阅读说明：本技术 测试受试者患有肝癌可能性的系统及方法 (System and method for testing possibility of liver cancer of subject ) 是由 鲁凤民 姚明解 许强 于 2021-08-13 设计创作，主要内容包括：本发明公开一种测试受试者患有肝癌可能性的系统及方法。该系统包括数据采集模块,其用于获取受试者的性别、年龄、异常凝血酶原(DCP)和甲胎蛋白(AFP)的数据；数据处理模块,其用于对所述数据采集模块中获取的数据进行处理,包括对DCP和AFP数据分别取对数函数,并进一步分别对性别、年龄、以及取对数函数后的DCP和AFP设置权重,由此计算评估值P(Y)。本发明的系统和方法解决了单个指标对肝癌的预测不能满足临床需求的问题。此外,本发明的系统能够以显著提高对肝癌筛查的灵敏度和特异度。(The invention discloses a system and a method for testing the possibility that a subject suffers from liver cancer. The system includes a data acquisition module for acquiring data of gender, age, abnormal prothrombin (DCP) and alpha-fetoprotein (AFP) of a subject; and the data processing module is used for processing the data acquired in the data acquisition module, and comprises the steps of respectively taking a logarithmic function for the DCP and AFP data, and further respectively setting weights for the gender, the age and the DCP and AFP after taking the logarithmic function, so as to calculate the evaluation value P (Y). The system and the method of the invention solve the problem that the prediction of the liver cancer by a single index cannot meet the clinical requirement. In addition, the system of the invention can obviously improve the sensitivity and specificity of screening liver cancer.)

1. A system for testing the likelihood that a subject has liver cancer, comprising:

a data acquisition module for acquiring data of gender, age, abnormal prothrombin DCP and alpha fetoprotein AFP of a subject;

and the data processing module is used for processing the data acquired in the data acquisition module, and comprises the steps of respectively taking a logarithmic function for the DCP and AFP data, and further respectively setting weights for the gender, the age and the DCP and AFP after taking the logarithmic function, so as to calculate the evaluation value P (Y).

2. The system of claim 1, wherein the evaluation value P (Y) is calculated using a model comprising,

，

wherein e is 2.71828, and β 0 represents the natural logarithm of the ratio of the occurrence probability of Y =1 to Y =0 in the absence of independent variables, i.e., when the gender, age, DCP, and AFP all take 0; the value range of beta 1 is 1.122 +/-0.269, the value range of beta 2 is 0.073 +/-0.008, the value range of beta 3 is 2.660 +/-0.213, and the value range of beta 4 is 0.578 +/-0.103.

3. The system of claim 2, wherein β 0 is in the range of-11.111 ± 0.656.

4. The system of claim 1, wherein the liver cancer comprises hepatocellular carcinoma.

5. The system of claim 4, wherein the hepatocellular carcinoma comprises an HBV-associated hepatocellular carcinoma.

6. The system of claim 1, wherein when the evaluation value p (y) is 0.28 or more, the subject is tested as a population at high risk of liver cancer, and the larger the evaluation value, the higher the risk.

7. The system of claim 1, wherein when the evaluation value P (Y) is 0.19 or more, the subject is tested as a population at high risk of developing early liver cancer, and the larger the evaluation value, the higher the risk.

8. The system of claim 1, further comprising a result display module for visually displaying the calculated evaluation value p (y).

9. The system of claim 1, wherein the data acquisition module is capable of acquiring diagnosis and treatment data from a hospital information system or uploading relevant data by the subject himself/herself, and then sending the diagnosis and treatment data to the data processing module.

10. A method for testing the likelihood that a subject has liver cancer, comprising the steps of:

a data acquisition step comprising acquiring data of sex, age, abnormal prothrombin DCP and alpha fetoprotein AFP of the subject, wherein the DCP and AFP data are acquired with reagents;

a data processing step including processing the acquired data, including taking a logarithmic function for the DCP and AFP data, respectively, and further setting weights for the gender, the age, and the DCP and AFP after taking the logarithmic function, respectively, thereby calculating the evaluation value p (y).

