A self-consistent set of reference values for 23 clinical chemical analytes.

Abstract Heparinized plasma of 528 blood donors was subjected to the 23 most frequently ordered chemical and enzymatic tests. The central fraction of the distribution of all results for each test was estimated. Out of the 528 donors a reference population has been selected. Because of the lack of other criteria, the result for any test of a blood donor was selected as a value belonging to the reference population if the results for the other 22 analytes of this particular donor lay within their own central fraction. On this basis an iterative procedure for the selection was programmed, considering the interaction between tests. The procedure was stopped when the reference limits for all 23 tests were converging. Fractions from 0.90 to 0.98 were applied to results for men and women donors separately. The elimination procedure and the criteria to select the best fitted fraction are discussed. The derived reference intervals are designated a "self-consistent set of reference values."

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Multicenter Evaluation of Five Assays for Myoglobin Determination

Clinical Chemistry ◽

10.1093/clinchem/46.10.1631 ◽

2000 ◽

Vol 46 (10) ◽

pp. 1631-1637 ◽

Cited By ~ 11

Author(s):

Martina Zaninotto ◽

Franca Pagani ◽

Sara Altinier ◽

Paolo Amboni ◽

Roberto Bonora ◽

...

Keyword(s):

Clinical Practice ◽

Rheumatoid Factor ◽

Reference Values ◽

Multicenter Study ◽

Method Comparison ◽

Correlation Coefficients ◽

Analytical Performance ◽

Men And Women ◽

Reference Limits

Abstract Background: Lacking assay standardization, different myoglobin methods may produce results that differ significantly. Methods: A multicenter study was carried out to compare the analytical performance of five commercially available assays for myoglobin measurement. Linearity, imprecision, interferences, and method comparison were studied according to NCCLS guidelines, whereas reference values were determined following IFCC recommendations. Results: The BNA and Opus showed relatively high imprecision (all but one total CV >7.4%). Other assays showed lower CVs, but they varied among laboratories, particularly at a normal myoglobin concentration (Access, 6.0–11%; Hitachi, 3.8–5.8%; Stratus, 3.4–6.5%). Results were lower in anticoagulated samples on the Access, in heparin and citrate samples on the Stratus, and in citrate samples on the BNA and Opus, and increased in heparin and EDTA samples on the Hitachi. Use of separator gel produced results significantly lower (P <0.001) on the Hitachi and higher (P = 0.016) on the Opus. Bilirubin, turbidity, and hemoglobin had no effect on evaluated methods, but rheumatoid factor affected the Access. In method comparisons, high correlation coefficients (≥0.98) were obtained. The Stratus gave higher results; however, the Access and BNA gave the lowest. The following upper reference limits (μg/L) for men and women, respectively, were obtained: Access, 70 and 52; BNA, 51 and 49; Hitachi, 67 and 58; Opus, 80 and 50; and Stratus, 86 and 63. Conclusion: The possibility of high imprecision and marked disagreement among commercial myoglobin assays should be carefully considered in clinical practice.

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Impact of Subgroup Prevalences on Partitioning of Gaussian-distributed Reference Values

Clinical Chemistry ◽

10.1093/clinchem/48.11.1987 ◽

2002 ◽

Vol 48 (11) ◽

pp. 1987-1999 ◽

Cited By ~ 49

Author(s):

Ari Lahti ◽

Per Hyltoft Petersen ◽

James C Boyd

Keyword(s):

