Committee On Reference Intervals And Decision Limits Research Articles

Derivation of sex and age-specific reference intervals for clinical chemistry analytes in healthy Ghanaian adults.

This study is aimed at establishing reference intervals (RIs) of 40 chemistry and immunochemistry analytes for Ghanaian adults based on internationally harmonized protocol by IFCC Committee on Reference Intervals and Decision Limits (C-RIDL). A total of 501 healthy volunteers aged≥18 years were recruited from the northern and southern regions of Ghana. Blood samples were analyzed with Beckman-Coulter AU480 and Centaur-XP/Siemen auto-analyzers. Sources of variations of reference values (RVs) were evaluated by multiple regression analysis (MRA). The need for partitioning RVs by sex and age was guided by the SD ratio (SDR). The RI for each analyte was derived using parametric method with application of the latent abnormal values exclusion (LAVE) method. Using SDR≥0.4 as threshold, RVs were partitioned by sex for most enzymes, creatinine, uric acid (UA), bilirubin, immunoglobulin-M. MRA revealed age and body mass index (BMI) as major source of variations of many analytes. LAVE lowered the upper limits of RIs for alanine/aspartate aminotransferase, γ-glutamyl transaminase and lipids. Exclusion of individuals with BMI≥30 further lowered the RIs for lipids and CRP. After standardization based on value-assigned serum panel provided by C-RIDL, Ghanaian RIs were found higher for creatine kinase, amylase, and lower for albumin and urea compared to other collaborating countries. The LAVE effect on many clinical chemistry RIs supports the need for the secondary exclusion for reliable derivation of RIs. The differences in Ghanaian RIs compared to other countries underscore the importance ofcountry specific-RIs for improved clinical decision making.

Establishment of reference intervals of clinical chemistry analytes for the adult population in Egypt

This is the first Egyptian nationwide study for derivation of reference intervals (RIs) for 34 major chemistry analytes. It was conducted as a part of the global initiative by the IFCC Committee on Reference Intervals and Decision Limits (C-RIDL) for establishing country-specific RIs based on a harmonized protocol. 691 apparently healthy volunteers aged ≥18 years were recruited from multiple regions in Egypt. Serum specimens were analyzed in two centers. The harmonization and standardization of test results were achieved by measuring value-assigned serum panel provided by C-RIDL. The RIs were calculated by parametric method. Sources of variation of reference values (RVs) were evaluated by multiple regression analysis. The need for partitioning by sex, age, and region was judged primarily by standard deviation ratio (SDR). Gender-specific RIs were required for six analytes including total bilirubin (TBil), aspartate and alanine aminotransferase (AST, ALT). Seven analytes required age-partitioning including glucose and low-density lipoprotein cholesterol (LDL-C). Regional differences were observed between northern and southern Egypt for direct bilirubin, glucose, and high-density-lipoprotein cholesterol (HDL-C) with all their RVs lower in southern Egypt. Compared with other collaborating countries, the features of Egyptian RVs were lower HDL-C and TBil and higher TG and C-reactive protein. In addition, BMI showed weak association with most of nutritional markers. These features were shared with two other Middle Eastern countries: Saudi Arabia and Turkey. The standardized RIs established by this study can be used as common Egyptian RI, except for a few analytes that showed regional differences. Despite high prevalence of obesity among Egyptians, their RVs of nutritional markers are less sensitive to increased BMI, compared to other collaborating countries.

Sources of variation and establishment of Russian reference intervals for major hormones and tumor markers

