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Objectives: Young laboratory medicine professionals (YLMPs) are the future of clinical laboratories. Although everyday practice shows significant differences among countries, especially during residency training, most of them face the same challenges. Besides promoting scientific, professional and clinical aspects of laboratory medicine in Europe, the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) should take into consideration YLMPs' concerns and interests to help them achieve excellence. The aim of this survey was to assess the opinion and expectations of YLMPs about their involvement in the activities of EFLM., Methods: An online survey was distributed to YLMPs in Europe through different channels. The questionnaire consisted of 21 items grouped into five sections: demographic questions, opinion about the current status of YLMPs within EFLM, YLMPs network, suggestions and opportunities, and scientific training and exchange. Where appropriate, responses from residents and specialists were compared., Results: A total of 329 valid responses were obtained from 53 different countries. Countries with the highest number of participants were Spain, Turkey, Croatia and Romania. A significant percentage would like to know more about EFLM and their activities (86%) and wish EFLM promoted networking and scientific exchanges (95%), for instance by means of a European YLMPs network (93%). EFLMLabX project was widely unknown (75%)., Conclusions: YLMPs demand better connection to share concerns about daily healthcare duties, to keep updated and to advance professionally. EFLM needs to improve their advertising through national societies to increase YLMPs' participation. In addition to international meetings and congresses, respondents have emphasized that workshops and other small group activities would significantly help promote laboratory medicine practice in Europe.

Measurement imprecision is usually calculated from measurement results of the same stabilized control material(s) obtained over time, and is therefore, principally, only valid at the concentration(s) of the selected control material(s). The resulting uncertainty has been obtained under reproducibility conditions and corresponds to the conventional analytical goals. Furthermore, the commutability of the control materials used determines whether the imprecision calculated from the control materials reflects the imprecision of measuring patient samples. Imprecision estimated by measurements of patient samples uses fully commutable samples, freely available in the laboratories. It is commonly performed by calculating the results of routine patient samples measured twice each. Since the duplicates are usually analysed throughout the entire concentration interval of the patient samples processed in the laboratory, the result will be a weighted average of the repeatability imprecision measured in the chosen measurement intervals or throughout the entire interval of concentrations encountered in patient care. In contrast, the uncertainty derived from many measurements of control materials over periods of weeks is usually made under reproducibility conditions. Consequently, the repeatability and reproducibility imprecision play different roles in the inference of results in clinical medicine. The purpose of the present review is to detail the properties of the imprecision calculated by duplicates of natural samples, to explain how it differs from imprecision calculated from single concentrations of control materials, and to elucidate what precautions need to be taken in case of bias, e.g. due to carry-over effects.

Measurement uncertainties in clinical chemistry are commonly regarded as heteroscedastic - having a constant relative standard deviation irrespective of the concentration of the measurand. The uncertainty is usually determined at two concentrations using stabilized control materials and assumed to represent the analytical goal. The purpose of the present study was to use duplicates of unselected patient samples to calculate the absolute and relative repeatability component of the intra-laboratory measurement uncertainty from duplicates, using the Dahlberg formula and analysis of variance components. Estimates were made at five different concentration intervals of ALT, AST, Calcium, Cholesterol, Creatinine, CRP, Triglycerides and TSH covering the entire concentration interval of the patient cohort. This partioning allows detailing their repeatability profiles. The calculations of the profiles were based on randomly selected results from sets of duplicates ranging from 12,000 to 65,000 pairs. The repeatability of the measurands showed substantial variability within the measuring interval. Therefore, characterizing imprecision profiles as purely homo- or heteroscedastic or by a single number may not be optimal for the intended use. The present data make a case for nuancing the evaluation of analytical goals and minimal differences of measurement results by establishing uncertainty profiles under repeatability conditions, using natural patient samples.

For many years the concept of patient-based quality control (QC) has been discussed and implemented in hematology laboratories; however, the techniques have not been widely implemented in clinical chemistry. This is mainly because of the complexity of this form of QC, as it needs to be optimized for each population and often for each analyte. However, the clear advantages of this form of QC, together with the ongoing realization of the shortcomings of "conventional" QC, have driven a need to provide guidance to laboratories to assist in deploying patient-based QC. This overview describes the components of a patient-based QC system (calculation algorithm, block size, truncation limits, control limits) and the relationship of these to the analyte being controlled. We also discuss the need for patient-based QC system optimization using patient data from the individual testing laboratory to reliably detect systematic errors while ensuring that there are few false alarms. The term patient-based real-time quality control covers many activities that use data from patient samples to detect analytical errors. These activities include the monitoring of patient population parameters such as the mean or median analyte value or using single within-patient changes such as the delta check. In this report, we will restrict the discussion to population-based parameters. This overview is intended to serve as a guide for the implementation of a patient-based QC system. The report does not cover the clinical evaluation of the population., (© 2019 American Association for Clinical Chemistry.)