Reference Interval ◽

Reference Population ◽

Reference Intervals ◽

Source Population ◽

Distributed Data ◽

New Model ◽

Common Reference ◽

Reference Limits ◽

Partitioning Problem ◽

Analytical Expressions

Abstract 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. We examine the significance of the unequal prevalence effect for the partitioning problem and quantify it for distance partitioning criteria by deriving analytical expressions to express these criteria as a function of the ratio of prevalences. An application example, illustrating various aspects of the importance of the prevalence effect, is also presented. Results: Dramatic shrinkage of the critical distances between reference limits of the subgroups needed for partitioning was observed as the ratio of prevalences, the larger one divided by the smaller one, was increased from unity. Because of this shrinkage, the same critical distances are not valid for all ratios of prevalences, but specific critical distances should be used for each particular value of this ratio. Although proportion criteria used in determining the need for reference interval partitioning are not dependent on the prevalence effect, this effect should be accounted for when these criteria are being applied by adjusting the sample sizes of the subgroups to make them correspond to the ratio of prevalences. Conclusions: The prevalences of subgroups in the reference population should be known and observed in the calculations for every reference interval study, irrespective of whether distance or proportion criteria are being used to determine the need for reference interval partitioning. We present detailed methods to account for the prevalences when applying each of these types of criteria. Analytical expressions for the distance criteria, to be used when high precision is needed, and approximate distances, to be used in practical work, are derived. General guidelines for partitioning gaussian distributed data are presented. Following these guidelines and using the new model, we suggest that partitioning can be performed more reliably than with any of the earlier models because the new model not only offers an improved correspondence between the critical distances and the critical proportions, but also accounts for the prevalence effect.

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Recommendation for the review of biological reference intervals in medical laboratories

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2016-0793 ◽

2016 ◽

Vol 54 (12) ◽

Cited By ~ 22

Author(s):

Joseph Henny ◽

Anne Vassault ◽

Guilaine Boursier ◽

Ines Vukasovic ◽

Pika Mesko Brguljan ◽

...

Keyword(s):

Expert Panel ◽

Clinical Chemistry ◽

Simple Procedure ◽

Reference Population ◽

Reference Intervals ◽

Medical Laboratories ◽

Reference Limits ◽

Original Procedure ◽

Selection Of

AbstractThis document is based on the original recommendation of the Expert Panel on the Theory of Reference Values of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), updated guidelines were recently published under the auspices of the IFCC and the Clinical and Laboratory Standards Institute (CLSI). This document summarizes proposals for recommendations on: (i) The terminology, which is often confusing, noticeably concerning the terms of reference limits and decision limits. (ii) The method for the determination of reference limits according to the original procedure and the conditions, which should be used. (iii) A simple procedure allowing the medical laboratories to fulfill the requirements of the regulation and standards. The updated document proposes to verify that published reference limits are applicable to the laboratory involved. Finally, the strengths and limits of the revised recommendations (especially the selection of the reference population, the maintenance of the analytical quality, the choice of the statistical method used…) will be briefly discussed.

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Reference ranges for clinical electrophysiology of vision

Documenta Ophthalmologica ◽

10.1007/s10633-021-09831-1 ◽

2021 ◽

Author(s):

C. Quentin Davis ◽

Ruth Hamilton

Keyword(s):

Reference Values ◽

False Negative ◽

Reference Interval ◽

Reference Intervals ◽

Clinical Electrophysiology ◽

Reference Ranges ◽

Physiological Measurement ◽

Negative Results ◽

Reference Limits ◽

Suitable Reference

Abstract Introduction Establishing robust reference intervals for clinical procedures has received much attention from international clinical laboratories, with approved guidelines. Physiological measurement laboratories have given this topic less attention; however, most of the principles are transferable. Methods Herein, we summarise those principles and expand them to cover bilateral measurements and one-tailed reference intervals, which are common issues for those interpreting clinical visual electrophysiology tests such as electroretinograms (ERGs), visual evoked potentials (VEPs) and electrooculograms (EOGs). Results The gold standard process of establishing and defining reference intervals, which are adequately reliable, entails collecting data from a minimum of 120 suitable reference individuals for each partition (e.g. sex, age) and defining limits with nonparametric methods. Parametric techniques may be used under some conditions. A brief outline of methods for defining reference limits from patient data (indirect sampling) is given. Reference intervals established elsewhere, or with older protocols, can be transferred or verified with as few as 40 and 20 suitable reference individuals, respectively. Consideration is given to small numbers of reference subjects, interpretation of serial measurements using subject-based reference values, multidimensional reference regions and age-dependent reference values. Bilateral measurements, despite their correlation, can be used to improve reference intervals although additional care is required in computing the confidence in the reference interval or the reference interval itself when bilateral measurements are only available from some of subjects. Discussion Good quality reference limits minimise false-positive and false-negative results, thereby maximising the clinical utility and patient benefit. Quality indicators include using appropriately sized reference datasets with appropriate numerical handling for reporting; using subject-based reference limits where appropriate; and limiting tests for each patient to only those which are clinically indicated, independent and highly discriminating.

