Bremer Zentrum For Laboratoriumsmedizin

Bremen, Germany

Bremer Zentrum For Laboratoriumsmedizin

Bremen, Germany

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Haeckel R.,Bremer Zentrum For Laboratoriumsmedizin | Wosniok W.,University of Bremen | Gurr E.,Abteilung Klinische Chemie und Zentrallabor Am Klinikum Links der Weser | Peil B.,Deutsche Akkreditierungsstelle GmbH
Clinical Chemistry and Laboratory Medicine | Year: 2015

The international standard ISO 15189 requires that medical laboratories estimate the uncertainty of their quantitative test results obtained from patients' specimens. The standard does not provide details how and within which limits the measurement uncertainty should be determined. The most common concept for establishing permissible uncertainty limits is to relate them on biological variation defining the rate of false positive results or to base the limits on the state-of-the-art. The state-of-the-art is usually derived from data provided by a group of selected medical laboratories. The approach on biological variation should be preferred because of its transparency and scientific base. Hitherto, all recommendations were based on a linear relationship between biological and analytical variation leading to limits which are sometimes too stringent or too permissive for routine testing in laboratory medicine. In contrast, the present proposal is based on a non-linear relationship between biological and analytical variation leading to more realistic limits. The proposed algorithms can be applied to all measurands and consider any quantity to be assured. The suggested approach tries to provide the above mentioned details and is a compromise between the biological variation concept, the GUM uncertainty model and the technical state-of-the-art. © 2015 by De Gruyter 2015.


Haeckel R.,Bremer Zentrum For Laboratoriumsmedizin | Wosniok W.,University of Bremen | Al Shareef N.,Ministry of Health Laboratory
Clinical Chemistry and Laboratory Medicine | Year: 2011

Method comparisons are indispensable tools for the extensive validation of analytic procedures. Laboratories often only want to know whether an established procedure (x-method) can be replaced by another one (y-method) without interfering with diagnostic purposes. Then split patients' samples are analyzed more or less simultaneously with both procedures designed to measure the same quantity. The measured values are usually presented graphically as a scatter or difference plots. The two methods are considered to be equivalent (comparable) if the data pairs scatter around the line of equality (x=y line) within permissible equivalence lines. It is proposed to derive these limits of permissible imprecision limits which are based on false-positive error rates. If all data pairs are within the limits, both methods lead to comparable false error rates. If one or more data pairs are outside the permissible equivalence limits, the x-method cannot simply be replaced by the y-method and further studies are required. The discordance may be caused either by aberrant values (outliers), non-linearity, bias or a higher variation of e.g., the y-values. The spread around the line of best fit can detect possible interferences if more than 1% of the data pairs are outside permissible spread lines in a scatter plot. Because bias between methods and imprecision can be inter-related, both require specific examinations for their identification. © 2011 by Walter de Gruyter Berlin Boston 2011.


Haeckel R.,Bremer Zentrum For Laboratoriumsmedizin | Wosniok W.,University of Bremen | Kratochvila J.,SEKK Pardubice | Carobene A.,Universitario ffaele
Clinical Chemistry and Laboratory Medicine | Year: 2012

Permissible limits for internal and external quality assurance are either based on biological variation or on the state of the art (technical feasibility). The former approach has a scien-tific basis, but, in some cases, leads to limits which are either not achievable under the present technology, or which are not stringent enough. If proficiency testing is mandatory, stringent limits which cannot be fulfilled by the majority of laboratories could lead to juristic consequences. Therefore, most national guidelines were based on the state of the art, however, without providing the underlying reasoning. A simple algorithm for permissible limits in external quality assessment schemes (EQAS) is proposed based on biological variation, technical feasibility and correlated to the rate of false positive results. The proposed limits are compared with some limits from several EQAS (RiliBÄK, SEKK, RCPA, CLIA, PROLARIT). The suggested limits are slightly more stringent than the German RiliBÄK, less stringent than the Australasian guidelines and agreed best with the Czech SEKK and the Italian PROLARIT scheme. The graphical presentation of permissible limits strictly derived of biological variation with the proposed limits led to straight lines with different slopes and a cross-over at the limits for quantities with a medium biological variation (e.g., trijodthyronine). The greatest discordance between the various recommendations was observed for calcium, chloride, hemoglobin A1c and sodium. © 2012 by Walter de Gruyter • Berlin • Boston.