11. A computer-readable storage medium, having stored thereon a computer program which, when executed by a processor, implements the method of testing the likelihood of a subject having liver cancer according to claim 10.

12. An electronic device, comprising: a processor; and

a memory for storing executable instructions of the processor;

wherein the processor is configured to perform the method of testing the likelihood of a subject having liver cancer according to claim 10 via execution of the executable instructions.

Technical Field

The invention relates to the field of biomedicine, in particular to a system and a method for testing the possibility of a subject suffering from liver cancer.

Background

Primary Liver Cancer (PLC) is the sixth most common malignancy in humans, the third leading cause of cancer-related deaths worldwide. The pathogenesis of liver cancer is not clear, and epidemiological studies prove that about 80 percent of liver cancers have Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection background, and other risk factors comprise alcoholic liver diseases, non-alcoholic fatty liver diseases, food polluted by aflatoxin after long-term intake and the like. Cirrhosis of the liver due to various causes is a major risk factor for the development of HCC. Different from Western countries such as Europe and America, China mainly takes HBV infection as a main factor. Among patients with liver cirrhosis and liver cancer in our country, the proportion caused by HBV infection is 77% and 86%, respectively. At present, with the wide development of antiviral treatment, the number of end-stage liver diseases such as liver cirrhosis, liver failure and the like caused by HBV infection is obviously reduced, but the incidence of liver cancer is not obviously reduced, and the liver cancer related to HBV infection is still one of common malignant tumors in China.

Early symptoms are not obvious in liver cancer patients, but most of the liver cancer patients are in the middle and late stages at the time of diagnosis, and the optimal treatment opportunity is missed. Currently, liver cancer treatment modalities mainly include: the liver cancer still has the characteristics of easy metastasis and relapse, high mortality rate and the like along with the improvement of diagnosis and treatment means and the screening and monitoring of high risk groups. In addition, although surgical resection and liver transplantation are important means for achieving effective treatment of HCC, the 5-year overall survival rate is still low, and the survival prognosis of patients is seriously affected. Therefore, early screening and diagnosis of HCC is imminent. Although the screening forms for HCC vary from guideline to guideline, single Ultrasound (US) or US combined with serum alpha-fetoprotein (AFP) examinations are currently performed every 6 months for high risk groups, which is still the HCC screening monitoring protocol recommended in most guidelines.

On the other hand, serum AFP is still the most frequently used serological marker for diagnosing HCC in clinic, but its sensitivity and specificity for diagnosing HCC are not good enough. Foreign guidelines do not recommend serum AFP as a screening diagnostic for HCC. An alpha-fetoprotein (Lens culinaris agglutinin-reactive fraction of AFP, AFP-L3) is one of the subtypes of AFP, and researches show that the sensitivity of liver cancer diagnosis can be improved by combining AFP with AFP-L3%. Abnormal prothrombin (DCP), also known as vitamin K deficient or antagonist ii induced protein (PIVKA ii), forms abnormal prothrombin in cancer cells due to the lack of post-translational carboxylation of prothrombin. Compared with other tumor serological indexes, the DCP has better specificity in diagnosing liver cancer and has better diagnostic value for small liver cancer.

Based on the above background, there is a need in the art to develop a method for predicting the risk of developing liver cancer. The current single index can not meet the clinical requirement on liver cancer prediction, so that the development of a convenient, quick and easily-popularized system is crucial to screening and monitoring HCC.

Disclosure of Invention

In response to the problems of the prior art, the present invention provides systems and methods for testing a subject for the likelihood of having liver cancer. The system comprises a data acquisition module and a data processing module for calculating liver cancer of the subject, so that convenient and quick HCC screening and monitoring are realized. Specifically, the present invention includes the following.

In a first aspect of the present invention, there is provided an assessment system for testing the likelihood that a subject has liver cancer, comprising:

a data acquisition module for acquiring data of gender, age, abnormal prothrombin DCP and alpha fetoprotein AFP of a subject;

and the data processing module is used for processing the data acquired in the data acquisition module, and comprises the steps of respectively taking a logarithmic function for the DCP and AFP data, and further respectively setting weights for the gender, the age and the DCP and AFP after taking the logarithmic function, so as to calculate the evaluation value P (Y).