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Functional reference limits: a case study of serum ferritin

Journal of Laboratory Medicine ◽

10.1515/labmed-2020-0127 ◽

2021 ◽

Vol 45 (2) ◽

pp. 69-77

Author(s):

Gorkem Sezgin ◽

Tze Ping Loh ◽

Corey Markus

Keyword(s):

Serum Ferritin ◽

Reference Population ◽

Reference Intervals ◽

Reference Limit ◽

Subclinical Disease ◽

Routinely Collected Data ◽

Reference Limits ◽

Relevant Reference ◽

The Relationship

Abstract Reference intervals depend on the distribution of results within a reference population and can be influenced by subclinical disease. Functional reference limits present an opportunity to derive clinically relevant reference limits from routinely collected data sources, which consist of mixed populations of unhealthy and healthy groups. Serum ferritin is a good example of the utility of functional reference limits. Several studies have identified clinically relevant reference limits through examining the relationship between serum ferritin and erythrocyte parameters. These ferritin functional limits often represent the inflection point at which erythrocyte parameters change significantly. Comparison of ferritin functional reference limits with those based on population distributional reference limits reveals that the lower reference limit may fall below the point at which patients become clinically unwell. Functional reference limits may be considered for any biomarker that exhibits a correlated relationship with other biomarkers.

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Objective Criteria for Partitioning Gaussian-distributed Reference Values into Subgroups

Clinical Chemistry ◽

10.1093/clinchem/48.2.338 ◽

2002 ◽

Vol 48 (2) ◽

pp. 338-352 ◽

Cited By ~ 31

Author(s):

Ari Lahti ◽

Per Hyltoft Petersen ◽

James C Boyd ◽

Callum G Fraser ◽

Nils Jørgensen

Keyword(s):

Reference Values ◽

Geographic Area ◽

Reference Intervals ◽

Critical Values ◽

Final Decision ◽

Gaussian Distributions ◽

New Model ◽

Reference Limit ◽

Common Reference ◽

Reference Limits

Abstract Background: The aim of this study was to develop new and useful criteria for partitioning reference values into subgroups applicable to gaussian distributions and to distributions that can be transformed to gaussian distributions. Methods: The proposed criteria relate to percentages of the subgroups outside each of the reference limits of the combined distribution. Critical values suggested as partitioning criteria for these percentages were derived from analytical bias quality specifications for using common reference intervals throughout a geographic area. As alternative partitioning criteria to the actual percentages, these were transformed mathematically to critical distances between the reference limits of the subgroup distributions, to be applied to each pair of reference limits, the upper and the lower, at a time. The new criteria were tested using data on various plasma proteins collected from ∼500 reference individuals, and the outcomes were compared with those given by the currently widely applied and recommended partitioning model of Harris and Boyd, the “Harris-Boyd model”. Results: We suggest 4.1% as the critical minimum percentage outside that would justify partitioning into subgroups, and 3.2% as the critical maximum percentage outside that would justify combining them. Percentages between these two values should be classified as marginal, implying that nonstatistical considerations are required to make the final decision on partitioning. The correlation between the critical percentages and the critical distances was mathematically precise in the new model, whereas this correlation is rather approximate in the Harris-Boyd model because focus on the difference between means in this model makes high precision hard to achieve. The application examples suggested that the new model is more radical than the Harris-Boyd model. Conclusions: New percentage and distance criteria, to be used for partitioning gaussian-distributed data, have been developed. The distance criteria, applied separately to both reference limit pairs of the subgroup distributions, seemed more reliable and correlated more accurately with the critical percentages than the distance criteria of the Harris-Boyd model. As opposed to the Harris-Boyd model, the new model is easily adjustable to new critical values of the percentages, should they need to be changed in the future.

