CN113504369A - Individual correction formula for eliminating positive interference of serum nerve specific enolase detection caused by specimen hemolysis and application thereof - Google Patents
Individual correction formula for eliminating positive interference of serum nerve specific enolase detection caused by specimen hemolysis and application thereof Download PDFInfo
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- G01N33/57488—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds identifable in body fluids
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Abstract
The invention belongs to the field of tumor marker detection, and particularly relates to an individualized correction formula for eliminating positive interference of serum nerve specific enolase detection caused by specimen hemolysis and application thereof, wherein the formula comprises the following steps: NSEcorr＝NSEmeas‑0.889×R×HImeas-3.159 xr; the formula is used for correcting the actually detected serum NSE value, so that the influence of high serum NSE value caused by hemolysis can be reduced, the serum NSE value calculated by the individual correction formula is closer to the true value of the serum NSE, and the accuracy of serum NSE detection is improved; the invention further provides application of the individual correction formula in diagnosis, recurrence metastasis monitoring and curative effect evaluation of lung cancer and neuroblastoma, and can effectively avoid interference or misleading of serum NSE false positive results on tumor diagnosis, recurrence metastasis monitoring and curative effect evaluation。
Description
Technical Field
The invention belongs to the field of tumor marker detection, and particularly relates to an individualized correction formula for eliminating positive interference of serum nerve specific enolase detection caused by specimen hemolysis and application thereof.
Background
The Neural Specific Enolase (NSE) containing gamma subunits is a main tumor marker of small cell lung cancer and neuroblastoma, and plays an irreplaceable important role in the aspects of diagnosis, curative effect judgment and recurrence metastasis monitoring of the two tumors. The NSE content of the serum of a plurality of small cell lung cancer patients is obviously increased, and the NSE content of the serum of a part of non-small cell lung cancer patients is also slightly increased. An increase in the amount of NSE in serum may indicate recurrent metastasis of the tumor months or even more than one year earlier than imaging. The NSE has short biological half-life period in human body, so the NSE has sensitive response to the treatment effect and is an important marker for judging the treatment effect.
Accurate serum NSE detection results can ensure the smooth proceeding of clinical diagnosis and treatment activities. However, the NSE concentration in the serum is easily affected by hemolysis of the blood sample, because the γ subunit NSE contained in the red blood cells is about thirty-six times of that in the serum, and improper operation of various steps before the blood sample is collected, transported, placed, centrifuged, etc., may cause the red blood cells to be broken, release NSE into the serum, and cause the increase of the serum NSE concentration, interference or misleading to clinical diagnosis and treatment. Because the content of NSE in the serum of normal people is very small (the reference value range is 0-16.3 mug/L), even if hemolysis which can not be identified by naked eyes, obvious false positive interference can be generated, and clinically, the clinical common result of the serum NSE test exceeds the reference value range, so that doctors and patients are questioned. Statistics show that the ratio of the hemolytic index of the serum sample of the hospitalized patient to the reference value range is about 32.6%. Furthermore, the numerical range of serum NSE concentration between 16.3 μ g/L and 50 μ g/L is very confusing in the clinical diagnosis of non-small cell lung cancer and small cell lung cancer, whether the NSE is derived from tumor cell release or specimen hemolysis is not distinguished, the ratio of the hemolysis index of the hospitalized patient serum specimen in the concentration interval higher than the reference value range is up to 45%, and the highest hemolysis index 183 is also present in the concentration interval. Therefore, accurate serum NSE results must be considered whether the sample is hemolyzed. The invention provides an individualized correction formula capable of eliminating NSE detection positive interference caused by specimen hemolysis and application thereof based on that a Roche biochemical immunoassay pipeline system (a Cobas c biochemical analysis series and a Cobas e immunoassay series) can detect serum NSE and serum hemolysis index and a laboratory transmission system can combine the information of the two.
Disclosure of Invention
In view of the problems identified in the background art, the present invention aims to provide an individualized correction formula for NSE detection results, which can eliminate false positive interference of serum NSE results caused by hemolysis of a specimen to be detected, and provides an application of the individualized correction formula in diagnosis, recurrence metastasis monitoring and efficacy evaluation of lung cancer and neuroblastoma as another object of the present invention.
Based on the purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides an individualized correction formula for eliminating positive interference in serum neural specific enolase detection caused by hemolysis of a specimen, specifically as follows:
NSEcorr＝NSEmeas-0.889×R×HImeas-3.159×R；
wherein NSEcorrThe serum NSE correction value is calculated by the individual correction formula; NSEmeasThe detection value of the serum NSE of the detected sample; HI (high-intensity)mensIs a specimen to be examinedA measurement value of the hemolytic index of (a); r is the ratio of NSE to HI of the red blood cells in the tested sample.
