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Background: Quantitative detection of glucose-6-phosphate dehydrogenase (G6PD) is commonly done to screen for G6PD deficiency. However, current reference intervals (RIs) of G6PD are unsuitable for evaluating G6PD-activity levels with local populations or associating G6PD variants with hemolysis risk to aid clinical decision-making. We explored appropriate RIs and clinical decision limits (CDLs) for G6PD activity in individuals from Guangzhou, China. Methods: We enrolled 5,852 unrelated individuals between 2020 and 2022 and screened their samples in quantitative assays for G6PD activity. We conducted further investigations, including G6PD genotyping, thalassemia genotyping, follow-up analysis, and statistical analysis, for different groups. Results: In Guangzhou, the RIs for the G6PD activities were 11.20–20.04 U/g Hb in male and 12.29–23.16 U/g Hb in female. The adjusted male median and normal male median (NMM) values were 15.47 U/g Hb and 15.51 U/g Hb, respectively. A threshold of 45% of the NMM could be used as a CDL to estimate the probability of G6PD variants. Our results revealed high hemolysis-risk CDLs (male: <10% of the NMM, female: <30% of the NMM), medium hemolysis-risk CDLs (male: 10%–45% of the NMM, female: 30%–79% of the NMM), and low hemolysis-risk CDLs (male: ≥45% of the NMM, female: ≥79% of the NMM). Conclusions: Collectively, our findings contribute to a more accurate evaluation of G6PD-activity levels within the local population and provide valuable insights for clinical decision making. Specifically, identifying threshold values for G6PD variants and hemolysis risk enables improved prediction and management of G6PD deficiency, ultimately enhancing patient care and treatment outcomes. [ABSTRACT FROM AUTHOR]

Background: Reference intervals, which define an interval in which a specific proportion of measurements from a healthy population are expected to fall, are commonly used in medical practice. Synthesizing information from multiple studies through meta-analysis can provide a more precise and representative reference interval than one derived from a single study. However, the current approaches for estimating the reference interval from a meta-analysis mainly rely on aggregate data and require parametric distributional assumptions that cannot always be checked. Methods: With the availability of individual participant data (IPD), non-parametric methods can be used to estimate reference intervals without any distributional assumptions. Furthermore, patient-level covariates can be introduced to estimate personalized reference intervals that may be more applicable to specific patients. This paper introduces quantile regression as a method to estimate the reference interval from an IPD meta-analysis under the fixed effects model. Results: We compared several non-parametric bootstrap methods through simulation studies to account for within-study correlation. Under fixed effects model, we recommend keeping the studies fixed and only randomly sampling subjects with replacement within each study. Conclusion: We proposed to use the quantile regression in the IPD meta-analysis to estimate the reference interval. Based on the simulation results, we identify an optimal bootstrap strategy for estimating the uncertainty of the estimated reference interval. An example of liver stiffness measurements, a clinically important diagnostic test without explicitly established reference range in children, is provided to demonstrate the use of quantile regression in estimating both overall and subject-specific reference intervals. [ABSTRACT FROM AUTHOR]

Congenital adrenal hyperplasia (CAH) is a rare, inherited disorder of adrenal steroid synthesis. In many countries it is part of the neonatal screening program enabling early diagnosis and treatment. In case of an abnormal neonatal screening result or when other differences of sexual development (DSD) are suspected, measurement of serum steroid hormones using liquid chromatography coupled to mass spectrometry (LC-MS/MS) is needed for further diagnosis. However, reliable age- and sex-specific reference intervals (RIs) for serum steroid hormones during the neonatal period are missing. We therefore aimed to establish LC-MS/MS based RIs for serum steroid hormones in neonates.Serum was obtained from healthy term neonates at two time points: 130 samples at day 3–8 (T1, time of the neonatal screening) and 126 samples at day 13–15 (T2, two weeks old). Concentrations of cortisol, cortisone, corticosterone, 11-deoxycortisol, 21-deoxycortisol, 11-deoxycorticosterone, testosterone, androstenedione, and 17-hydroxyprogesterone (17-OHP) were measured using LC-MS/MS.RIs (in nmol/L) were established for T1 and T2: cortisone (19.3–215;18.0–212), cortisol (10.0–407;8.4–446), corticosterone (<31;<50), 11-deoxycortisol (0.73–4.6;0.70–3.6), 17-OHP (<4.9;<5.1), androstenedione (0.3–1.8;0.3–2.7), 11-deoxycorticosterone (<0.2;<0.2), and 21-deoxycortisol (<1;<1), respectively. Testosterone differed between boys and girls: RIs at T1 and T2 for boys were 0.27–4.3 and 0.63–13.9, and for girls<0.30 and <0.47, respectively.We established LC-MS/MS based RIs for cortisol, cortisone, corticosterone, 11-deoxycortisol, 21-deoxycortisol, 11-deoxycorticosterone, testosterone, androstenedione, and 17-OHP in neonates in the first and second week of life. [ABSTRACT FROM AUTHOR]

Iron deficiency anemia is a significant global health concern, diagnosed by measuring hemoglobin concentrations in combination with plasma ferritin concentration. This study investigated the variability in ferritin reference intervals among laboratories in the Netherlands and examined how this affects the identification of iron-related disorders.Ferritin reference intervals from 52 Dutch ISO15189-certified medical laboratories were collected. Ferritin, hemoglobin and mean corpuscular volume data of non-anemic apparently healthy primary care patients, measured by four laboratory platforms (Beckman, Abbott, Siemens, and Roche), were collected (n=397,548). Median ferritin levels were determined per platform, stratified by sex and age. The proportion of ferritin measurements outside of the reference interval was calculated using the reference intervals from the 52 laboratories (using a total of n=1,093,442 ferritin measurements). Lastly, ferritin data from 3,699 patients as captured in general practitioner (GP) data from the PHARMO Data Network were used to assess the variation of abnormal ferritin measurements per GP.Median plasma ferritin concentrations were approximately four times higher in men and twice as high in postmenopausal women compared to premenopausal women. Moreover, there are substantial differences in the median plasma ferritin concentration between the four platforms. However, even among laboratories using the same platform, ferritin reference intervals differ widely. This leads to significant differences in the percentages of measurements classified as abnormal, with the percentage of ferritin measurements below the reference limit in premenopausal women ranging from 11 to 53 %, in postmenopausal women from 3 to 37 %, and in men from 2 to 19 %. The percentage of ferritin measurements above the reference limit in premenopausal women ranged from 0.2 to 11 %, in postmenopausal women from 3 to 36 % and in men from 7 to 32 %.The lack of harmonization in ferritin measurement and the disagreement in plasma ferritin reference intervals significantly impact the interpretation of the iron status of patients and thereby the number of iron disorder diagnoses made. Standardization or harmonization of the ferritin assays and establishing uniform reference intervals and medical decision limits are essential to reduce the substantial variability in clinical interpretations of ferritin results. [ABSTRACT FROM AUTHOR]

The diagnosis of diseases is a complex process involving the integration of multiple parameters obtained from various sources, including laboratory findings. The interpretation of laboratory data is inherently comparative, necessitating reliable references for accurate assessment. Different types of references, such as reference intervals, decision limits, action limits, and reference change values, are essential tools in the interpretation of laboratory data. Although these references are used to interpret individual laboratory data, they are typically derived from population data, which raises concerns about their reliability and consequently the accuracy of interpretation of individuals' laboratory data. The accuracy of diagnosis is critical to all subsequent steps in medical practice, making the estimate of reliable references a priority. For more precise interpretation, references should ideally be derived from an individual's own data rather than from population averages. This manuscript summarizes the current sources of references used in laboratory data interpretation, examines the references themselves, and discusses the transition from population-based laboratory medicine to personalized laboratory medicine. [ABSTRACT FROM AUTHOR]

The interpretation of laboratory data is a comparative procedure. Physicians typically need reference values to compare patients' laboratory data for clinical decisions. Therefore, establishing reliable reference data is essential for accurate diagnosis and patient monitoring. Human metabolism is a dynamic process. Various types of systematic and random fluctuations in the concentration/activity of biomolecules are observed in response to internal and external factors. In the human body, several biomolecules are under the influence of physiological rhythms and are therefore subject to ultradian, circadian and infradian fluctuations. In addition, most biomolecules are also characterized by random biological variations, which are referred to as biological fluctuations between subjects and within subjects/individuals. In routine practice, reference intervals based on population data are used, which by nature are not designed to capture physiological rhythms and random biological variations. To ensure safe and appropriate interpretation of patient laboratory data, reference intervals should be personalized and estimated using individual data in accordance with systematic and random variations. In this opinion paper, we outline (i) the main variations that contribute to the generation of personalized reference intervals (prRIs), (ii) the theoretical background of prRIs and (iii) propose new methods on how to harmonize prRIs with the systematic and random variations observed in metabolic activity, based on individuals' demography. [ABSTRACT FROM AUTHOR]