Introduction: An increase in analytical imprecision (expressed as CV a ) can introduce additional variability (i.e. noise) to the patient results, which poses a challenge to the optimal management of patients. Relatively little work has been done to address the need for continuous monitoring of analytical imprecision., Methods: Through numerical simulations, we describe the use of moving standard deviation (movSD) and a recently described moving sum of outlier (movSO) patient results as means for detecting increased analytical imprecision, and compare their performances against internal quality control (QC) and the average of normal (AoN) approaches., Results: The power of detecting an increase in CV a is suboptimal under routine internal QC procedures. The AoN technique almost always had the highest average number of patient results affected before error detection (ANPed), indicating that it had generally the worst capability for detecting an increased CV a . On the other hand, the movSD and movSO approaches were able to detect an increased CV a at significantly lower ANPed, particularly for measurands that displayed a relatively small ratio of biological variation to CV a. CONCLUSION: The movSD and movSO approaches are effective in detecting an increase in CV a for high-risk measurands with small biological variation. Their performance is relatively poor when the biological variation is large. However, the clinical risks of an increase in analytical imprecision is attenuated for these measurands as an increased analytical imprecision will only add marginally to the total variation and less likely to impact on the clinical care., (Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Reliable and accurate reference intervals (RIs) for laboratory analyses are an integral part of the process of correct interpretation of clinical laboratory test results. RIs given in laboratory reports have an important role in aiding the clinician in interpreting test results in reference to values for healthy populations. Since the 1980s, the International Federation of Clinical Chemistry (IFCC) has been proactive in establishing recommendations to clarify the true significance of the term 'RIs, to select the appropriate reference population and statistically analyse the data. The C28-A3 guideline published by the Clinical and Laboratory Standards Institute (CLSI) and IFCC is still the most widely-used source of reference in this area. In recent years, protocols additional to the Guideline have been published by the IFCC, Committee on Reference Intervals and Decision Limits (C-RIDL), including all details of multicenter studies on RIs to meet the requirements in this area. Multicentric RIs studies are the most important development in the area of RIs. Recently, the C-RIDL has performed many multicentric studies to obtain common RIs. Confusion of RIs and clinical decision limits (CDLs) remains an issue and pediatric and geriatric age groups are a significant problem. For future studies of RIs, the genetic effect would seem to be the most challenging area. 
The aim of the review is to present the current theory and practice of RIs, with special emphasis given to multicenter RIs studies, RIs studies for pediatric and geriatric age groups, clinical decision limits and partitioning by genetic effects on RIs.

Background: Accurate and reliable testing reports play an important role in the prevention, diagnosis, treatment and prognosis of disease. However, little is known about the appropriateness of laboratory testing reporting in China. This national survey takes clinical biochemistry as an example to investigate the state of reporting appropriateness in our country., Methods: An electronic questionnaire was sent to 1209 laboratories. The participants were asked to retrospectively evaluate the error rates of the following quality indicators: report template integrity, report content filling integrity, report delay, report recall, non-conformities between instrument and laboratory information system (LIS) data, non-conformities between report and request, report notification error, and report modification. Mann-Whitney and Kruskal-Wallis tests were used to identify the potential impacts of reporting appropriateness., Results: A total of 662 of the 1209 laboratories (55%) submitted the survey results, with three returning incomplete data. For the integrity of the report, only 31% of the laboratories had a complete report template that contained all of 21 elements. In addition, the overall error rate of content filling integrity was 45.9% for 19,770 pieces of reports. The overall σ-values of other six quality indicators were all >4, and no significant difference was found among different departments. Group comparison suggested that reporting electronically had a better performance., Conclusions: The laboratory reporting system in China needs to improve, particularly the integrity of the report. Strengthening information technology will not only promote reporting appropriateness, but also guarantee accurate, standardized and traceable data collection and long-term monitoring.

The US National Toxicology Program recommends the use of the parametric multiple comparison procedures of Dunnett and Williams for the evaluation of repeated toxicity studies. For endpoints where either increasing or decreasing effects are of toxicological relevance, we recommend the use of the two-sided Dunnett test exclusively. For the many other endpoints, where a priori only one direction is of toxicological relevance, however, we recommend the combination of Dunnett and Williams test. In particular, we recommend the so-called Umbrella-protected Williams test which offers insights for all interesting monotone and non-monotone alternatives while only suffering a marginal loss in power compared to the Dunnett test. We illustrate the power difference analytically and compare the approach for different endpoint types using three real data examples to alternative tests available. Nonparametric tests, which are suitable for the evaluation of skewed distributed or scores data, are also considered. Particular attention is given to the different interpretations of the findings revealed by the different test. R programs used for the analyses are provided.

Background: The objective of this study was to determine the upper normal limit of serum alanine aminotransferase level in a population-based study in Golestan Province, northeast Iran., Methods: From the randomly invited individuals (2,292), 698 out of the 916 males and 1,351 out of the 1,376 females participated in the study (participation rate: 76.2% and 98.1%, respectively). One hundred and twenty-one participants were excluded due to positive hepatitis B surface antigen or hepatitis C virus antibody and/or drinking more than 20 grams of alcohol per day. A total of 1,928 participants (1300 females) were included. The upper normal limit of serum alanine aminotransferase level was defined as the 95th percentile., Results: The upper normal limit of serum alanine aminotransferase level in normal weight and nondiabetics was significantly lower than the total study group (36 versus 45 U/L). Serum alanine aminotransferase level was independently associated with male gender, body mass index, and diabetes mellitus (OR=2.05; 95%CI: 1.44 - 2.94, OR=2.76; 95%CI: 1.84 - 4.13, and OR=2.96; 95%CI: 1.56 - 5.61, respectively)., Conclusion: Considering the lower calculated upper normal limit in normal weight nondiabetic participants in this study, we recommend setting new upper normal limit for serum alanine aminotransferase level. It seems reasonable to set upper normal limit for serum alanine aminotransferase level in males and females separately.

Context: Harmonization and standardization of results among different clinical laboratories is necessary for clinical practice guidelines to be established., Objective: To evaluate the state of the art in measuring 10 routine chemistry analytes., Design: A specimen prepared as off-the-clot pooled sera and 4 conventionally prepared specimens were sent to participants in the College of American Pathologists Chemistry Survey. Analyte concentrations were assigned by reference measurement procedures., Participants: Approximately 6000 clinical laboratories., Results: For glucose, iron, potassium, and uric acid, more than 87.5% of peer groups meet the desirable bias goals based on biologic variability criteria. The remaining 6 analytes had less than 52% of peer groups that met the desirable bias criteria., Conclusions: Routine measurement procedures for some analytes had acceptable traceability to reference systems. Conventionally prepared proficiency testing specimens were not adequately commutable with a fresh frozen specimen to be used to evaluate trueness of methods compared with a reference measurement procedure.

