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

AbstractObjectivesA multicenter study was organized to explore sources of variation (SVs) of reference values (RVs) for 24 major immunochemistry analytes and to determine reference intervals (RIs) for the Russian population.MethodsAccording to IFCC Committee on Reference Intervals and Decision Limits (C-RIDL) protocol, 793 healthy volunteers were recruited in St. Petersburg, Moscow, and Yekaterinburg. Serum samples were tested for five tumor markers, 19 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.ResultsSDR 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%); for insulin, those with BMI≥28 kg/m2 (29.9%); for the thyroid panel, those with anti-thyroid antibodies (10.3% in males; 24.5% in 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 α-fetoprotein and all sex-hormones except testosterone. RIs were generally derived by parametric method after Gaussian transformation using modified Box-Cox formula. Exceptions were growth hormone, estradiol, and progesterone, for which nonparametric method was required due to bimodal distribution and/or insufficient detection limit.ConclusionRIs 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.

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

PLoS ONE ◽

10.1371/journal.pone.0234284 ◽

2021 ◽

Vol 16 (1) ◽

pp. e0234284

Author(s):

Anna Ruzhanskaya ◽

Kiyoshi Ichihara ◽

Svetlana Evgina ◽

Irina Skibo ◽

Nina Vybornova ◽

...

Keyword(s):

Tumor Markers ◽

Sex Hormones ◽

Parametric Method ◽

Smoking Habit ◽

Bimodal Distribution ◽

Reference Intervals ◽

Careful Consideration ◽

Russian Population ◽

Serum Samples ◽

Sources Of Variation

Objectives 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. Methods 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. Results 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. Conclusion 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.

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Establishment of reference intervals for immunoassay analytes of adult population in Saudi Arabia

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2019-1049 ◽

2020 ◽

Vol 58 (8) ◽

pp. 1302-1313 ◽

Cited By ~ 3

Author(s):

Anwar Borai ◽

Kiyoshi Ichihara ◽

Abdulaziz Masaud ◽

Waleed Tamimi ◽

Suhad Bahijri ◽

...

Keyword(s):

Vitamin D ◽

Saudi Arabia ◽

Adult Population ◽

Reference Intervals ◽

Careful Consideration ◽

Upper Limits ◽

Sources Of Variation ◽

Vitamin D Supplements ◽

Saudi Arabians ◽

Abbott Architect

AbstractBackgroundThis is a second part of report on the IFCC global multicenter study conducted in Saudi Arabia to derive reference intervals (RIs) for 20 immunoassay analytes including five tumor makers, five reproductive, seven other hormones and three vitamins.MethodsA total of 826 apparently healthy individuals aged ≥18 years were recruited in three clinical laboratories located in western, central and eastern Saudi Arabia using the protocol specified for the global study. All serum specimens were measured using Abbott, Architect analyzers. Multiple regression analysis (MRA) was performed to explore sources of variation of each analyte: age, body mass index (BMI), physical exercise and smoking. The magnitude of variation of reference values (RVs) attributable to sex, age and region was calculated by ANOVA as a standard deviation ratio (SDR). RIs were derived by the parametric (P) method.ResultsMRA revealed that region, smoking and exercise were not relevant sources of variation for any analyte. Based on SDR and actual between-sex differences in upper limits (ULs), we chose to partition RIs by sex for all analytes except for α-fetoprotein and parathyroid hormone (PTH). Age-specific RIs were required in females for ferritin, estradiol, progesterone, testosterone, follitropin, luteotropin and prolactin (PRL). With prominent BMI-related increase, RIs for insulin and C-peptide were derived after excluding individuals with BMI > 32 kg/m2. Individuals taking vitamin D supplements were excluded in deriving RIs for vitamin D and PTH.ConclusionsRIs of major immunoassay analytes specific for Saudi Arabians were established in careful consideration of various biological sources of variation.