The urinary normetanephrine to creatinine ratio (uNMN/Cr) and urinary metanephrine to creatinine ratio (uMN/Cr) are commonly evaluated for the diagnosis of pheochromocytomas (PCC) in dogs. This study aimed to establish reference intervals for uNMN/Cr and uMN/Cr in 56 healthy dogs in Japan and to investigate the effect of urine collection methods on these measurements in 15 non-PCC dogs. The upper limits of reference intervals for uNMN/Cr and uMN/Cr were 124.4 nmol/mmol (90% confidence interval [CI] 107.7-137.0) and 121.1 nmol/mmol (90% CI 102.8-145.1), respectively. Both uNMN/Cr and uMN/Cr were significantly higher when urine was collected in the hospital compared to at home. Several factors, including the method of urine collection, should be considered when utilizing these reference intervals. [ABSTRACT FROM AUTHOR]

Although there are several indirect methods that can be used to verify reference limits, they have a common weakness in that they assume a low proportion of pathological values. This paper investigates whether a Gaussian decomposition algorithm can identify the non-pathological fraction even if it is not the main subset of mixed data. All investigations are carried out in the R programming environment. The mclust package is used for Gaussian mixture modelling via the expectation maximization (EM) algorithm. For right-skewed distributions, logarithms of the original values are taken to approximate the Gaussian model. We use the Bayesian information criterion (BIC) for evaluation of the results. The reflimR and refineR packages serve as comparison procedures. We generate synthetic data mixtures with known normal distributions to demonstrate the feasibility and reliability of our approach. Application of the algorithm to real data from a Nigerian and a German population produces results, which help to interpret reference intervals of reflimR and refineR that are obviously too wide. In the first example, the mclust analysis of hemoglobin in Nigerian women supports the medical hypothesis that an anemia rate of more than 50 % leads to falsely low reference limits. Our algorithm proposes various scenarios based on the BIC values, one of which suggests reference limits that are close to published data for Nigeria but significantly lower than those established for the Caucasian population. In the second example, the standard statistical analysis of creatine kinase in German patients with predominantly cardiac diseases yields a reference interval that is clearly too wide. With mclust we identify overlapping fractions that explain this false result. Gaussian mixture modelling does not replace standard methods for reference interval estimation but is a valuable adjunct when these methods produce discrepant or implausible results. [ABSTRACT FROM AUTHOR]

Rationale: Spirometry reference equations that are derived from a large, nationally representative general population are warranted in China, and the impact of using prebronchodilator (pre-BD) and post-BD spirometry reference values has yet to be assessed in Chinese populations. Objectives: To present the pre-BD and post-BD spirometry reference values for Chinese adults using the China Pulmonary Health (CPH) Study. Methods: A reference population of 17,969 healthy, nonsmoking participants in the CPH Study was used to calculate the pre- and post-BD reference values for FEV1, FVC, and FEV1/FVC ratio. Pre- and post-BD reference values were applied to the entire CPH population (N = 50,991) to illustrate the divergence between the use of different references in determining disease prevalence and severity grading. Measurements and Main Results: The prevalences of airflow limitation were 5.36% using the pre-BD reference and 8.02% using the post-BD reference. Individuals who had a post-BD FEV1/FVC ratio lower than the post-BD reference value but higher than the pre-BD reference value were found to have significantly higher rates of self-reported respiratory symptoms and significantly lower values on spirometry indicators than those whose post-BD FEV1/FVC ratio was greater than the post-BD reference value. An additional 3.51% of participants were identified as having grade II–IV chronic obstructive pulmonary disease using the post-BD FEV1 predicted values. Conclusions: This study generated and applied pre- and post-BD spirometry reference values in a nationally representative Chinese adult population. Post-BD reference values may serve as an additional criterion in identifying individuals at risk for obstructive pulmonary diseases, and their diagnostic and prognostic values should be further investigated. [ABSTRACT FROM AUTHOR]

Objective: To explore the distribution of thrombin–antithrombin complex (TAT), plasmin-α2-antiplasmin inhibitor complex (PIC), thrombomodulin (TM), and tissue plasminogen activator-inhibitor complex (t-PAIC) in healthy older Chinese adults, and establish the reference intervals (RIs). Methods: The Biotech Shine i2900 chemiluminescence immune assay was used to measure the plasma concentrations of TAT, PIC, TM, and t-PAIC in 1628 adults ≥ 60 years. The RIs were established using the 2.5th and 97.5th percentiles of the distribution. Results: TAT levels were lower in males than females across all ages. Differences between the ages of 60–79 and ≥ 80 in both sex groups were statistically significant, with an upward trend with age. PIC levels showed no difference between the sexes but increased with age in both groups. TM levels did not differ between the sex groups, with slight fluctuation with age. The level in females aged 60–69 was slightly higher than that in the other groups; the difference was statistically significant. T-PAIC levels were not significantly different between the sex groups, with less fluctuation with sex and age. The level in males ≥ 80 years old was slightly lower than that in the other groups; the difference was statistically significant. The RIs for all markers in healthy older Chinese adults were determined and statistically reported by age and sex. For TAT, the RIs for males aged 60–79 and ≥ 80 are 0.51–2.30 ng/mL and 0.88–3.72 ng/mL, respectively, whereas for females aged 60–79 and ≥ 80, the RIs are 0.68–2.82 ng/mL and 1.02–3.67 ng/mL, respectively. For PIC, the RIs for the age groups 60–69, 70–79, and ≥ 80 are 0.10–0.89 µg/mL, 0.12–1.00 µg/mL, and 0.21–1.04 µg/mL, respectively. The RI of TM for females aged 60–69 is 3.32–13.22 TU/mL, whereas it is 2.96–13.26 TU/mL for the other groups. The RI of t-PAIC for males aged ≥ 80 is 1.63–10.68 ng/mL, whereas it is 2.33–11.34 ng/mL for the other groups. Conclusions: Discrepancies exist in thrombus markers among different sex and age groups. The RIs of TAT, PIC, TM and t-PAIC for healthy older Chinese adults were successfully established. [ABSTRACT FROM AUTHOR]

Introduction: Ferroportin (Fpn) is the only known iron exporter and plays an essential role in iron homeostasis. Serum concentrations of Fpn in health and/or diseased states are still mostly unknown. Therefore, the aim of this study was to determine the concentration of Fpn in the serum of women of reproductive age (WRA) for the first time, and to establish whether there is a difference in the concentration of Fpn according to ferritin status. Materials and methods: This research included 100 WRA (18-45 years, C-reactive protein (CRP) < 5 mg/L, hemoglobin > 120 g/L). Serum Fpn was measured using Enzyme Linked Immunosorbent Assay (ELISA) method on the analyzer EZ Read 800 Plus (Biochrom, Cambridge, UK). Reference interval was calculated using the robust method. Results: The median concentration of Fpn in the whole study group was 9.74 (5.84-15.69) μg/L. The subgroup with ferritin concentration > 15 μg/L had a median Fpn concentration 15.21 (10.34-21.93) μg/L, which significantly differed from Fpn concentration in the subgroup with ferritin concentration ≤ 15 μg/L (5.93 (4.84-8.36) μg/L, P < 0.001). The reference limits for the Fpn were 2.26-29.81 μg/L with 90% confidence intervals (CI) of 1.78 to 2.83 and 25.37 to 34.33, respectively. Conclusions: The proposed reference interval could help in the future research on iron homeostasis both in physiological conditions and in various disorders, because this is the first study that measured Fpn concentration in a certain gender and age group of a healthy population. [ABSTRACT FROM AUTHOR]

Vitamin B1 (thiamine pyrophosphate (TPP)) and B6 (pyridoxal 5'- phosphate (PLP)) deficiencies pose significant health risks. The current measurement method employs High-Performance Liquid Chromatography (HPLC), though, Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS) is considered a more sensitive and selective analytical method. However, there is a lack of LC-MS/MS-based reference intervals. Moreover, none of the existing reference intervals are established in Danish populations. Therefore, the aim of this study was to establish a reference interval for whole blood concentrations of TPP and PLP in Danish blood donors using LC-MS/MS. Blood samples were collected from healthy Danish blood donors and analysed using the reagent kit, MassChrom® Vitamins B1 and B6 in whole blood (Chromsystems Instruments & Chemicals GmbH, Munich, Germany) for quantitative determination of both TPP and PLP concentration in whole blood, using LC-MS/MS. Reference intervals were determined with non-parametric methods as the 2.5th and 97.5th percentile and presented with 90% confidence intervals (CI). In total 120 blood donors were included. The concentrations of TTP or PLP were not statistically different between sexes just as age did not affect the concentrations, hence, combined reference intervals were employed. The resulting reference intervals are: TPP, nmol/L: 101.0 (90% CI: 96.4–108.5) − 189.0 (90% CI: 184.7–192.0) and PLP, nmol/L: 64.0 (90% CI: 60.9–66.7) − 211.8 (90% CI: 168.3–231.0). In conclusion, reference intervals for whole blood TTP and PLP in a healthy Danish population were established based on a LC-MS/MS method. Furthermore, the reference intervals were not affected by age or sex. [ABSTRACT FROM AUTHOR]