The measurement of TSH receptor antibody (TRAb) has been recommended to predict the risk of neonatal hyperthyroidism (NH) in pregnant women with Graves' disease (GD). For the first generation TRAb (TRAb1) assay with commercial kit (Brahms, Berlin, Germany; or Cosmic co., Tokyo, Japan) an arbitrary limit of 40 U/l or 50% was suggested to indicate risk when measured late in pregnancy. In order to substitute TRAb1 with the second generation TRAb using porcine TSH receptor (pTRAb2) and human recombinant TSH receptor (hTRAb2) and the third generation TRAb (TRAb3) assay for this purpose, we measured TRAb in these four methods late in pregnancy in a total of 62 pregnant women with Graves' disease. The data showed that no cases with TRAb1 >50% has been missed if the TRAb1 assay was replaced by the pTRAb2, hTRAb2 or TRAb3 assay using their equivalent cut-off value of 70%, 10 IU/l, and 75%, respectively, but that an additional group of women would have been included in the risk group, especially in the TRAb3 assay. Next, the effect of maternal TRAb on thyroid function of offspring was studied in the 47 pregnant women with GD (43 with TRAb1 <50% and 4 with TRAb1 >50% during late pregnancy). In 2 women who gave birth to hyperthyroid children at days 6 and 14 of life, the maternal sera had strongly positive levels of TRAb1 (73.5% and 84.1%), pTRAb2 (84.9% and 91.5%), hTRAb2 (40.68 IU/L and 89.70 IU/L) and TRAb3 (92.1% and 93.5%) late in pregnancy, with one case displaying high positive (1114.3%) thyroid stimulating antibody (TSAb) level and the other case had moderate positive (433%) TSAb level. Of the remaining 45 women, 43 had TRAb1 <50% and the other 2 had TRAb >50% including 1 with low TSAb positive and 1 with positive thyroid stimulating blocking antibody (TSBAb) and negative TSAb; all of them gave birth to euthyroid children. Finally, a serial study regarding TRAb in 23 women with Graves' disease during pregnancy showed that TRAb1, pTRAb2, hTRAb2, TRAb3 value and TSAb level decreased significantly as pregnancy progressed. In conclusion, the present study supported TRAb as a useful marker to predict the risk of NH.

Quantitative data on the components of biological variation (BV) are used for several purposes, including calculating the reference change value (RCV) required for the assessment of the significance of changes in serial results in an individual. Pathology may modify the set point in diseased patients and, more importantly, the variation around that set-point. Our aim was to collate all published BV data in situations other than health. We report the within-subject coefficient of variation (CV(I)) for 66 quantities in 34 disease states. We compared the results with the CV(I) determined in healthy individuals and examined whether the data derived in specific diseases could be useful for clinical applications. For the majority of quantities studied, CV(I) values are of the same order in disease and health: thus the use of RCV derived from healthy subjects for monitoring patients would be reasonable. However, for a small number of quantities considered to be disease specific markers, the CV(I) differed from those in health. This could mean that RCV derived from healthy CV(I) may be inappropriate for monitoring patients in certain diseases. Hence, disease-specific RCVs may be clinically useful.

Background: Excessive use of significant figures in numerical data gives a spurious impression of laboratory imprecision to clinicians. We describe reporting practices in 24 Asia-Pacific laboratories, assess whether these reporting formats and those used in the literature can be justified based on actual laboratory performance and outline how to choose the appropriate number of significant places., Methods: Thirty-two laboratories in Asia-Pacific were surveyed as to their reporting practices for serum creatinine, ferritin, sodium and TSH. Imprecision data from the General Serum Chemistry program from the RCPA-AACB Quality Assurance Program (QAP) were used to assess whether the reporting unit magnitude implicitly suggested in Tietz, the RCPA Manual and the General Serum Chemistry program itself was justified., Results: There was a 75% response rate to the survey, with laboratories generally reporting data using unjustifiable deciles. Unit sizes from the RCPA manual, Tietz and the RCPA-AACB QAP were not justified by the majority of laboratories in the RCPA-AACB QAP., Conclusions: The reporting unit size used by many laboratories is not justified by present laboratory performance using a 95% probability level. A consensus on appropriate reporting unit size is needed to encourage laboratories to change their present reporting formats.

Measurement of circulating B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) can identify patients with heart failure and guide therapy. The limit of detection, linearity, imprecision, method comparison, analytic concordance, and reference intervals of the Access 2 BNP (Biosite, San Diego, CA), ADVIA Centaur BNP (Bayer Diagnostics, Tarrytown, NY), AxSYM BNP (Abbott Diagnostics, Abbott Park, IL), and E170 NT-proBNP (Roche Diagnostics, Indianapolis, IN) methods were evaluated. The Triage meter BNP assay (Biosite) was the comparison method. Imprecision testing showed total coefficients of variation of 4.1%, 4.4%, 5.5%, and 0.8% for the Access 2, ADVIA Centaur, AxSYM, and E170, respectively. Relative to the Triage meter, method comparison revealed a slope of 0.96 and r = 0.95, a slope of 0.77 and r = 0.92, a slope of 1.13 and r = 0.94, and a slope of 8.8 and r = 0.80 for the Access 2, ADVIA Centaur, AxSYM, and E170, respectively. Overall analytic concordance values with the Triage meter were 95.9%, 92.9%, 92.4%, and 84.3% for the Access 2, ADVIA Centaur, AxSYM, and E170, respectively. All automated natriuretic peptide methods showed acceptable analytic performance.

