Rainer Haeckel

Recommendations and opinions for the use of point-of-care testing for hospitals and primary care: summary of a 1999 symposium.

As part of a symposium on laboratory medicine, a colloquium on point-of-care testing was held in June 1999 where four experts were invited to produce recommendations and opinions on the use of point-of-care testing under various clinical venues. Each commented on costs for providing POCT services. A total of eleven recommendations and four opinions were rendered and discussed in an open forum. While one expert concluded that some forms of POCT are less expensive than central laboratory testing if entire laboratory workstations are eliminated, another expert suggested that POCT offered little advantage if rapid transport systems are available. A recommendation was made that POCT be considered for analytes that have a required reporting turnaround time of <30 min, and that the goals for precision and accuracy should be dictated by the clinical need and not by analytical limitations. Recommendations for POCT in specific clinical situations include use of glycated hemoglobin and urine albumin testing with personal glucose monitoring at the time of consultation, use of glycated albumin for gestational diabetes, leukocyte esterase and nitrite testing in urine to screen for urinary tract infections, coagulation tests for monitoring patients on oral anticoagulant therapy and in the operating room, testing for H. pylori for patients with dyspepsia, and cardiac markers and urine drugs-of-abuse testing in the emergency department.

A plea for intra-laboratory reference limits. Part 1. General considerations and concepts for determination.

Abstract Accurate results for quantitative procedures can be useless if the reference limits for the interpretation of laboratory results are unreliable. Recent concepts for quality management systems require that laboratories pay more attention to identification and verification of reference limits. Scientific recommendations often claim that each laboratory should determine intra-laboratory reference limits, which should be reviewed periodically. This recommendation is currently neglected by most laboratories; instead they use reference limits from external sources, despite various problems of transference. Prospective and retrospective methods either using or neglecting disease prevalences (polymodal or unimodal concepts, respectively) and applying different statistical approaches for determining reference limits have been described. The various procedures are reviewed with regard to their diagnostic sensitivity, specificity and (non-)efficiency. The present gold standard is the reference limit concept according to IFCC recommendations (a unimodal prospective approach). This concept, together with trueness-based standardization, is the most useful basis for harmonization of the decision-making process with laboratory results, despite complex problems of traceability and transference. This harmonization is at present only achieved for a limited number of analytes for which SI units and traceability can be technically realized. For the majority of measurands in laboratory medicine, much research is still required and results cannot be expected in the near future. For these measurands, a need remains for internal, efficient and simple identification of population-based reference limits. Therefore, newer retrospective concepts were developed that use large data sets from laboratory information systems to derive intra-laboratory reference limits. These approaches appear promising and should be further developed. Clin Chem Lab Med 2007;45:1033–42.

A plea for intra-laboratory reference limits. Part 2. A bimodal retrospective concept for determining reference limits from intra-laboratory databases demonstrated by catalytic activity concentrations of enzymes.

Abstract Background: The current recommendations for establishing intra-laboratory reference limits (RLs) cannot be fulfilled by most laboratories because of the expense involved. In the current study, a bimodal method was developed to derive RLs from data stored in a laboratory information system without any assumption concerning the distribution of the diseased subgroup. Methods: A smoothed kernel density function (Dmix) was estimated for the distribution of combined data for non-diseased and diseased adult subjects. It was assumed that the “central” part of the distribution represents the non-diseased population, which was defined and used to estimate a Gaussian distribution of either the original values or Box-Cox transformed data. This normal distribution was now considered the distribution of the non-diseased subgroup (Dnd). Percentiles were calculated to obtain retrospective RLs. The density function of the diseased subgroup (Dd) was calculated by subtracting the non-diseased density function from Dmix (Dd=Dmix–Dnd). The intersection point of the Dnd and Dd curves identified the RL with the highest diagnostic efficiency. Results: The model was applied to catalytic activity concentrations of several enzymes with data from different laboratories. The RLs obtained were similar to recently published consensus values. Differences between laboratories were small but significant. Gender stratification was necessary for alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutymaltransferse (γ-GT), not significant for lipase and amylase and inconsistent among the laboratories for alkaline phosphatase (AP) and lactate dehydrogenase (LDH). Age stratification was only tested for two groups (18–49 and ≥50 years) and was significant for AST (females only), γ-GT and lipase, not significant for amylase and inconsistent for AP, LDH and ALT. For γ-GT, further stratification for age in decades was necessary for males. Creatine kinase MB (CK-MB) values were not stratified owing to the low number of data available. Conclusions: Retrospective RLs derived from intra-laboratory data pools for the catalytic activity concentration of enzymes using a modified procedure plausibly agreed with published consensus values. However, most RLs varied significantly among laboratories, thus supporting the “old” plea for intra-laboratory RLs. Clin Chem Lab Med 2007;45:1043–57.

