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Influence of DIN EN ISO 15189 on the correctness of results in clinical virology

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LaboratoriumsMedizin
From the journal LaboratoriumsMedizin Volume 40 Issue s1

Abstract

To date more than 400 medical laboratories in Germany are accredited based on DIN EN ISO 15189 (Medical laboratories – requirements for quality and competence). In Germany, a new version of the DIN EN ISO 15189 has been published in 2014. This standard includes overall criteria but no requirements specific for certain disciplines of laboratory medicine. The present study examined how technical requirements, mainly for quality assurance and analytic methods, influence the correctness of results in clinical virology. Experts from laboratories, industry, DAkkS (German Accreditation Body) and from standardization have been interviewed. The qualitative content analysis showed that fulfilling technical requirements increased the correctness of examination results and minimized the risks for patient care and safety. Furthermore, we studied how effective internal quality controls, assay-controls as well as additional controls, assure HIV-p24-antigen and anti-HBs results. Additional controls recommended by DIN EN ISO 15189 (so called “run controls”) clearly indicated inaccuracies of HIV antigen measurement that were undetected by manufacturer’s controls. Also for anti-HBs examination, such internal controls provided by the manufacturer did not guarantee correct results. Therefore, we conclude that fulfilling DIN EN ISO 15189, usually confirmed by accreditation, has a positive influence on correctness of results in clinical virology, ultimately improving patient care.

Reviewed Publication:

Wieland E.

Keywords: accreditation; clinical virology; correctness of results; ISO 15189; patient safety; patient treatment

Introduction

Having highly reliable results in medical laboratory diagnostics is an essential prerequisite for high quality and safety in patient care, which is the focus of every medical treatment [1–3]. Diagnostic findings, including laboratory findings, are the basis of a rational medical approach [4].

In order to reduce and minimize errors in medicine, including laboratory medicine, quality management and, increasingly, risk management systems have been developed and implemented for years [5–8]. The application of ISO standards takes center stage, both internationally and nationally. The implementation of required standards can be confirmed by way of accreditation in the field of medical laboratory diagnostics [2]. The standard applied in this case is ISO 15189 (in Germany: DIN EN ISO 15189), which is based on a highly regulated approach whose main objective is the continuous improvement of quality and safety in laboratory services both for the patient and further users of laboratory services [9]. DIN EN ISO 15189 was first published in 2003 and has since become the “gold standard” of external quality testing. ISO 15189 was revised in 2007 and 2012; the most recent German version dates to 2014 [10, 11].

Objectives of the study

The influence of DIN EN ISO 15189 on the reliability of results in clinical virology and any related safety in patient care was examined in this study on the basis of interviews with experts and experimental laboratory data. Emphasis was placed on the importance of quality control materials and the interpretation of results of internal quality checks.

The interviews were to clarify whether weaknesses or errors in examinations and tests were connected to non-compliance with required standards.

Since DIN EN ISO 15189 contains only general requirements that apply to all disciplines of medical laboratory diagnostics, but no specific criteria for certain specialties, such as virology [12], this study was also to illustrate the interpretation of the standard in the specialized field of virus diagnostics.

Materials and methods

The findings from the interviews with experts (five quality managers and five medical staff members) at ten university departments of clinical virology were evaluated; the departments are all accredited according to DIN EN ISO 15189. This is a representative sample, because there are a total of around 20 accredited departments of clinical virology in Germany. They are regarded as opinion leaders and formers in virological diagnostics. Furthermore, the head of quality assurance and the head of quality management of an international manufacturer of in-vitro diagnostic products as well as one representative of the German Accreditation Body (DAkkS) and standardization in Germany were interviewed.

Qualitative research methods were applied to the expert interviews [13, 14]. The interviews with the experts were conducted in accordance with a guideline developed specifically for this study. The following aspects were covered:

  • quality control materials;

  • participation in proficiency tests and analysis of their results;

  • alternative procedure in the absence of proficiency tests;

  • comparability of results;

  • data and evaluation of results of quality assurance;

  • documentation of test methods;

  • verification of commercially available tests;

  • validation of test methods;

  • general issues, such as questions as to whether the standard should be supplemented, whether special requirements for virus diagnostics should be devised, or whether reliability of results has improved since accreditation.

For the representatives of industry and DAkkS, two further guidelines were prepared from the interviews with the laboratories.