Background: There is a plethora of supposedly evidence-based published clinical guidelines, most often prepared under the auspices of professional bodies. Many guidelines contain numerical laboratory test results as criteria for clinical action, very often simply quoted as single numbers. Every test result is subject to a number of sources of variation. Analytical imprecision and within-subject biological variation are particularly important. The influence of both of these on the dispersion of a single test result and on the number of samples required to make clinical decisions can be easily calculated using simple formulae. The effect of performing replicate analyses of one sample and of taking multiple samples can also be easily investigated. Authors of scientific statements, clinical guidelines, and practice recommendations should undertake such calculations before promulgating their efforts in the public domain. Guidelines on cholesterol and high sensitivity C-reactive protein have been examined using these approaches and these investigations allow the following conclusions., Conclusions: Analytical imprecision should be made low. If analytical imprecision is generally greater than biological variation, then reduction in analytical imprecision is valuable. If biological variation is greater than imprecision, then collection of more than one sample from an individual prior to decision-making is useful.

Background: According to recent International Organization for Standardization (ISO) standards, the limit of detection (LoD) of an assay should be estimated taking both type I (alpha) and II (beta) errors into account. The suggested procedure, however, supposes gaussian distributions of both blank and sample measurements and a linear calibration curve. In clinical chemistry, asymmetric, nongaussian blank distributions are common, and the calibration curve may be nonlinear. We present a partly nonparametric procedure that takes these aspects into account., Methods: Using theoretical distribution models and simulation studies, we developed a LoD estimation procedure suitable for the field of clinical chemistry that is partly based on nonparametric statistics., Results: For sample size n, the nonparametrically determined 95th percentile of the blank measurements obtained as the value of the [n(95/100) + 0.5]th ordered observation defines the limit for results significantly exceeding zero [limit of blank (LoB)]. The LoD is the lowest value that is likely to yield a result exceeding the LoB. LoD is estimated as: LoB + cbeta x SDS, where SDS is the analytical SD of a sample with a low concentration; cbeta = z(1 - beta)/[1 - 1/(4 x f)]; z(1 - beta) is the standard normal deviate; and f is the number of degrees of freedom for estimation of SD(S). c(beta) is approximately equal to 1.65 for a type II error of 5%. Approaches and needed tabular values for calculation of confidence limits are presented as well as sample size. Worked examples are given to illustrate estimation and verification of the limit of detection. Simulation results are used to document performance., Conclusion: The proposed procedure appears useful for application in the field of clinical chemistry and promotes a standardized approach for estimating LoDs of clinical chemistry assays.

Background: A proposal to calculate and use the reference change value (RCV) as an objective guide for interpreting the numerical results obtained in clinical laboratory serial testing is introduced in this study., Methods: A database showing the results of a compilation of 191 publications on biological variation and including information on a number of analytes provided the standardized criterion based on biology for calculating the RCVs., Results: For each of the 261 analytes included in the study, the RCV was determined using Harris's formula, replacing analytical imprecision with the desirable specification of analytical quality based on half the within-subject biological variation at 95% probability levels. The result is a guide for a common criterion to identify clinically significant changes in serial results., Conclusions: The RCV concept is an approach that can be offered by laboratories to assess changes in serial results. The RCV data in this study are presented as a point of departure for a widely applicable objective guide to interpret changes in serial results.

The Harris-Boyd method, recommended for partitioning biochemical reference data into subgroups by the NCCLS, and a recently proposed new method for partitioning were compared in three case studies concerning stratification by countries (Denmark, Finland, Norway, and Sweden) of reference data collected in the Nordic Reference Interval Project (NORIP) for the enzymes alkaline phosphatase (ALP), creatine kinase (CK), and gamma-glutamyl transpeptidase (GGT). The new method is based on direct estimation of the proportions of two subgroups outside the reference limits of the combined distribution, while the Harris-Boyd method uses easy-to-calculate test parameters as correlates for these proportions. The decisions on partitioning suggested by the Harris-Boyd method deviated from those obtained by using the new method for each of the three enzymes when considering pair-wise partitioning tests. The reasons for the poor performance, as it seems to be, of the Harris-Boyd method were discussed. Stratification of reference data into more than two subgroups was considered as both a theoretical problem and a practical one, using the four country-specific distributions for each enzyme as illustration. Neither the Harris-Boyd method nor the new method seems ideal to solve the partitioning problem in the case of several subgroups. The results obtained by using prevalence-adjusted values for the proportions seemed, however, to warrant the conclusion to be made that there are no major differences in terms of the partitioning criteria between the levels of each of the three enzymes in the four countries. Because these three enzymes include those two tests (CK, GGT), which in the preliminary analyses of the project data had shown largest variation between countries, the tentative conclusion was drawn that application of common reference intervals in the Nordic countries is feasible, not only for the three enzymes examined in the present study but for all of the tests involved in the NORIP project.

As part of the Nordic Reference Interval Project we present reference intervals for alanine transaminase (ALT), aspartate transaminase (AST), creatine kinase (CK), lactate dehydrogenase (LD), alkaline phosphatase (ALP), gamma-glutamyltransferase (GT), amylase (AMY) and pancreatic type of AMY in blood of adult males and females. A total of 3036 reference persons, all of whom considered themselves to be in good health, were recruited by 102 Nordic clinical biochemical laboratories. Exclusions were undertaken on the basis of predefined biochemical and clinical criteria. Enzyme activities in serum and plasma were measured in the different laboratories using various commercially available routine measurement systems at 37 degrees C. Only results obtained with the International Federation of Clinical Chemistry (IFCC) compatible measuring systems were selected for estimation of the enzyme reference intervals. The final number of results on each enzyme varied from 459 (LD) to 2300 (ALT). The 2.5 and 97.5 percentile reference limits were calculated by a non-parametric method in accordance with the IFCC recommendations, using the Refval 4.0 data program. Statistical partitioning testing was undertaken to decide whether the reference intervals ought to be partitioned according to gender and/or age. For most of the enzymes, but not for all, the upper reference limits were found to be higher than those that have been in general use until now.

