metabolite comprising 1, 2, 3, or 4 of: itaconic acid, phosphoethanolamine, gamma-carboxy-L-glutamic acid, phosphorylcholine;
2) Performing clinical diagnosis on the subjects, and dividing the subjects into a carotid aneurysm patient group and a healthy control group;
3) And constructing a diagnosis model according to the detection result of the step 1) and the diagnosis result of the step 2).
Preferably, the blood metabolites include itaconic acid, phosphoethanolamine and phosphorylcholine.
Preferably, the blood metabolite is a combination of itaconic acid, phosphoethanolamine and phosphorylcholine.
The terms "subject" or "suspected patient" may be used interchangeably. The term includes, but is not limited to, humans, non-human animals. The term does not indicate a particular age or sex, and thus, is intended to cover adult and neonatal subjects as well as fetuses, regardless of sex.
Preferably, the method of constructing the diagnostic model includes, but is not limited to, classification and logistic regression (Logistic Regression), K-Nearest Neighbor algorithm (kNN), naive Bayes (NB), support vector machines (Support Vector Machine, SVM), decision Trees (DT), random Forests (RF), regression trees (Classificationand Regression Trees, CART), gradient lifting Decision trees (Gradient Boosting DecisionTree, GBDT), xgboost (eXtreme Gradient Boosting), lightweight gradient lifting machines (LightGradient Boosting Machine, lightGBM), gradient lifting machines (Gradient Boosting Machines, GBM), LASSO (Least Absolute Shrinkage and Selection Operator, LASSO), convolutional neural networks (Convolutional Neural Networks, CNN), and the like.
Preferably, the method for detecting the concentration of a blood metabolite comprises: one or more of nuclear magnetic resonance spectroscopy (Nuclear magnetic resonance (NMR) spectroscopy), mass spectrometry (Mass spectrometry), chromatography (chromatogrj), fourier transform ion cyclotron resonance (Fourier-transform ion cyclotron resonance), ion mobility spectroscopy (ion-mobility spectrometry), electrochemical detection (electrochemical detection), raman spectroscopy (Raman spectroscopy), or radio-labeling (radiolabl).
Preferably, the method of clinical diagnosis comprises CT (Computed Tomography, i.e. computed tomography) examination, digital Subtraction Angiography (DSA), magnetic Resonance Imaging (MRI), magnetic Resonance Angiography (MRA), histopathological examination.
In particular, the CT examination includes neck flat scan, neck enhancement, and head and neck CT vascular imaging (CTA).
In particular, the application is diagnosed by the CTA method.
Preferably, the method of collecting blood or plasma from patients with carotid aneurysms and healthy controls is conventional in the art.
As used herein, the term "healthy control" refers to a subject or group of subjects diagnosed by a physician as not having a carotid aneurysm based on qualitative or quantitative test results, including the methods of clinical diagnosis described herein.
In another aspect, the application provides the use of a reagent for detecting blood metabolites including 1, 2, 3 or 4 of the following: itaconic acid, phosphoethanolamine, gamma-carboxy-L-glutamic acid, phosphorylcholine.
Preferably, the blood metabolites include itaconic acid, phosphoethanolamine and phosphorylcholine.
Preferably, the reagent for detecting a blood metabolite is a reagent for detecting the concentration (abundance) of a blood metabolite.
Preferably, the reagent for detecting a blood metabolite comprises reagents used in the following methods: one or more of nuclear magnetic resonance spectroscopy (Nuclear magnetic resonance (NMR) spectroscopy), mass spectrometry (Mass spectrometry), chromatography (chromatogrj), fourier transform ion cyclotron resonance (Fourier-transform ion cyclotron resonance), ion mobility spectroscopy (ion-mobility spectrometry), electrochemical detection (electrochemical detection), raman spectroscopy (Raman spectroscopy), or radio-labeling (radiolabl). In particular, the detection is performed using an ultra performance liquid chromatograph PREMIER in embodiments of the present application, methods of use and detection principles of which are well known in the art.
Preferably, the detection is performed on a sample from the subject, the sample being blood or plasma.
Preferably, a standard for the reagents and/or blood metabolites that process the sample may also be included in the product.
Preferably, the product comprises a kit, a chip and a test strip.