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Reference intervals for 33 biochemical analytes in healthy Indian population: C-RIDL IFCC initiative

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2018-0152 ◽

2018 ◽

Vol 56 (12) ◽

pp. 2093-2103 ◽

Cited By ~ 6

Author(s):

Swarup A.V. Shah ◽

Kiyoshi Ichihara ◽

Alpa J. Dherai ◽

Tester F. Ashavaid

Keyword(s):

Parametric Method ◽

Reference Intervals ◽

Specific Reference ◽

Appreciable Effect ◽

Test Results ◽

Gender And Age ◽

Sources Of Variation ◽

Overnight Fasting ◽

Nested Analysis ◽

Non Parametric

Abstract Background In 2011, the IFCC Committee on Reference Intervals and Decision Limits (C-RIDL) initiated a worldwide multicenter study on references values facilitating the implementation of country-specific reference intervals (RIs). There has been no well-designed RI study in India. This study aims to derive RIs for 33 major biochemical analytes in carefully selected healthy Indians as defined in C-RIDL protocol. Methods A total of 512 healthy Indians were recruited. Sera collected from overnight fasting blood samples were measured collectively for the analytes. Multiple regression analysis (MRA) and nested analysis of variance (ANOVA) were used to identify the potential sources of variation (SV) of test results. RI were derived by both parametric and non-parametric methods for comparison. The need for secondary exclusion by latent abnormal values exclusion (LAVE) method was examined. Results MRA results indicated that both age and BMI were apparent SV for many analytes in both sexes. ANOVA revealed that partition of RIs by gender and age was required for 17 analytes (TC, HDL-C, TG, hsCRP, ALB, AST, ALT, ALP, GGT, TBil, Urea, CRE, UA, Fe, TTR, CK and IgM) and 5 (Glu, ALB, TC, ALP and Urea), respectively. RIs by parametric method were generally narrower than by non-parametric method, reflecting distorted peripheral distributions of test results. The LAVE method had no appreciable effect on RIs possibly due to inconsistency among abnormal values of related analytes. Conclusions This study has for the first time provided comprehensive RIs information in healthy Indians. The final RIs adopted were those derived by parametric method without LAVE procedure.

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Cross-Method Comparison of Serum Androstenedione Measurement Using Three Different Assays: The Siemens Immulite Immunoassay, the Roche Elecsys Immunoassay, and an LC/MS-MS Assay

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1486 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A730-A731

Author(s):

Ruhan Wei ◽

Kathleen Bowers ◽

Grace M Kroner ◽

Drew Payto ◽

Jessica Colon Franco

Keyword(s):