According to the system for testing the possibility of liver cancer of the subject, the evaluation value P (Y) is preferably calculated by using the following model,

，

wherein e is 2.71828, and β 0 represents the natural logarithm of the ratio of the occurrence probability of Y =1 to Y =0 in the absence of independent variables, i.e., sex, age, DCP, AFP all take 0; the value range of beta 1 is 1.122 +/-0.269, the value range of beta 2 is 0.073 +/-0.008, the value range of beta 3 is 2.660 +/-0.213, and the value range of beta 4 is 0.578 +/-0.103.

According to the system for testing the possibility of liver cancer of the subject, the value of beta 0 is preferably-11.111 +/-0.656.

The system for testing the likelihood that a subject has liver cancer according to the present invention preferably, the liver cancer includes but is not limited to hepatocellular carcinoma.

The system for testing the likelihood that a subject has liver cancer according to the present invention preferably comprises, but is not limited to, HBV-associated hepatocellular carcinoma.

According to the system for testing the possibility of liver cancer of the subject, preferably, when the evaluation value P (Y) is 0.28 or more, the subject is tested as a population at high risk of liver cancer.

According to the system for testing the possibility of liver cancer of the subject, preferably, when the evaluation value P (Y) is 0.19 or more, the subject is tested as a population at high risk of liver cancer in early stage.

The system for testing the possibility of liver cancer of a subject according to the present invention preferably further comprises a result display module for visually displaying the calculated evaluation value p (y).

According to the system for testing the possibility of liver cancer of the subject, preferably, the data acquisition module can acquire diagnosis and treatment data from a hospital information system, and then send the diagnosis and treatment data to the data processing module.

In a second aspect of the present invention, there is provided a method of testing the likelihood that a subject has liver cancer, comprising the steps of:

a data acquisition step comprising acquiring data of sex, age, abnormal prothrombin DCP and alpha fetoprotein AFP of the subject, wherein the DCP and AFP data are acquired with reagents;

a data processing step including processing the acquired data, including taking a logarithmic function for the DCP and AFP data, respectively, and further setting weights for the gender, the age, and the DCP and AFP after taking the logarithmic function, respectively, thereby calculating the evaluation value p (y).

In a third aspect of the present invention, there is provided a computer readable storage medium having stored thereon a computer program which, when executed by a processor, implements the method of the second aspect for testing a subject for a likelihood of having liver cancer.

In a fourth aspect of the present invention, there is provided an electronic apparatus comprising: a processor; and

a memory for storing executable instructions of the processor;

wherein the processor is configured to execute, via execution of the executable instructions, the method of the second aspect for testing the likelihood that a subject has liver cancer.

Drawings

Figure 1 is a flow chart of HCC-related diagnostic criteria.

FIG. 2 is a ROC curve illustrating the diagnosis of HCC by serological markers alone, in combination with detection and GADA model.

FIG. 3 is a ROC curve for another exemplary serological marker alone, in combination with detection and GADA model for the diagnosis of HCC.

Detailed Description

Reference will now be made in detail to various exemplary embodiments of the invention, the detailed description should not be construed as limiting the invention but rather as a more detailed description of certain aspects, features and embodiments of the invention.

It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. Further, for numerical ranges in this disclosure, it is understood that the upper and lower limits of the range, and each intervening value therebetween, is specifically disclosed. Every smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in a stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference herein for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.

In the present invention, the system for testing the possibility of liver cancer in a subject comprises: a data acquisition module for acquiring gender, age, abnormal prothrombin, alpha fetoprotein for a subject; and the risk module is used for calculating the data acquired by the data acquisition module so as to calculate the risk value of the possibility that the subject has the liver cancer, and grouping the subjects according to the grouping parameters prestored in the system so as to judge the risk of the subject suffering from the liver cancer. The concrete description is as follows:

after analyzing up to 16 known indexes, the inventor finds that an excellent model for predicting liver cancer can be constructed by the combination of four indexes of gender, age, abnormal prothrombin DCP and alpha fetoprotein AFP of a subject. Through clinical data analysis, the gender and the age are found to have statistical significance in liver cancer diagnosis, and the test method based on the factors can remarkably improve the sensitivity and specificity of liver cancer detection (such as HCC detection), and has the efficacy obviously superior to other indexes in a single or any combined detection mode.