Serum erythropoietin (sEPO) is an initial screening tool for distinguishing polycythemia vera (PV) from secondary erythrocytosis (SE), but defining 'subnormal' sEPO levels for PV diagnosis remains contentious, complicating its clinical utility. This study compares the diagnostic performance of sEPO across established subnormal limits, including reference interval (RI), clinical decision limit (CDL), and functional reference limit. sEPO levels were analyzed in 393 healthy donors (HDs) and 90 patients (41 PV and 49 SE), who underwent bone marrow biopsy and genetic tests due to erythrocytosis. The RI (2.5–97.5 percentile from HDs) of sEPO was 5.3–26.3 IU/L. A CDL of 3.1 IU/L, determined by ROC analysis in erythrocytosis patients, had a sensitivity of 80.5% and specificity of 87.8% for diagnosing PV. A functional reference limit of 7.0 IU/L, estimated based on the relationship between sEPO and hemoglobin, hematocrit, and WBC, increased sensitivity to 97.6% but decreased specificity to 46.7%. Using 5.3 IU/L as a 'subnormal' limit identified all three JAK2-negative PV cases, increasing the sensitivity and negative predictive value to 97.6% and 97.0%, respectively. Combining the RI, CDL, and functional reference limit may improve PV diagnostic accuracy. [ABSTRACT FROM AUTHOR]

Secretoneurin (SN) is a novel cardiac biomarker that associates with the risk of mortality and dysfunctional cardiomyocyte Ca2+ handling in heart failure patients. Reference intervals for SN are unknown. SN was measured with a CE-marked ELISA in healthy community dwellers from the fourth wave of the Trøndelag Health Study (HUNT4) conducted in 2017–2019. The common, sex and age specific 90th, 95th, 97.5th and 99th percentiles were calculated using the non-parametric method and outlier exclusion according to the Reed test. The applicability of sex and age specific reference intervals were investigated using Harris and Boyd test. We also estimated the percentiles in a subset with normal findings on echocardiographic screening. The total cohort included 887 persons (56.4 % women). After echocardiographic screening 122 persons were excluded, leaving a total of 765 persons (57.8 % women). The 97.5th percentile (95 % CI in brackets) of SN was 59.7 (57.5–62.1) pmol/L in the total population and 58.6 (57.1–62.1) pmol/L after echocardiography screening. In general, slightly higher percentiles were found in women and elderly participants, but less than 4 % in these subgroups had concentrations deviating from the common 97.5th percentile. Low BMI or eGFR was also associated with higher concentrations of SN. Upper reference limits for SN were similar amongst healthy adult community dwellers regardless of prescreening including cardiac echocardiography or not. Women and elderly showed higher concentrations of SN, but the differences were not sufficiently large to justify age and sex stratified upper reference limits. [ABSTRACT FROM AUTHOR]

Background: This cross-sectional study aimed to explore the variation trend of renal function for healthy pregnant women at different gestational ages and aimed to establish RIs for renal function set tests according to the trimester of pregnancy. Methods: A total of 120 healthy pregnant women and 40 healthy non-pregnant women were enrolled in this study and divided into early trimester (1 - 13 weeks of gestation, n = 40), second trimester (14 - 27 weeks of gestation, n = 40), third trimester (≥ 28 weeks of gestation, n = 40), and a non-pregnant women group (n = 40). Analytes of UA, BUN, Cr, β2-MG, Cys-C, RBP, NAG, CO2, HCY, C1q, and NGAL were measured by using the analytical systems of the Second Xiangya Hospital. The RIs were defined by using non-parametric 95% intervals. Results: The RIs for UA, Cr, β2-MG, NAG, CO2, Hcy, and C1q were established for the first and second trimester group and the third trimester group. There were huge differences after pregnancy. The RIs for BUN were different for the 1 - 13 weeks group and the after 14 weeks group. There were significant differences for NGAL in pregnant and non-pregnant women, but not for Cys-C and RBP. Conclusions: The RIs for renal function tests in pregnant women were established, thus providing clinical reference intervals for the clinicians. [ABSTRACT FROM AUTHOR]

Objective To determine reference intervals (RI) for fasting blood insulin (FBI) in Brazilian adolescents, 12 to 17 years old, by direct and indirect approaches, and to validate indirectly determined RI. Methods Two databases were used for RI determination. Database 1 (DB1), used to obtain RI through a posteriori direct method, consisted of prospectively selected healthy individuals. Database 2 (DB2) was retrospectively mined from an outpatient laboratory information system (LIS) used for the indirect method (Bhattacharya method). Results From DB1, 29345 individuals were enrolled (57.65 % female) and seven age ranges and sex partitions were statistically determined according to mean FBI values: females: 12 and 13 years-old, 14 years-old, 15 years-old, 16 and 17 years-old; and males: 12, 13 and 14 years-old, 15 years-old, 16 and 17 years-old. From DB2, 5465 adolescents (67.5 % female) were selected and grouped according to DB1 partitions. The mean FBI level was significantly higher in DB2, on all groups. The RI upper limit (URL) determined by Bhattacharya method was slightly lower than the 90 % CI URL directly obtained on DB1, except for group female 12 and 13 years old. High agreement rates for diagnosing elevated FBI in all groups on DB1 validated indirect RI presented. Conclusion The present study demonstrates that Bhattacharya indirect method to determine FBI RI in adolescents can overcome some of the difficulties and challenges of the direct approach. [ABSTRACT FROM AUTHOR]

Abstract Background Reference intervals, which define an interval in which a specific proportion of measurements from a healthy population are expected to fall, are commonly used in medical practice. Synthesizing information from multiple studies through meta-analysis can provide a more precise and representative reference interval than one derived from a single study. However, the current approaches for estimating the reference interval from a meta-analysis mainly rely on aggregate data and require parametric distributional assumptions that cannot always be checked. Methods With the availability of individual participant data (IPD), non-parametric methods can be used to estimate reference intervals without any distributional assumptions. Furthermore, patient-level covariates can be introduced to estimate personalized reference intervals that may be more applicable to specific patients. This paper introduces quantile regression as a method to estimate the reference interval from an IPD meta-analysis under the fixed effects model. Results We compared several non-parametric bootstrap methods through simulation studies to account for within-study correlation. Under fixed effects model, we recommend keeping the studies fixed and only randomly sampling subjects with replacement within each study. Conclusion We proposed to use the quantile regression in the IPD meta-analysis to estimate the reference interval. Based on the simulation results, we identify an optimal bootstrap strategy for estimating the uncertainty of the estimated reference interval. An example of liver stiffness measurements, a clinically important diagnostic test without explicitly established reference range in children, is provided to demonstrate the use of quantile regression in estimating both overall and subject-specific reference intervals.

Abstract Objective To explore the distribution of thrombin–antithrombin complex (TAT), plasmin-α2-antiplasmin inhibitor complex (PIC), thrombomodulin (TM), and tissue plasminogen activator-inhibitor complex (t-PAIC) in healthy older Chinese adults, and establish the reference intervals (RIs). Methods The Biotech Shine i2900 chemiluminescence immune assay was used to measure the plasma concentrations of TAT, PIC, TM, and t-PAIC in 1628 adults ≥ 60 years. The RIs were established using the 2.5th and 97.5th percentiles of the distribution. Results TAT levels were lower in males than females across all ages. Differences between the ages of 60–79 and ≥ 80 in both sex groups were statistically significant, with an upward trend with age. PIC levels showed no difference between the sexes but increased with age in both groups. TM levels did not differ between the sex groups, with slight fluctuation with age. The level in females aged 60–69 was slightly higher than that in the other groups; the difference was statistically significant. T-PAIC levels were not significantly different between the sex groups, with less fluctuation with sex and age. The level in males ≥ 80 years old was slightly lower than that in the other groups; the difference was statistically significant. The RIs for all markers in healthy older Chinese adults were determined and statistically reported by age and sex. For TAT, the RIs for males aged 60–79 and ≥ 80 are 0.51–2.30 ng/mL and 0.88–3.72 ng/mL, respectively, whereas for females aged 60–79 and ≥ 80, the RIs are 0.68–2.82 ng/mL and 1.02–3.67 ng/mL, respectively. For PIC, the RIs for the age groups 60–69, 70–79, and ≥ 80 are 0.10–0.89 µg/mL, 0.12–1.00 µg/mL, and 0.21–1.04 µg/mL, respectively. The RI of TM for females aged 60–69 is 3.32–13.22 TU/mL, whereas it is 2.96–13.26 TU/mL for the other groups. The RI of t-PAIC for males aged ≥ 80 is 1.63–10.68 ng/mL, whereas it is 2.33–11.34 ng/mL for the other groups. Conclusions Discrepancies exist in thrombus markers among different sex and age groups. The RIs of TAT, PIC, TM and t-PAIC for healthy older Chinese adults were successfully established.

