CN117007822A - Marker for screening risk of schizophrenia and application thereof - Google Patents
Marker for screening risk of schizophrenia and application thereof Download PDFInfo
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Classifications
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- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
- G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
- G16H50/20—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for computer-aided diagnosis, e.g. based on medical expert systems
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/573—Immunoassay; Biospecific binding assay; Materials therefor for enzymes or isoenzymes
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6872—Intracellular protein regulatory factors and their receptors, e.g. including ion channels
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
- G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/92—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving lipids, e.g. cholesterol, lipoproteins, or their receptors
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/475—Assays involving growth factors
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/90—Enzymes; Proenzymes
- G01N2333/902—Oxidoreductases (1.)
- G01N2333/904—Oxidoreductases (1.) acting on CHOH groups as donors, e.g. glucose oxidase, lactate dehydrogenase (1.1)
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/30—Psychoses; Psychiatry
- G01N2800/302—Schizophrenia
Abstract
The invention relates to the field of disease diagnosis, in particular to a marker for screening risk of schizophrenia and application thereof. The kit, the system and the device based on total cholesterol, IDH2 protein and PPARgamma protein have very high consistency with the clinical diagnosis result of schizophrenia, show very excellent performance, and have the advantages of simple and convenient detection method, easy operation and very good clinical application prospect.
Description
Technical Field
The invention relates to the field of disease diagnosis, in particular to a marker for screening risk of schizophrenia and application thereof.
Background
Schizophrenia is one of the most common serious mental diseases in clinic, seriously endangers the physical and mental health of human beings, and brings heavy burden to society and families. Although schizophrenia has been of great concern, the cause of schizophrenia is very complex, and its cause has not been clearly concluded so far. In addition, as with other mental diseases, diagnosis of schizophrenia mainly depends on clinical manifestations and lacks related diagnosis indexes such as physiology, biochemistry and the like, so that the diagnosis is easily influenced by cultural level and subjective consciousness of patients, and misdiagnosis and missed diagnosis are often caused. Therefore, the search for an objective, effective, convenient and feasible biological marker is a clinical problem to be solved urgently.
The biomarker has wide clinical application, and can be used for early diagnosis of diseases, and also can be used for formulation of treatment schemes of the diseases, prognosis judgment of the diseases, drug efficacy evaluation and the like. At present, molecular markers for diagnosing the schizophrenia based on genes in blood plasma and blood serum exist, but most of the molecular markers are single biomarkers, the sensitivity and the specificity of the molecular markers are poor, clinical requirements cannot be met, the deficiency can be effectively overcome by combining multiple markers, and the markers which can be effectively combined are lack of being used for screening the schizophrenia.
Disclosure of Invention
The invention aims to solve the problems that: the schizophrenia risk screening tool is high in detection rate, high in sensitivity and good in result repeatability, and is suitable for screening of large-scale crowds.
The specific technical scheme of the invention is as follows:
use of IDH2 protein, total cholesterol and/or ppary protein for the preparation of a marker for risk screening for schizophrenia.
The invention also provides the use of a reagent for detecting total cholesterol concentration, IDH2 protein expression level and/or PPARgamma protein expression level in a blood sample for preparing a kit, a system and/or a device for screening risk of schizophrenia.
Further, the blood sample is blood, serum or plasma, preferably human peripheral blood serum; the reagent includes a reagent for enzyme-linked immunosorbent assay, a reagent for immunoblotting, a reagent for immunoelectrophoresis, a reagent for tissue immunostaining, a reagent for immunoprecipitation analysis, a reagent for radioimmunoassay, a reagent for complement fixation analysis, a reagent for fluorescence-activated cell sorting, a reagent for mass analysis, or a reagent for protein microarray.
The invention also provides a kit for screening for risk of developing schizophrenia comprising reagents for detecting total cholesterol concentration, IDH2 protein expression level and/or PPARgamma protein expression level in a blood sample.
