A dynamic reference change value model applied to ongoing assessment of the steady state of a biomarker using more than two serial results.

Background: Reference change values are used to assess the significance of a difference in two consecutive results from an individual. Reference change value calculations provide the limits for significant differences between two results due to analytical and inherent biological variations. Often more than two serial results are available.

Valid analytical performance specifications for combined analytical bias and imprecision for the use of common reference intervals.

Background Many clinical decisions are based on comparison of patient results with reference intervals. Therefore, an estimation of the analytical performance specifications for the quality that would be required to allow sharing common reference intervals is needed. The International Federation of Clinical Chemistry (IFCC) recommended a minimum of 120 reference individuals to establish reference intervals.

Reprint of "Influence of analytical bias and imprecision on the number of false positive results using Guideline-Driven Medical Decision Limits".

Background: Diagnostic decisions based on decision limits according to medical guidelines are different from the majority of clinical decisions due to the strict dichotomization of patients into diseased and non-diseased. Consequently, the influence of analytical performance is more critical than for other diagnostic decisions where much other information is included. The aim of this opinion paper is to investigate consequences of analytical quality and other circumstances for the outcome of "Guideline-Driven Medical Decision Limits".

Influence of analytical bias and imprecision on the number of false positive results using Guideline-Driven Medical Decision Limits.

Background: Diagnostic decisions based on decision limits according to medical guidelines are different from the majority of clinical decisions due to the strict dichotomization of patients into diseased and non-diseased. Consequently, the influence of analytical performance is more critical than for other diagnostic decisions where much other information is included. The aim of this opinion paper is to investigate consequences of analytical quality and other circumstances for the outcome of "Guideline-Driven Medical Decision Limits".

The theory of reference values: an unfinished symphony.

The history of the theory of reference values can be written as an unfinished symphony. The first movement, allegro con fuoco, played from 1960 to 1980: a mix of themes devoted to the study of biological variability (intra-, inter-individual, short- and long-term), preanalytical conditions, standardization of analytical methods, quality control, statistical tools for deriving reference limits, all of them complex variations developed on a central melody: the new concept of reference values that would replace the notion of normality whose definition was unclear. Additional contributions (multivariate reference values, use of reference limits from broad sets of patient data, drug interferences) conclude the movement on the variability of laboratory tests.

Design of tumor biomarker-monitoring trials: a proposal by the European Group on Tumor Markers.

A major application of tumor biomarkers is in serial monitoring of cancer patients, but there are no published guidelines on how to evaluate biomarkers for this purpose. The European Group on Tumor Markers has convened a multidisciplinary panel of scientists to develop guidance on the design of such monitoring trials. The panel proposes a 4-phase model for biomarker-monitoring trials analogous to that in use for the investigation of new drugs.

How accurate are clinical activity indices for scoring of disease activity in inflammatory bowel disease (IBD)?

Clinical activity indices are essential instruments in monitoring inflammatory bowel diseases such as Crohn's disease (CD) and ulcerative colitis (UC). To subclassify components of disease indices in CD and UC, investigate technical noise in estimation of the indices, establish a signal-to-noise ratio (SNR), evaluate correlation between indices and calculate the reference change value (RCV) for selected biochemical variables in individual cases, 50 patients with CD and 49 patients with UC were included in the study. Qualitative index variables were assessed for scoring errors.

Establishment of a serum thyroid stimulating hormone (TSH) reference interval in healthy adults. The importance of environmental factors, including thyroid antibodies.

It has previously been shown that thyroid antibodies affect thyroid stimulating hormone (TSH) concentrations in men and women and that TSH levels are predictive of future thyroid disease. We investigated the validity of the National Academy of Clinical Biochemistry (NACB) guidelines regarding the TSH reference interval by studying 1512 individuals. Two hundred and fifty had at least one thyroid antibody, 121 were taking medications other than estrogens and occasional analgesics, and 105 reported a family history of thyroid disease.