Age- and Sex-Specific Dynamics in 22 Hematologic and Biochemical Analytes from Birth to Adolescence

BACKGROUND Pediatric laboratory test results must be interpreted in the context of interindividual variation and age- and sex-dependent dynamics. Reference intervals as presently defined for separate age groups can only approximate the age-related dynamics encountered in pediatrics. Continuous reference intervals from birth to adulthood are not available for most laboratory analytes because of the ethical and practical constraints of defining reference intervals using a population of healthy community children. We applied an indirect method to generate continuous reference intervals for 22 hematologic and biochemical analytes by analyzing clinical laboratory data from blood samples taken during clinical care of patients. METHODS We included samples from 32 000 different inpatients and outpatients (167 000 samples per analyte) from a German pediatric tertiary care center. Measurements were performed on a Sysmex-XE 2100 and a Cobas Integra 800 during clinical care over a 6-year period. The distribution of samples considered normal was estimated with an established indirect statistical approach and used for the calculation of reference intervals. RESULTS We provide continuous reference intervals from birth to adulthood for 9 hematology analytes (hemoglobin, hematocrit, red cell indices, red cell count, red cell distribution width, white cell count, and platelet count) and 13 biochemical analytes (sodium, chloride, potassium, calcium, magnesium, phosphate, creatinine, aspartate transaminase, alanine transaminase, γ-glutamyltransferase, alkaline phosphatase, lactate dehydrogenase, and total protein). CONCLUSIONS Continuous reference intervals capture the population changes in laboratory analytes during pediatric development more accurately than age groups. After local validation, the reference intervals provided should allow a more precise consideration of these dynamics in clinical decision making.

A new concept to derive permissible limits for analytical imprecision and bias considering diagnostic requirements and technical state-of-the-art.

Abstract 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.

Indirect determination of pediatric blood count reference intervals

Abstract 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 well-suited 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.

Indirect reference intervals of plasma and serum thyrotropin (TSH) concentrations from intra-laboratory data bases from several German and Italian medical centres

Abstract 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.

Pediatric reference intervals for alkaline phosphatase

Abstract Background: Interpretation of alkaline phosphatase activity in children is challenging due to extensive changes with growth and puberty leading to distinct sex- and age-specific dynamics. Continuous percentile charts from birth to adulthood allow accurate consideration of these dynamics and seem reasonable for an analyte as closely linked to growth as alkaline phosphatase. However, the ethical and practical challenges unique to pediatric reference intervals have restricted the creation of such percentile charts, resulting in limitations when clinical decisions are based on alkaline phosphatase activity. Methods: We applied an indirect method to generate percentile charts for alkaline phosphatase activity using clinical laboratory data collected during the clinical care of patients. A total of 361,405 samples from 124,440 patients from six German tertiary care centers and one German laboratory service provider measured between January 2004 and June 2015 were analyzed. Measurement of alkaline phosphatase activity was performed on Roche Cobas analyzers using the IFCC’s photometric method. Results: We created percentile charts for alkaline phosphatase activity in girls and boys from birth to 18 years which can be used as reference intervals. Additionally, data tables of age- and sex-specific percentile values allow the incorporation of these results into laboratory information systems. Conclusions: The percentile charts provided enable the appropriate differential diagnosis of changes in alkaline phosphatase activity due to disease and changes due to physiological development. After local validation, integration of the provided percentile charts into result reporting facilitates precise assessment of alkaline phosphatase dynamics in pediatrics.

Observed, unknown distributions of clinical chemical quantities should be considered to be log-normal: a proposal

Abstract The distribution of many quantities in laboratory medicine are considered to be Gaussian if they are symmetric, although, theoretically, a Gaussian distribution is not plausible for quantities that can attain only non-negative values. If a distribution is skewed, further specification of the type is required, which may be difficult to provide. Skewed (non-Gaussian) distributions found in clinical chemistry usually show only moderately large positive skewness (e.g., log-normal- and χ2 distribution). The degree of skewness depends on the magnitude of the empirical biological variation (CVe), as demonstrated using the log-normal distribution. A Gaussian distribution with a small CVe (e.g., for plasma sodium) is very similar to a log-normal distribution with the same CVe. In contrast, a relatively large CVe (e.g., plasma aspartate aminotransferase) leads to distinct differences between a Gaussian and a log-normal distribution. If the type of an empirical distribution is unknown, it is proposed that a log-normal distribution be assumed in such cases. This avoids distributional assumptions that are not plausible and does not contradict the observation that distributions with small biological variation look very similar to a Gaussian distribution. Clin Chem Lab Med 2010;48:1393–6.

Permissible limits for uncertainty of measurement in laboratory medicine

Abstract 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.