In another aspect, the application provides a method of diagnosing a carotid aneurysm, the method comprising detecting a sample of a subject, detecting the concentration of a blood metabolite, and determining whether the subject is ill based on the detection result; alternatively, the method comprises determining whether the subject is ill based on the measured concentration of the blood metabolite;
the blood metabolites include 1, 2, 3 or 4 of the following: itaconic acid, phosphoethanolamine, gamma-carboxy-L-glutamic acid, phosphorylcholine.
Preferably, the blood metabolites include itaconic acid, phosphoethanolamine and phosphorylcholine.
In a specific example, the methods disclosed herein comprise indicating a likelihood of a disease of a carotid aneurysm based on an increase or decrease in 1, 2, 3, or 4 blood metabolites.
In another aspect, the present application provides a diagnostic system for carotid aneurysm (CBT), comprising a judging device (judging module, judging unit) for judging whether a subject is carotid aneurysm according to the concentration of blood metabolite; the blood metabolites include 1, 2, 3 or 4 of the following: itaconic acid, phosphoethanolamine, gamma-carboxy-L-glutamic acid, phosphorylcholine.
Preferably, the blood metabolites include itaconic acid, phosphoethanolamine and phosphorylcholine.
Further, the diagnostic system may also include a data detection system and/or a data input and output interface; the data detection system is used for detecting the biomarker in the sample to obtain a detection value; the input interface in the data input and output interface is used for inputting the detection value of the biomarker, and the output interface is used for outputting the analysis result of whether the individual is lung cancer or not after the detection value is analyzed by the data analysis module.
Implementation of the methods and/or systems of embodiments of the present application may include performing or completing selected tasks manually, automatically, or a combination thereof. Moreover, the actual instrumentation and equipment of the embodiments of the method and/or system according to the present application could implement several selected tasks by hardware, by software, or by firmware or by a combination thereof using an operating system. Furthermore, the present application may take the form of a computer program product embodied on one or more computer-usable storage media (including, but not limited to, disk storage, CD-ROM, optical storage, and the like) having computer-usable program code embodied therein.
In yet another aspect, the application provides the use of a system as described above in the diagnosis of carotid body aneurysm (CBT).
The blood metabolites of the present application can be identified according to their HMDB IDs, specifically, HMDB ID of itaconic acid is HMDB0002092, HMDB ID of phosphoethanolamine is HMDB0000224, HMDB ID of γ -carboxy-L-glutamic acid is HMDB0041900, and HMDB ID of phosphorylcholine is HMDB0001565.
Based on the verification of the external cohort, ROC curves of the blood metabolites of the present application in diagnosing carotid aneurysms are shown in fig. 3-6, with higher prediction accuracy as the curves approach the upper left corner. As can be seen from the ROC curve, the AUC values are all >0.8, said AUC (Area Under Curve) being the area of the lower part of the curve, used to represent the prediction accuracy; the higher the AUC value, i.e., the larger the area under the curve, the higher the prediction accuracy.
The carotid body tumor (carotid body tumor, CBT) of the present application is a rare chemoreceptor tumor that occurs in the carotid body, located at the carotid bifurcation. Coronary angiography (CTA) or Magnetic Resonance Angiography (MRA) is the method of choice for diagnosing carotid aneurysms.
Compared with the prior art, the technical scheme of the application has the following beneficial effects: provides an accurate diagnosis marker of the carotid aneurysm and provides an important basis for accurately diagnosing the carotid aneurysm in clinic.
Drawings
Fig. 1 is a diagram of the results of carotid angiography of patients with carotid aneurysms.
Fig. 2 is a graph of the results of a pathological examination of a patient with carotid body aneurysm.
Fig. 3 is a graph of ROC curve of itaconic acid in carotid aneurysm diagnosis.
Fig. 4 is a graph of ROC curve of phosphoethanolamine in carotid aneurysm diagnosis.
Fig. 5 is a graph of ROC curve of gamma-carboxy-L-glutamic acid in carotid aneurysm diagnosis.
Fig. 6 is a graph of ROC curve of phosphorylcholine in carotid aneurysm diagnosis.
Fig. 7 is a graph of ROC curve for a combination of itaconic acid, phosphoethanolamine and phosphorylcholine in carotid aneurysm diagnosis.
