Study On Biological Variation Of Serum Tumor Markers And Its Application

Objectives:Detection of serum tumor markers plays an important role in secondary and tertiary prevention of tumors.However,due to the imperfection of relevant industry standards,most of the performance specifications of serum tumor marker projects have no reliable source,which makes it impossible to carry out effective performance evaluation in combination with the quality requirements of clinical laboratories.At the same time,along with 2019,the United States center for Medicare and Medicaid Services(Centers for Medicare and Medicaid Services,CMS)and the Centers for Disease Control and Prevention(CDC(Centers for diseases Control and Prevention,CDC)in the federal register(CMS-3355-P)released the ability validation rules in clinical laboratory commonly used sources of performance specification is based on the current technical level of export quality requirements,It is expressly stated that it is not applicable to the use of a single laboratory to establish quality requirements.Therefore,the second level of performance specification source,namely the quality requirement derived from biological variation,should be the main source of laboratory performance specification.Therefore,this study intends to study the biological variation of serum tumor markers without or with few reliable biological variation data at home and abroad,and obtain the intra-individual biological variation(CV_I)and inter-individual biological variation(CV_G)through experiments,and derive the performance specifications of the three grades of"best","appropriate"and"lowest".The derived performance specifications were used to verify and confirm the performance of the selected serum tumor markers,including linear range,accuracy,precision,detection ability and bottle opening stability,so as to provide performance indicators meeting the quality requirements for clinical practice.Methods:1.Biological variation:13 items of serum tumor markers in clinical use were selected.Based on a review of the literature and the latest research progress on the website of the European Federation of Clinical Chemistry and Laboratory Medicine(EFLM),biological variation studies were carried out on projects with little or no relevant reports,and the results of this experiment were compared with those supported by reliable data.Healthy volunteers were recruited according to the requirements,and samples were collected for a period of six months.The long-term CV_I and CV_G were calculated by selecting the appropriate experimental method,and the allowable total error,allowable deviation and allowable unprecision at the three levels of"optimal","appropriate"and"lowest"were derived by the internationally recognized formula.2.Performance verification and performance verification:strictly according to the program performance evaluation of the American Clinical&Laboratory Standards Institute(CLSI)and China’s health industry standards,the performance specification was derived from the biological variation data of this study as the quality requirement.Precision verification,accuracy verification,linear range performance confirmation of CLSI EP6-A scheme,detection capability performance confirmation of CLSI EP17-A2 scheme and bottle opening stability performance confirmation of CLSI EP25 scheme were carried out for the selected 13 serum tumor marker projects according to the CLSI EP15-A3 scheme.Results:1.Biological variation:Among the 13 research projects,6 of the EFLM websites have relatively complete data support.Compared with the results of this study,there is no statistical dif Ference between the NSE project and the foreign data(P>0.05).Domestic population of AFP and CEA CV_I and CV_G are much smaller than the foreign population(P<0.01),the corresponding data of HE4 CV_I and CV_Gcorresponding data were significantly greater than the foreign population(P<0.05),and f-PSA,PSA project,both CV_Iwere greater than foreign groups corresponding data(P<0.01),and corresponding data CV_Gwere less than foreign crowd(P<0.01).The EFLM websites of 8 projects in CA50,CA19-9,CA125,CA72-4,CA153,Fer,SCC and CYFRA21-1 have no access to CV_I and CV_G data.Dif Ferent performance specifications have been derived based on CV_I and CV_Gdata obtained in this study.2.Performance verification and performance verification:Performance verification is mainly carried out for precision and accuracy,while performance verification is mainly carried out for linear range,detection ability and bottle opening stability.Among them,the precision verification,in the midst of all the validation of115 samples,more than 90%of the validation samples are passed the lab according to the biological variation export permission is not the quality of the precision requirements,at the same time the CEA,PSA,f-PSA,CA19-9,SCC,CA72-4 and Fer projects such as the individual sample not precision results cannot be achieved during the factory specifications declared in the quality level,not through further verification calculation.In terms of accuracy verification,all imported brands can meet the requirements of the performance specification derived from biological variation.The percentage deviation of the overall medical determination level value of CA50 project,which only uses domestic reagents,is larger than the allowable relative bias derived from biological variation.The traceability system of the detection system needs to be strengthened.Linear range performance qualification,imported brands and domestic brands of linear range derived on the basis of biological variation allowed not precision level set the clinical significance of critical value(Pct Bnd),related to AFP,CEA,NSE,HE4,CA50,CA19-9,Fer,CA72-4,SCC and Cyfra21-1,10 projects linear range slightly smaller than the manufacturer specifications declared in the linear range;The linear range of PSA,f-PSA,CA125 is wider than that stated in the manufacturer’s specification.In terms of detection ability,the performance of limit of blank(LoB)was confirmed to be better than that of the three projects in AFP.LoB in the remaining 15 projects was slightly worse than that in Pro GRP.In other words,the detection ability declared by the manufacturer could not be reached under the environmental conditions of this experiment.The performance of limit of quantitation(LoQ)was confirmed.Since most of the projects did not provide LoQ declared by the manufacturer,the allowable error was derived according to the biological variation in this study,and the LoQ of 13 projects was obtained for use by the laboratory with the same quality requirements as the necessary index.Kaiping stability performance qualification aspect,on the basis of this study biology variation data,export of this lab is to allow bias level,the stability of the reagent metrics this scheme selection is measured drift(reagent under certain conditions the change of the value),five projects namely,NSE,Fer,CYFRA21-1,the number of days of SCC stability for 33days,39 days,41 days,30 days,are worse than(or equal to)manufacturer statement stable number of days,with quality requirements in the laboratory should focus on the above reagents stable performance.Conclusions:In this study,the long-term biological variation data of Chinese adults with 13serum tumor markers including AFP were obtained,and the corresponding performance specifications of"optimal","appropriate"and"lowest"grades were derived by CV_I and CV_G.Based on the above performance specifications and in combination with CLSI and the industry standard scheme of China’s ministry of health,the performance verification and performance confirmation of 13 tumor marker projects were carried out.In the experiment,only CA50 was domestic reagent,and the rest were imported reagent.In the aspect of precision verification,90%of the samples passed the precision verification,and only a few of the individual samples failed to pass the validation of the projects.Therefore,clinical attention should be paid to them.All the imported brands were verified to be correct,but the performance of CA50 project was poor.The reason may be that the domestic reagent traceability system needs to be further developed.In terms of linear range,most of the projects have good linear range,and a few of the projects that cannot reach the manufacturer’s declaration level are recommended to make corresponding clinical reexamination rules.In terms of the ability to detect,the Lo B of most projects is poor compared with the performance confirmation results of the specification.Lo Q of all projects is confirmed,which facilitates the clinical laboratory to analyze the low-value results and issue accurate reports.In terms of bottle opening stability,most items can meet the manufacturer’s stated stability period under the new performance specification.Through the performance confirmation,the biological variation data of this study basically meets the performance specification derived by the clinical laboratory,and is relatively reasonable and reliable.Through the performance specification,the necessary performance parameters of the detection system can be obtained objectively.At the same time,the clinical laboratory should carry out at least the performance confirmation of linear range,Lo Q and bottle opening stability according to their respective quality requirements,so as to serve the clinical work.