Nomogram of age-specific anti-Müllerian hormone levels in healthy Egyptian females

Background Anti-Müllerian hormone (AMH) is an important determinant of ovarian reserve in fertility workups in many clinical settings. Thus, we investigated the age dependent decline in AMH specific to the Egyptian population and sought to establish an age dependent reference interval parametrically. Methods Serum samples were collected from 841 apparently healthy women. AMH was measured using an electro-chemiluminescent technique. Box-Cox power transformation was used to make the AMH distribution Gaussian for parametric derivation of reference intervals. Results Power of 0.4 was found optimal for Gaussian transformation of AMH reference values. We demonstrate the strong negative relation between circulating AMH and female age with Spearman’s correlation coefficient of rS = −0.528. Age-specific reference interval was determined for every 5 years of age from 16 to 49, and nomogram was constructed by smoothing the lines connecting adjacent lower and upper reference limits. Conclusion The age-specific reference intervals and the age-AMH nomogram could be valuable in the clinical practice of in reproductive medicine. To our knowledge, this is the first study to confirm AMH levels in Egyptian females. We were able to explore age-related AMH levels specific to Egyptian females in the fertile age group and to treat skewed AMH data in a multi-step scheme using power transformation. Thus, a more accurate nomogram was constructed accommodating a profile delineated for a wide age range and a rescaled AMH axis improving its usability.

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Pediatric reference intervals for 1,25-dihydroxyvitamin D using the DiaSorin LIAISON XL assay in the healthy CALIPER cohort

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2017-0767 ◽

2018 ◽

Vol 56 (6) ◽

pp. 964-972 ◽

Cited By ~ 7

Author(s):

Victoria Higgins ◽

Dorothy Truong ◽

Nicole M.A. White-Al Habeeb ◽

Angela W.S. Fung ◽

Barry Hoffman ◽

...

Keyword(s):

Children And Adolescents ◽

Critical Role ◽

Reference Interval ◽

Reference Intervals ◽

Biologically Active ◽

Specific Reference ◽

Healthy Children ◽

Serum Samples ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D

Abstract Background: 1,25-dihydroxyvitamin D (1,25(OH)2D), the biologically active vitamin D metabolite, plays a critical role in calcium and phosphate homeostasis. 1,25(OH)2D is measured to assess calcium and phosphate metabolism, particularly during periods of profound growth and development. Despite its importance, no reliable pediatric reference interval exists, with those available developed using adult populations or out-dated methodologies. Using the fully automated chemiluminescence immunoassay by DiaSorin, we established 1,25(OH)2D pediatric reference intervals using healthy children and adolescents from the CALIPER cohort. Methods: Serum samples from healthy subjects (0 to <19 years) were analyzed for 1,25(OH)2D using the DiaSorin LIAISON XL assay and age-specific reference intervals were established. The Mann-Whitney U-test was used to determine seasonal differences. Pooled neonatal and infantile samples were quantified using liquid chromatography tandem mass spectrometry (LC-MS/MS) to determine if elevated concentrations during the first year of life may be attributed to cross-reacting moieties. Results: Three reference interval age partitions were required with highest levels in subjects 0 to <1 year (77–471 pmol/L), which declined and narrowed after 1 year (113–363 pmol/L) and plateaued at 3 years (108–246 pmol/L). 1,25(OH)2D concentration was not significantly affected by seasonal variation or sex. Elevated 1,25(OH)2D concentrations in neonatal and infantile samples may be the result of an interfering substance. The absence of 3-epi-1,25-dihydroxyvitamin D in the pooled samples makes it unlikely to be the interfering moiety. Conclusions: Pediatric reference intervals for 1,25(OH)2D were established to improve test result interpretation in children and adolescents. 1,25(OH)2D is elevated in a proportion of neonates and infants, which may be the result of a cross-reacting moiety.

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In Search of Normality for Vitamin K1: Establishing Age-Dependent Reference Intervals in the Danish Population

The Journal of Applied Laboratory Medicine ◽

10.1093/jalm/jfaa017 ◽

2020 ◽

Vol 5 (3) ◽

pp. 531-543

Author(s):

Ida Boegh Andersen ◽

Claus Lohman Brasen ◽

Anne Schmedes ◽

Ivan Brandslund ◽

Jonna Skov Madsen

Keyword(s):