Detailed Description
The present application is further described in terms of the following examples, which are given by way of illustration only, and not by way of limitation, of the present application, and any person skilled in the art may make any modifications to the equivalent examples using the teachings disclosed above. Any simple modification or equivalent variation of the following embodiments according to the technical substance of the present application falls within the scope of the present application.
Example 1 blood collection and screening for Metabolic markers
Diagnosis of the subject: all patients were determined to have carotid aneurysms by preoperative cervical artery CTA examination and surgical histopathological examination. The examination results were as follows: (1) CTA imaging changes: CTA examination of the neck of a carotid body tumor patient (fig. 1) revealed that the carotid bifurcation was seen as a lump-like rich blood supply soft tissue density shadow. (2) CTA pathological changes: pathological examination of the surgically excised tissue of patients with carotid aneurysms (fig. 2) and HE staining results showed that the lesions were consistent with morphological changes in CBT.
Blood collection and analysis of the subject: obtaining a plasma sample of a patient with a carotid aneurysm; the control was a healthy subject without carotid aneurysm compared to the control plasma metabolite expression.
Specific materials, reagents, and collection methods for blood collection and analysis of metabolite expression are as follows:
1. materials and reagents
(1) Instrument:
6500+ high resolution mass spectrometer was purchased from AB Sciex company; the ultra performance liquid chromatograph PREMIER was purchased from Waters corporation.
(2) Reagent:
chromatographic grade acetonitrile and methanol are produced by Waters company; ammonium acetate was purchased from Sigma; ammonia water was purchased from Fisher Chemical company.
2. Experimental method
(1) Sample collection flow: blood samples of carotid aneurysms patients and controls were collected using EDTA anticoagulated blood collection tubes, centrifuged at 2000g at 4 degrees for 15min, and the supernatant was aspirated for storage at-80 ℃ in a refrigerator.
(2) The experimental process comprises the following steps: 200 [ mu ] L of pure water is added into 100 [ mu ] L of samples, and then 1200 [ mu ] L of extracting solution (methanol: acetonitrile, v: v=1:1) containing isotope internal standard is added into the samples, so that vortex mixing is carried out uniformly. Ultrasonic treatment with ice water bath for 15min, standing at-40deg.C for 2h, centrifuging at 12000rpm for 15min, collecting supernatant, centrifuging, concentrating, and drying. 100 mu L of a 60% acetonitrile redissolved sample is added, ice water bath ultrasonic treatment is carried out for 5min, centrifugation is carried out for 15min at 12000rpm, and the supernatant is taken and added into a sample loading bottle. Meanwhile, preparing a standard substance mixed solution, sequentially diluting the mixed solution into a series of standard solutions with a concentration, performing on-machine detection, and drawing a standard curve.
The target compound was chromatographed using a ACQUITY UPLC PREMIER (Waters) ultra performance liquid chromatograph. Liquid chromatography phase A is 20% acetonitrile (containing 10mmol/L ammonium acetate), phase B is 90% acetonitrile (containing 10mmol/L ammonium acetate); the AB phase was adjusted to ph=9 with aqueous ammonia. Mass spectrometry was performed in multi-reaction monitoring (MRM) mode using SCIEX 6500 qtrap+ triple quadrupole mass spectrometer with the following mass spectral parameters:
CurtainGas=35psi，IonSprayVoltage=+5000V/-4500V，Temperature=500℃，IonSourceGas1=50psi，IonSourceGas2=50psi。
(3) Data analysis: all mass spectrometry data acquisition and target compound quantitative analysis were performed by SCIEX Analyst Work Station and BIOTREE Bio bid software, and target metabolite concentrations in samples were calculated using standard curves.
660 metabolites were tested for expression by targeting metabolites to 5 diagnosed carotid aneurysmal patient (n=5, 3 men and 2 women, average age 41.8 years) plasma samples. 4 differentially expressed metabolites with a fold change of 1.5-fold or more and a p-value of <0.05 were screened as candidate diagnostic CBT markers (table 1) in comparison with 5 control samples (n=5, 3 men and 2 women, mean age 40.6 years) without carotid aneurysms, the fold change in table 1 being the disease group divided by the normal control group.