Creation of a low-risk reference group and reference interval of fasting venous plasma glucose.

Reference intervals are recommended for naturally occurring quantities and required in the evaluation of new components in order to provide clinically useful information. The aim of the present study is to present a method for selecting reference individuals for the determination of fasting venous plasma glucose (f-vPG) reference intervals and ways to determine if disease groups can share reference intervals with an ideal reference population. Reference subjects were randomly selected, eligibility was judged according to predetermined inclusion and exclusion criteria.

Reference intervals for serum proteins: similarities and differences between adult Caucasian and Asian Indian males in Yorkshire, UK.

The aim of this study was to investigate similarities and differences in the distribution of serum concentrations of nine proteins in two racial groups (Caucasian and Asian Indian) of adult males living in the same geographical area (Leeds, Bradford, UK) for at least two generations. This is part of a larger study to determine the need for separating reference intervals for racial and ethnic groups worldwide. The distributions of concentrations for all proteins evaluated in the Indians fit In-Gaussian distributions, indicating probable homogeneity.

Should we maintain the 95 percent reference intervals in the era of wellness testing? A concept paper.

The reference interval is probably the most widely used decision-making tool in clinical practice, with a modern use aiming at identifying wellness during health check and screening. Its use as a diagnostic tool is much less recognised and may be obsolete. The present study investigates the consequences of the new practice for the interpretation of prospective value, negative vs.

Graphical interpretation of confidence curves in rankit plots.

A well-known transformation from the bell-shaped Gaussian (normal) curve to a straight line in the rankit plot is investigated, and a tool for evaluation of the distribution of reference groups is presented. It is based on the confidence intervals for percentiles of the calculated Gaussian distribution and the percentage of cumulative points exceeding these limits. The process is to rank the reference values and plot the cumulative frequency points in a rankit plot with a logarithmic (In=log(e)) transformed abscissa.

Effect of analytical quality on establishing common reference intervals and their use.

In the Nordic Reference Interval Project (NORIP), reference intervals were established for 25 common clinical biochemical quantities. In the project, samples from more than 3000 reference individuals collected in the 102 participating laboratories from all five Nordic countries were analysed locally. In order to maintain a high level of analytical quality and to document this quality, a common calibrator/reference preparation (CAL) and a number of control samples were analysed together with the reference samples.

Descriptive analytical data and consequences for calculation of common reference intervals in the Nordic Reference Interval Project 2000.

In the Nordic Reference Interval Project (NORIP), data from 102 Nordic clinical chemical laboratories were obtained. Each laboratory reported analytical data on up to 25 of the most commonly used clinical biochemical properties, including results from each of a minimum of 25 reference individuals. A reference material consisting of a liquid frozen pool of serum with values traceable to reference methods (used as the project "calibrator" for non-enzymes to correct reference values) was measured together with other serum pool controls in each laboratory in the same analytical series as the project samples.

Reference individuals, blood collection, treatment of samples and descriptive data from the questionnaire in the Nordic Reference Interval Project 2000.

The rules for recruitment of reference individuals, inclusion and preparation of individuals, blood collection, treatment of samples (and control materials) and analysis at the 102 medical laboratories attending the Nordic Reference Interval Project (NORIP) are given as well as the rules for central exclusion of reference individuals. The individuals (18-91-year-olds) should be evenly distributed on age and gender groups. The 3002 reference individuals who contributed at least one reference value to the finally suggested reference intervals were characterized using the information in the questionnaire.

Prerequisites for establishing common reference intervals.

Establishment of common reference intervals for homogeneous populations within regions is based on the same basic principles as the IFCC recommendations for individual laboratories, but a few additional prerequisites are needed. Thus, the need for common standardization and traceability during production of the reference values and with the application of the common reference intervals in the laboratories becomes crucial. Furthermore, the external control system must be geared to the purpose, using matrix-correct control materials with concentration values traceable to the same reference methods, and validation of results according to analytical quality specifications designed for the use of common reference intervals.