Aim: The healthy ranges for serum alanine aminotransferase (ALT) levels are less well studied. The aim of this study was to define the upper limit of normal (ULN) for serum ALT levels, and to assess factors associated with serum ALT activity in apparently healthy blood donors., Methods: A total of 1,939 blood donors were included. ALT measurements were performed for all cases using the same laboratory method. Healthy ranges for ALT levels were computed from the population at the lowest risk for liver disease. Univariate and multivariate analyses were performed to evaluate associations between clinical factors and ALT levels., Results: Serum ALT activity was independently associated with body mass index (BMI) and male gender, but not associated with age. Association of ALT with BMI was more prominent in males than in females. Upper limit of normal for non-overweight women (BMI of less than 25) was 34 U/L, and for non-overweight men was 40 U/L., Conclusion: Serum ALT is strongly associated with sex and BMI. The normal range of ALT should be defined for male and female separately.

A group of neurologists and clinical neurochemists representing twelve countries worked towards a consensus on laboratory techniques to improve the quality of analysis and interpretation of cerebrospinal fluid (CSF) proteins. Consensus was approached via a virtual Lotus Notes-based TeamRoom. This new approach respecting multicultural differences, common views, and minority opinions, is available in http://www.teamspace.net/ CSF, presenting the implicit, complementary version of this explicit, printed consensus. Three key recommendations were made: CSF and (appropriately diluted) serum samples should be analyzed together in one analytical run, i.e., with reference to the same calibration curve. Results are evaluated as CSF/serum quotients, taking into account the non-linear, hyperbolic relation between immunoglobulin (Ig)- and albumin-quotients rather than using the linear IgG index or IgG synthesis rate. Controls should include materials with values within the reference ranges (IgM: 0.5-1.5 mg/l; IgA: 1-3 mg/l; IgG: 10-30 mg/l and albumin: 100-300 mg/l). The physiological, methodological and clinical significance of CSF/serum quotients is reviewed. We confirmed the previous consensus on oligoclonal IgG, in particular the usefulness of the five typical interpretation patterns. The group compared current external and internal quality assurance schemes and encouraged all members to maintain national or local traditions. Values for acceptable imprecision in the CSF quality assurance are proposed.

The new selective access analyser Cobas Integra 800 from Roche Diagnostics was evaluated in an international multicentre study at six sites. Routine simulation experiments showed good performance and full functionality of the instrument and provocation of anomalous situations generated no problems. The new features on Cobas Integra 800, namely clot detection and dispensing control, worked according to specifications. The imprecision of Cobas Integra 800 fulfilled the proposed quality specifications regarding imprecision of analytical systems for clinical chemistry with few exceptions. Claims for linearity, drift, and carry-over were all within the defined specifications, except urea linearity. Interference exists in some cases, as could be expected due to the chemistries applied. Accuracy met the proposed quality specifications, except in some special cases. Method comparisons with Cobas Integra 700 showed good agreement; comparisons with other analysis systems yielded in several cases explicable deviations. Practicability of Cobas Integra 800 met or exceeded the requirements for more than 95% of all attributes rated. The strong points of the new analysis system were reagent handling, long stability of calibration curves, high number of tests on board, compatibility of the sample carrier to other Roche systems, and the sample integrity check for more reliable analytical results. The improvement of the workflow offered by the 5-position rack and STAT handling like on Cobas Integra 800 makes the instrument attractive for further consolidation in the medium-sized laboratory, for dedicated use of special analytes, and/or as back-up in the large routine laboratory.

Aims: To investigate the research productivity of all staff in chemical pathology., Methods: Chemical pathologists or biochemical scientists were identified from publicly available sources. All journals, their impact factors (IFs), and individual publications over the period of 1995 to 1999 were identified from electronic databases. Each publication was subclassified with respect to type of publication, number and position of author, and subspecialty to which the article referred., Results: Research output over the period comprised 6162 articles, originating from 1399 individuals, 264 of whom were medically qualified. Specialty initiated research accounted for 26% of the total publications and 80% of the research was performed in teaching hospitals. Research output was highly skewed because 49% of individuals published a letter or more, 20% published one original piece of research over five years, but only 4% were research active, as defined by one publication each year. International standard research, defined as one paper each year in journals with IF > 4, was achieved by 1% of the profession, mostly aged > 55 years. Skewed distributions of publication rates were found in all age deciles. The possession of higher research degrees correlated with higher output in all age deciles., Conclusions: Those working in chemical pathology are active in initiating and conducting research, although at a low level. Because longterm activity in research correlates with the possession of higher research degrees and the opportunity to carry out research from early in career pathways, priority should be given to encouraging research in training, given the small and ageing profile of international quality research in the profession in the UK.