Further, the blood sample is blood, serum or plasma, preferably human peripheral blood serum; the reagent includes a reagent for enzyme-linked immunosorbent assay, a reagent for immunoblotting, a reagent for immunoelectrophoresis, a reagent for tissue immunostaining, a reagent for immunoprecipitation analysis, a reagent for radioimmunoassay, a reagent for complement fixation analysis, a reagent for fluorescence-activated cell sorting, a reagent for mass analysis, or a reagent for protein microarray, preferably a reagent for enzyme-linked immunosorbent assay.
The invention also provides a system for screening risk of schizophrenia, which comprises the following modules:
and a data acquisition module: obtaining the total cholesterol concentration, IDH2 protein expression level and/or PPARgamma expression level in the blood sample;
a database module: the clinical characteristics of healthy human bodies and schizophrenic human bodies and the total cholesterol concentration in blood samples are used for forming a database by the IDH2 protein expression level and/or PPARgamma expression level data, and the database is randomly split into a training set and a testing set;
a machine learning module: constructing a random forest model;
training module: training the random forest model by using a training set to obtain a trained random forest model;
and a testing module: verifying the trained random forest model by using the test set;
and a result output module: outputting the result of high or low risk of developing schizophrenia.
Further, the blood sample is blood, serum or plasma, preferably human peripheral blood serum; the clinical features include age, gender and BMI.
The invention also provides a construction method of the system, which comprises the following steps:
(1) Constructing a data acquisition module for inputting data of total cholesterol concentration, IDH2 protein expression level and/or PPARgamma expression level;
(2) Collecting clinical characteristics of natural people with healthy and schizophrenia and total cholesterol concentration in blood samples, IDH2 protein expression level and/or PPARgamma expression level data, and constructing a database module; randomly splitting data in a database into a training set and a testing set;
(3) Constructing a random forest model by adopting a random forest algorithm to obtain a machine learning module;
(4) Constructing a training module for analyzing and training the random forest model by adopting a training set;
(5) Constructing a test module for verifying and optimizing the trained random forest model by using the test set;
(6) An output module that outputs the calculation result of the machine learning module is constructed.
The invention also provides a device for screening the risk of schizophrenia, which comprises the following devices:
1) The detection device comprises: the detection device is internally provided with reagents for detecting the total cholesterol concentration, the IDH2 protein expression level and the PPARgamma protein expression level in a blood sample;
2) Analysis device: the analysis device is internally provided with a data input port for receiving the detection result of the detection device;
the analysis model Y=1/(1+e) is built in the analysis device (1.634*TC-0.00107*IDH2-0.03664*PPARγ+10.883 ) Calculating the probability Y of schizophrenia based on the total cholesterol concentration, IDH2 protein expression level and PPARgamma expression level, for discriminating schizophreniaRisk of symptoms.
Further, the blood sample is blood, serum or plasma, preferably human peripheral blood serum; a Y greater than 0.5 indicates a high risk of developing schizophrenia, and a Y less than 0.5 indicates a low risk of developing schizophrenia.
The invention discovers the relation between total cholesterol, IDH2 and PPARgamma and schizophrenia, and the change of the total cholesterol level of each group of people is detected and analyzed by collecting peripheral blood of healthy control and schizophrenia patients and a biochemical kit, and the change of the IDH2 and PPARgamma level of each group of people is detected and analyzed by ELISA; as a result, it was found that the serum total cholesterol level was significantly reduced in schizophrenic patients, and that both IDH2 and pparγ levels were significantly increased, compared to healthy controls. Furthermore, the invention further demonstrates the reliability and specificity of total cholesterol, IDH2 and PPARgamma as combined markers for diagnosing schizophrenia and/or evaluating the risk of developing schizophrenia by constructing a diagnosis model for schizophrenia and ROC curve analysis.
The kit and the device for simultaneously detecting the total cholesterol concentration, the IDH2 protein expression level and/PPARgamma protein expression level in the blood sample have the advantages of extremely high consistency of detection results and clinical diagnosis results of schizophrenia, extremely excellent performance, simple detection method, low cost, easy operation and extremely good clinical application prospect.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
FIG. 1 is a graph showing the quantitative results of total cholesterol in peripheral serum of schizophrenic patients and healthy controls.