The individual correction formula provided by the invention can eliminate the increase of NSE detection value caused by hemolysis and avoid NSE false positive result, and the NSE correction value calculated by the formula can reflect the real serum NSE value.
Further, when HI is usedmeas5 or less or NSEmeasWhen the NSE is less than or equal to 16.3, the NSE does not need to be corrected by the individual correction formulameasCorrecting; when HI is presentmeas> 5 and NSEmeasAt > 16.3, the NSE is corrected using the above individualized correction formulameasCorrection to obtain NSEcorr。
The reference value range of the NSE content of the serum of a normal person is 0-16.3 mug/L, the reference value range of the haemolysis index HI of the serum of the normal person is 0-5, and the median value is 2; so when HI meas5 or less or NSEmeasWhen the value is less than or equal to 16.3, the detected serum is in a normal hemolytic index range or the detected serum NSE is in a normal reference range, and the detection value of the serum NSE does not need to be corrected by using an individualized correction formula. When HI is presentmeas> 5 and NSEmeasIf the value is more than 16.3, the hemolytic index in the abnormal range of the serum to be detected is shown, and the influence of hemolytic symptoms on the detection of NSE in the serum needs to be considered, so that the NSE needs to be corrected by the individualized correction formulameasCorrection to obtain NSEcorr。
In a second aspect, the present invention provides the use of the above-described individualized correction formula for the monitoring of recurrent metastases and the assessment of efficacy of lung cancer and neuroblastoma.
The serum NSE is an important marker of the lung cancer and the neuroblastoma, and the detection accuracy of the serum NSE directly influences the application effect of the marker in the relapse metastasis monitoring and the curative effect evaluation of the lung cancer and the neuroblastoma, so that the individual correction formula provided by the invention is adopted to correct the detection result of the serum NSE, the result capable of more truly reflecting the serum NSE value is obtained, the increase of the serum NSE detection result caused by hemolysis is favorably eliminated, the interference or misguidance of the serum NSE false positive result on the relapse metastasis monitoring and the curative effect evaluation of the tumor is effectively avoided, and the application effect of the serum NSE as the tumor marker is improved.
Further, based on the above application, when HI is usedmeas5 or less or NSEmeasWhen the NSE is less than or equal to 16.3, the NSE does not need to be corrected by the individual correction formulameasCorrecting; when HI is presentmeas> 5 and NSEmeasWhen the clinical requirement is more than 16.3, whether the NSE needs to be subjected to the individualized correction formula or not is evaluated according to the clinical requirementmeasCorrection to obtain NSEcorr。
Further, the clinical requirement evaluation refers to the NSE of the human body under test in the current testmeasWhether greater than the NSE of the human body to be detected in the last detectionmeas(ii) a If NSE detected this timemeasNSE less than last detectedmeasThen the NSE detected at this time does not need to be corrected by the individual correction formulameasCorrecting; if NSE detected this timemeasGreater than the most recently detected NSEmeasThen the individual correction formula is used to correct the NSE detected this timemeasCorrection to obtain NSEcorrReporting corrected NSEcorrAnd remark NSEmeasAnd HImeas。
Namely, when the NSE value of the serum of the tested human body shows a descending trend and shows no warning clinical significance, the individual correction formula is not needed to be used for carrying out the NSEmeasCorrected, reportable NSEmeasValue and notes hemolytic index HImeasAnd (4) finishing. When the NSE value of the serum of the tested human body shows an ascending trend, particularly when the increment exceeds 25 percent, the method has warning clinical significance, and the individual correction formula provided by the invention needs to be used for carrying out the NSEmeasCorrection is performed and the corrected NSE result (NSE) is reportedcorr) And remark NSEmeasAnd HImeas。
In a third aspect, the present invention provides the use of the above-described individualized correction formula in the diagnosis of lung cancer and neuroblastoma.
