Thoughts and expectations of young professionals about the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM).

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.

Repeatability imprecision from analysis of duplicates of patient samples and control materials.

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 repeatability profiles of eight frequently requested measurands in clinical chemistry determined by duplicate measurements of patient samples.

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.

Patient-Based Real-Time Quality Control: Review and Recommendations.

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.

National survey on appropriateness of clinical biochemistry reporting in China.

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.

Statistical evaluation of toxicological assays: Dunnett or Williams test-take both.

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.

The upper normal limit of serum alanine aminotransferase in Golestan Province, northeast Iran.

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.

Moving standard deviation and moving sum of outliers as quality tools for monitoring analytical precision.

INTRODUCTION: An increase in analytical imprecision (expressed as CVa) 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 CVa 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 CVa. On the other hand, the movSD and movSO approaches were able to detect an increased CVa at significantly lower ANPed, particularly for measurands that displayed a relatively small ratio of biological variation to CVa. CONCLUSION: The movSD and movSO approaches are effective in detecting an increase in CVa 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.

Over-reporting significant figures--a significant problem?

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.

Within-subject biological variation in disease: collated data and clinical consequences.

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.

Reference intervals: current status, recent developments and future considerations.

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.

Performance characteristics of four automated natriuretic peptide assays.

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.

Estimating the budgetary impact of setting the medicare clinical laboratory fee schedule at the national limitation amount.

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.

Exponentially adjusted moving mean procedure for quality control. An optimized patient sample control procedure.

The idea of using patient samples as the basis for control procedures elicits a continuing fascination among laboratorians, particularly in the current environment of cost restriction. Average of normals (AON) procedures, although little used, have been carefully investigated at the theoretical level. The performance characteristics of Bull's algorithm have not been thoroughly delineated, however, despite its widespread use. The authors have generalized Bull's algorithm to use variably sized batches of patient samples and a range of exponential factors. For any given batch size, there is an optimal exponential factor to maximize the overall power of error detection. The optimized exponentially adjusted moving mean (EAMM) procedure, a variant of AON and Bull's algorithm, outperforms both parent procedures. As with any AON procedure, EAMM is most useful when the ratio of population variability to analytical variability (standard deviation ratio, SDR) is low.

Frequency of problems during clinical molecular-genetic testing.

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%).

Total research productivity in a pathology discipline.

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.

Analytical goals for rectilinear calibration functions.

Analytical goals for rectilinearity based on within-subject biological variation have not yet been advocated. On the other hand, the statistical tests to evaluate rectilinearity may be too restrictive for clinical purposes. If rectilinearity of the least-squares regression is rejected by the statistical test used, we propose to compare the systematic error introduced using such a regression line as the calibration function, with the allowable total error. Since total error ideally should be less than the within-subject biological coefficient of variation (C.V.Bw) the goal for rectilinearity we propose is that the maximum allowable systematic relative error produced by the calibration function (LoRi) when a lack of rectilinearity really occurs is: LoRi < C.V.Bw -1.96 C.V.M, where C.V.M is the between-run metrological coefficient of variation of the measurement procedure, corresponding to the value of concentration under study.

Multivariate discriminant analysis of biochemical parameters for the differentiation of clinically confounding liver diseases.

We describe a series of studies on the contribution of laboratory medicine to the differential diagnosis of clinically confounding diseases in the field of chronic hepatobiliary diseases. Ascitic cholesterol and lactate dehydrogenase (LD), selected by multivariate discriminant analysis (MDA) from a multitude of serum and ascitic analytes, correctly classified 100% of patients with malignant ascites or non-malignant ascites. In addition, ascitic pseudouridine differentiated hepatocarcinoma (HC) from cirrhotic ascites with a diagnostic effectiveness (overall discrimination power) of 90%. A panel of analytes constituted by serum gamma-glutamyltransferase (GGT), the GGT isoenzyme complexed with low- and very low-density lipoprotein, aspartate aminotransferase, copper, hepatic alkaline phosphatase (AP), the LD-5 isoenzyme and alpha-fetoprotein (AFP), selected by the MDA, correctly classified 93% of about 200 cases of cirrhosis or HC. Finally, MDA also identified an equation, based on serum values of the LD-4/LD-5 and carcinoembryonic antigen/AFP ratios, AP and iron that correctly classified 96% of HC or secondary liver neoplasia cases in 100 patients. This approach based on panels of analytes selected by a sophisticated statistical analysis is a rapid and non-invasive contribution to the differential diagnosis of chronic liver disease including neoplasia.

Test result variation and the quality of evidence-based clinical guidelines.

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.