FIG. 2 is a graph showing the quantitative results of IDH2 in the peripheral serum of schizophrenic patients and healthy controls.
FIG. 3 is a graph showing the quantitative results of PPARgamma in the peripheral serum of schizophrenic patients and healthy controls.
Fig. 4 is the ROC curve results for a diagnosis model of schizophrenia constructed with total cholesterol, IDH2 and ppary levels in the training set and in the test set.
Detailed Description
The raw materials and equipment used in the invention are all known products and are obtained by purchasing commercial products.
EXAMPLE 1 relation of Total cholesterol, IDH2 and PPARgamma levels in peripheral serum and schizophrenia
1. Clinical treatment
The study subjects were peripheral serum samples of 166 schizophrenic patients and 79 healthy controls. Diagnosis of schizophrenia is diagnosed and confirmed by two psychiatrists with abundant clinical experience according to the diagnosis criteria in the manual for diagnosis and statistics of mental diseases (fourth edition) (DSM IV), respectively, and the positive and negative symptoms scale (PANSS) is used to assess the severity of symptoms of schizophrenia. The mental disease patients all recruit the first hospital mental department affiliated to the university of Chongqing medical science, and the samples of the healthy control person come from the first hospital physical examination center affiliated to the university of Chongqing medical science. The clinical characteristics of the subjects are shown in table 1:
table 1: demographic and clinical characteristics of the subject
Note that: HCs: healthy people with non-mental illness; schizophernia: patients with schizophrenia; marking “a” Representing chi-square test; marking “b” Representing the Mann-Whitney U test.
5mL of median elbow vein blood of all subjects is obtained, the mixture is stood for 30min at room temperature, centrifuged for 15min at 1000 Xg, serum is taken and split charging is carried out, and the serum is frozen in a refrigerator at-80 ℃.
2. Detection method
Positive and negative symptom scales (Positive and Negative Syndrome Scale; PANSS) were used to assess the severity of schizophrenic symptoms.
Detecting the total cholesterol content in a serum sample by using a Rogowski COBAS C8000 full-automatic biochemical analyzer; the human IDH2 ELISA kit (product number: JL 47327) of Shanghai Jiang Lai company is used for detecting the IDH2 level in the serum sample according to the specification of the kit, and the detection range of the kit is 100mIU/L-2400mIU/L; the PPARgamma level in the serum sample was detected using the human PPARgamma ELISA kit (cat# MM-13769H 1) from Jiangsu enzyme-immune company according to the kit instructions, the detection range of the kit being 20ng/L-480ng/L.
3. The invention model establishment
Data analysis (one)
All data were statistically analyzed using SPSS20.0 and R4.0 software. Data are expressed as mean ± standard error, using statistical analysis of t-test, chi-square test, or non-parametric Mann-Whitney U test, with p <0.05 considered statistically significant.
(II) construction of diagnosis model for schizophrenia
The random forest machine learning model is adopted, so that the method is simple and easy to operate, and the generated schizophrenia diagnosis model has higher sensitivity and specificity; the method comprises the following steps: subjects were divided into training sets (healthy controls, n=52; schizophrenic patients, n=113) and test sets (healthy controls, n=27; schizophrenic patients, n=53), and after correction for age, sex and BMI, diagnostic models were established with total cholesterol, IDH2 and pparγ levels in the training set samples:
Y＝1/(1+e (1.634*TC-0.00107*IDH2-0.03664*PPARγ+10.883) (note: Y represents the probability of developing schizophrenia, if the Y value is greater than 0.5, it is determined that the risk of developing schizophrenia is high, if the Y value is less than 0.5, it is determined that the risk of developing schizophrenia is low, TC represents the total cholesterol concentration measured in the peripheral serum, IDH2 represents the IDH2 level measured in the peripheral serum, PPARy represents the IDH2 level measured in the peripheral serum), and test verification is performed in the test set sample; using GraphPad Prism8.3 software analysis of the subject working characteristics of the model, drawing ROC curves, the area under the curve (AUC) of ROC at 0.9-1 indicated excellent diagnostic efficacy.