Objective: To determine reference intervals (RI) for fasting blood insulin (FBI) in Brazilian adolescents, 12 to 17 years old, by direct and indirect approaches, and to validate indirectly determined RI. Methods: Two databases were used for RI determination. Database 1 (DB1), used to obtain RI through a posteriori direct method, consisted of prospectively selected healthy individuals. Database 2 (DB2) was retrospectively mined from an outpatient laboratory information system (LIS) used for the indirect method (Bhattacharya method). Results: From DB1, 29345 individuals were enrolled (57.65 % female) and seven age ranges and sex partitions were statistically determined according to mean FBI values: females: 12 and 13 years-old, 14 years-old, 15 years-old, 16 and 17 years-old; and males: 12, 13 and 14 years-old, 15 years-old, 16 and 17 years-old. From DB2, 5465 adolescents (67.5 % female) were selected and grouped according to DB1 partitions. The mean FBI level was significantly higher in DB2, on all groups. The RI upper limit (URL) determined by Bhattacharya method was slightly lower than the 90 % CI URL directly obtained on DB1, except for group female 12 and 13 years old. High agreement rates for diagnosing elevated FBI in all groups on DB1 validated indirect RI presented. Conclusion: The present study demonstrates that Bhattacharya indirect method to determine FBI RI in adolescents can overcome some of the difficulties and challenges of the direct approach.

Motasim Jawi,1 Hadiah Bassam Al Mahdi,2,3 Hussam Daghistani,4,5 Yousef Almoghrabi,4,5 Rami Algahtani,6 Dalal Tawati,7 Mohammed R Algethami,8 Yasser Noorelahi,9 Zuhier Awan4 1Department of Physiology, College of Medicine, University of Jeddah, Jeddah, Saudi Arabia; 2Al Borg Medical Laboratories, Al Borg Diagnostics, Research and Development Unit, Jeddah, Saudi Arabia; 3Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia; 4Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; 5Regenerative Medicine Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; 6Department of Medicine, College of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia; 7Department of Obstetrics and Gynecology, King Abdullah Medical Complex, Jeddah, Saudi Arabia; 8Department of Family and Community Medicine, College of Medicine, University of Jeddah, Jeddah, Saudi Arabia; 9Department of Radiology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi ArabiaCorrespondence: Motasim Jawi, Department of Physiology, College of Medicine, University of Jeddah, Jeddah, Saudi Arabia, Tel +966 569191939, Email mmjawi@uj.edu.saPurpose: Blood Lp(a) concentration is recognized as an independent risk factor for cardiovascular disease (CVD). Population-based lipoprotein(a) (Lp[a]) research in Saudi Arabia is rare. Thus, the primary goal of this pilot study was to identify age- and sex-specific reference ranges for Lp(a) levels, in addition to the associations between Lp(a) levels and other atherosclerotic markers in Saudi individuals.Patients and methods: A five-year retrospective study of Lp(a) and lipid markers in Saudi patients was conducted using the Al-Borg diagnostics database (2015– 2020). The population sample consisted of 361 Saudi individuals aged 18– 93 years (162 males, 199 females). An immunoturbidimetric technique was used to determine Lp(a) concentration.Results: The mean and median Lp(a) levels in the study population were 35 nmol/L and 50 nmol/L, respectively. Sex and age did not influence Lp(a) values. Lp(a) values showed a minor correlation with other atherosclerotic markers when the Pearson correlation coefficient was used. In Saudi Arabia, the distribution of Lp(a) concentrations is skewed to the left, favoring lower values.Conclusion: Lp(a) levels in individuals residing in Saudi Arabia were comparable to those observed in other ethnic groups. Additionally, standardizing Lp(a) measurements according to sex and age may enhance broader applicability and facilitate comparisons across different populations. However, larger studies are required to provide more comprehensive data for comparison.Keywords: lipoprotein(a), lipids, cardiovascular disease, reference range, reference interval, Saudi Arabia

Background/Objectives: We present a software package called reflimR (Version 1.0.6), which enables rapid and transparent verification of reference intervals from routine laboratory measurements. Our method makes it easy to compare the results with specified target values and facilitates the interpretation of deviations using traffic light colors. Methods: The algorithm includes three procedural steps: (a) definition of an appropriate distribution model, based on Bowley's quartile skewness, (b) iterative truncation, based on a modified boxplot method to obtain the central 95% of presumably inconspicuous results, and (c) extrapolation of reference limits from a truncated normal quantile–quantile plot. Results: All algorithms have been combined into one consolidated library, which can be called in the R environment with a single command reflim (x). Using an example dataset included in the package, we demonstrate that our method can be applied to mixed data containing a substantial proportion of pathological values. It leads to similar results as the direct guideline approach as well as the more sophisticated indirect refineR software package. As compared to the latter, reflimR works much faster and needs smaller datasets for robust estimates. For the interpretation of the results, we present an intuitive color scheme based on tolerance ranges (permissible uncertainty of laboratory results). We show that a relatively high number of published reference limits require careful reevaluation. Conclusions: The reflimR package closes the gap between direct guideline methods and the more sophisticated indirect refineR method. We recommend reflimR for the rapid routine verification of large amounts of reference limits and refineR for a careful analysis of unclear or doubtful results from this check. [ABSTRACT FROM AUTHOR]

Simple Summary: Some trace elements are essential for the health of vertebrates, but only limited data are available on blood levels in tortoises. The aim of this study was therefore to measure trace elements in heparinized blood plasma of Hermann's tortoises (Testudo hermanni) (n = 520) from March to September 2022 using inductively coupled plasma mass spectrometry (ICP-MS) and to establish specific reference intervals. Additionally, the influence of sex, season, and region of sample collection on the measured values were evaluated. Significant (p ≤ 0.05) sex-specific, seasonal, and regional differences were found for a number of trace elements indicating that all of these factors should be considered when establishing and interpreting blood trace element levels in tortoises. Some trace elements are essential for the health of vertebrates, but little is known about their function, the amounts required, and the factors influencing their metabolism in tortoises. The aim of this study was therefore to measure trace elements (chromium (Cr), cobalt (Co), copper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), molybdenum (Mo), selenium (Se), zinc (Zn)) in heparinized blood plasma of Hermann's tortoises (Testudo hermanni) (n = 520) from March to September 2022 using inductively coupled plasma mass spectrometry (ICP-MS) and to establish specific reference intervals. Additionally, the influence of sex, season, and region of sample collection on the measured values were evaluated. Significant (p ≤ 0.05) sex-specific differences were found for Cu, Mg, and Mn; seasonal differences were found for Cr, Cu, Mn, Mo, and Se; and the region in which the tortoises were kept significantly impacted Cr, Cu, Fe, Mg, Mo, and Se levels. The results show that all of these factors should be consider when establishing and interpreting blood trace element levels in tortoises. [ABSTRACT FROM AUTHOR]

Background: CA19-9 is elevated in pancreatic cancer and other malignancies, and commonly used in clinical practice. Unfortunately, CA19-9 immunoassays are not harmonized, and reference intervals may differ between assays. The aim of this study was to establish the reference interval of the ADVIA Centaur/Atellica IM CA19-9 assay in an apparently healthy Singapore adult population. Methods: This is a retrospective cross-sectional study. De-identified data from Health Screening participants were extracted from our database. Subjects with biochemical results suggesting anaemia, diabetes mellitus, viral hepatitis or abnormal liver, and renal and tumour markers were excluded. Outlier and subclass analyses by age and sex were performed. CA19-9 reference limits and 90% confidence intervals were then determined for candidate subclasses. Results: Data from 12,174 subjects (5846 males and 6328 females) were available after exclusion criteria were applied. CA19-9 results did not follow a normal distribution and were higher in females compared to males (P <.001). Although CA19-9 means were statistically different between certain age groups, the evaluable 99th percentile reference limits were not statistically different. The overall 99th percentile reference limits for the Centaur/Atellica CA19-9 assay was 37 U/mL for males 21–80 years, and 60 U/mL for females 21–80 years. Conclusions: Our results suggest that separate CA19-9 reference intervals should be applied for males and females. [ABSTRACT FROM AUTHOR]