Arzideh F.,University of Bremen | Wosniok W.,University of Bremen | Haeckel R.,Bremer Zentrum For Laboratoriumsmedizin
Clinical Chemistry and Laboratory Medicine | Year: 2011

Background: The dogma of establishing intra-laboratory reference limits (RLs) and their periodic review cannot be fulfilled by most laboratories due to the expenses involved. Thus, most laboratories adopt external sources for their RLs, often neglecting the problems of transferability. This is particularly problematic for analytes with a large diversity of existing RLs, as for example thyrotropin (TSH). Several attempts were taken to derive RLs from the large data pools stored in modern laboratory information systems. These attempts were further developed to a more sophisticated indirect procedure. The new approach can be considered a combined concept because it pre-excludes some subjects by direct criteria a-posterior. In the current study, the applicability of the new concept for modern protein bindings assays was examined for estimating RLs of serum and plasma TSH with data sets from several German and Italian laboratories. Methods: A smoothed kernel density function was estimated for the distribution of the total mixed data of the sample group (combined data of non-diseased and diseased subjects). It was assumed that the "central" part of the distribution of all data represents the non-diseased ("healthy") population. The central part was defined by truncation points using an optimisation method, and was used to estimate a Gaussian distribution of the values of presumably non-diseased subjects after Box-Cox transformation of the empirical data. This distribution was now considered as the distribution of the non-diseased subgroup. The percentiles of this parametrical distribution were calculated to obtain RLs. Results: RLs determined by the indirect combined decomposition technique led to similar RLs as found by several recent study reports using a direct method according to international recommendations. Furthermore, the RLs obtained from 13 laboratories in two different European regions re-flected the well-known differences of various analytical procedures. Stratification for gender and age was necessary in contrast to earlier reports. With increasing age, an increase of the upper RL and the reference range was observed. Hospitalisation also affected the RLs. Common RLs appeared acceptable only within the same analytical systems. Some laboratories used RLs which were not appropriate for the population served. Conclusions: The proposed strategy of combining exclusion criteria with a resolution technique led to retrospective RLs from intra-laboratory data pools for TSH which were comparable with directly determined RLs. Differences between laboratories were due primarily to the well-known bias of the different analytical procedures and to the status of the population. © 2011 by Walter de Gruyter Berlin New York.


Arzideh F.,University of Bremen | Wosniok W.,University of Bremen | Haeckel R.,Bremer Zentrum For Laboratoriumsmedizin
Clinica Chimica Acta | Year: 2010

Background: The current dogma of establishing intra-laboratory reference limits (RLs) and their periodical reviewing cannot be fulfilled by most laboratories due to the expenses involved. Thus, most laboratories adopt external sources for their RLs often neglecting the problems of transferability. Therefore, several attempts were undertaken to derive RLs from the large data pools stored in modern laboratory information systems. These attempts were further developed to a more sophisticated indirect procedure. The new model can be considered a combined approach because it pre-excludes some subjects by direct criteria. In the current study, the new concept was applied to estimate RLs for serum and plasma creatinine from several German and Italian laboratories. Methods: A smoothed kernel density function was estimated for the distribution of the total mixed data of the sample group (combined data of non-diseased and diseased subjects). It was assumed that the "central" part of the distribution of all data represents the non-diseased ("healthy") population. The central part was defined by truncation points using an optimisation method, and was used to estimate a Gaussian distribution of the values of presumably non-diseased subjects after Box-Cox transformation of the empirical data. This distribution was now considered as the distribution of the non-diseased subgroup. The percentiles of this parametrical distribution were calculated to obtain RLs. Results: RLs determined by the indirect combined decomposition technique led to similar RLs as the classical direct method. Furthermore, the RLs obtained from 14 laboratories in 2 different European regions reflected the well-known differences of various analytical procedures. Stratification for gender and age was necessary. With rising age, an increase of the upper RL and of the reference range was observed. Hospitalization appeared also to affect the RLs. The new approach led to RLs in an artificially mixed population of diseased and non-diseased subjects (selected by clinical criteria) which were identical to RLs determined by a direct method applied to the non-diseased subgroup. Conclusions: The proposed strategy of combining exclusion criteria with a resolution technique led to plausible retrospective RLs from intra-laboratory data pools for creatinine. Differences between laboratories were mainly due to the well-known bias of the different analytical procedures. © 2009 Elsevier B.V. All rights reserved.


Haeckel R.,Bremer Zentrum For Laboratoriumsmedizin | Wosniok W.,University of Bremen
Clinical Chemistry and Laboratory Medicine | Year: 2011

Background: Permissible limits of analytical imprecision and bias are usually derived either from biological variability or from the state of the art. Both concepts require information from external sources which often lack transparency and are difficult to integrate in medical decision-making. Additionally, physicians may be interested in knowing the probability of decision errors due to analytical uncertainty. Therefore, an approach was developed which combines all three concepts. Methods: The empirical (observed) biological variation was derived from reference ranges used by the laboratory (CVE). CVE was corrected to get the biological variation in the theoretical absence of analytical imprecision (CVC). Relatively simple equations were derived from the relationship between biological variation and the analytical imprecision (CVA) to calculate permissible imprecision and bias. Five quality classes are proposed for the various analytes reflecting the false-positive error rates (FPR). These classes characterize analytical procedures according to their theoretical specificity (FPR). Thus, the new approach combines the theoretical base of biological variation with the technical state-of-the-art. Results and conclusions: As practical examples, the permissible imprecision and bias limits were estimated for a selection of quantities. The limits found were more realistic than present proposals based on Cotlove's rule (fixed fraction of biological variation), but slightly more stringent than national consensus values based on the state-of-the-art. Imprecision and bias do not affect FPR equally, and, therefore, should be assessed separately. It is proposed to insert monthly imprecision and bias results calculated after each control cycle in a table with five quality classes. This table provides a simple overview of the analytical quality performance of the entire laboratory with one glance and can be handled on the Excel platform. © 2011 by Walter de Gruyter Berlin New York.