The data sources of the 4 index data in the data acquisition module of the present invention preferably can be from batch imported table data, data acquired from a Hospital Information System (HIS), inspection reports, Electronic Medical Record (EMR) data, Picture Archiving and Communication Systems (PACS) data, Hospital laboratory Information management System (LIS) data, and the like.

Optionally, the data may further include batch imported data, data input by multiple terminals such as a smartphone terminal, data uploaded by photographing an original medical record, follow-up data input by a patient WeChat terminal, and the like.

The data can be collected through various possible collection ways, such as a blood detection instrument, a doctor, a computer used by a nurse for work, a smart phone used by a patient and the like; the detection device is based on the known abnormal prothrombin and alpha fetoprotein detection methods and has certain data processing and storage capacities. Such detection devices include, but are not limited to, the Roche cobalt e601 full-automatic electrochemical immunoassay analyzer, the LUMIPULSE G1200 full-automatic immunoassay analyzer.

In the invention, the function of the data processing module comprises respectively taking a logarithmic function for the DCP and AFP data, and further respectively setting weights for the DCP and AFP after taking the logarithmic function, thereby calculating the evaluation value P (Y). Specifically, the evaluation value p (y) can be calculated by, for example, the GADA model formula:

。

those skilled in the art will appreciate that the various exemplary embodiments of the invention described herein may be implemented in software, or in combination with hardware as necessary. Therefore, embodiments according to the present invention may be embodied in the form of a software product, which may be stored in a non-volatile storage medium (which may be a CD-ROM, a usb disk, a removable hard disk, etc.) or on a network, and includes instructions for causing a computing device (which may be a personal computer, a server, a mobile terminal, or a network device, etc.) to perform a method according to the present invention.

In an exemplary embodiment, the program product of the present invention can employ any combination of one or more readable media. The readable medium may be a readable signal medium or a readable storage medium. The readable storage medium may be, for example, but not limited to, an electronic, magnetic, optical, electromagnetic, infrared, or semiconductor system, apparatus, or device, or any combination of the foregoing. More specific examples of readable storage media include, but are not limited to: an electrical connection having one or more wires, a portable disk, a hard disk, a Random Access Memory (RAM), a read-only memory (ROM), an erasable programmable read-only memory (EPROM or flash memory), an optical fiber, a portable compact disc read-only memory (CD-ROM), an optical storage device, a magnetic storage device, or any suitable combination of the foregoing.

In the present invention, a computer readable signal medium may comprise a propagated data signal with readable program code embodied therein, either in baseband or as part of a carrier wave. Such a propagated data signal may take many forms, including, but not limited to, electro-magnetic, optical, or any suitable combination thereof. A readable signal medium may also be any readable medium that is not a readable storage medium and that can communicate, propagate, or transport a program for use by or in connection with an instruction execution system, apparatus, or device.

Correspondingly, based on the same inventive concept, the invention also provides the electronic equipment.

In an exemplary embodiment, the electronic device is in the form of a general purpose computing device. Components of the electronic device may include, but are not limited to: at least one processing unit, at least one memory unit, and a bus connecting different system components including the memory unit and the processing unit.

Wherein the storage unit stores a program code, which can be executed by the processing unit, wherein the processing unit at least comprises the data processing module of the invention, so that the processing unit executes the method of the invention. The memory unit may include a readable medium in the form of a volatile memory unit, such as a random access memory unit (RAM) and/or a cache memory unit, and may further include a read only memory unit (ROM).

The storage unit may also include a program/utility having a set (at least one) of program modules including, but not limited to: an operating system, one or more application programs, other program modules, and program data, each of which, or some combination thereof, may comprise an implementation of a network environment.

The bus may be any of several types of bus structures including a memory unit bus or memory unit controller, a peripheral bus, an accelerated graphics port, a processing unit, or a local bus using any of a variety of bus architectures.

The electronic device may also communicate with one or more external devices (e.g., keyboard, pointing device, bluetooth device, etc.), with one or more devices that enable a user to interact with the electronic device, and/or with any devices (e.g., router, modem, etc.) that enable the electronic device to communicate with one or more other computing devices.