Vitamin K ◽

Serum Vitamin ◽

Reference Intervals ◽

Specific Reference ◽

Vitamin K1 ◽

Serum Samples ◽

Lower Serum ◽

Limit Of Quantitation ◽

Significant Difference ◽

Age Dependent

Abstract Background A growing body of evidence suggests that vitamin K has beneficial effects on human health, especially cardiovascular and bone health. Vitamin K1 (phylloquinone), the predominant form of vitamin K in blood, is regarded as an indicator of vitamin K status, but to our knowledge no reference intervals (RIs) have been established for vitamin K1. Methods In this population-based study, vitamin K1 was measured in serum from 3808 Caucasian individuals without diabetes from 26 to 78 years of age. The need for gender- and age-partitioned vitamin K1 reference intervals was evaluated using Lahti’s method, and exclusion criteria were defined to obtain as healthy a study group as possible. The excluded subgroups were tested for differences in mean serum vitamin K1 levels. Serum vitamin K1 levels were quantified using an in-house newly developed, validated, and highly sensitive online SPE-LC-MS/MS method with a limit of quantitation of (LOQ) 0.05 nmol/L. Results The reference interval for serum vitamin K1 was 0.22 to 3.95 nmol/L for individuals aged 26 to 44 years and 0.35 to 3.70 nmol/L for individuals aged 45 to 78. Similar age-specific reference intervals were established for vitamin K1-triglyceride ratio being 0.20 to 3.16 and 0.31 to 3.44, respectively. No significant difference was found between genders. Serum vitamin K1 was detectable in all serum samples. Individuals with known comorbidity were found to have significantly lower serum vitamin K1 compared to those without comorbidity. Current smokers had lower serum vitamin K1 compared to nonsmokers. Conclusion Age-dependent reference intervals were established for serum vitamin K1 and vitamin K1-triglyceride ratio in a well-defined, healthy Caucasian population. Lower serum vitamin K1 levels were found in individuals with known comorbidity, suggesting an association between serum vitamin K1 and disease status. Further studies are needed to determine an optimal serum vitamin K1 level.

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Determination of a Beckman Coulter AU turbidometric method-specific caeruloplasmin reference interval

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/0004563221989360 ◽

2021 ◽

pp. 000456322198936

Author(s):

Olivia E Kaye ◽

Paul Cook

Keyword(s):

Renal Stones ◽

Reference Interval ◽

Reference Intervals ◽

University Hospital ◽

Specific Reference ◽

Serum Samples ◽

Rank Analysis ◽

Local Reference ◽

Local Determination

Background Method-dependent variation of caeruloplasmin measurement is significant and necessitates the requirement for assay-specific reference intervals. Local determination becomes necessary in the absence of suitable published or manufacturer-quoted reference intervals. Methods Applicability of the Beckman Coulter AU-quoted reference interval was determined by assay of 20 surplus serum samples from patients attending the medical renal stones clinic at University Hospital Southampton. Subsequently, 60 additional samples were collected for local reference interval determination. Samples were analysed for caeruloplasmin using the Beckman Coulter AU turbidometric kit on an AU680 analyser. Outliers were removed, and non-parametric rank analysis of the results was performed. Results The Beckman Coulter-quoted reference interval of 200–600 mg/L was unsuitable with 40% of the verification samples falling below 200 mg/L. A caeruloplasmin reference interval of 150–320 mg/L was established. Conclusion Users should be aware the quoted Beckman Coulter AU turbidometric reference interval may not be appropriate. We have established a method-specific adult reference interval for routine use.

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EXPRESS: Method dependent variation in TSH and FT4 reference intervals in pregnancy: a systematic review

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/00045632211026955 ◽

2021 ◽

pp. 000456322110269

Author(s):

O E Okosieme ◽

Medha Agrawal ◽

Danyal Usman ◽

Carol Evans

Keyword(s):