The Institute of Medicine (IOM) of the National Academy of Sciences was commissioned by Congress to study the current system for the payment of diagnostic clinical laboratory services provided to Medicare beneficiaries. The current system was established in 1984 and has grown in complexity and is of diminishing contemporary relevance. The IOM recommended that a single, rational, nationalfee schedule be established and that it be initially based on the National Limitation Amount (NLA) currently mandated as the national fee cap. To estimate the potential budgetary impact of this recommendation, we merged the 1999 Part B Extract and Summary System and the 1999 Clinical Diagnostic Laboratory Fee Schedule (CLFS). By using an estimated 193 million allowed services from this data set and the current mean fee of $9.14 per test, current spending is approximately $1,768 million. The impact of raising the CLFS to the NLA will be approximately $1,792 million, or $9.26 per test. The estimated cumulative budgetary effect, factoring in the current forecast for the Consumer Price Index, is an increase of approximately $993 million over 5 years and $2,359 million over 10 years.

There is a growing pressure on clinical chemistry laboratories to conform to quality standards that require the evaluation and expression of the uncertainty of results of measurement. Nevertheless, there is some reluctance to accept the uncertainty concept in the analytical community due to difficulty in evaluating uncertainty in practice. For example, often the uncertainty of some uncertainty components is not known very well in clinical chemistry measurements, such as those associated with matrix effects or with the values of the calibrators. Moreover, it is not clear how to interpret uncertainty in relation to diagnostic criteria, reference ranges and other decision limits in clinical chemistry practice. Hence, the value of reporting the uncertainty of the measurement result is not obvious. In this paper it is suggested a relatively simple, logical procedure for evaluating measurement uncertainty based on the principles in the Guide for the Expression of Uncertainty of Measurement (GUM). The measurement process is partitioned into elements that are well known to the analyst, namely sampling, calibration, and analysis. The corresponding model function expresses the result of a measurement as the value obtained by the analytical procedure multiplied by the correction factors for sampling bias, for bias caused by the calibrators, and for other types of bias. Under normal conditions, when the measurement procedure is validated and corrected for all known bias, the expected value of each correction factor is one. The uncertainty that remains with regard to sampling, manufacturing of calibrators and other types of bias is combined with the analytical imprecision to yield a combined uncertainty of a result of measurement. The advantages of this approach are: (i) Data from the method validation, internal quality control and from participation in external quality control schemes can be used as input in the uncertainty evaluation process. (ii) The partition of the measurement into well-defined tasks highlights the different responsibilities of the clinical chemistry laboratory and of the manufacturer of reagents and calibrators. (iii) The approach can be used to harmonize the uncertainty evaluation process, which is particularly relevant for laboratories seeking accreditation under ISO 17025. The application of the proposed model is demonstrated by evaluating the uncertainty of a result of a measurement of prolactin in human serum. In the example it is shown how to treat the uncertainty associated with a calibrator supplied with a commercial analytical kit, and how to evaluate the uncertainty associated with matrix effects.

COBAS INTEGRA 400 is a random-access analytical system consolidating assays for clinical chemistry analytes, electrolytes, serum proteins, drugs of abuse and therapeutic drugs. Analytical performance and practicability of the instrument were evaluated in seven laboratories over a 2-year period in parallel with system development. Good within-run and total imprecision for all assays was observed with a few exceptions for specimen pools with low concentration or activity. The coefficients of variation for total imprecision were well below 3.0% for clinical chemistry analytes and electrolytes, and below 5.0% for serum proteins and therapeutic drugs. Method comparisons demonstrated a good agreement with the various systems used for comparison, with slopes varying typically from 0.94 to 1.05, and Spearman correlation coefficient generally > 0.975. Accuracy was verified by recovery of controls and certified reference materials within 90 to 110% of target values. Assay ranges were linear within +/- 5%. No carry-over on reagent or sample pipetting systems was observed. Manufacturer-specified interference limits and onboard stabilities of reagents were confirmed. A time study for calculating direct personnel times and total processing time was carried out in three laboratories under different conditions including consolidated, STAT and dedicated use. On a scenario-independent basis, the total working time was shorter on the COBAS INTEGRA 400 than on routine systems in all three laboratories. Personnel time, in particular, was significantly reduced when compared to routine instruments. In general, system practicability was judged very positively in all laboratories. Owing to its versatility, the instrument is best placed as a consolidated workstation in small- to medium-sized laboratories or as an instrument for special determinations such as serum proteins, drugs, urinalysis or emergency analyses in large laboratories.

Hospitals in Sweden differ greatly in their use of laboratory tests. These differences seem to be due to traditions and regional differences. The cost of a single laboratory test is often low, but since many tests are used in great numbers, the consequences of false or misleading results can be very costly. Recently, several intervention studies have been carried out in Sweden with the aim of optimizing clinical chemistry testing routines in primary care. These studies show that it is possible to reduce the cost to primary care by SEK 100 million per year while increasing clinical utility. SEK 100 million is approximately 10% of the total cost of clinical chemistry testing in primary care. It should also be possible to reduce this cost in secondary and tertiary care. Hospitals order more tests than primary care, and thus the potential savings are larger. We have studied ordering routines at eleven Swedish hospitals. Comparisons were made in the form of ratios between related laboratory tests, in order to reduce the effects of differences of scale between the laboratories that were studied. The large variation between hospitals indicates that an ongoing discussion between clinicians and laboratories could reduce costs. We have used the figures from this comparison and calculated the potential savings for seven frequently used tests. The potential yearly savings in Sweden for these tests alone is approximately SEK 150 million. We estimate that this is just half of the amount that could be saved if all tests were included.