Background: To accurately assess hypogammaglobulinemia at birth, it is essential to determine the reference intervals of serum immunoglobulin (IgG) levels in newborns. In the present study, we determined the gestational age (GA)-/birth weight (BW)-dependent percentile-based reference intervals of serum IgG levels and converted them into simple formulas for practical use. Methods: Serum IgG levels were measured in cord blood from 2902 newborns delivered at 22 to 41 weeks of GA or 264 to 4642 g of BW after exclusion of those with congenital disorders. Linear regression analysis was used to correlate GA and UC-IgG levels and BW and UC-IgG levels. After calculation of the percentile values of UC-IgG levels for each GA or BW, the distributions were approximated by the least-squares method. Fitness was evaluated by the coefficient of determination (R 2 ). Results: Significant positive correlations were found both between GA and UC-IgG levels (r s = 0.790, P < 0.001) and BW and UC-IgG levels (r s = 0.626, P < 0.001). The distribution of the 5%ile of UC-IgG levels (Y) by GA or BW (X) was approximated as a straight line (Y = 37.5 *X – 775.8; Y = 0.161 *X + 95.34, respectively). The fitness was stronger in the GA-derived formula than the BW-derived formula (R 2 = 0.973 vs 0.913). Conclusions: We established GA-/BW-dependent reference percentile-based intervals for serum IgG levels using cord blood from 2902 newborns without congenital disorders. Using GA-dependent reference intervals may be useful for assessing hypogammaglobulinemia at birth. [ABSTRACT FROM AUTHOR]

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Introduction Methods Results Conclusion Reticulocyte count and novel derived parameters provide insight into the effectiveness of erythropoiesis and may be useful tools in the classification and diagnosis of anemias. However, there is no standardisation, so we consider it necessary that each laboratory evaluates the parameters according to its own methodology and instrumentation and establishes its own reference ranges. Our aim was to establish the reference intervals (RIs) of reticulocyte profile provided by the Beckman Coulter DxH 900 haematological autoanalyzer in our reference population.One hundred and seventy‐five healthy adults (18 to 62 years) were included. Subjects were collected from the blood donation centre of the Hospital Clínico San Carlos (Madrid, Spain) upon informed consent. Whole blood was collected and assayed for 14 haematological parameters on the Beckman Coulter DxH 900 analyzer in the haematology laboratory of the Clinical Analysis Department. RIs were established as per Clinical and Laboratory Standards Institute EP28‐A3c guidelines using three different statistical approaches.RIs estimated using the non‐parametric method and the Harrell‐Davis bootstrap method were very similar. RIs estimated by the robust method were narrower. Gender partitioning was required for two haematological parameters (low haemoglobin density (LHD) and microcytic anaemia factor (MAF)). The rest of the parameters did not need to be partitioned according to Lahti's method.RIs have been established for 14 hematologic parameters of the reticulocyte profile for the Beckman Coulter DxH 900 haematology analyzer using a healthy cohort of adult subjects. [ABSTRACT FROM AUTHOR]

Evidence derived from laboratory medicine plays a pivotal role in the diagnosis, treatment monitoring, and prognosis of various diseases. Reference intervals (RIs) are indispensable tools for assessing test results. The accuracy of clinical decision-making relies directly on the appropriateness of RIs. With the increase in real-world studies and advances in computational power, there has been increased interest in establishing RIs using big data. This approach has demonstrated cost-effectiveness and applicability across diverse scenarios, thereby enhancing the overall suitability of the RI to a certain extent. However, challenges persist when tests results are influenced by age and sex. Reliance on a single RI or a grouping of RIs based on age and sex can lead to erroneous interpretation of results with significant implications for clinical decision-making. To address this issue, the development of next generation of reference interval models has arisen at an historic moment. Such models establish a curve relationship to derive continuously changing reference intervals for test results across different age and sex categories. By automatically selecting appropriate RIs based on the age and sex of patients during result interpretation, this approach facilitates clinical decision-making and enhances disease diagnosis/treatment as well as health management practices. Development of next-generation reference interval models use direct or indirect sampling techniques to select reference individuals and then employed curve fitting methods such as splines, polynomial regression and others to establish continuous models. In light of these studies, several observations can be made: Firstly, to date, limited interest has been shown in developing next-generation reference interval models, with only a few models currently available. Secondly, there are a wide range of methods and algorithms for constructing such models, and their diversity may lead to confusion. Thirdly, the process of constructing next-generation reference interval models can be complex, particularly when employing indirect sampling techniques. At present, normative documents pertaining to the development of next-generation reference interval models are lacking. In summary, this review aims to provide an overview of the current state of development of next-generation reference interval models by defining them, highlighting inherent advantages, and addressing existing challenges. It also describes the process, advanced algorithms for model building, the tools required and the diagnosis and validation of models. Additionally, a discussion on the prospects of utilizing big data for developing next-generation reference interval models is presented. The ultimate objective is to equip clinical laboratories with the theoretical framework and practical tools necessary for developing and optimizing next-generation reference interval models to establish next-generation reference intervals while enhancing the use of medical data resources to facilitate precision medicine. [ABSTRACT FROM AUTHOR]

Introduction: Cell population data (CPD) parameters may be putative biomarkers for the screening of various diseases including some infections and myelodysplastic syndrome. This study aimed to establish the age‐ and sex‐specific reference intervals (RIs) for the CPD parameters in the Korean population. Methods: The reference population for the RIs of CPD parameters comprised 124 856 subjects aged 20–99 years. CPD parameters were obtained from Sysmex XN‐2000 (Kobe, Japan) datasets from 17 health promotion centers in 13 South Korean cities. We determined significant partitions for age and sex, and calculated RIs according to Clinical and Laboratory Standards Institute C28‐A3 guidelines. Results: The side scattered light intensity in the neutrophil area and the lymphocyte area did not require sex‐related partitioning except in those over the age of 50, among whom the lower limit (LL) and upper limit (UL) were lower in females. However, the side scattered light distribution width in the lymphocyte area required age‐ and sex‐related partitioning, in which LL and UL were higher in females. The LL and UL of the fluorescent light distribution width were higher in males in the neutrophil area and higher in females in the lymphocyte area, but age‐related partitioning was not required. The forward scattered light intensity in the neutrophil area, lymphocyte area, and monocyte area did not require age‐related partitioning in males. Conclusion: This study has determined comprehensive age‐ and sex‐specific RIs for CPD parameters, which could help to prove the clinical significance of these parameters in the Sysmex XN‐2000. [ABSTRACT FROM AUTHOR]

Objective To establish the derived indicators from blood cell analysis of the elderly in Anning region of Yunnan province, lymphocyte to monocyte ratio (LMR), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) reference interval, Observed differences from multicenter surveys, To determine the necessity to establish this reference interval. Methods The analysis results of people above 60 years old for physical examinations in the information system of Anning First People’s Hospital from June 2022 to September 2022 were collected retrospectively. The biological reference interval for healthy elderly people in Anning City was established according to the indirect method in the international CLSI EP28-A3c guidelines. Results A total of 8 877 cases were included. Red blood cell count (RBC), hemoglobin (HGB), hematocrit (HCT), mean red blood cell hemoglobin concentration (MCHC), platelet count (PLT), and lymphocyte percentage (LYM%) decreased with age, and the difference between men and women was statistically significant ( P < 0.05) . Only the broadband coefficient of variation of red blood cell volume distribution (RDWCV) increased with age. White blood cell count (WBC), absolute value of neutrophils (NEU#), absolute value of eosinophils (EOS#), percentage of neutrophils (NEU%), percentage of eosinophils (EOS%), mean red cell volume (MCV), standard deviation of red blood cell volume distribution width (RDWSD), platelet volume distribution width (PDW) were statistically significant only between men and women (P < 0.05), while the remaining items were not significant by age and sex (P > 0.05). NLR increased with age, and men were significantly higher than women of the same age. Both LMR and PLR were higher in females than in males. Conclusion The results of WBC, RBC, HGB, PLT and HCT in the self-built reference interval were quite different from the reference interval of the multi-center survey. [ABSTRACT FROM AUTHOR]