Systematic Review ◽

Reference Interval ◽

First Trimester ◽

Reference Intervals ◽

Assay Method ◽

Specific Reference ◽

Upper Limits ◽

Wide Range ◽

Assay Methods ◽

In Pregnancy

Background: Gestational TSH and FT4 reference intervals may differ according to assay method but the extent of variation is unclear and has not been systematically evaluated. We conducted a systematic review of published studies on TSH and FT4 reference intervals in pregnancy. Our aim was to quantify method-related differences in gestation reference intervals, across four commonly used assay methods, Abbott, Beckman, Roche, and Siemens. Methods: We searched the literature for relevant studies, published between January 2000 and December 2020, in healthy pregnant women without thyroid antibodies or disease. For each study, we extracted trimester-specific reference intervals (2.5â97.5 percentiles) for TSH and FT4 as well as the manufacturer provided reference interval for the corresponding non-pregnant population. Results: TSH reference intervals showed a wide range of study-to-study differences with upper limits ranging from 2.33 to 8.30 mU/L. FT4 lower limits ranged from 4.40â13.93 pmol/L, with consistently lower reference intervals observed with the Beckman method. Differences between non-pregnant and first trimester reference intervals were highly variable, and for most studies the TSH upper limit in the first trimester could not be predicted or extrapolated from non-pregnant values. Conclusions: Our study confirms significant intra and inter-method disparities in gestational thyroid hormone reference intervals. The relationship between pregnant and non-pregnant values is inconsistent and does not support the existing practice in some laboratories of extrapolating gestation references from non-pregnant values. Laboratories should invest in deriving method-specific gestation reference intervals for their population.

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Evaluation of Thyroid Function in Pregnant Women Using Automated Immunoassays

Clinical Chemistry ◽

10.1093/clinchem/hvab009 ◽

2021 ◽

Author(s):

K Aaron Geno ◽

Matthew S Reed ◽

Mark A Cervinski ◽

Robert D Nerenz

Keyword(s):

Pregnant Women ◽

Equilibrium Dialysis ◽

Reference Interval ◽

First Trimester ◽

Reference Intervals ◽

Free Thyroxine ◽

Specific Reference ◽

Childbearing Age ◽

Thyroid Autoantibody ◽

The Impact

Abstract Introduction Automated free thyroxine (FT4) immunoassays are widely available, but professional guidelines discourage their use in pregnant women due to theoretical under-recoveries attributed to increased thyroid hormone binding capacity and instead advocate the use of total T4 (TT4) or free thyroxine index (FTI). The impact of this recommendation on the classification of thyroid status in apparently euthyroid pregnant patients was evaluated. Methods After excluding specimens with thyroid autoantibody concentrations above reference limits, thyroid-stimulating hormone (TSH), FT4, TT4, and T-uptake were measured on the Roche Cobas® platform in remnant clinical specimens from at least 147 nonpregnant women of childbearing age and pregnant women at each trimester. Split-sample comparisons of FT4 as measured by the Cobas and equilibrium dialysis were performed. Results FT4 decreased with advancing gestational age by both immunoassay and equilibrium dialysis. TSH declined during the first trimester, remained constant in the second, and increased throughout the third, peaking just before delivery. Interpretation of TT4 concentrations using 1.5-times the nonpregnant reference interval classified 13.6% of first trimester specimens below the lower reference limit despite TSH concentrations within trimester-specific reference intervals. Five FTI results from 480 pregnant individuals (about 1.0%) fell outside the manufacturer’s reference interval. Conclusions Indirect FT4 immunoassay results interpreted in the context of trimester-specific reference intervals provide a practical and viable alternative to TT4 or FTI. Declining FT4 and increasing TSH concentrations near term suggest that declining FT4 is not an analytical artifact but represents a true physiological change in preparation for labor and delivery.

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Experience with the Urinary Tetrasaccharide Metabolite for Pompe Disease in the Diagnostic Laboratory

Metabolites ◽

10.3390/metabo11070446 ◽

2021 ◽

Vol 11 (7) ◽

pp. 446

Author(s):

Jennifer T. Saville ◽

Maria Fuller

Keyword(s):

Pompe Disease ◽

Late Onset ◽

Reference Interval ◽

Laboratory Diagnosis ◽

Reference Intervals ◽

Confirmatory Test ◽

Diagnostic Laboratory ◽

Age Related ◽

Initial Drop ◽

Monitoring Treatment

Following clinical indications, the laboratory diagnosis of the inherited metabolic myopathy, Pompe disease (PD), typically begins with demonstrating a reduction in acid alpha-glucosidase (GAA), the enzyme required for lysosomal glycogen degradation. Although simple in concept, a major challenge is defining reference intervals, as even carriers can have reduced GAA, and pseudodeficiencies complicate interpretation. Here, we developed a mass spectrometric assay for quantification of a urinary glycogen metabolite (tetrasaccharide) and reported on its utility as a confirmatory test for PD in a diagnostic laboratory. Using two age-related reference intervals, eight returned tetrasaccharide concentrations above the calculated reference interval but did not have PD, highlighting non-specificity. However, retrospective analysis revealed elevated tetrasaccharide in seven infantile-onset (IOPD) cases and sixteen late-onset (LOPD) cases, and normal concentrations in one heterozygote. Prospective tetrasaccharide analysis in nine individuals with reduced GAA confirmed IOPD in one, LOPD in six and identified two heterozygotes. Using this metabolite as a biomarker of therapeutic response was not overly informative; although most patients showed an initial drop following therapy initiation, tetrasaccharide concentrations fluctuated considerably and remained above reference intervals in all patients. While useful as a confirmation of PD, its utility as a biomarker for monitoring treatment warrants further investigation.