Clinical Performance ◽

Polycystic Ovary ◽

Pediatric Population ◽

Method Comparison ◽

Reference Intervals ◽

Healthy Children ◽

Healthy Male ◽

Serum Samples ◽

Female Sex Hormones ◽

Deming Regression

Abstract Introduction: Androstenedione is a common precursor of male and female sex hormones produced by the adrenal glands and gonads. Serum androstenedione is a helpful biomarker in the diagnostic workup of a subset of patients with polycystic ovary syndrome (PCOS), the investigation of virilizing endocrinopathies, and for monitoring pediatric patients with congenital adrenal hyperplasia. The gold standard for the measurement of androstenedione is LC-MS/MS. A newly developed androstenedione competitive immunoassay is now available in the US, the Roche Elecsys Androstenedione (ASD) immunoassay. Until recently, the Siemens Immulite assay was the only non-radioimmunologic immunoassay available. We characterized the analytical and clinical performance of the ASD across different patient populations and in comparison to the Immulite and an LC-MS/MS assay. Methods and materials: The experiments performed were: linearity and analytical measuring range (AMR), precision (intra- and inter-assay), and accuracy. Androstenedione was measured on de-identified residual serum samples (n=40) using the ASD and Immulite immunoassays and an LC-MS/MS assay. The reference intervals (RIs) provided by Roche for healthy male (0.280-1.52 ng/mL), healthy female (0.490-1.31 ng/mL), postmenopausal women (0.187-1.07 ng/mL), healthy children (<0.519 ng/mL), and patients with PCOS (0.645-3.47 ng/mL) were verified with at least 20 specimens, according to CLSI C28A3. Statistical analysis was performed using EP Evaluator and R program. Results: The ASD had a linear response across the AMR of 0.3 to 10.0 ng/mL. The inter- and intra-assay coefficients of variation were 4.5% and 2.0% or lower, at concentrations 0.5-6.7 ng/mL, respectively. The ASD and LC-MS/MS assays had a mean bias of -0.0542 ng/mL (-2%), Deming regression of y = 1.000 [0.961; 1.039] x - 0.0548 [-0.1806; 0.0709], and r = 0.9930. The Immulite assay had a mean bias of 1.15 ng/mL (44%) and 1.22 ng/mL (32%) compared to the LC-MS/MS and ASD assays, respectively. The recommended RIs from Roche for healthy male, female, and postmenopausal female groups were successfully verified in our patient population. However, the androstenedione concentrations for the healthy children and PCOS groups were outside of the suggested RIs, with concentrations up to 1.41 ng/mL and 0.527-2.24 ng/mL, respectively. Unlike published elsewhere, hormone therapies such as contraceptive pills and steroid treatments did not significantly affect serum androstenedione concentrations in healthy females and patients with PCOS. Conclusion: The ASD is superior to the Immulite immunoassay, and it has excellent comparability with the LC-MS/MS for serum androstenedione measurement. The RIs published by Roche may not be universally transferable; verification is recommended, and establishing RIs for the pediatric population may be necessary.

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A multicenter nationwide reference intervals study for common biochemical analytes in Turkey using Abbott analyzers

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2014-0228 ◽

2014 ◽

Vol 52 (12) ◽

Cited By ~ 20

Author(s):

Yesim Ozarda ◽

Kiyoshi Ichihara ◽

Diler Aslan ◽

Hulya Aybek ◽

Zeki Ari ◽

...

Keyword(s):

Reference Values ◽

Parametric Method ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

Turkish Population ◽

Reference Intervals ◽

Test Results ◽

Age Related ◽

Sources Of Variation ◽

Exclusion Method

AbstractA nationwide multicenter study was organized to establish reference intervals (RIs) in the Turkish population for 25 commonly tested biochemical analytes and to explore sources of variation in reference values, including regionality.Blood samples were collected nationwide in 28 laboratories from the seven regions (≥400 samples/region, 3066 in all). The sera were collectively analyzed in Uludag University in Bursa using Abbott reagents and analyzer. Reference materials were used for standardization of test results. After secondary exclusion using the latent abnormal values exclusion method, RIs were derived by a parametric method employing the modified Box-Cox formula and compared with the RIs by the non-parametric method. Three-level nested ANOVA was used to evaluate variations among sexes, ages and regions. Associations between test results and age, body mass index (BMI) and region were determined by multiple regression analysis (MRA).By ANOVA, differences of reference values among seven regions were significant in none of the 25 analytes. Significant sex-related and age-related differences were observed for 10 and seven analytes, respectively. MRA revealed BMI-related changes in results for uric acid, glucose, triglycerides, high-density lipoprotein (HDL)-cholesterol, alanine aminotransferase, and γ-glutamyltransferase. Their RIs were thus derived by applying stricter criteria excluding individuals with BMI >28 kg/mWith the lack of regional differences and the well-standardized status of test results, the RIs derived from this nationwide study can be used for the entire Turkish population.

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Establishment of reference intervals of biochemical analytes for South African adults: a study conducted as part of the IFCC global multicentre study on reference values

Journal of Medical Laboratory Science & Technology of South Africa ◽

10.36303/jmlstsa.2021.3.1.64 ◽

2021 ◽

pp. 8-23

Author(s):

FC Smit ◽

K Ichihara ◽

J George ◽

E Blanco-Blanco ◽

M Hoffmann ◽

...