Context The Roche prolactin immunoassay is used throughout the world. It reports higher values than the Siemens immunoassay but the manufacturer-defined reference intervals are similar. Patient results are often above the Roche upper limit but within the Siemens interval, causing diagnostic confusion. Objective Establish new reference intervals for the Roche and Siemens prolactin immunoassays. Methods We established new reference intervals for the Roche and Siemens immunoassays using 374 specimens from healthy outpatients. We performed chart review for unnecessary testing and treatment for 298 patients in a 6-month period with at least 1 Roche prolactin value above the manufacturer-defined upper limit and below our new upper limit. Results The new upper limit for the Roche assay was 37.8 ng/mL (females) and 22.8 ng/mL (males). The manufacturer-defined limits were 23.3 ng/mL and 15.2 ng/mL, respectively. New intervals for the Siemens assay matched the manufacturer. No cases of clinically significant pathophysiologic prolactin excess were identified in patients with values between the manufacturer-defined upper reference limit and our new Roche upper limit. Unnecessary further evaluation in these patients included 459 repeat prolactin measurements, 57 macroprolactin measurements, 39 magnetic resonance imaging studies, and 28 endocrine referrals. Eleven patients received dopamine agonists. The minimum cost of excess care using Medicare reimbursement rates was $34 134, with substantially higher amounts billed to patients and their insurance providers. Conclusion Adoption of new upper reference limits for the Roche prolactin assay of 37.8 ng/mL (females) and 22.8 ng/mL (males) would not delay diagnosis or necessary intervention in patients with clinically significant pituitary tumors but would reduce unnecessary evaluation in patients without pathophysiologic prolactin excess. [ABSTRACT FROM AUTHOR]

Objectives: The aims of our study were to establish a reference interval for glycated albumin (GA) in gestational week 30, to investigate whether GA can replace or reduce the need for oral glucose tolerance test (OGTT) in pregnancy, and to reassess the usefulness of body mass-index (BMI), age and fasting glucose in detection of gestational diabetes (GDM). Design: and methods: We measured GA in 486 healthy pregnant women. Reference interval was calculated using the central 95 % of the results. ROC curves were created to assess the ability of GA, fasting glucose and BMI separately to detect GDM, and logistic regression analysis was used to estimate risk of developing GDM given the level of the same markers. Finally, multiple logistic regression analysis based on GA, fasting glucose and BMI was used to find a strategy of predicting a patient's risk of GDM. Results: The reference interval for GA at week 30 of gestation is 6.8–10.3 %. The analysis has a low AUC (0.53) with respect to detecting GDM. It increases slightly to 0.64 when corrected for BMI, as GA is inversely correlated to BMI. Combining GA with fasting glucose and BMI at gestational weeks 16–20 could raise the AUC to 0.80. Conclusion: GA cannot be recommended to replace OGTT for the diagnosis of GDM. Nor can it be used to identify women at risk of developing GDM. GA combined with fasting glucose and BMI in early pregnancy could be a useful model to estimate risk of GDM.

ABSTRACT Objective: Fasting insulin and the homeostasis model assessment of insulin resistance (HOMA-IR) index are relatively simple and reliable noninvasive markers of insulin resistance (IR). Given the relevance of correctly diagnosing IR, we emphasize the importance of establishing reliable reference intervals (RIs) for these markers. This study aimed to determine the RIs of fasting insulin and HOMA-IR index in adults living in Rio de Janeiro and, secondarily, to verify potential RI differences between sexes. Subjects and methods: Serum insulin levels of 146,497 individuals (ages 20-60 years) who underwent blood sampling in the state of Rio de Janeiro were obtained retrospectively through access to an extensive laboratory database. Insulin was measured using the electrochemiluminescence immunoassay method. After applying exclusion criteria, 21,684 individuals (18,576 [86%] women) were included. The RIs were estimated using a computational mining approach that integrates a selection of R packages. Results: The 95% RIs in women and men and in the overall population were, respectively, 2.54-13.30 μU/mL (15.3-80.12 pmol/L), 2.43-11.89 μU/mL (14.6-71.7 pmol/L), and 2.52-13.14 μU/mL (15.2-79.2 pmol/L) for fasting insulin levels and 0.39-2.86, 0.38-2.81, and 0.39-2.86 for HOMA-IR values. Despite significant differences in insulin levels and HOMA-IR index between men and women, the use of sex-specific RIs was not justified. Conclusion: The RIs of fasting insulin levels and HOMA-IR values found in the overall population can be applied to both sexes. Thus, for our population, we suggest the RIs of 2.52-13.14 μU/mL (15.1-78.8 pmol/L) for fasting insulin and 0.39-2.86 for the HOMA-IR index.

Background and aims: Appropriate continuous reference intervals (RIs) for serum insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGFBP-3) are important for diagnosing growth hormone deficiency or excess. Material and methods: We retrospectively reviewed serum IGF-1 and IGFBP-3 levels in Korean children aged 0–17 years who were diagnosed as healthy during a short stature workup in the outpatient clinics of three hospitals. IGF-1 and IGFBP-3 levels were measured using various immunoassays, including Liaison XL for IGF-1, an immunoradiometric assay (IRMA) for IGFBP-3 (n = 5522), and Immulite 2000 (n = 3036) and cobas e801 (n = 314). We established RIs from the 2.5th to 97.5th percentile RI curves using the lambda–mu–sigma (LMS) method for each sex group. Results: Pediatric serum continuous IGF-1 and IGFBP-3 reference percentiles by LMS method were found to be immunoassay method-dependent, but aligned relatively well with the manufacturers’ RIs. IGFBP-3 levels displayed notable discrepancies among the different immunoassay methods. Conclusion: Age- and sex-specific pediatric LMS based continuous reference intervals are method dependent and they should be calculated for dynamic parameters that show variations throughout childhood.

The article discusses the urgent need to adopt age-specific upper reference limits for thyroid-stimulating hormone (TSH) in the elderly. TSH is an important biomarker for thyroid function, and its levels tend to increase in elderly individuals. However, this does not necessarily indicate hypothyroidism, and using a single reference range for TSH in all age groups can lead to misdiagnoses and unnecessary treatment. The article highlights the importance of age-specific reference ranges for accurate diagnosis and management of thyroid disorders in the elderly. [Extracted from the article]

Abstract Background The aim is to establish and verify reference intervals (RIs) for serum tumor markers for an apparently healthy elderly population in Southwestern China using an indirect method. Methods Data from 35,635 apparently healthy elderly individuals aged 60 years and above were obtained in West China Hospital from April 2020 to December 2021. We utilized the Box-Cox conversion combined with the Tukey method to normalize the data and eliminate outliers. Subgroups are divided according to gender and age to examine the division of RIs. The Z-test was used to compare differences between groups, and 95% distribution RIs were calculated using a nonparametric method. Results In the study, we observed that the RIs for serum ferritin and Des-γ-carboxy prothrombin (DCP) were wider for men, ranging from 64.18 to 865.80 ng/ml and 14.00 to 33.00 mAU/ml, respectively, compared to women, whose ranges were 52.58 to 585.88 ng/ml and 13.00 to 29.00 mAU/ml. For other biomarkers, the overall RIs were established as follows: alpha-fetoprotein (AFP) 0–6.75 ng/ml, carcinoembryonic antigen (CEA) 0–4.85 ng/ml, carbohydrate antigen15-3 (CA15-3) for females 0–22.00 U/ml, carbohydrate antigen19-9 (CA19-9) 0–28.10 U/ml, carbohydrate antigen125 (CA125) 0–20.96 U/ml, cytokeratin 19 fragment (CYFRA21-1) 0–4.66 U/ml, neuron-specific enolase (NSE) 0–19.41 ng/ml, total and free prostate-specific antigens (tPSA and fPSA) for males 0–5.26 ng/ml and 0–1.09 ng/ml. The RIs for all these biomarkers have been validated through our rigorous processes. Conclusion This study preliminarily established 95% RIs for an apparently healthy elderly population in Southwestern China. Using real-world data and an indirect method, simple and reliable RIs for an elderly population can be both established and verified, which are suitable for application in various clinical laboratories.

Introduction: Direct ways of establishing reference intervals for analytes are time-consuming and costly. Bhattacharya analysis is an indirect way to mathematically derive reference intervals from the results of analytes in a hospital database and is practically a simple and inexpensive alternative to direct methods. Methods: Data of serum uric acid, magnesium, and plasma homocysteine levels measured in the department of clinical biochemistry over 3 years were extracted from the hospital database along with the age, gender, and location of the patients. Bhattacharya analysis was performed by identifying underlying Gaussian distribution within the non-Gaussian distribution of the patient data by log transformation of the distribution of the data. Reference intervals for each of the analytes were calculated from the identified Gaussian distribution. Results: The reference interval for serum uric acid was 1.49–8.97 mg/dL in men and 2.13–6.14 in women, serum magnesium in adults was 1.19–3.21 mg/dL, and plasma homocysteine in adults was 4.6–21 μg/dL. Conclusion: Using Bhattacharya analysis, we were able to derive reference intervals for analytes from our hospital data.