The expert interviews were limited to 20–30 min [15]. The consistent use of standardized guidelines rendered the results comparable and better structured [16]. According to Berger [17], each new survey instrument is to be tested on a suitable subject prior to being used. As such, the validity of the guideline was put to the test twice in advance. The interviews were logged using audio recordings and subsequent transcription. The interviews were evaluated by means of qualitative content analysis. The content was processed gradually on the basis of theory and the category system that had been derived from the interview material [14]. Content analysis is a conventional method to analyze text material from various sources – from media products to interview data [18]. In this case, a summarizing content analysis was used, which condenses the material [19].

Apart from the expert interviews, experimental data were collected from the virology laboratory of the Max von Pettenkofer Institute. These data help to go deeper into some of the questions and interview content by adding practical example results. The following questions were discussed in this context and supplemented by experimental data:

Quality control materials
In commercial tests, do you use further controls other than the test-internal controls supplied by the manufacturer? If so, which ones and for which tests?
Quality assurance data
Did it happen that test results were not correct and/or could not be released, despite the quality controls being in the proper range? Why was that?

In the case of the anti-HBs test, each run has a defined sensitivity limit that can fluctuate, depending on the values of the negative control. It is calculated from the mean extinction of the three negative controls plus 0.08. The frequency and extent with which the respective sensitivity limits fluctuated in each batch were examined. The sensitivity limits were then grouped as follows: <8 IU/L, 8.1–9.9 IU/L, 10 IU/L, >10 IU/L. The frequency distribution was determined.

In addition, the correlation by way of the Pearson correlation coefficient and the coefficient of determination was applied in the evaluation in connection with the analysis of the HIV-p24 antigen.

Results

Internal and external quality assurance

Results from the expert interviews

DIN EN ISO 15189 requires laboratories to participate in proficiency tests [20]. proficiency tests are an effective tool to uncover any weaknesses in test procedures and take any necessary corrective measures [21, 22]. Seven of the laboratories surveyed have improved analytical methods thanks to proficiency tests. Informal laboratory comparisons have been implemented for parameters not offered as part of proficiency tests.

Internal and external quality assurance for a limited number of virological parameters is mandatory in Germany under Part B3 “Direct detection and characterization of infectious agents” of RiliBÄK (Guidelines of the German Federal Medical Society). However, this concerns only around half the relevant proficiency tests offered by university institutes and reference institutions.

In molecular biology, proficiency tests are evaluated by INSTAND e.V. using the consensus method. The final value to be assigned is determined on the basis of the consensus value derived from the population submitted, with the results of the reference laboratories being factored in [23, 24]. The majority of laboratories surveyed use such proficiency tests to calibrate their standards.

The experts interviewed do not deem it necessary to include specific requirements for virological diagnostics in DIN EN ISO 15189. While there is a need for additional proficiency tests and improved standardization, special requirements in the standard are not expected. According to the industry, standardization is the responsibility of standardization bodies, but standardization bodies believe that the industry has an urgent responsibility to take charge of standardization.

Run controls

Results from the expert interviews

DIN EN ISO 15189 recommends the use of additional quality control materials (run controls) apart from the manufacturer’s test-internal controls [20]. These controls can serve to check the robustness of the analytical process as well as the reproducibility of the results [25]. None of the laboratories surveyed used run controls in all of the processes. One laboratory did not use any at all. Most laboratories used run controls with varying frequency, and for different tests (Figure 1). The use of run controls depends on the individual risk assessment of false measured values and the expenditure associated with the implementation of such controls. Most of the experts interviewed agree that run controls can improve the quality of testing.

Figure 1: Run controls used in 10 interviewed laboratories.
Figure 1:

Run controls used in 10 interviewed laboratories.

Results from the experimental data analysis

The Institute of Virology at the Max von Pettenkofer Institute has been using an additional, internally produced antigen control in HIV antibody testing with a combo ELISA assay for many years. The antigen control is a viral lysate derived from the cell-culture supernatant of an HIV-1 group M subtype B-virus culture [26]. The diluted virus supernatant is adjusted in such a manner that the extinction in the combo ELISA is about twice the limit value. Subsequently, aliquots of this dilution are prepared and stored at a temperature of –20 °C for several years. Each week, a tube is thawed out and consumed in the upcoming five tests or so per week. During this time, the tube thus started is stored at 2–8 °C without any noticeable change in the respective extinction. Thanks to the stability of such control material, batch-based changes in the basic sensitivity of the screening test are clearly and verifiably visible.