Concerns have been raised about the quality of DNA-based genetic testing, but few data are available on the problems that occur during clinical genetic testing. We sought to determine the frequency and severity of such problems in US laboratories. Problems were defined as events that could or did impair patient care significantly. Data on the frequency and severity of adverse events during genetic testing were collected from laboratories by anonymous mail questionnaire and detailed on-site inspection. The surveyed laboratories (n = 42) reported significant problems in 0.33% of tests performed; the corresponding value in the inspected laboratories (n = 2) was 0.38%. Sixty percent of problems occurred in the pretest phase, 32% in the laboratory phase, and 8% in the posttest phase or multiple phases. The average level of actual harm resulting from these problems was low. Moderate or high levels of harm occurred in only 0.008% of total cases. No lawsuits, judgments, or disciplinary actions were taken against the laboratories in 277,000 tests performed. The overall frequency of problems in a given laboratory did not correlate with laboratory age, test volume, accreditation status, proficiency testing performance, or institution type (academic, private nonprofit, private for profit). In conclusion, significant problems during genetic testing occur infrequently (< 0.5% in most laboratories), and problems resulting in moderate or high levels of harm to patients are rare (0.008%).

Urinary electrolytes are invaluable in the differential diagnosis and treatment of certain acid-base diseases. We have evaluated the accuracy and precision of three different automated chemistry analyzers and a chloridometer (Corning 925 Chloridometer, Hitachi 717 and 917 and Vitros 950) for chloride, sodium and potassium using standard solutions. Data indicate that the ISE modules on the Hitachi 717 and 917 analyzers measure sodium and potassium accurately and precisely throughout the studied concentration range. The Vitros 950 system had the poorest precision and accuracy performance at the low levels of sodium and potassium. The chloride ion-selective membranes on the Hitachi analyzers seriously overestimate the chloride concentration at all levels. The manual dilution method on the Vitros 950 analyzer for chloride measurements showed good precision and accuracy only at the higher chloride levels. For chloride determination the chloridometer displayed the best accuracy with good precision. We recommend that laboratories use chloridometers for the measurement of urinary chloride, and that the CAP include low chloride samples in their proficiency testing program for urine chloride.

We examine the effect of systematic bias and random error, quality control, and intraperson biological variation on the National Cholesterol Education Program (NCEP) clinical classifications for reported lipid measurements. We consider misclassification to occur if a true lipid homeostatic set point is within a desirable range but the reported lipid value is in a high-risk range, or if a true lipid homeostatic set point is in a high-risk range but the reported lipid value is in a desirable range. To evaluate the overall adequacy of the NCEP guidelines to ensure correct patient classification, we construct operating characteristic curves for total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. We demonstrate that if laboratories are meeting the NCEP guidelines for inherent bias and analytic precision and are using standard quality-control (QC) procedures incorporating at least two QC samples per analytical run from each of two QC pools (for a total of 4 QC samples), the current NCEP guidelines are adequate to ensure (probability >0.90) correct patient classifications regardless of the size of the systematic bias of the laboratory or increased random analytic error. Thus we suggest that at least two concentrations of QC material be included in the QC scheme to ensure that the measurement system is operating within desired specifications across the entire range of desirable and high-risk lipid concentrations and to ensure with high probability that patients are correctly classified.

Context: Better procedures are needed whereby national proficiency testing survey providers can assess and improve the accuracy of laboratory measurements in clinical chemistry., Setting: The 1994 College of American Pathologists Comprehensive Chemistry Survey., Design: This study of matrix effects and the accuracy of laboratory measurements for 11 analytes linked the logistics of the Survey to definitive methods at the National Institutes of Standards and Technology, reference methods at the Centers for Disease Control and Prevention, proficiency testing materials, and a fresh frozen serum sample. The data were analyzed with a statistical model of laboratory measurements., Results: (1) Matrix biases affected the results reported from 69% of the 644 peer group/survey specimen pairs evaluated. (2) Because of matrix biases, the reference value was the correct target value only 32% of the time; thus, the traceability established by definitive method and reference method value assignments on Chemistry Survey specimens did not assure accuracy on patient samples. (3) In contrast to matrix biases, the error caused by random matrix effects with proficiency testing samples was about the same as that caused by random specimen effects with fresh frozen serum, and both were less than within-run random analytic error. (4) Calibration biases occurred in 73% of the 180 peer groups evaluated, and, after matrix biases were removed, the total variance of interlaboratory measurements was due to peer group calibration bias (48%), within-peer-group random calibration error (31 %), within-run random error (14%), and random specimen effects (7%)., Conclusions: An opportunity exists to improve method calibration accuracy in clinical chemistry. With improved design, national proficiency testing surveys can monitor and help reduce method calibration error by converting reported survey results to a true accuracy base that predicts accuracy on patient samples. For medical purposes, the correct target values on artificial (matrix-modified) chemistry materials are reference values adjusted for the matrix bias of each peer group. Matrix biases estimated by the use of fresh frozen serum can be used as factors to transfer the accuracy of definitive methods from artificial reference materials to patient samples.

Application of Deming regression analysis to interpret method comparison data presupposes specification of the squared analytical error ratio (lambda), but in cases involving only single measurements by each method, this ratio may be unknown and is often assigned a default value of one. On the basis of simulations, this practice was evaluated in situations with real error ratios deviating from one. Comparisons of two electrolyte methods and two glucose methods were simulated. In the first case, misspecification of lambda produced a bias that amounted to two-thirds of the maximum bias of the ordinary least-squares regression method. Standard errors and the results of hypothesis-testing also became misleading. In the second situation, a misspecified error ratio resulted only in a negligible bias. Thus, given a short range of values in relation to the measurement errors, it is important that lambda is correctly estimated either from duplicate sets of measurements or, in the case of single measurement sets, specified from quality-control data. However, even with a misspecified error ratio, Deming regression analysis is likely to perform better than least-squares regression analysis.