Further, based on the application, when HI is usedmeas5 or less or NSEmeasWhen the NSE is less than or equal to 16.3, the NSE does not need to be corrected by the individual correction formulameasCorrecting; when HI is presentmeas> 5 and NSEmeasAt > 16.3, the NSE is corrected using the above individualized correction formulameasCorrection to obtain NSEcorrReport NSEcorrAnd remark NSEmeasAnd HImeas。
Similarly, when HI ismeas5 or less or NSEmeasWhen the value is less than or equal to 16.3, the detected serum is in a normal hemolytic index range or the detected serum NSE is in a normal reference range, and the detection value of the serum NSE does not need to be corrected by using an individualized correction formula. When HI is presentmeas> 5 and NSEmeasIf the value is more than 16.3, the hemolytic index in the abnormal range of the serum to be detected is shown, and the influence of hemolytic symptoms on the detection of NSE in the serum needs to be considered, so that the NSE needs to be corrected by the individualized correction formulameasCorrection to obtain NSEcorrBy corrected serum NSE value (NSE)corr) The real NSE value in the serum can be reflected better, and a relatively reliable diagnosis result can be provided based on the result.
Compared with the prior art, the invention provides the individualized correction formula for eliminating the positive interference of the serum nerve specific enolase detection caused by specimen hemolysis, the actually detected serum NSE value is corrected by utilizing the formula, the influence of the higher serum NSE value caused by the hemolysis phenomenon can be reduced, the serum NSE value calculated by the individualized correction formula is closer to the true value of the serum NSE, and the accuracy of the serum NSE detection is improved. The invention further provides application of the individual correction formula in diagnosis, recurrence metastasis monitoring and curative effect evaluation of lung cancer and neuroblastoma, and interference or misleading of serum NSE false positive results on tumor diagnosis, recurrence metastasis monitoring and curative effect evaluation can be effectively avoided.
Drawings
FIG. 1 is a diagram illustrating the applicable conditions of the individualized correction formula according to the present invention.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples. It will be understood by those skilled in the art that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The test methods used in the examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are commercially available unless otherwise specified.
Example 1 construction of individualized correction formulas
The embodiment provides a method for constructing an individualized correction formula for eliminating positive interference of serum nerve specific enolase detection caused by specimen hemolysis, the individualized correction formula is obtained through a hemolysis excitation test, and the specific construction process is as follows:
s1: establishment of control serum hemolytic index reference value range: control sera were from healthy physical population and serum NSE results were within the reference range (0-16.3. mu.g/L). Factors causing erythrocyte disruption were strictly controlled in the pre-test steps (blood collection, transport and centrifugation), and serum Hemolysis Index (HI) was measured with a Cobas c 702 biochemical analyzer. Through statistical analysis, the range of the hemolysis index reference value is determined to be 0-5, and the median value is determined to be 2.
S2: determination of the erythrocyte NSE/HI ratio: taking a proper amount of red blood cells from a blood routine specimen of a detected human body, washing for three times, dissolving the red blood cells by distilled water to obtain a red blood cell dissolving solution, detecting the hemolytic index of the red blood cells by a Cobas c 702 biochemical analyzer, detecting the NSE concentration of the red blood cells by a Cobas e 602 immunoassay analyzer, wherein the ratio of the NSE concentration value to the hemolytic index is the NSE/HI ratio of the red blood cells of the detected human body.
S3: hemolysis challenge test: and (3) adding erythrocyte lysate into the serum samples of the control group, performing hemolysis excitation on the serum samples of the control group, and determining the hemolysis index HI and NSE concentrations after the hemolysis excitation.
S4: construction of an individualized correction formula: and carrying out nonlinear fitting on the NSE value of the serum of the control group, the NSE/HI ratio of the red blood cells, the NSE value after hemolysis excitation and the HI value to obtain the individualized correction formula. The specific formula is as follows:
NSEcorr＝NSEmeas-0.889×R×HImeas-3.159×R；
wherein NSEcorrThe serum NSE correction value is calculated by an individual correction formula; NSEmeasThe serum NSE detection value is obtained by detecting the sample serum after the excitation by a Roche electrochemiluminescence immunoassay system; HI (high-intensity)mensThe detected value of the Roche hemolytic index of the sample after the excitation is obtained; r is the ratio of NSE to HI of the red blood cells.