The measured values (represented as a mean value of S/CO extinction/sample relative to the extinction/cutoff of a batch) of this additional antigen control highly correlate with the antigen sensitivity limits of the individual assay batches. The Pearson correlation coefficient was 0.83 over a period of 5 years (see Figure 2). The line illustrates how well the values correlate. A reduced sensitivity in the antigen analysis is therefore quickly detected. The antigen sensitivity limit of a batch can be requested separately from the manufacturer, but the testing of these laboratory-internal control provides additional information if there is a weakness in the antigen sensitivity of the respective test of the day. External factors, such as transport, storage and handling of test-internal controls, come into play here. Internally produced run controls, therefore, yield good significance and predictive validity. In 0.4‰ of the tests (1 of 2210 tests), an error in the test procedure was discovered thanks to this additional control. In the actual case, a mistake had been made in the dilution of the positive control; the cutoff calculated from this control was too high. While the positive control was still within the specified range, the internally produced antigen control was outside the acceptable limits (1–3 times the cutoff), which meant that the test run could not be approved.

Figure 2: S/Co-mean of the antigen-control in dependent on the antigen detection limit (pg/L); shown are the single lots of the HIV-Combo-tests, points represent the mean of a lot, totally 727 individual measurements; strong correlation.
Figure 2:

S/Co-mean of the antigen-control in dependent on the antigen detection limit (pg/L); shown are the single lots of the HIV-Combo-tests, points represent the mean of a lot, totally 727 individual measurements; strong correlation.

Furthermore, the test-internal controls supplied by the manufacturer with the combo ELISA are intended only for the detection of antibodies, ignoring proof of antigen. The control for the antigen detection was then established through this additional run control.

Run controls for further tests were established as well due to the experiences described above.

Importance and significance of test-internal controls

Results from the experimental data analysis

Systematic errors and deviations may occur even if the test-internal quality controls are within the standard range. Figure 3 shows the frequency distribution of anti-HBs sensitivity limits for the individual batches. They were grouped into <8 IU/L (as specified by the manufacturer), 8.1–9.9 IU/L, 10 U/L (international immunity limit), and >10 IU/L. The sensitivity limit, often at >10 IU/L, seems problematic, because immune patients may exhibit false-negative results. This state of affairs led to a complaint with the test manufacturer as well as laboratory-internal corrective measures. The test plate was then processed at a separate device, which reduced the standing time of the reaction mixtures. As a result, the extinction of the negative control and, thus, the calculated sensitivity limit were lower.

Figure 3: Distribution of anti-HBs sensitivity in six consecutive lots. Test-inherent controls have always been valid. 6* labels lot 6 after intern corrective action, which increased the sensitivity from 2.9% to 63.3% between 8.1 to 9.9 IU/L.
Figure 3:

Distribution of anti-HBs sensitivity in six consecutive lots. Test-inherent controls have always been valid. 6* labels lot 6 after intern corrective action, which increased the sensitivity from 2.9% to 63.3% between 8.1 to 9.9 IU/L.

The sensitivity limit did not reach the international immunity limit of 10 IU/L in 42 out of 858 runs. But the values of the test-internal controls were always within the specified range. The expected quality of the test is not always guaranteed even if the manufacturer’s controls are within the specified tolerance range.

Results from the expert interviews

The interviews revealed that not all experts were familiar with the situation described above. Two laboratory experts reported never to have experienced such a situation. One industry representative could not imagine such a scenario.

In exceptional cases, test results can be released if internal quality controls of a test are not within the standard range, but the release will have to be justified and documented appropriately (“special approvals”). Five of the questioned laboratories do so at least a (Figure 4).

Figure 4: Exceptional approvals in 10 interviewed laboratories.
Figure 4:

Exceptional approvals in 10 interviewed laboratories.

According to DIN EN ISO 15189, analyses of patient samples must be repeated in the event of “clinically significant errors in test results” and where the rules of quality control are violated [20]. The standard also requires a decided mechanism for the release of results by authorized, competent staff.

Many institutes use self-developed (in house) tests (e.g. adenovirus PCR, parvovirus B19-PCR). This means they also generate the standard ranges for the controls themselves. Trends can be detected early with narrow limits, because control sample results exceed standard ranges sooner and faster in the event of deviations. By contrast, the ranges specified by the manufacturers of commercial tests are often very broad, so that controls only rarely exceed the limits set by the manufacturer. In some cases, it is also quite obvious why the results of controls are not within the standard range, such as for reproducible processing errors that affect only one of the controls.