Haeckel R.,Bremer Zentrum For Laboratoriumsmedizin | Wosniok W.,University of Bremen | Streichert T.,Universitatsklinik Cologne
Clinical Chemistry and Laboratory Medicine | Year: 2015

The organizers of the first EFLM Strategic Conference "Defining analytical performance goals" identified three models for defining analytical performance goals in laboratory medicine. Whereas the highest level of model 1 (outcome studies) is difficult to implement, the other levels are more or less based on subjective opinions of experts, with models 2 (based on biological variation) and 3 (defined by the state-of-the-art) being more objective. A working group of the German Society of Clinical Chemistry and Laboratory Medicine (DGKL) proposes a combination of models 2 and 3 to overcome some disadvantages inherent to both models. In the new model, the permissible imprecision is not defined as a constant proportion of biological variation but by a non-linear relationship between permissible analytical and biological variation. Furthermore, the permissible imprecision is referred to the target quantity value. The biological variation is derived from the reference interval, if appropriate, after logarithmic transformation of the reference limits. © 2015 by De Gruyter.


Zierk J.,Friedrich - Alexander - University, Erlangen - Nuremberg | Arzideh F.,University of Bremen | Haeckel R.,Bremer Zentrum For Laboratoriumsmedizin | Rascher W.,Friedrich - Alexander - University, Erlangen - Nuremberg | And 2 more authors.
Clinical Chemistry and Laboratory Medicine | Year: 2013

Background: Determination of pediatric reference intervals (RIs) for laboratory quantities, including hematological quantities, is complex. The measured quantities vary by age, and obtaining samples from healthy children is difficult. Many widely used RIs are derived from small sample numbers and are split into arbitrary discrete age intervals. Use of intra-laboratory RIs specific to the examined population and analytical device used is not yet fully established. Indirect methods address these issues by deriving RIs from clinical laboratory databases which contain large datasets of both healthy and pathological samples. Methods: A refined indirect approach was used to create continuous age-dependent RIs for blood count quantities and sodium from birth to adulthood. The dataset for each quantity consisted of 60,000 individual samples from our clinical laboratory. Patient samples were separated according to age, and a density function of the proportion of healthy samples was estimated for each age group. The resulting RIs were merged to obtain continuous RIs from birth to adulthood. Results: The obtained RIs were compared to RIs generated by identical laboratory instruments, and to population- specific RIs created using conventional methods. This comparison showed a high concordance of reference limits and their age-dependent dynamics. Conclusions: The indirect approach reported here is wellsuited to create continuous, intra-laboratory RIs from clinical laboratory databases and showed that the RIs generated are comparable to those created using established methods. The procedure can be transferred to other laboratory quantities and can be used as an alternative method for RI determination where conventional approaches are limited.


Haeckel R.,Bremer Zentrum For Laboratoriumsmedizin | Sonntag O.,Bio Rad Laboratories GmbH
LaboratoriumsMedizin | Year: 2012

The validation of analytical procedures in laboratory medicine has been discussed by many authors and several recommendations have been elaborated by working groups and standardization bodies. However, some problems have not sufficiently been solved, for example, permissible limits for the comparability between methods (permissible equivalence), what is the best statistical procedure for estimating the function of the fitting line in scatter plots, and permissible limits for the spread around the fitting line. The present article attempts to summarize the present state-of-the-art and to provide answers to some of the open problems. © 2012 by Walter de Gruyter Berlin Boston.


Haeckel R.,Bremer Zentrum For Laboratoriumsmedizin | Gurr E.,Abteilung Klinische Chemie | Keller T.,ACOMED statistik
LaboratoriumsMedizin | Year: 2016

Many laboratories observe that requirements of the Guideline of the German Medical Association RiliBÄK for the internal quality assurance are difficult to fulfill in the lower part of the measurement interval (e.g. thrombocyte count at 50·109/L). With 10 measurands, the RiliBÄK contain special limits for lower measurement quantities. But, these limits lead to artificial "jumps" and even may be too stringent in the very low region of the measurement interval. Requirements which are too stringent usually lead to repeats and unnecessary costs, and to unnecessary time delay. The DGKL working group Guide Limits proposes variable permissible limits depending on the measurand concentration applied in the control material. Then, in the 10 critical cases, higher permissible limits are obtained in the very low part of measurement intervals. The control materials used in ring trials should contain concentrations close to the lower decision limits. Then, the permissible limits provided by the RiliBÄK also appear too stringent in the lower part of the measurement intervals of many measurands. © 2016 Walter de Gruyter GmbH, Berlin/Boston.

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