A multicenter study was organized to explore sources of variation (SVs) of reference values (RVs) for 22 major immunochemistry analytes and to determine reference intervals (RIs) for the Russian population. According to IFCC Committee on Reference Intervals and Decision Limits (C-RIDL) protocol, 758 healthy volunteers were recruited in St. Petersburg, Moscow, and Yekaterinburg. Serum samples were tested for five tumor markers, 17 hormones and related tests by Beckman Coulter's UniCel DxI 800 immunochemistry analyzer. SVs were explored using multiple regression analysis and ANOVA. Standard deviation ratio (SDR) of 0.4 was used as primary guide for partitioning RIs by gender and age. SDR for between-city difference was <0.4 for all analytes. Secondary exclusion of individuals was done under the following conditions: for female sex-hormones, those with contraceptives (8%); for CA19-9, those supposed to have negative Lewis blood-group (10.5% males and 11.3% females); for insulin, those with BMI≥28 kg/m2 (31%); for the thyroid panel, those with anti-thyroid antibodies (10.3% males; 24.5% females), for CEA those with smoking habit (30% males and 16% females). Gender-specific RIs were required for all analytes except CA19-9, CA15-3, thyroid-related tests, parathyroid hormone, and insulin. Age-specific RIs were required for alpha-fetoprotein, CEA, all sex-hormones for females, FSH and progesterone for both sexes. RIs were generally derived by parametric method after Gaussian transformation using modified Box-Cox formula. Exceptions were growth hormone, estradiol for females in postmenopause, and progesterone for females in premenopause, for which nonparametric method was required due to bimodal distribution and/or insufficient detection limit. RIs for major hormones and tumor markers specific for the Russian population were derived based on the up-to-date internationally harmonized protocol by careful consideration of analyte-specific SVs.

Establishing reference intervals for major biochemical analytes for the Russian population: a research conducted as a part of the IFCC global study on reference values

ObjectivesBecause reference intervals (RIs) for biochemistry analytes matched to the Russian population are not well defined, we joined the global study on reference values (RVs) coordinated by the IFCC Committee on Reference Intervals and Decision Limits (C-RIDL). MethodsAccording to the C-RIDL harmonized protocol, 793 healthy volunteers were recruited in Saint-Petersburg, Moscow, and Yekaterinburg. Serum samples were tested for 34 biochemistry analytes. Sources of variation of RVs were explored using multiple regression analysis. The need for partitioning RVs by sex and age were judged using standard deviation ratio based on ANOVA. Latent abnormal values exclusion (LAVE) method was applied to reduce the influence of individuals with metabolic syndrome and/or inappropriate sampling conditions. RIs were computed by the parametric method. ResultsNo appreciable between-city differences were observed. Partition of RVs by sex was required for 17 analytes. Age-related changes in RVs were observed in many analytes, especially in females. The trend was exaggerated in nutritional and inflammatory markers that were closely associated with body mass index (BMI), because BMI increases prominently with age. Therefore, for those analytes, volunteers with BMI > 28 kg/m2 were excluded in determining RIs for age-specific RIs. The LAVE method was effective in lowering the upper limits of the RIs for nutritional and inflammatory markers. ConclusionRIs matched to the Russian population were established for 34 biochemical analytes using up-to-date methods in detailed consideration of sources of variation of RVs. The majority of Russian RIs are similar to those of Caucasian populations among the participating countries.

Establishing and using reference intervals

Abstract Reference intervals (RIs) and clinical decision limits (CDLs) are fundamental tools used by healthcare and laboratory professionals to interpret patient laboratory test results. The traditional method for establishing RIs, known as the direct approach, is based on collecting samples from members of a preselected reference population, making the measurements and then determining the intervals. For challenging groups such as pediatric and geriatric age groups, indirect methods are appointed for the derivation of RIs in the EP28-A3c guideline. However, there has been an increasing demand to use the indirect methods of deriving RIs by the use of routine laboratory data stored in the laboratory information system. International Federation of Clinical Chemistry (IFCC), Committee on Reference Intervals and Decision Limits (C-RIDL) is currently working on the study for the comparison of the conventional (direct) and alternative (indirect) approaches for the determination of reference intervals. As a matter of fact that, the process of developing RIs is often beyond the capabilities of an individual laboratory due to the complex, expensive and time-consuming process to develop them. Therefore, a laboratory can alternatively transfer and verify RIs established by an external source (i.e. manufacturers’ package inserts, publications). IFCC, C-RIDL has focused primarily on RIs and has performed multicenter studies to obtain common RIs in recent years. However, as the broader responsibility of the Committee, from its name, includes “decision limits”, the C-RIDL also emphasizes the importance of the correct use of both RIs and CDLs and to encourage laboratories to specify the appropriate information to clinicians as needed.