The performance measure traditionally used in the quality-control (QC) planning process is the probability of rejecting an analytical run when an out-of-control error condition exists. A shortcoming of this performance measure is that it doesn't allow comparison of QC strategies that define analytical runs differently. Accommodating different analytical run definitions is straightforward if QC performance is measured in terms of the average number of patient samples to error detection, or the average number of patient samples containing an analytical error that exceeds total allowable error. By using these performance measures to investigate the impact of different analytical run definitions on QC performance demonstrates that during routine QC monitoring, the length of the interval between QC tests can have a major influence on the expected number of unacceptable results produced during the existence of an out-of-control error condition.

Various viewpoints have been offered regarding the appropriate use of scatter plots or difference plots (bias plots or residual plots) in comparing analytical methods. In many of these discussions it seems the basic concepts of identity (within inherent imprecision) and acceptability based on analytical goals (analytical quality specifications) have been forgotten. With the increasing number of Reference Methods in laboratory medicine, these basic concepts are becoming more important in validation of field methods. Here we describe a simple and effective graphical test of these hypotheses (identity and acceptability) by use of difference plots. These plots display the underlying hypothesis before the measured differences are plotted and allow interpretation of the results according to specific criteria. We further describe simple but effective interpretations of the data, when the hypothesis is not fulfilled, by using two data sets drawn from comparisons of field methods for S-creatinine with a Reference Method for this analyte. The difference plot is a graphical tool with related simple statistics for comparison of a field method with a Reference Method, focusing on (a) identity within the inherent analytical imprecision or (b) acceptability within analytical quality specifications. Calculation of the standard deviation of the differences is an indispensable tool for evaluation of aberrant-sample bias (matrix effects).

During a down-sizing of residency programs at a State University Medical School, hospital based residents' positions were eliminated. It was determined to find out the characteristics of the residents who graduated from the Laboratory Medicine Program, to compare women graduates with men graduates, and to compare IMGs with United States Graduates. An assessment of a 25 year program in laboratory medicine which had graduated 100 residents showed that there was no statistically significant difference by chi 2 analysis in positions (laboratory directors or staff), in certification (American Board of Pathology [and subspecialties], American Board of Medical Microbiology, American Board of Clinical Chemistry) nor in academic appointments (assistant professor to full professor) when the male graduates were compared with the female graduates or when graduates of American medical schools were compared with graduates of foreign medical schools. There were statistically significant associations by chi 2 analysis between directorship positions and board certification and between academic appointments and board certification. Of 100 graduates, there were 57 directors, 52 certified, and 41 with academic appointments. Twenty-two graduates (11 women and 11 men) attained all three.

We have studied 219353 individual clinical chemistry results obtained in methods comparison studies. Each result was prospectively compared with its replicate, comparative, or repeat value to identify differences from expected values. Unacceptable results were defined as differing from the expected values by < or = 7 SDs or CVs. We believe these differences represent special-cause variation and should be expressed as unacceptable rates per million results (ppm). We observed 447 ppm unacceptables: 196 ppm in control samples and 251 ppm in patients' samples. Results judged likely to alter patient care occurred at a rate of 41 ppm. To better understand the magnitude of these rates, we compared these results with reports of error rates in HIV testing and the airline industry. The measurements reported were made for the purpose of quality improvement, not judgment or discovery. The significance of these findings for laboratorians, manufacturers, and regulators is discussed.

Not all of the many approaches to quality control are equally effective. Nonconformities in laboratory testing are caused basically by excessive process variation and mistakes. Statistical quality control can effectively control process variation, but it cannot detect or prevent most mistakes. Because mistakes or blunders are frequently the dominant source of nonconformities, we conclude that statistical quality control by itself is not effective. I explore the 100% inspection methods essential for controlling mistakes. Unlike the inspection techniques that Deming described as ineffective, the new "source" inspection methods can detect mistakes and enable corrections before nonconformities are generated, achieving the highest degree of quality at a fraction of the cost of traditional methods. Key relationships between task complexity and nonconformity rates are also described, along with cultural changes that are essential for implementing the best quality-control practices.

Numerous outcome measures can be used to characterize and compare the performance of alternative quality-control (QC) strategies. The performance measure traditionally used in the QC planning process is the probability of rejecting an analytical run when a critical out-of-control error condition exists. Another performance measure that naturally fits within the total allowable error paradigm is the probability that a reported test result contains an analytical error that exceeds the total allowable error specification. In general, the out-of-control error conditions associated with the greatest chance of reporting an unacceptable test result are unrelated to the traditionally defined "critical" error conditions. If the probability of reporting an unacceptable test result is used as the primary performance measure, worst-case QC performance can be determined irrespective of the magnitude of any out-of-control error condition that may exist, thus eliminating the need for the concept of a "critical" out-of-control error.

A quality-control chart based on exponentially weighted moving averages (EWMA) has, in the past few years, become a popular tool for controlling inaccuracy in industrial quality control. In this paper, I explain the principles of this technique, present some numerical examples, and by computer simulation compare EWMA with other control charts currently used in clinical chemistry. The EWMA chart offers a flexible instrument for visualizing imprecision and inaccuracy and is a good alternative to other charts for detecting inaccuracy, especially where small shifts are of interest. Detection of imprecision with EWMA charts, however, requires special modification.

We report the results of an external quality assessment scheme for serum total cholesterol measurement involving about 100 Italian laboratories participating in an epidemiological study of post myocardial infarction. Two frozen human serum pools with Abell-Kendall assigned values are distributed quarterly at the laboratories (up to now seven events occurred); the obtained results are evaluated and discussed. In one exercise (# 5) duplicated measurements were repeated on three different days. Eighty-five to 98% of the laboratories obtained results within the total error limits (+/- 8.9%). But, while precision (calculated on the six replicates of exercise # 5) is good (90% of the laboratories obtained CV < 3%), inaccuracy problems are evident in every event. Indeed the mean bias from the reference method value ranged from 1.54 and 3.49% in the various events.