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Reference Values for Apolipoproteins A-I and B in Healthy Subjects, by Age

Clinical Chemistry ◽

10.1093/clinchem/38.4.566 ◽

1992 ◽

Vol 38 (4) ◽

pp. 566-569 ◽

Cited By ~ 10

Author(s):

G Zunić ◽

Z Jelić-Ivanović ◽

S Spasić ◽

A Stojiljković ◽

N Majkić-Singh

Keyword(s):

Reference Values ◽

Healthy Subjects ◽

Reference Intervals ◽

Nonparametric Method ◽

Apo B ◽

Men And Women ◽

Frequency Distributions ◽

Laboratory Results

Abstract We determined reference values of apolipoproteins A-I (apo A-I) and B (apo B) in serum from a population of 448 healthy subjects (265 men and 183 women, ages 18 to 61 years) by a kinetic immunonephelometric procedure. Frequency distributions of apo A-I were normal, whereas those of apo B were not and yielded asymmetrical curves. Thus, reference intervals for apo A-I were determined as mean +/- 2SD (1.08-1.89 g/L), but a nonparametric method was used for determining reference intervals for apo B (0.60-1.94 g/L). Apo B concentrations were significantly higher (P less than 0.001) in men than in women (0.63-2.01 g/L, mean 1.21 g/L; and 0.54-1.91 g/L, mean 1.08 g/L, respectively). No significant differences for apo A-I between men and women were observed. Concentrations of both proteins increased with age, but apo B increased more than apo A-I. We conclude that not only sex but also the age of the subjects must be considered in interpreting laboratory results for apolipoproteins.

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SEX AND AGE CORRELATED REFERENCE VALUES OF SERUM THYROGLOBULIN MEASURED BY A MODIFIED RADIOIMMUNOASSAY

Acta Endocrinologica ◽

10.1530/acta.0.0900440 ◽

1979 ◽

Vol 90 (3) ◽

pp. 440-450 ◽

Cited By ~ 38

Author(s):

Ulla Feldt-Rasmussen ◽

Per Hyltoft Petersen ◽

John Date

Keyword(s):

Reference Values ◽

Incubation Time ◽

Blood Donors ◽

Logarithmic Transformation ◽

Serum Thyroglobulin ◽

Double Antibody ◽

Kendall’S Τ ◽

Significant Difference ◽

Reference Limits ◽

Antithyroglobulin Antibodies

ABSTRACT The aim of the present investigation was to describe variations in serum thyroglobulin in relation to sex and age in a group of normal persons. The method used was a modified double antibody radioimmunoassay characterized by pre-incubation at 37°C of standard or sample with antiserum, resulting in a reduced total incubation time. Both sensitivity and precision were comparable to other published methods. Of the 152 blood-donors initially investigated, 7 were excluded due to the presence of antithyroglobulin antibodies as evidenced by a radioassay. Both sexes were equally represented with an even distribution of ages from 20-65 years. Increased serum thyroglobulin with increasing age was demonstrated, the correlation being significant in women (Kendall's τ, P < 0.001). Detectable concentrations of serum thyroglobulin (above 1.7 μg/l) were found in 94 %. Based on the logarithmic transformation, the upper reference limits were determined for men ≦ 40 years: 36 μg/l, > 40 years: 44 μg/l (difference between groups not significant, P > 0.05), and for women ≦ 40 years: 30 μg/l, > 40 years: 60 μg/l (significant difference, P < 0.005).

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Reference Values for 30 Common Biochemistry Analytes Across 5 Different Analyzers in Neonates and Children 30 Days to 18 Years of Age

Clinical Chemistry ◽

10.1373/clinchem.2019.306431 ◽

2019 ◽

Vol 65 (10) ◽

pp. 1317-1326 ◽

Cited By ~ 9

Author(s):

Monsurul Hoq ◽

Susan Matthews ◽

Vicky Karlaftis ◽

Janet Burgess ◽

Jessica Cowley ◽

...