Such communication may be through an input/output (I/O) interface. Also, the electronic device may communicate with one or more networks (e.g., a Local Area Network (LAN), a Wide Area Network (WAN), and/or a public network, such as the internet) via a network adapter. The network adapter communicates with other modules of the electronic device over the bus. It should be appreciated that although not shown in the figures, other hardware and/or software modules may be used in conjunction with the electronic device, including but not limited to: microcode, device drivers, redundant processing units, external disk drive arrays, RAID systems, tape drives, and data backup storage systems, among others.

The diagnostic value of the system or method of the invention can be assessed by, for example, calculating an evaluation index such as the area under the working characteristic curve (AUC), sensitivity, specificity, etc., of the subject. Where AUC, also known as the area under the receiver operating characteristic curve, is defined as the area under the ROC curve bounded by coordinate axes, the area having a value ranging between 0.5 and 1. The closer the AUC is to 1.0, the higher the authenticity of the assay. Wherein, the AUC has lower accuracy when being 0.5 to 0.7, certain accuracy when the AUC is 0.7 to 0.9, and higher accuracy when the AUC is more than 0.9. And when the value is equal to 0.5, the authenticity is lowest, and the application value is not high. In particular embodiments, the system of the invention has an area under the working characteristic curve of the subject of not less than 0.860, also preferably not less than 0.900, such as 0.920, 0.930, 0.940, 0.950, 0.960, 0.970, 0.980, even 0.990.

Examples

1. Criteria and basic information for study inclusion

Diagnostic and grouping criteria for subjects

Diagnosis of CHB: according to the diagnostic criteria of chronic hepatitis B prevention and treatment guidelines (2015 updated), the ALT is continuously or repeatedly increased or liver histology lesions are present, namely hepatitis B virus surface antigen (HBsAg) and/or hepatitis B virus DNA are positive for more than 6 months.

HBV-related cirrhosis: firstly, the etiology shows clear HBV infection evidence; ② clinical diagnosis or histology suggest evidence of cirrhosis. Other common causes of liver cirrhosis such as HCV infection, alcohol and drugs are clarified or excluded by medical history or corresponding examination. Clinically, the liver cirrhosis is divided into five stages according to the liver cirrhosis complication. Stage 1: no varicose veins and ascites; stage 2: varicose veins, no bleeding and ascites; stage 3: ascites, no bleeding with or without varicose veins; stage 4: bleeding with or without ascites; stage 5: sepsis. In which stage 1 to 2 is compensatory cirrhosis and stage 3 to 5 is uncompensated cirrhosis. Imaging, biochemical or hematological examination of compensated cirrhosis of the liver has evidence of hepatocyte synthesis dysfunction or portal hypertension, or histology is consistent with diagnosis of cirrhosis, but there are no serious complications associated with decompensated cirrhosis; patients with liver cirrhosis in the decompensation stage can have other serious complications such as esophageal and gastric variceal bleeding, hepatic encephalopathy, ascites and the like.

HCC-related diagnostic criteria: the patients with accurate pathological diagnosis or clinical diagnosis of liver cancer are further verified and diagnosed by imaging, and the diagnosis standard of primary liver cancer diagnosis and treatment standard (2017), which is specifically shown in the diagnosis flow chart 1, is met.

2. Statistical analysis

And selecting a proper description statistical analysis method according to the distribution characteristics of the variables. For the data satisfying normal distribution, the average number and standard deviation are used in statistical descriptionShowing that the comparison among a plurality of groups adopts analysis of variance, and the comparison between two groups adopts Student-Newman-Keul method test; continuously variable which does not meet normal distribution is represented by using median (interquartile interval), and the comparison among groups is tested by using Mann-whitney U; classification transformerThe amounts are expressed as frequency (%) and the comparisons between groups are by χ²And (6) checking. A Logistic regression model is adopted to carry out regression analysis on 16 indexes of age, sex, AFP-L3%, DCP, laminin, C-reactive protein, transferrin, ceruloplasmin, alkaline phosphatase, gamma-glutamyltranspeptidase, lymphocyte count, international standardized ratio, platelet count, APRI, FIB-4 and the like of a patient to establish a GADA model. And (3) calculating the area under the working characteristic curve (AUC), sensitivity, specificity and the like of the testee to evaluate each diagnosis index and the efficiency of the diagnosis model, and comparing the areas under the curve by adopting a Delong method. The significance test is a two-sided test, with test level α = 0.05. Statistical analysis was performed using SPSS 24.0 and Medcalc.