Example 2 clinical validation of individualized correction formulas
In this embodiment, an autologous control is used, and the accuracy of the NSE value obtained by the individual correction formula constructed in example 1 is evaluated by calculating the NSE value obtained by detecting after hemolysis challenge using the individual correction formula constructed in example 1 based on the serum NSE detection value with normal hemolysis index. The specific test process is as follows:
serum samples from 47 hospitalized patients were selected and all had normal hemolytic indices. Using an autologous control, baseline NSE values (covering the measurable range of reagent detection) were determined, followed by artificial hemolysis and a re-determination of post-hemolysis NSE values. The red blood cell NSE/HI ratio was determined from a blood routine from the same patient. The mean difference between the formulaically corrected NSE and pre-hemolytic baseline NSE values, analyzed by Bland-Altman, was 1.92%, the standard deviation of the difference was 5.23%, and the difference was independent of the magnitude of the hemolytic index. The 95% confidence limit for the mean difference ranged from-8.33% to 12.77%, which is less than the acceptable range for NSE test items (+ -20%). The above statistical analysis results show that: the performance of the individual correction formula of the invention has no difference with the performance of the original detection method. Namely, the serum NSE value calculated by the individual correction formula of the invention is close to the true value of the serum NSE, so that the influence of high serum NSE value caused by hemolysis can be reduced, and the accuracy of serum NSE detection can be improved.
Example 3 application of individualized correction formula to diagnosis, recurrence metastasis monitoring and efficacy assessment of lung cancer and neuroblastoma
This example provides the application of a personalized corrective formula to the monitoring of recurrent metastases and the assessment of efficacy of lung cancer and neuroblastoma, as shown in FIG. 1, when HI meas5 or less or NSEmeasWhen the NSE is less than or equal to 16.3, the NSE does not need to be corrected by the individual correction formulameasCorrecting; when HI is presentmeas> 5 and NSEmeasWhen the clinical requirement is more than 16.3, whether the NSE needs to be subjected to the individualized correction formula or not is evaluated according to the clinical requirementmeasCorrection to obtain NSEcorr. The clinical requirement evaluation refers to the NSE of the human body to be detected in the current detectionmeasWhether greater than the NSE of the human body to be detected in the last detectionmeas(ii) a If NSE detected this timemeasNSE less than last detectedmeasThen the NSE detected at this time does not need to be corrected by the individual correction formulameasCorrecting; if NSE detected this timemeasGreater than the most recently detected NSEmeasThen the individual correction formula is used to correct the NSE detected this timemeasCorrection to obtain NSEcorrReporting corrected NSEcorrAnd remark NSEmeasAnd HImeas。
Based on the above principle, the examination of the serum NSE results is divided into the following three cases:
1. the hemolytic index is normal: namely HImeasAnd (5) directly reporting the NSE detection result.
2. The hemolytic index is increased, but the NSE result is within the reference value range, i.e. HImeas＞5，NSEmeasLess than or equal to 16.3, the NSE detected is a safe value clinically, no correction is needed, the NSE value can be reported, and meanwhile, the hemolytic index value is remarked.
3. Increased hemolytic index and NSE value exceeding the reference value range, i.e. HImeas> 5 and NSEmeas> 16.3, clinical use in recurrence metastasis monitoring and efficacy assessment, if NSEmeasThe value is smaller than the last NSE detection result, the trend of lower and lower serum NSE is presented, no warning clinical significance is provided, no correction is needed, the NSE value can be reported, and the hemolytic index value is remarked(ii) a Clinically for recurrence metastasis monitoring and efficacy assessment, if the value is greater than the last NSE test, especially if it increases by more than 25%, there is a trend that serum NSE is higher and higher, with warning clinical significance, the present invention needs to use the individualized correction formula, report the corrected NSE results, and note the hemolytic index and the original NSE test value containing hemolytic effect. For diagnosis, it is necessary to use individualized formulas to report corrected NSE results and to note the hemolytic index and the original NSE test values containing hemolytic effects.
Example 4 specific application example of individualized correction formula
The embodiment provides a specific application example of the individualized correction formula in embodiment 1, and the specific process is as follows:
1. individualized index detection
(1) Serum NSE detection: the instrument adopts a Roche immunoassay analyzer cobas e series; the reagent adopts an Elecsys NSE detection kit.
(2) Serum hemolytic index HI assay: the instrument adopts a Roche immunoassay analyzer cobas c series; the reagent used was Serum Index Gen2(SI 2).
(3) Erythrocyte NSE/HI ratio determination: aspirate 20 μ L of red blood cells from a blood routine into a 20mL centrifuge tube, add 10mL of physiological saline, gently wash the red blood cells with a pipette, centrifuge at 1800 Xg for 5 minutes, decant the supernatant, and retain the bottom red blood cells. And (3) washing for three times to obtain concentrated red blood cells, adding 1.5ml of distilled water into the concentrated red blood cells, shaking and centrifuging to obtain red blood cell hemolysis solution, and respectively measuring NSE and HI of the red blood cell hemolysis solution to obtain the ratio of NSE to HI of the red blood cells.
And detecting certain serum NSE, hemolytic index HI and ratio of NSE/HI of erythrocytes of the patient by using the individual index detection.