Background: The aim is to establish and verify reference intervals (RIs) for serum tumor markers for an apparently healthy elderly population in Southwestern China using an indirect method. Methods: Data from 35,635 apparently healthy elderly individuals aged 60 years and above were obtained in West China Hospital from April 2020 to December 2021. We utilized the Box-Cox conversion combined with the Tukey method to normalize the data and eliminate outliers. Subgroups are divided according to gender and age to examine the division of RIs. The Z-test was used to compare differences between groups, and 95% distribution RIs were calculated using a nonparametric method. Results: In the study, we observed that the RIs for serum ferritin and Des-γ-carboxy prothrombin (DCP) were wider for men, ranging from 64.18 to 865.80 ng/ml and 14.00 to 33.00 mAU/ml, respectively, compared to women, whose ranges were 52.58 to 585.88 ng/ml and 13.00 to 29.00 mAU/ml. For other biomarkers, the overall RIs were established as follows: alpha-fetoprotein (AFP) 0–6.75 ng/ml, carcinoembryonic antigen (CEA) 0–4.85 ng/ml, carbohydrate antigen15-3 (CA15-3) for females 0–22.00 U/ml, carbohydrate antigen19-9 (CA19-9) 0–28.10 U/ml, carbohydrate antigen125 (CA125) 0–20.96 U/ml, cytokeratin 19 fragment (CYFRA21-1) 0–4.66 U/ml, neuron-specific enolase (NSE) 0–19.41 ng/ml, total and free prostate-specific antigens (tPSA and fPSA) for males 0–5.26 ng/ml and 0–1.09 ng/ml. The RIs for all these biomarkers have been validated through our rigorous processes. Conclusion: This study preliminarily established 95% RIs for an apparently healthy elderly population in Southwestern China. Using real-world data and an indirect method, simple and reliable RIs for an elderly population can be both established and verified, which are suitable for application in various clinical laboratories. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Methods Results Conclusion To establish a normal reference interval for amniotic sac diameter (ASD) between 7 + 0 and 9 + 6 weeks' gestation and its relative size in relation to gestational sac diameter (GSD) and the embryo crown–rump length (CRL).This was a prospective, cross‐sectional study of consecutive women presenting to the Early Pregnancy Unit, University College Hospital, London, UK, between August 2022 and June 2023. We included live, normally sited, singleton pregnancies with a normal 20‐week anomaly scan. We collected 120 cases per gestational week, from 7 + 0 to 9 + 6 weeks' gestation, totaling 360 cases. We performed an inter‐ and intraobserver variability assessment in the measurement of mean ASD in 30 patients. Regression analyses were used to establish reference intervals for GSD and CRL, ASD and CRL, GSD and ASD, and GSD/ASD ratio and CRL. A fitted regression line was calculated, along with a 90% prediction interval and R2 value.There was good interobserver agreement (mean ± SD difference, 0.007 ± 1.105 mm (95% limits of agreement (LoA), −2.160 to 2.174 mm)) and good intraobserver agreement for Observer A (mean ± SD difference, −0.080 ± 0.741 mm (95% LoA, −1.532 to 1.372 mm)) and Observer B (mean ± SD difference, −0.014 ± 0.919 mm (95% LoA, −1.814 to 1.786 mm)) in the measurement of mean ASD. Regression analyses showed a statistically significant association between each pair of values (P < 0.001 for all). There was a significant quadratic association between mean GSD and CRL (R2 = 56%), mean GSD and ASD (R2 = 60%) and GSD/ASD ratio and CRL (R2 = 68%), and a significant cubic association between mean ASD and CRL (R2 = 90%). The regression equations were used to quantify the values of ASD and GSD/ASD ratios for a range of CRL values and gestational ages.Our study has produced comprehensive reference intervals for amniotic sac size in early pregnancy, which could be used in routine clinical practice. © 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Background: Initial evaluation of the hypothalamus–pituitary–thyroid axis is done by measuring serum free thyroxine (fT4) and thyrotropin concentrations. For correct interpretation of these measurements, reliable age-specific reference intervals (RIs) are fundamental. Since neonatal fT4 RIs conforming to the Clinical and Laboratory Standards Institute guidelines are not available for all assays, we set out to create literature-based uniform age-specific neonatal fT4 RIs that may be used for every assay. Methods: For meta-analysis of individual participant fT4 concentrations, we systematically searched MEDLINE and Embase (search date December 6, 2023; PROSPERO registration CRD42016041871). We searched for studies reporting fT4 concentrations in healthy term newborns aged 2–27 days, born to mothers without thyroid disease in iodine-sufficient regions. Authors were invited to supply data. Due to standardization differences between assays, data could not be combined for meta-analysis directly, and we attempted to normalize the data using two distinct methods. Results: We obtained 4206 fT4 concentrations from 20 studies that used 13 different assays from 6 manufacturers. First, we set out to normalize fT4 data using the mean and standard deviation of (assay-specific) adult RIs. fT4 concentrations were transformed into Z-scores, assuming a normal distribution. Using a linear mixed-effects model (LMM), we still found a significant difference between fT4 concentration across studies (p < 0.001), after this normalization. As a second approach, we normalized the fT4 concentrations using data from a method/assay comparison study. We used the relationship between the Cobas assay and the other assays as a reference point to convert all values to Cobas values. However, this method also failed to produce consistent results, with significant differences between the normalized data (LMM p < 0.001). Conclusions: We conclude that our attempts at normalizing fT4 assay results were unsuccessful. Confounders related to our unsuccessful analysis may be assay related and/or biological. These findings have significant implications for patient care, since relying on RIs from literature may result in erroneous interpretation of results. Therefore, we strongly recommend to establish local RIs for accurate interpretation of serum fT4 concentrations in neonates. [ABSTRACT FROM AUTHOR]

Background Elevated homocysteine (Hcy) level during pregnancy is positively associated with various gestational-specific diseases. However, there is no uniform standard for the reference interval (RI) of Hcy in pregnancy. Methods From January 2017 to January 2019, 14,530 singleton pregnant women registered at our institute were included for the establishment of trimester-specific RIs of Hcy with both the nonparametric approach and the indirect Hoffmann method, followed by pregnancy outcome association analysis conducted with logistic regression. Results The serum Hcy level in the nonpregnant group was significantly higher than that of pregnant women. A relatively decreased Hcy concentration was observed in the second trimester when compared with that of the first or third trimester. The direct RIs of Hcy in the first or third, and second trimesters were 4.6 to 8.0 mmol/L (merged) and 4.0 to 6.4 mmol/L, respectively, which showed no significant difference compared with the RI derived from the indirect Hoffmann method. In the subsequent risk analysis, the first trimester Hcy was found to be negatively associated with GDM development; whereas the third trimester Hcy conferred increased risk of postpartum hemorrhage after delivery. Conclusion Having established trimester-specific RIs, our study sheds light on the complicated roles of Hcy in pregnancy-related complications. [ABSTRACT FROM AUTHOR]

Monocyte distribution width (MDW) is a new biomarker used as an early indicator of sepsis (ESId). It is often aids in the identification of patients who may develop sepsis. This study aims to establish the MDW reference interval (RI) within the healthy population of blood donors using EDTA-K2 as anticoagulant. Many hospitals use this biomarker as a means of identifying patients who present to the hospital with sepsis. A total of 274 samples obtained from healthy donors were analyzed. MDW measurements were taken within 2 h post-extraction. The RI was estimated using various statistical methodologies, including the recommended CLSI EP28-A3c guideline, non-parametric and robust methods, along with the Harrell-Davis bootstrap method applied to the entire sample. The RI estimated through non-parametric method was 14.77 CI90 % (14.36–14.97)–21.13 CI90 % (20.89–21.68); RI using the robust method was 15.64–19.05 and RI using the Harrell-Davis bootstrap method was 14.73 CI90 % (14.53–14.92)–21.14 CI90 % (20.88–21.40). Based on clinical applicability, we recommend utilizing the RI derived from the non-parametric method, aligning with the CLSI recommendations. Furthermore, we consider that our results can be taken as a reference in other laboratories that serve a population similar to our study cohort. [ABSTRACT FROM AUTHOR]