Full blood count and white cell differential count reference ranges obtained from a healthy urban South African population residing in the Western Cape of South Africa.

Research has suggested that individuals of African descent have lower white cell and neutrophil counts than Caucasians. These differences could lead to incorrect clinical decisions, and therefore, ethnic-specific reference ranges are required. The Western Cape region of South Africa is uniquely diverse, comprising Caucasian, Mixed Ancestry and those of African descent. The aim of this study was to compare the full blood count and differential counts across the three major ethnic groups residing in this area and to propose appropriate RIs. The study formed part of the international project led by the Committee on Reference Intervals and Decision Limits (C-RIDL), and therefore, the strict guidelines laid out by the committee were followed. Full blood count and differential counts were performed on a Beckman Coulter ACT 5 diff AL analyser within 2-4hours of collection and were reported as mean (standard deviation), 2.5th and 97.5th percentiles. Comparisons were analysed using Spss v25 and Statistica v13, and a P value of<0.05 was considered significant. Reference ranges for Caucasian and Mixed Ancestry individuals were similar while white cell (P=0.016), monocyte (P<0.001), neutrophil (P=0.034) and red cell indices were significantly different amongst the three population groups. There were however no statistical and clinical significant differences between the eosinophil, lymphocyte, red cell and platelet counts across the three groups. In conclusion, subjects of Mixed Ancestry, in this region, have similar reference intervals to those of European descent, while lower white cell and neutrophil counts in Africans have been confirmed.

Indirect methods for reference interval determination - review and recommendations.

Reference intervals are a vital part of the information supplied by clinical laboratories to support interpretation of numerical pathology results such as are produced in clinical chemistry and hematology laboratories. The traditional method for establishing reference intervals, known as the direct approach, is based on collecting samples from members of a preselected reference population, making the measurements and then determining the intervals. An alternative approach is to perform analysis of results generated as part of routine pathology testing and using appropriate statistical techniques to determine reference intervals. This is known as the indirect approach. This paper from a working group of the International Federation of Clinical Chemistry (IFCC) Committee on Reference Intervals and Decision Limits (C-RIDL) aims to summarize current thinking on indirect approaches to reference intervals. The indirect approach has some major potential advantages compared with direct methods. The processes are faster, cheaper and do not involve patient inconvenience, discomfort or the risks associated with generating new patient health information. Indirect methods also use the same preanalytical and analytical techniques used for patient management and can provide very large numbers for assessment. Limitations to the indirect methods include possible effects of diseased subpopulations on the derived interval. The IFCC C-RIDL aims to encourage the use of indirect methods to establish and verify reference intervals, to promote publication of such intervals with clear explanation of the process used and also to support the development of improved statistical techniques for these studies.

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.

Statistical considerations for harmonization of the global multicenter study on reference values

The global multicenter study on reference values coordinated by the Committee on Reference Intervals and Decision Limits (C-RIDL) of the IFCC was launched in December 2011, targeting 45 commonly tested analytes with the following objectives: 1) to derive reference intervals (RIs) country by country using a common protocol, and 2) to explore regionality/ethnicity of reference values by aligning test results among the countries. To achieve these objectives, it is crucial to harmonize 1) the protocol for recruitment and sampling, 2) statistical procedures for deriving the RI, and 3) test results through measurement of a panel of sera in common.For harmonized recruitment, very lenient inclusion/exclusion criteria were adopted in view of differences in interpretation of what constitutes healthiness by different cultures and investigators. This policy may require secondary exclusion of individuals according to the standard of each country at the time of deriving RIs. An iterative optimization procedure, called the latent abnormal values exclusion (LAVE) method, can be applied to automate the process of refining the choice of reference individuals.For global comparison of reference values, test results must be harmonized, based on the among-country, pair-wise linear relationships of test values for the panel. Traceability of reference values can be ensured based on values assigned indirectly to the panel through collaborative measurement of certified reference materials. The validity of the adopted strategies is discussed in this article, based on interim results obtained to date from five countries. Special considerations are made for dissociation of RIs by parametric and nonparametric methods and between-country difference in the effect of body mass index on reference values.