2. Serum NSE detection result auditing and reporting process
And (3) opening a Huoqiao test information system (LIS), entering a tumor marker detection result auditing interface, leading the patient to flood, leading the serum NSE detection value to be 30.86 mu g/L, exceeding the normal reference value range, comparing historical results, finding that the last test result is 10.24 mu g/L, leading the difference of the two results to be three times, and having warning clinical significance. The hemolytic index was found to be 69, which exceeded the normal value. The patient data is checked, the pathological diagnosis is lung squamous carcinoma, and the patient is a postoperative patient, and the diagnosis is followed.
According to the NSE detection value, multiple considered directions exist in the clinical aspect, and the small cell lung cancer is suspected, or the non-small cell lung cancer is suspected, or the histologic type of the small cell lung cancer is converted during the treatment process of the suspected non-small cell lung cancer, or the suspected metastasis recurs. In order to avoid misleading clinical diagnosis and treatment, it is necessary to correct the value of NSE affected by hemolysis.
A conventional sample of blood taken on the same day was flooded and the red blood cell NSE/HI ratio was determined to be 0.309. mu.g/L.
The corrected NSE correction value is calculated using the following correction formula:
NSEcorr＝NSEmeas–0.889×R×HImeas–3.159×R＝30.86–0.889×0.309×69–3.159×0.309＝10.93μg/L
the corrected result of serum NSE is 10.93 mug/L, within the reference value range (0-16.3 mug/L), the positive clinical significance in the aspect of diagnosis is eliminated, and secondly, the difference between the corrected result and the last historical result is 6.73%, the increase is not more than 25%, and the warning clinical significance of relapse and transfer is not achieved.
The final serum NSE results were reported as 10.93. mu.g/L, and the remarks on the report: 1. the hemolytic index of the sample is 69, and the original detection result influenced by the hemolysis of the sample is 30.86 mu g/L; 2. the result reported after being corrected by the individualized formula is 10.93 mug/L, and the result is only used for clinical reference.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (7)
1. A personalized corrective formula for eliminating positive interferences in serum neural specific enolase detection due to hemolysis in a specimen, wherein the personalized corrective formula is as follows:
NSEcorr＝NSEmeas-0.889×R×HImeas-3.159×R；
wherein NSEcorrThe serum NSE correction value is calculated by the individual correction formula; NSEmeasThe detection value of the serum NSE of the detected sample; HI (high-intensity)mensIs the detection value of the hemolytic index of the detected sample; r is the ratio of NSE to HI of the red blood cells in the tested sample.
2. The individualized correction formula according to claim 1, wherein when HI ismeas5 or less or NSEmeas16.3, without using the individualized correction formula of claim 1 for NSEmeasCorrecting; when HI is presentmeas> 5 and NSEmeasAt > 16.3, using the individualized correction formula of claim 1 for NSEmeasCorrection to obtain NSEcorr。
3. Use of the individualized correction formula of claim 1 for recurrent metastasis monitoring and efficacy assessment of lung cancer and neuroblastoma.
4. Use according to claim 3, when HI ismeas5 or less or NSEmeasWhen the NSE is less than or equal to 16.3, the NSE does not need to be corrected by the individual correction formulameasCorrecting; when HI is presentmeas> 5 and NSEmeasAt > 16.3, assessing whether NSE requires the use of the individualized correction formula of claim 1 based on clinical needmeasCorrection to obtain NSEcorr。
5. The use of claim 4, wherein the clinical need assessment is of the NSE of a subject being tested for the current assaymeasWhether greater than the NSE of the human body to be detected in the last detectionmeas(ii) a If NSE detected this timemeasLess than last detectionNSE ofmeasThen the NSE detected at this time does not need to be corrected by the individual correction formulameasCorrecting; if NSE detected this timemeasGreater than the most recently detected NSEmeasThen the individual correction formula is used to correct the NSE detected this timemeasCorrection to obtain NSEcorrReporting corrected NSEcorrAnd remark NSEmeasAnd HImeas。
6. Use of the individualized correction formula according to claim 1 or 2 for the diagnosis of lung cancer and neuroblastoma.
7. Use according to claim 6, when HI ismeas5 or less or NSEmeas16.3, without using the individualized correction formula of claim 1 for NSEmeasCorrecting; when HI is presentmeas> 5 and NSEmeasAt > 16.3, using the individualized correction formula of claim 1 for NSEmeasCorrection to obtain NSEcorrReport NSEcorrAnd remark NSEmeasAnd HImeas。
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