As was learned through the interviews, the results are released in two stages: A technical assistant conducts a technical validation. Then, the results are forwarded to the diagnosing physician or qualified scientist for an independent review and medical validation. The release of the results is a decision taken in the individual case that depends on the test, the raw values of the controls, the overall picture of the assay, and the stability of the results over time.

Consequently, the application of DIN EN ISO 15189 requires that test results that are deemed problematic in terms of the controls be checked thoroughly and that only test results with a high degree of certainty of results and, thus, patient safety be released.

Measurement uncertainty

Results from the expert interviews

Another main element of the survey was the significance of measurement uncertainty. A continuous determination and evaluation of the standard deviation, the mean and the coefficient of variation of the measured results improve the reliability of results [27].

The survey found that three of the accredited laboratories surveyed did not determine measurement uncertainty in the analytical phase continuously, even though this is a requirement under DIN EN ISO 15189 [20]. Only one laboratory determined the measurement uncertainty both for quantitative and qualitative test methods. The other laboratories did determine measurement uncertainty, but only in respect of quantitative methods. The responses received were divided into four groups. Three laboratories tracked measurement uncertainty occasionally, not for all required test methods, or without statistical evaluation. Two further laboratories analyzed duplicate determinations, and four laboratories looked at the variance of standards. Only one laboratory evaluated continuously the coefficients of variation, means and standard deviations of the controls, and also had specifications in place for this. The conditions of the controls for in-house methods can be determined using the 1s, 2s or 3s ranges of the standards. In the case of commercial tests, the ranges can be compared with the customary 3s ranges of the manufacturers. If the performance requirements regarding measurement uncertainty are not complied with, deficiencies in tests will come to light that affect, for example, the stability and reproducibility of analytical methods. This is true even if the values are (still) within the standard ranges in the event of fluctuations in a test method. In this context, the values must be evaluated periodically, and the individual segments of the analytical method must be taken into account.

DIN EN ISO 15189 requires that uncertainty must be determined and surveilled regularly [20], providing a solid basis for evaluating the performance of test methods. The survey shows that estimating measurement uncertainty, including limits needs to be improved.

Validation and verification

Results from the expert interviews

Eight of the 10 laboratories surveyed said that they took into account the requirements of the guidelines issued by GfV (Society of Virology) and DVV (German Association for the Control of Virus Diseases) as a supplement to the standard [25].

When asked whether limits for the performance characteristics of validation and verification, such as precision, had been defined, the following answers were given:

  • Rabenau et al. has been applied (authors’ note: no limits have been specified in Rabenau et al.)

  • Defined internally

  • None defined so far

  • Internal calculation parameters

  • Individually for each value, decided case by case

  • PCR: cycle threshold (CT) within three cycles.

Overall, the answers to this question were not sufficiently comprehensive. The impression was that the laboratories had not defined adequate values. If such limits, for example, on the basis of publications, are not defined, there is a risk that results of lower-quality tests may be accepted.

DIN EN ISO 15189 prevents this risk insofar as the standard requires that validation and/or verification be planned, checked and released for routine operation by an authorized person [20].

Reliability of results

Results from the expert interviews

The experts from the laboratories predominantly affirmed the question as to whether reliability of results had improved since obtaining accreditation under DIN EN ISO 15189. Only one laboratory stated that reliability of results had not improved since accreditation. The laboratory in question had been accredited for 3 years. According to the person interviewed, the laboratory’s work had been of high quality even before the accreditation, and did not have to introduce many new measures.

Discussion

Internal and external quality assurance

The standard criteria for ensuring the quality of analytical methods (section 5.6 of the standard) are part of the central requirements under DIN EN ISO 15189 [20].

Test-internal controls of the manufacturer form the basis of quality assurance. They must be within a defined range according to the manufacturer’s specifications. In the event of clinically significant errors, DIN EN ISO 15189 calls for the sample analysis to be repeated. Under certain conditions, the test result may be given special approval and be released, with reasons being given. Around five of the laboratories surveyed apply such a special approval a few times a year, and even up to a few times a week (see Figure 4).

Even where the raw data of controls are within the standard range, test errors may occur, as has been shown for anti-HBs. The sensitivity of the anti-HBs test did not reach the international immunity limit of 10 IU/L in all runs. Quantitative antibody detection tests may fluctuate [28], but there is still an international immunity limit for anti-HBs [29, 30]. Valid test-internal controls, provided by the manufacturer, may give the user a false sense of security.