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Pediatric reference interval verification for endocrine and fertility hormone assays on the Abbott Alinity system

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2021-0337 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Mary Kathryn Bohn ◽

Siobhan Wilson ◽

Alexandra Hall ◽

Khosrow Adeli

Keyword(s):

Clinical Decision Making ◽

De Novo ◽

Reference Interval ◽

Clinical Decision ◽

Reference Intervals ◽

Healthy Children ◽

Confidence Limits ◽

Test Results ◽

Serum Samples ◽

Abbott Architect

Abstract Objectives The Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) has developed an extensive database of reference intervals (RIs) for several biomarkers on various analytical systems. In this study, pediatric RIs were verified for key immunoassays on the Abbott Alinity system based on the analysis of healthy children samples and comparison to comprehensive RIs previously established for Abbott ARCHITECT assays. Methods Analytical performance of Alinity immunoassays was first assessed. Subsequently, 100 serum samples from healthy children recruited with informed consent were analyzed for 16 Alinity immunoassays. The percentage of test results falling within published CALIPER ARCHITECT reference and confidence limits was determined. If ≥ 90% of test results fell within the confidence limits, they were considered verified based on CLSI guidelines. If <90% of test results fell within the confidence limits, additional samples were analyzed and new Alinity RIs were established. Results Of the 16 immunoassays assessed, 13 met the criteria for verification with test results from ≥ 90% of healthy serum samples falling within the published ARCHITECT confidence limits. New CALIPER RIs were established for free thyroxine and prolactin on the Alinity system. Estradiol required special considerations in early life. Conclusions Our data demonstrate excellent concordance between ARCHITECT and Alinity immunoassays, as well as the robustness of previously established CALIPER RIs for most immunoassays, eliminating the need for de novo RI studies for most parameters. Availability of pediatric RIs for immunoassays on the Alinity system will assist clinical laboratories using this new platform and contribute to improved clinical decision-making.

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Impact of age, body weight and metabolic risk factors on steroid reference intervals in men

Acta Endocrinologica ◽

10.1530/eje-19-0928 ◽

2020 ◽

Vol 182 (5) ◽

pp. 459-471

Author(s):

Marco Mezzullo ◽

Guido Di Dalmazi ◽

Alessia Fazzini ◽

Margherita Baccini ◽

Andrea Repaci ◽

...

Keyword(s):

Risk Factors ◽

Reference Intervals ◽

Metabolic Risk Factors ◽

Specific Reference ◽

Metabolic Risk ◽

Cross Sectional ◽

Cholesterol Ratio ◽

Age Related ◽

Reference Limits ◽

17 Hydroxyprogesterone

Objective To evaluate the independent impact of age, obesity and metabolic risk factors on 13 circulating steroid levels; to generate reference intervals for adult men. Design Cross-sectional study. Methods Three hundred and fifteen adults, drug-free and apparently healthy men underwent clinical and biochemical evaluation. Thirteen steroids were measured by LC-MS/MS and compared among men with increasing BMI. Moreover, the independent impact of age, BMI and metabolic parameters on steroid levels was estimated. Upper and lower reference limits were generated in steroid-specific reference sub-cohorts and compared with dysmetabolic sub-cohorts. Results We observed lower steroid precursors and testosterone and increase in estrone levels in men with higher BMI ranges. By multivariate analysis, 17-hydroxyprogesterone and dihydrotestosterone decreased with BMI, while cortisol decreased with waist circumference. Estrone increased with BMI and systolic blood pressure. Testosterone decreased with worsening insulin resistance. 17-hydroxypregnenolone and corticosterone decreased with increasing total/HDL-cholesterol ratio. Age-related reference intervals were estimated for 17-hydroxypregnenolone, DHEA, 17-hydroxyprogesterone, corticosterone, 11-deoxycortisol, cortisol and androstenedione, while age-independent reference intervals were estimated for progesterone, 11-deoxycorticosterone, testosterone, dihydrotestosterone, estrone and estradiol. Testosterone lower limit was 2.29 nmol/L lower (P = 0.007) in insulin resistant vs insulin sensitive men. Furthermore, the upper limits for dihydrotestosterone (−0.34 nmol/L, P = 0.045), cortisol (−87 nmol/L, P = 0.045–0.002) and corticosterone (−10.1 nmol/L, P = 0.048–0.016) were lower in overweight/obese, in abdominal obese and in dyslipidaemic subjects compared to reference sub-cohorts, respectively. Conclusions Obesity and mild unmedicated metabolic risk factors alter the circulating steroid profile and bias the estimation of reference limits for testosterone, dihydrotestosterone, cortisol and corticosterone. Applying age-dependent reference intervals is mandatory for steroid precursors and corticosteroids.