Example 2 validation of blood Metabolic markers in CBT diagnostics
To evaluate the sensitivity and specificity of the metabolic markers screened in carotid aneurysm diagnosis, we performed external targeted metabolic mass spectrometry validation in new 25 CBT patients (n=25, 13 men 12 women, average age 43.2 years) and 25 healthy control samples (n=25, 13 men 12 women, average age 41.0 years) against the metabolites in table 1, and plotted ROC curves for the above markers distinguishing carotid aneurysm patients from healthy controls.
The AUC value for itaconic acid in table 1 was 0.930, sensitivity 96% and specificity 80% as analyzed by ROC curve (fig. 3); the AUC value for phosphoethanolamine was 0.843, sensitivity was 76%, specificity was 86% (fig. 4); AUC value of γ -carboxy-L-glutamic acid was 0.818, sensitivity was 72%, specificity was 84% (fig. 5); the AUC value for phosphorylcholine was 0.800, sensitivity was 76% and specificity was 80% (fig. 6).
The combination of the three metabolites itaconic acid, phosphoethanolamine and phosphorylcholine has good diagnostic effect on carotid aneurysm diagnosis, and the area under ROC curve AUC value is 0.958 (fig. 7).
Claims (10)
1. A method of constructing a diagnostic model of carotid aneurysm, the method comprising the steps of:
1) Collecting a concentration measurement of blood metabolites of carotid aneurysmal patients and healthy controls, the blood metabolites comprising 1, 2, 3, or 4 of: itaconic acid, phosphoethanolamine, gamma-carboxy-L-glutamic acid, phosphorylcholine;
2) Constructing a diagnostic model according to the information collected in the step 1);
alternatively, the method comprises the steps of:
1) Collecting blood or plasma from a subject, and detecting the concentration of a blood metabolite comprising 1, 2, 3, or 4 of: itaconic acid, phosphoethanolamine, gamma-carboxy-L-glutamic acid, phosphorylcholine;
2) Performing clinical diagnosis on the subjects, and dividing the subjects into a carotid aneurysm patient group and a healthy control group;
3) And constructing a diagnosis model according to the detection result of the step 1) and the diagnosis result of the step 2).
2. The method of claim 1, wherein the blood metabolites comprise itaconic acid, phosphoethanolamine and phosphorylcholine.
3. The method of claim 1, wherein the method of constructing the diagnostic model is classification and logistic regression, k-nearest neighbor algorithm, naive bayes, support vector machine, decision tree, random forest, regression tree, gradient lifting decision tree, xgboost, lightweight gradient lifting machine, LASSO, or convolutional neural network.
4. The method of claim 1, wherein the method for detecting the concentration of the blood metabolite comprises: nuclear magnetic resonance spectroscopy, mass spectrometry, chromatography, fourier transform ion cyclotron resonance, ion mobility spectroscopy, electrochemical detection, raman spectroscopy, or radio-labelling.
5. The method of claim 1, wherein the method of clinical diagnosis comprises CT, digital subtraction angiography, magnetic resonance imaging, magnetic resonance angiography, or histopathological examination.
6. Use of a reagent for detecting blood metabolites including 1, 2, 3 or 4 of the following: itaconic acid, phosphoethanolamine, gamma-carboxy-L-glutamic acid, phosphorylcholine.
7. The use of claim 6, wherein the blood metabolites comprise itaconic acid, phosphoethanolamine and phosphorylcholine.
8. The use according to claim 6, wherein the product comprises a standard for reagents and/or blood metabolites for treating a sample.
9. The use according to claim 6, wherein the reagent for detecting a blood metabolite comprises reagents used in any one or more of the following methods: nuclear magnetic resonance spectroscopy, mass spectrometry, chromatography, fourier transform ion cyclotron resonance, ion mobility spectroscopy, electrochemical detection, raman spectroscopy, or radio-labelling.
10. A diagnostic system for carotid aneurysms, the system comprising a means for determining whether a subject is a carotid aneurysm based on the concentration of blood metabolites comprising 1, 2, 3, or 4 of: itaconic acid, phosphoethanolamine, gamma-carboxy-L-glutamic acid, phosphorylcholine.
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