4. Results
Results of total cholesterol levels in peripheral serum of schizophrenic patients and healthy controls are shown in table 2 and fig. 1, results of IDH2 levels in peripheral serum of schizophrenic patients and healthy controls are shown in table 3 and fig. 2, results of pparγ levels in peripheral serum of schizophrenic patients and healthy controls are shown in table 4 and fig. 3, and diagnostic efficacy analysis of a diagnostic model established based on serum total cholesterol, IDH2 and pparγ levels is shown in fig. 4.
TABLE 2 results of total cholesterol levels in serum for schizophrenic patients and healthy controls
| HCs | schizophrenia | p value | |
| Sample size (n) | 79 | 166 | - |
| Mean value of total cholesterol level.+ -. Standard error (mM) | 5.91±0.14 | 3.93±0.08 | 1.37E-29 |
Note that: HCs: healthy people with non-mental illness; schizophernia: patients with schizophrenia;
as can be seen from table 2 and fig. 1, the total cholesterol level in serum of schizophrenic patients was significantly reduced compared to the non-psychotic healthy control, and the differences between the two groups were very significant (p-value 1.37E-29).
TABLE 3 results of IDH2 levels in serum of schizophrenic patients and healthy controls
| HCs | schizophrenia | p value | |
| Sample size (n) | 79 | 166 | - |
| Mean value.+ -. Standard error (mIU/L) | 1.62±4.21 | 1.93±4.89 | 5.22E-05 |
As can be seen from table 3 and fig. 2, IDH2 levels in serum of schizophrenic patients were significantly elevated compared to non-psychotic healthy controls, and the differences were very significant in both groups (p-value 5.22E-05).
TABLE 4 results of PPARgamma levels in serum of schizophrenic patients and healthy controls
| HCs | schizophrenia | p value | |
| Sample size (n) | 79 | 166 | - |
| Mean value.+ -. Standard error (ng/L) | 4.51±4.27 | 4.99±3.19 | 3.56E-22 |
As can be seen from table 4 and fig. 3, pparγ levels in serum of schizophrenic patients were significantly elevated compared to non-psychotic healthy controls, and the differences were very significant in both groups (p-value 3.56E-22).
Fig. 4 shows that the area under the ROC curve of the model in the training set is 0.9489, and the area under the ROC curve of the model in the test set is 0.9609, both of which are between 0.9 and 1, indicating excellent results for the working characteristics of subjects constructing the model at levels of total cholesterol, IDH2 and pparγ in the training set. It is proved that the total cholesterol, IDH2 and PPARgamma can be used as the joint diagnosis marker of the schizophrenia, and provide effective basis for clinical diagnosis of the schizophrenia.
Experimental results show that total cholesterol, IDH2 and PPARgamma can be used for clinically assisting diagnosis of schizophrenia. And through model establishment, it is proved that total cholesterol, IDH2 and PPARgamma can be used as joint markers of schizophrenia, and effective basis is provided for diagnosing schizophrenia.
In summary, the kit and the risk screening system of the invention can screen the risk degree of the population to be tested for schizophrenia by detecting the levels of total cholesterol, IDH2 and PPARy in peripheral serum: if total cholesterol levels are low and protein levels of IDH2 and pparγ are high, the risk of having schizophrenia is high; if the total cholesterol level is high and the protein levels of IDH2 and pparγ are low, the risk of having schizophrenia is low. In addition, by constructing a model, the invention proves that the total cholesterol, IDH2 and PPARgamma can be used as joint diagnosis markers of the schizophrenia, provides effective basis for assisting clinical diagnosis of the schizophrenia, and has good clinical application prospect.
Claims (10)
- Use of idh2 protein, total cholesterol and/or ppary protein for the preparation of a marker for risk screening for schizophrenia.
- 2. Use of a reagent for detecting total cholesterol concentration, IDH2 protein expression level and/or pparγ protein expression level in a blood sample for the preparation of a kit, system and/or device for screening for risk of developing schizophrenia.