The Nordic Reference Interval Project 2000: recommended reference intervals for 25 common biochemical properties.

Each of 102 Nordic routine clinical biochemistry laboratories collected blood samples from at least 25 healthy reference individuals evenly distributed for gender and age, and analysed 25 of the most commonly requested serum/plasma components from each reference individual. A reference material (control) consisting of a fresh frozen liquid pool of serum with values traceable to reference methods (used as the project "calibrator" for non-enzymes to correct reference values) was analysed together with other serum pool controls in the same series as the project samples. Analytical data, method data and data describing the reference individuals were submitted to a central database for evaluation and calculation of reference intervals intended for common use in the Nordic countries.

Reference change values and power functions.

Repeated samplings and measurements in the monitoring of patients to look for changes are common clinical problems. The "reference change value", calculated as zp x [2 x (CVI2 + CVA2)](1/2), where zp is the z-statistic and CVI and CVA are within-subject and analytical coefficients of variation, respectively, has been used to detect whether a measured difference between measurements is statistically significant. However, a reference change value only detects the probability of false-positives (type I error), and for this reason, a model to calculate the risk of missing significant changes in serial results from individuals (probability of false-negatives) is investigated in this work by means of power functions.

Soluble CD163: a marker molecule for monocyte/macrophage activity in disease.

By immunoprecipitation we have identified a soluble plasma form of CD163 (sCD163), the IL-6 inducible macrophage-receptor for clearing haptoglobin-haemoglobin complexes. A sandwich ELISA for measuring sCD163 was established and used to determine the sCD163 levels in normal subjects and patients with inflammatory and myeloproliferative diseases. In normal subjects, the concentration of sCD163 was high (median 1.

Reproducibility of S-insulin and B-glucose responses in two identical oral glucose tolerance tests.

Recently, the diagnostic criteria for type 2 diabetes mellitus have been changed, but there are disagreements about which measurements should be used. In contrast to the American Diabetes Association (ADA), The World Health Organization (WHO) still recognizes fasting and 2-h glucose concentrations measured on either plasma or whole blood as diagnostic tools. Insulin sensitivity and insulin secretion are both assumed to be involved in the pathogenesis of type 2 diabetes.

Upper reference limit, analytical quality specifications and clinical use of haemoglobin A1C.

Haemoglobin A1c (HbA1c) is now the key component for monitoring glycaemic control in diabetes mellitus (DM), especially for its close relation to diabetes complications. However, treatment goals in terms of HbA1c concentrations have been difficult to define and compare because of lack of international standardization and lack of common reference values of HbA1c concentrations. The aims of our study were to document our HbA1c analysis and make it traceable to international reference laboratories with the aid of current reference preparations, to establish a reference interval based on a low-risk population, and to evaluate the analytical quality specifications, which could meet clinical needs.

Impact of subgroup prevalences on partitioning of Gaussian-distributed reference values.

Background: The aims of this report were to examine how unequal subgroup prevalences in the source population may affect reference interval partitioning decisions and to develop generally applicable guidelines for partitioning gaussian-distributed data.

Methods: We recently proposed a new model for partitioning reference intervals when the underlying data distribution is gaussian. This model is based on controlling the proportions of the subgroup distributions that fall outside each of the common reference limits, using the distances between the reference limits of the subgroup distributions as functions to these proportions.

Can capillary whole blood glucose and venous plasma glucose measurements be used interchangeably in diagnosis of diabetes mellitus?

According to new proposals from the American Diabetes Association (ADA) and WHO, venous peripheral plasma is the preferred system for measuring glucose for diagnosing diabetes mellitus. Owing to the instability of glucose in plasma after blood sampling, strict well-defined and standardized preanalytical conditions are essential to ensure that glucose concentration measured in plasma reflects real blood glucose in the patient. This is in contrast to the capillary whole blood measurements, which are easy to perform and well established.