Keyword(s):

Reference Values ◽

Polynomial Regression ◽

Total Error ◽

Reference Intervals ◽

Specific Reference ◽

Mixed Effect ◽

Fractional Polynomial ◽

Reference Limits ◽

Effect Regression ◽

The Mean

Abstract BACKGROUND Age-specific reference intervals (RIs) have been developed for biochemistry analytes in children. However, the ability to interpret results from multiple laboratories for 1 individual is limited. This study reports a head-to-head comparison of reference values and age-specific RIs for 30 biochemistry analytes for children across 5 analyzer types. METHODS Blood was collected from healthy newborns and children 30 days to <18 years of age. Serum aliquots from the same individual were analyzed on 5 analyzer types. Differences in the mean reference values of the analytes by the analyzer types were investigated using mixed-effect regression analysis and by comparing maximum variation between analyzers with analyte-specific allowable total error reported in the Westgard QC database. Quantile regression was used to estimate age-specific RIs using power variables in age selected by fractional polynomial regression for the mean, with modification by sex when appropriate. RESULTS The variations of age-specific mean reference values between analyzer types were within allowable total error (Westgard QC) for most analytes, and common age-specific reference limits were reported as functions of age and/or sex. Analyzer-specific reference limits for all analytes on 5 analyzer types are also reported as functions of age and/or sex. CONCLUSIONS This study provides quantitative and qualitative measures of the extent to which results for individual children can or cannot be compared across analyzer types, and the feasibility of RI harmonization. The reported equations enable incorporation of age-specific RIs into laboratory information systems for improving evidence-based clinical decisions in children.

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Holotranscobalamin and Total Transcobalamin in Human Plasma: Determination, Determinants, and Reference Values in Healthy Adults

Clinical Chemistry ◽

10.1373/clinchem.2005.054619 ◽

2006 ◽

Vol 52 (1) ◽

pp. 129-137 ◽

Cited By ~ 54

Author(s):

Helga Refsum ◽

Carole Johnston ◽

Anne Berit Guttormsen ◽

Ebba Nexo

Keyword(s):

Reference Values ◽

Multivariate Regression ◽

Blood Donors ◽

Magnetic Beads ◽

Plasma Concentrations ◽

Reference Intervals ◽

Younger Women ◽

Study Participants ◽

Microbiological Assays

Abstract Background: We developed microbiological assays (MBAs) to identify determinants and to establish reference values for cobalamin bound to transcobalamin [holotranscobalamin (holoTC)] and total TC in plasma. Methods: We captured holoTC with magnetic beads with TC antibodies and used a conventional MBA for cobalamin measurements. Total TC was determined as holoTC after TC was saturated with cyanocobalamin. The new assays were compared with published methods. Determinants and reference values were determined in 500 blood donors, ages 18–69 years. Results: Determination of cobalamin, holoTC, and TC by MBA required <150 μL. HoloTC and TC by MBA correlated with holoTC by RIA (r = 0.95) and TC by ELISA (r = 0.79), respectively. Between-day CVs for holoTC and total TC were 4%–9%. Women had lower holoTC than men, but only at age ≤45 years. In multivariate regression analyses, holoTC was positively associated with age (in women only), creatinine (in men only), and plasma concentrations of total TC, folate, and cysteine, but inversely correlated with homocysteine and methylmalonic acid. For all study participants, total TC was associated with holoTC and number of TCN2 766C alleles; in female participants only, total TC was also associated with age, homocysteine, and cysteine. Reference values were 670–1270 pmol/L for TC and 42–157 pmol/L for holoTC, but they differed according to age and sex. Conclusions: Our MBAs for TC and holoTC required low plasma volume and performed acceptably compared with other methods. Determinants of holoTC and TC differed between men and women and according to age. Separate reference intervals for holoTC should be considered in younger women.

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