- 3. Use according to claim 2, wherein the blood sample is blood, serum or plasma, preferably human peripheral blood serum; the reagent includes a reagent for enzyme-linked immunosorbent assay, a reagent for immunoblotting, a reagent for immunoelectrophoresis, a reagent for tissue immunostaining, a reagent for immunoprecipitation analysis, a reagent for radioimmunoassay, a reagent for complement fixation analysis, a reagent for fluorescence-activated cell sorting, a reagent for mass analysis, or a reagent for protein microarray.
- 4. A kit for screening for the risk of developing schizophrenia, characterized in that it comprises reagents for detecting the concentration of total cholesterol, the expression level of IDH2 protein and/or the expression level of pparγ protein in a blood sample.
- 5. Kit according to claim 4, wherein the blood sample is blood, serum or plasma, preferably human peripheral blood serum; the reagent includes a reagent for enzyme-linked immunosorbent assay, a reagent for immunoblotting, a reagent for immunoelectrophoresis, a reagent for tissue immunostaining, a reagent for immunoprecipitation analysis, a reagent for radioimmunoassay, a reagent for complement fixation analysis, a reagent for fluorescence-activated cell sorting, a reagent for mass analysis, or a reagent for protein microarray, preferably a reagent for enzyme-linked immunosorbent assay.
- 6. A system for screening for risk of developing schizophrenia, comprising: the device comprises the following modules:and a data acquisition module: obtaining the total cholesterol concentration, IDH2 protein expression level and/or PPARgamma expression level in the blood sample;a database module: the clinical characteristics of healthy human bodies and schizophrenic human bodies and the total cholesterol concentration in blood samples are used for forming a database by the IDH2 protein expression level and/or PPARgamma expression level data, and the database is randomly split into a training set and a testing set;a machine learning module: constructing a random forest model;training module: training the random forest model by using a training set to obtain a trained random forest model;and a testing module: verifying the trained random forest model by using the test set;and a result output module: outputting the result of high or low risk of developing schizophrenia.
- 7. The system of claim 6, wherein the blood sample is blood, serum or plasma, preferably human peripheral blood serum; the clinical characteristics include age, gender and body mass index BMI.
- 8. A method of constructing a system as claimed in claim 6 or 7, comprising the steps of:(1) Constructing a data acquisition module for inputting data of total cholesterol concentration, IDH2 protein expression level and/or PPARgamma expression level;(2) Collecting clinical characteristics of natural people with healthy and schizophrenia and total cholesterol concentration in blood samples, IDH2 protein expression level and/or PPARgamma expression level data, and constructing a database module; randomly splitting data in a database into a training set and a testing set;(3) Constructing a random forest model by adopting a random forest algorithm to obtain a machine learning module;(4) Constructing a training module for analyzing and training the random forest model by adopting a training set;(5) Constructing a test module for verifying and optimizing the trained random forest model by using the test set;(6) An output module that outputs the calculation result of the machine learning module is constructed.
- 9. A device for screening for risk of developing schizophrenia, characterized in that: comprises the following devices:1) A detection device; the detection device is internally provided with reagents for detecting the total cholesterol concentration, the IDH2 protein expression level and the PPARgamma protein expression level in a blood sample;2) Analysis device: the analysis device is internally provided with a data input port for receiving the detection result of the detection device;the analysis model Y=1/(1+e) is built in the analysis device (1.634*TC-0.00107*IDH2-0.03664*PPARγ+10.883 ) Based on the total cholesterol concentration, IDH2 protein expression level and pparγ expression level, a schizophrenia disease probability Y is calculated for discriminating the risk of developing schizophrenia.
- 10. The device according to claim 9, wherein the blood sample is blood, serum or plasma, preferably human peripheral blood serum; a Y greater than 0.5 indicates a high risk of developing schizophrenia, and a Y less than 0.5 indicates a low risk of developing schizophrenia.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202310981057.3A CN117007822A (en) | 2023-08-04 | 2023-08-04 | Marker for screening risk of schizophrenia and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202310981057.3A CN117007822A (en) | 2023-08-04 | 2023-08-04 | Marker for screening risk of schizophrenia and application thereof |
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