Keyword(s):

South African ◽

Reference Values ◽

Clinical Chemistry ◽

Parametric Method ◽

Density Lipoprotein ◽

Reference Intervals ◽

Mixed Ancestry ◽

Serum Samples ◽

Age Related ◽

Non Parametric

Objective: This study was conducted as a part of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) global study for establishing reference intervals (RIs) of common laboratory tests for the South African population considering gender, ethnicity, age and body mass index (BMI). Methods: The researchers recruited 1 143 apparently healthy volunteers aged 18–65: 551 African (Afr) and 592 non-African (NAfr) (comprising 383 Caucasian and 209 Mixed Ancestry). Serum samples were measured for 40 chemistry and immunochemistry analytes. The standard deviation ratio (SDR) guided the need for partitioning reference values according to gender, ethnicity and age using a threshold of ≥ 0.4. The latent abnormal values exclusion (LAVE) method was applied to reduce influences of latent diseases before deriving RIs using both parametric and non-parametric methods. Results: Based on SDRsex, males showed higher albumin, uric acid, creatinine, AST, CK and ferritin. Based on SDRRC, Afr compared to NAfr showed (i) higher total protein, amylase, CRP, immunoglobulin G and A and (ii) lower total bilirubin, total cholesterol, low-density lipoprotein cholesterol (LDL-C), ALT and cholinesterase. Both age-related changes in glucose and LDL-C, and BMI-related changes in ALT, ALP and LDH were more prominent in NAfr. RIs were determined according to gender, age and ethnicity. The LAVE method was effective in lowering the upper RI limits (UL) of nutritional markers such as γGT and CRP. Compared to the non-parametric method, the parametric method gave narrower confidence intervals of ULs for analytes with skewed distributions. Conclusion: Establishing RIs by considering ethnicity was essential in many analytes in South Africa. Age and BMI-related changes differed greatly between Afr and NAfr.

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Determination of reference intervals for knee motor functions specific to patients undergoing knee arthroplasty

PLoS ONE ◽

10.1371/journal.pone.0249564 ◽

2021 ◽

Vol 16 (4) ◽

pp. e0249564

Author(s):

Hideyuki Ito ◽

Kiyoshi Ichihara ◽

Kotaro Tamari ◽

Tetsuya Amano ◽

Shigeharu Tanaka ◽

...

Keyword(s):

Motor Function ◽

Knee Arthroplasty ◽

Parametric Method ◽

Reference Intervals ◽

Variable Degree ◽

Test Results ◽

Timed Up And Go ◽

Motor Functions ◽

Age Related ◽

Sources Of Variation

Background In patients with knee osteoarthritis (KOA) undergoing knee arthroplasty (KA), lower-limb motor function tests are commonly measured during peri-surgical rehabilitation. To clarify their sources of variation and determine reference intervals (RIs), a multicenter study was performed in Japan. Methods We enrolled 545 KOA patients (127 men; 418 women; mean age 74.2 years) who underwent KA and followed a normal recovery course. The surgical modes included total KA (TKA), minimally invasive TKA (MIS-TKA), and unicompartmental KA (UKA). Motor functions measured twice before and two weeks after surgery included timed up-and-go (TUG), maximum walking speed (MWS), extensor and flexor muscle strength (MS), and knee range of motion (ROM). Multiple regression analysis was performed to evaluate their sources of variation including sex, age, BMI, and surgical mode. Magnitude of between-subgroup differences was expressed as SD ratio (SDR) based on 3-level nested ANOVA. SDR≥0.4 was set as the threshold for requiring RIs specific for each subgroup. Results Before surgery, age-related changes exceeding the threshold were observed for TUG and MWS. Between-sex difference was noted for extensor and flexor MS, but extension and flexion ROMs were not influenced by sex or age. After surgery, in addition to similar influences of sex and age on test results, surgical modes of UKA and MIS-TKA generally had a favorable influence on MWS, extensor MS, and flexion ROM. All motor function test results showed a variable degree of skewness in distribution, and thus RIs were basically derived by the parametric method after Gaussian transformation of test results. Conclusions This is the first study to determine RIs for knee motor functions specific to KOA patients after careful consideration of their sources of variation and distribution shapes. These RIs facilitate objective implementation of peri-surgical rehabilitation and allow detection of patients who deviate from the normal course of recovery.

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