3. Basic information and clinical characteristics of patients

The study included a total of 2190 chronic hepatitis B virus infected patients. The analysis includes 989 chronic hepatitis B patients, 575 chronic hepatitis B related cirrhosis patients and 626 chronic hepatitis B virus infection related liver cancer patients. Further analysis shows that 692 cases (69.97%) of male chronic hepatitis B patients, 426 cases (74.09%) of male cirrhosis patients, 556 cases (88.82%) of male liver cancer patients and the proportion of the male population in different liver disease cases have statistical significance (the proportion of the male population in different liver disease cases is shown in the specification (the formula is shown in the specification))P<0.001) and gradually increases with the proportion of the severity of the disease. The mean age of patients with chronic hepatitis B is 40.25 + -12.71 years, the mean age of patients with liver cirrhosis is 52.97 + -11.48 years, the mean age of patients with liver cancer is 55.00 + -11.79 years, and the ages of patients are statistically different in different groups (1)P<0.001) and the highest age among patients with liver cancer, see in particular the table below.

TABLE 1 comparison of the basic information of the subjects and clinical indices of different patients with liver disease

4. Establishment of GADA model and comparison of diagnosis value of GADA model to liver cancer

4.1 creation of GADA model

By analyzing 16 indexes such as age, sex, AFP-L3%, DCP, laminin, C-reactive protein, transferrin, ceruloplasmin, alkaline phosphatase, gamma-glutamyltranspeptidase, lymphocyte count, international normalized ratio, platelet count, APRI and FIB-4 of a patient, the combination of the four indexes of sex, age, DCP and AFP is confirmed to be particularly valuable for liver cancer prediction. The specific model construction process is shown in tables 2 and 3. And taking a logarithmic function on the DCP and the AFP to obtain a GADA (Gamma-hepatic dysfunction syndrome) fitting model of the HCC. The GADA model formula is:

wherein e takes a value of 2.71828, β 0 is a natural logarithm of a ratio of occurrence probability of Y =1 and Y =0 in the absence of independent variables, i.e., sex, age, DCP and AFP all take 0, and the value range of the study is (-11.111 ± 0.656), optimally-11.111, β 1 takes a value range (1.122 ± 0.269), optimally 1.122; the value range of beta 2 is (0.073 +/-0.008), and the optimal value range is 0.073; the value range of beta 3 is (2.660 +/-0.213), and the optimal value range is 2.660; the value range of beta 4 is (0.578 +/-0.103), and the optimal value range is 0.578. The optimal model is as follows:

。

TABLE 2GADA model-related parameters

Note: gender female =0, male = 1.

TABLE 3 relevant parameters not included in the equations

4.2 evaluation of the value of the GADA model on HCC

AUROC for diagnosing HBV-HCC by independently detecting AFP, AFP-L3% and DCP in serum is 0.762(95%CI: 0.744, 0.780)、0.748(95%CI: 0.729, 0.766)、0.891(95%CI0.877, 0.903), the diagnosis efficiency of DCP is optimal, and the AUC for diagnosing HBV-related HCC is higher than AFP and AFP-L3% (P is both<0.001). Further results showed that AFP at an optimum cut-off of 10.5 ng/ml corresponds to a sensitivity and specificity of 71.57% and 69.37%, respectively. When 20 ng/ml, which is a clinically common cut-off value, is used, the corresponding sensitivity and specificity are 64.22% and 75.32%, respectively. AFP-L3% at an optimum cutoff of 2.03%, the corresponding sensitivity and specificity were 71.73% and 69.18%, respectively. When 10% was used as the cutoff value, the corresponding sensitivity and specificity were 36.10% and 94.82%, respectively. The sensitivity and specificity of DCP were 78.27% and 94.05% respectively at an optimal cut-off of 51 mAU/mL. Similarly, when the clinically recommended cutoff value of 40ng/ml was used, the corresponding sensitivity and specificity were 81.79% and 88.36%, respectively. The comparison shows that no matter the optimal cut-off value obtained by using the ROC curve in the research or the diagnosis threshold value recommended clinically, the AUC of HCC diagnosed by the DCP is obviously higher than that of AFP and AFP-L3%, and the DCP obviously improves the sensitivity of HCC diagnosis under the condition of maintaining equivalent specificity (AFP and AFP-L3%).