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Distribution of HOMA-IR in a population-based cohort and proposal for reference intervals

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2021-0643 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Bassel Matli ◽

Andreas Schulz ◽

Thomas Koeck ◽

Tanja Falter ◽

Johannes Lotz ◽

...

Keyword(s):

Insulin Resistance ◽

Fasting Glucose ◽

Reference Group ◽

Reference Interval ◽

Population Based ◽

Reference Intervals ◽

Health Study ◽

Specific Reference ◽

Model Assessment ◽

Significant Difference

Abstract Objectives Insulin resistance (IR) is a hallmark of type 2 diabetes mellitus (DM). The homeostatic model assessment of insulin resistance (HOMA-IR) provides an estimate for IR from fasting glucose and insulin serum concentrations. The aim of this study was to obtain a reference interval for HOMA-IR for a specific insulin immunoassay. Methods The Gutenberg Health Study (GHS) is a population-based, prospective, single-center cohort study in Germany with 15,030 participants aged 35–74 years. Fasting glucose, insulin, and C-peptide were available in 10,340 participants. HOMA-IR was calculated in this group and three reference subgroups with increasingly more stringent inclusion criteria. Age- and sex-dependent distributions of HOMA-IR and reference intervals were obtained. In a substudy three insulin assays were compared and HOMA-IR estimated for each assay. Results Among the 10,340 participants analyzed there were 6,590 non-diabetic, 2,901 prediabetic, and 849 diabetic individuals. Median (interquartile range [IQR]) HOMA-IR was 1.54 (1.13/2.19), 2.00 (1.39/2.99), and 4.00 (2.52/6.51), respectively. The most stringently selected reference group consisted of 1,065 persons. Median (IQR) HOMA-IR was 1.09 (0.85/1.42) with no significant difference between men and women. The 97.5th percentile was 2.35. There was a non-significant trend towards higher values with older age. Comparison of three immunoassays for insulin showed an unsatisfactory correlation among the assays and systematic differences in calculated HOMA-IR. Conclusions We present HOMA-IR reference intervals for adults derived by more or less stringent selection criteria for the reference cohort. In addition we show that assay specific reference intervals for HOMA-IR are required.

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Establishment of variation source and age-related reference interval models for 22 common biochemical analytes in older people using real-world big data mining

Age and Ageing ◽

10.1093/ageing/afaa096 ◽

2020 ◽

Vol 49 (6) ◽

pp. 1062-1070

Author(s):

Chaochao Ma ◽

Liangyu Xia ◽

Xinqi Chen ◽

Jie Wu ◽

Yicong Yin ◽

...

Keyword(s):

Big Data ◽

Older People ◽

Real World ◽

Reference Interval ◽

Reference Intervals ◽

Ageing Population ◽

Factors Affecting ◽

Age Related ◽

The Status ◽

Source Models

Abstract Background the ageing population has increased in many countries, including China. However, reference intervals (RIs) for older people are rarely established because of difficulties in selecting reference individuals. Here, we aimed to analyse the factors affecting biochemical analytes and establish RI and age-related RI models for biochemical analytes through mining real-world big data. Methods data for 97,220 individuals downloaded from electronic health records were included. Three derived databases were established. The first database included 97,220 individuals and was used to build age-related RI models after identifying outliers by the Tukey method. The second database consisted of older people and was used to establish variation source models and RIs for biochemical analytes. Differences between older and younger people were compared using the third database. Results sex was the main source of variation of biochemical analytes for older people in the variation source models. The distributions of creatinine and uric acid were significantly different in the RIs of biochemical analytes for older people established according to sex. Age-related RI models for biochemical analytes that were most affected by age were built and visualized, revealing various patterns of changes from the younger to older people. Conclusion the study analysed the factors affecting biochemical analytes in older people. Moreover, RI and age-related RI models of biochemical analytes for older people were established to provide important insight into biological processes and to assist clinical use of various biochemical analytes to monitor the status of various diseases for older people.

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