The standard DIN EN ISO 15189 underlines the relevance to quality assurance of using quality control materials provided by an “independent third party” and recommends the use of such control materials in addition to, or instead of, the controls supplied by the manufacturer [20].

Therefore, the laboratories used such additional controls, or run controls, at their own discretion in one or several methods. The individual laboratories differed in terms of the number and purpose of the assays with run controls. The validity of run controls has been shown in this study on the basis of data for determining HIV antigen control, which also checks the antigen detection in the HIV combo test – the manufacturer’s controls do not do this.

External quality assurance – mostly applied in the way of proficiency tests– gives laboratories an efficient tool to verify, and improve if necessary, the quality of the tests used – in addition to evaluating how the laboratory implement and perform the tests [31]. However, six of the laboratories surveyed used this tool to “calibrate” their internal standards of molecular biology on the basis of proficiency test results. This must be seen as critical, because it is the most commonly used method that dominates here. In molecular biology, the assigned value is determined in the proficiency test from the consensus value of all results submitted. This includes the results of the reference laboratories. It comes at the risk, though, of a national “standardization” brought on by the test most commonly used. In this context, it is essential to note that the standard DIN EN ISO/IEC 17043 [24] applicable to providers of qualification tests with respect to consensus value determination demands that providers of proficiency tests must document and explain the basis on which the consensus method has been selected.

Participation in proficiency tests, as required under DIN EN ISO 15189, helps to improve reliability of results through periodic, external controls. The common practice employed by some laboratories – that is, to adapt their standards to proficiency test results – does not comply with the standard and goes against the principles of calibration for analytical methods.

Unlike RiliBÄK, which calls for participation in proficiency tests only for a limited number of virological parameters at this point, DIN EN ISO 15189, and especially accreditation under this standard, clearly emphasizes how important proficiency tests are to all analytical methods offered by a laboratory.

Validation, verification and measurement uncertainty of analytical methods

Rabenau et al. once noted that there were deficits in the validation (in-house methods) and verification (commercial tests) of virological diagnostics: there was a frequent lack of data concerning intra- and inter-assay precision as well as reproducibility [32]. The specifications for validation and verification are described only in conceptual terms in DIN EN ISO 15189, without illustrating specific requirements for individual disciplines [12]. As the interviews with experts have shown, almost all Clinical virology laboratories in Germany, therefore, work according to the guidelines of GfV and DVV [25], which supplement and specify the demands of the standard. Since the standard does not include any precise instructions about the number of samples to be tested for validation and/or verification purposes, or the frequency with which they are to be tested, the clear provisions of the guidelines do represent a meaningful addition. But neither the standard nor the guidelines contain limit values for the performance characteristics, such as precision, specificity or sensitivity. This is left up to the laboratories, which must define them under the current state of the art.

It may be concluded that the standard DIN EN ISO 15189 does provide for principles and concepts regarding the verification and validation of analytical methods, but so far there have not been any detailed criteria, including for specific disciplines.

Instead, upon the introduction of new analytical methods, DIN EN ISO 15189 focuses on the planning, evaluation and documentation of the necessary and actual performance characteristics, including the authorized release of the validation documentation. This is to reduce the risk of lower-quality analytical methods with poor reliability of results being used in routine diagnostics.

In terms of the assessment and periodic review of measurement uncertainty regarding analytical methods, the findings of this study confirm that there is an ongoing need for medical laboratories to make improvements in this field. A future significant measure may be the current ISO standardization project with the working title “Medical laboratories – Practical guide for the estimation of measurement of uncertainty” [33]. The relevant standardization body ISO Technical Committee (TC) 212 is currently working on international guidelines for medical laboratories regarding the estimation of measurement uncertainty. These guidelines will also contain examples of determining measurement uncertainty with respect to analytical methods used in different disciplines, including virology.

Completeness of the standard

The experts interviewed for this study believe that the contents of DIN EN ISO 15189 are adequate with respect to the given purpose. Most of them consider it unnecessary to add to the standard further requirements specific to virology. The GfV and DVV [25] guidelines on validation and verification, have been added by the national sector committee “Medical Laboratories” to the standard mandatory for accreditation. Apart from this, there are also so-called discipline checklists in Germany; for virology, they date back to 2004 and are currently being revised [34]. In addition, the RiliBÄK requirements are also an obligatory part of the accreditation criteria. Since 2001, the MIQs – quality standards in clinical microbiology – have also included specifications for nucleic-acid amplification techniques [35].