We further evaluated the efficacy of AFP, AFP-L3% and DCP combined diagnosis, and the results showed that AUC for liver cancer diagnosis by combined detection of each index is closer to that of single DCP, and that the efficacy of HCC diagnosis by DCP combined AFP-L3 detection is highest, with AUC of 0.902(95%CI: 0.888, 0.914) but the difference is not statistically significant (P) compared to DCP alone or in combination with other indicators>0.05). The efficacy of DCP combined with other indexes for detecting and diagnosing liver cancer is obviously superior to AFP and AFP-L3% (P)<0.05). The GADA model has a diagnostic value AUC of 0.940(0.929, 0.949) for liver cancer, a Jordan index of 0.746, and a cut-off of 0.28 corresponding to sensitivity and specificity of 82.57% and 92.01%, respectively. The comparison shows that the efficiency of GADA diagnosing liver cancer is obviously superior to that of other indexes (P is all detected separately or jointly)<0.01). ROC curves for the serological markers alone, in combination with detection and the GADA model for the diagnosis of HCC see figure 2. AFP, AFP-L3%The diagnostic value of DCP alone, combined assay and GADA model for HBV-associated HCC is shown in the table below.

TABLE 4 diagnostic value of different protocols for HBV-associated HCC

4.3 diagnostic value of AFP, AFP-L3%, DCP single index, combination and GADA model on early liver cancer

In addition to comparing the diagnostic value of AFP, AFP-L3% and DCP for total liver cancer, the study further explored their diagnostic efficacy for early stage liver cancer. The analysis result shows that the AUC of DCP for diagnosing early liver cancer is 0.761, which is obviously superior to AFP (0.761 vs 0.608, P <0.001) and AFP-L3% (0.761 vs 0.630, P < 0.001). In addition, when the cutoff value of the DCP is 42.78 ng/mL, the corresponding sensitivity and specificity are 59.90% and 89.77% respectively, compared with AFP and AFP-L3%, the sensitivity of the DCP for diagnosing liver cancer is higher than that of the DCP for diagnosing liver cancer on the premise of ensuring higher diagnosis accuracy, which has an important role in screening and auxiliary diagnosis of early liver cancer and can avoid missed diagnosis of part of early liver cancer patients. Further research shows that AUC of the DCP combined with other indexes for diagnosing liver cancer is obviously higher than AFP and AFP-L3% (P < 0.001); the AUC of the AFP-L3% combined DCP for diagnosing early liver cancer is better than that of other index combinations (P <0.001), the AUC of the AFP-L3% combined DCP is not obviously improved, but the sensitivity of the AFP-L3% combined DCP for diagnosing liver cancer is obviously higher than that of other indexes or combination forms. It is noted that the AUC for diagnosing early stage liver cancer in the GADA model is 0.862(0.845, 0.878), and when the cutoff threshold is 0.19, the sensitivity and specificity are 72.28% and 85.17%, respectively. The comparison shows that the GADA efficacy for diagnosing early liver cancer is also obviously superior to other indexes (P values are all less than 0.01) in a single or any combined detection mode, and the results are shown in Table 5 and FIG. 3.

TABLE 5 value of different protocols for diagnosing early stage liver cancer

While the present invention has been described with reference to exemplary embodiments, it is to be understood that the invention is not limited to the disclosed exemplary embodiments. Many modifications and variations may be made to the exemplary embodiments of the present description without departing from the scope or spirit of the present invention. The scope of the claims is to be accorded the broadest interpretation so as to encompass all modifications and equivalent structures and functions.