At the international level, the necessity for an interpretative supplement to the ISO 15189 standard’s re quirements was recognized with the publication of the English version in 2012. Aside from the aforementioned guidelines on estimating measurement uncertainty, ISO TC 212 is currently working on a “technical specification” regarding error and risk management with application examples across various disciplines of laboratory diagnostics [36], as well as a new standard concerning the validation of analytical methods in diagnostic molecular-biological procedures for infectious diseases [37]. Specifications on pre-analytical requirements for the extraction of nucleic acids from various tissues for the purpose of further molecular-biological analysis have already been published at the European level [38].

These standardization projects demonstrate the need for further and specific instructions on various subfields in which medical laboratories are active.

Reliability of results

As concerns the statements on reliability of results made by those surveyed, one should keep in mind that the establishment of a QM system in compliance with RiliBÄK [39] has been mandatory in Germany since 2008. Nevertheless, the majority of laboratories surveyed have expressed the opinion that the quality of medical test results has improved since the adoption of DIN EN ISO 15189. This statement is borne out by both experimental data and the qualitative content analysis of the expert interviews conducted for this study. The studies of Rabenau and Steinhorst [40] and Allen [41], which also show an improvement in the quality of laboratory diagnostics as a result of DIN EN ISO 15189, have been confirmed and continued in this study.

Outlook

In summary, this study has demonstrated that the implementation of DIN EN ISO 15189 has a positive effect on the reliability of results in virological diagnostics, suggesting that accreditation makes sense not only from a perspective of market interests, but also, and above all, due to continuous quality improvement. The implementation of the standard’s requirements leads to a noticeable improvement in the documentation and quality assurance of analytical methods, such as in the establishment of in-house procedures, which are attributed great importance at university facilities of clinical virology. Since only two institutions among the group of university-based virology departments are not accredited at this time, it was not possible to assemble a valid control group consisting of non-accredited laboratories. Non-university laboratories have not been surveyed either, because they usually do not have such a specialized spectrum of analytical methods as one finds with university institutions. However, one can assume that the findings of this study can also be applied to non-university hospital laboratories and private laboratories. But the process of continuous improvement is at the center of every quality management system. As this study shows, there is still considerable room for improvement even among accredited laboratories.

There may well be great interest in seeing further standardization efforts designed to enhance and supplement the general requirements of the standard by including specific instructions on measurement uncertainty, error and risk management, as well as the validation of analytical methods.

Acknowledgments

The authors wish to express their gratitude to Prof. Dr. Gürtler for his invaluable support in preparing this study. The authors would also like to thank Dr. Jäger, Prof. Dr. Eberle and Dr. Nitschko for lively discussions.

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: None declared.

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

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Article note:

Original German online version at: http://www.degruyter.com/view/j/labm.2016.40.issue-3/labmed-2016-0008/labmed-2016-0008.xml?format=INT. The German article was translated by Compuscript Ltd. and authorized by the authors.

Received: 2016-1-12
Accepted: 2016-3-11
Published Online: 2016-6-28

©2016 by De Gruyter

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  2. Quality control and validation in flow cytometry
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  4. Surrogate markers of insulin resistance in subjects with metabolic syndrome – data of the Berlin Aging Study II
  5. Thyroid disorders: diagnosis and therapeutic approaches 2015
  6. Influence of DIN EN ISO 15189 on the correctness of results in clinical virology
  7. Cerebrospinal fluid cytology: a highly diagnostic method for the detection of diseases of the central nervous system
https://doi.org/10.1515/labmed-2016-0037
Keywords for this article
accreditation; clinical virology; correctness of results; ISO 15189; patient safety; patient treatment
Creative Commons
BY-NC-ND 3.0

Articles in the same Issue

  1. Laboratory testing for systemic autoimmune diseases
  2. Quality control and validation in flow cytometry
  3. Reference intervals for iron-related blood parameters: results from a population-based cohort study (LIFE Child)
  4. Surrogate markers of insulin resistance in subjects with metabolic syndrome – data of the Berlin Aging Study II
  5. Thyroid disorders: diagnosis and therapeutic approaches 2015
  6. Influence of DIN EN ISO 15189 on the correctness of results in clinical virology
  7. Cerebrospinal fluid cytology: a highly diagnostic method for the detection of diseases of the central nervous system
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