Glomerular filtration rate (GFR) estimating equations based on rescaled serum creatinine (SCr/Q) have shown better performance, where Q represents the median SCr for age- and sex-specific healthy populations. However, there remains a scarcity of investigations in China to determine this value. We aimed to develop Chinese age- and sex-specific reference intervals (RIs) and Q-values for SCr and to validate the equations incorporating new Q-values. We included 117,345 adults from five centers for establishing RIs and Q-values, and 3,692 participants with reference GFR (rGFR, 99mTc-DTPA renal dynamic imaging measurement) for validation. Appropriate age partitioning was determined using the decision tree method. Lower and upper reference limits and medians were calculated using the refineR algorithm, and Q-values were determined accordingly. We evaluated the full age spectrum (FAS) and European Kidney Function Consortium (EKFC) equations incorporating different Q-values considering bias, precision (interquartile range, IQR), and accuracy (percentage of estimates within ±20 % [P20] and ±30 % [P30] of rGFR). RIs for males were: 18–79 years, 55.53–92.50 μmol/L; ≥80 years, 54.41–96.43 μmol/L. RIs for females were: 18–59 years, 40.42–69.73 μmol/L; 60–79 years, 41.16–73.69 μmol/L; ≥80 years, 46.50–73.20 μmol/L. Q-values were set at 73.82 μmol/L (0.84 mg/dL) for males and 53.80 μmol/L (0.61 mg/dL) for females. After validation, we found that the adjusted equations exhibit less bias, improved precision and accuracy, and increased agreement of GFR categories. We determined Chinese age- and sex-specific RIs and Q-values for SCr. The adjustable Q-values provide an effective alternative to obtain valid equations for estimating GFR. [ABSTRACT FROM AUTHOR]

Background and Objectives: Pregnancy introduces various interfering factors that, alongside individual variations, impact the assessment of thyroid function tests. This underscores the necessity of defining trimester-specific reference intervals for thyroid-stimulating hormone (TSH) levels. Differences in population characteristics, including ethnicity, socio-economic factors, iodine prophylaxis, and obesity, emphasize the need to establish trimester-specific TSH ranges for women of reproductive age in the respective region or center. The aim of the present study was to establish first- and second-trimester-specific reference intervals for TSH and free thyroxine (FT4) in a relevant pregnant population. Materials and Methods: A retrospective monocenter analysis utilized the electronic database of Ob/Gyn Hospital "Dr. Shterev", Sofia, Bulgaria. The analysis involved data from 497 pregnant and 250 non-pregnant women, all without evidence of thyroid dysfunction or a family history thereof, no indication of taking medication interfering with thyroid function, no evidence of levothyroxine treatment, and no history of sterility treatment. To establish the limits of the TSH reference range, the percentile method was applied using a bootstrapping procedure following the recommendations of the International Federation of Clinical Chemistry (IFCC). Results: Trimester-specific reference intervals for TSH and FT4 in our center were established as follows: first trimester—0.38–2.91 mU/L, FT4-12.18–19.48 pmol/L; second trimester—0.72–4.22 mIU/L and 9.64–17.39 pmol/L, respectively. We also established the normal reference range for the non-pregnant control group, which is similar to that applicable in our laboratory. Conclusions: Our results differ from the fixed limits recommended by the American Thyroid Association, European Thyroid Association, and Endocrine Society Guidelines. Following the relevant established intervals would significantly impact timely diagnosis and therapy requirements for a substantial proportion of pregnant women. [ABSTRACT FROM AUTHOR]

Clustering algorithms are usually iterative procedures. In particular, when the clustering algorithm aims to optimise an objective function like in k-means clustering or Gaussian mixture models, iterative heuristics are required due to the high non-linearity of the objective function. This implies higher computational costs and the risk of finding only a local optimum and not the global optimum of the objective function. In this paper, we demonstrate that in the case of one-dimensional clustering with one main and one noise cluster, one can formulate an objective function, which permits a closed-form solution with no need for an iteration scheme and the guarantee of finding the global optimum. We demonstrate how such an algorithm can be applied in the context of laboratory medicine as a method to estimate reference intervals that represent the range of "normal" values. [ABSTRACT FROM AUTHOR]

The reference intervals and median values of serum vitamin B12 level in blood from patients among the Latvian population were established for different age groups with a two-year step using data for a large number of patients, accumulated in E. Gulbis Laboratory in Latvia. The data represents the general population of Latvia. An indirect in silico method, developed in E. Gulbis laboratory for determination of serum vitamin B12 blood level reference intervals, was used. Strong elevation of serum vitamin B12 blood level was observed in children who were between 2 and 10 years old. The paper discusses the serum vitamin B12 values for children and a different serum vitamin B12 reference interval for young children is suggested. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is common in older rabbits. The renal biomarkers blood urea and creatinine can be insensitive as indicators of renal disease in rabbits. Symmetric dimethylarginine (SDMA) has been shown to be an earlier and more sensitive biomarker for the assessment of glomerular filtration rate and the evaluation of CKD in several animal species. An immunoassay for SDMA has been validated in a number of species. The purpose of this study was to validate the SDMA immunoassay for rabbit serum and plasma and to determine the normal rabbit reference interval (RI) for SDMA. Clinically healthy rabbits (n = 167) between 5 months and 8 years of age, of any breed or sex, participated in the study. Heparinized plasma or serum was collected for clinical chemistry and used for assay validation. Analytical validation of the SDMA immunoassay for rabbit serum and plasma was performed and included assessment of assay accuracy, precision, analytical sensitivity, linearity, interference testing, and plasma/serum bias. The SDMA reference interval (RI) was determined. The SDMA immunoassay met all set quality requirements assessed in analytical validation. The RI for SDMA was determined to be between 4–18 µg/dL. The SDMA immunoassay demonstrated acceptable performance in both rabbit serum and heparinized plasma as determined by the validation criteria. The utility of SDMA as a biomarker of renal disease in rabbits has not been determined yet. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the real-world performance and reference intervals of the Binding Site Freelite serum free light chain (SFLC) assay (Thermo Fisher Scientific), a global standard for diagnosis, prognostication, and response assessment for monoclonal gammopathies. Methods An informatics-based approach was used to retrospectively evaluate concordance between SFLC and the orthogonal Sebia HYDRASYS immunofixation assay results in a large clinical data set consecutively reported between 2010 and 2020. Results Among patients with monoclonal-negative results by both SFLC and Sebia HYDRASYS immunofixation assays, 25% (1226/5057) had κ/λ ratios (KLRs) outside the manufacturer-defined and International Myeloma Working Group–cited normal reference interval of 0.26 to 1.65. These results were consistent over the study period and were not affected by sex, age, impaired kidney function, or assay antisera lot variation. Assay drift, in addition to other potential factors, affected the KLR distribution. Using International Statistical Classification of Diseases (ICD) codes, kidney function data, and the central 95% of KLR values generated on the Optilite platform (Thermo Fisher Scientific), we derived a new reference interval of 0.67 to 2.13, reducing the KLR false-positive rate to 8%. However, normal KLR persisted among 16% (14/85) of samples with free λ chains by immunofixation, warranting caution during interpretation. Conclusions Our analysis indicated that revision of Freelite SFLC reference intervals improves assay interpretation and should prompt reconsideration of Freelite reference intervals worldwide. [ABSTRACT FROM AUTHOR]

Bone-turnover marker (BTM) measurements in the blood or urine reflect the bone-remodeling rate and may be useful for studying and clinically managing metabolic bone diseases. Substantial evidence supporting the diagnostic use of BTMs has accumulated in recent years, together with the publication of several guidelines. Most clinical trials and observational and reference-interval studies have been performed in the Northern Hemisphere and have mainly involved Caucasian populations. This review focuses on the available data for populations from the Asia-Pacific region and offers guidance for using BTMs as diagnostic biomarkers in these populations. The procollagen I N-terminal propeptide and ß-isomerized C-terminal telopeptide of type-I collagen (measured in plasma) are reference BTMs used for investigating osteoporosis in clinical settings. Premenopausal reference intervals (established for use with Asia-Pacific populations) and reference change values and treatment targets (used to monitor osteoporosis treatment) help guide the management of osteoporosis. Measuring BTMs that are not affected by renal failure, such as the bone-specific isoenzyme alkaline phosphatase and tartrate-resistant acid phosphatase 5b, may be advantageous for patients with advanced chronic kidney disease. Further studies of the use of BTMs in individuals with metabolic bone disease, coupled with the harmonization of commercial assays to provide equivalent results, will further enhance their clinical applications. [ABSTRACT FROM AUTHOR]

Reference intervals play an important role in medicine, for instance, for the interpretation of blood test results. They are defined as the central 95% values of a healthy population and are often stratified by sex and age. In recent years, so-called indirect methods for the computation and validation of reference intervals have gained importance. Indirect methods use all values from a laboratory, including the pathological cases, and try to identify the healthy sub-population in the mixture of values. This is only possible under certain model assumptions, i.e., that the majority of the values represent non-pathological values and that the non-pathological values follow a normal distribution after a suitable transformation, commonly a Box–Cox transformation, rendering the parameter λ of the Box–Cox transformation as a nuisance parameter for the estimation of the reference interval. Although indirect methods put high effort on the estimation of λ , they come to very different estimates for λ , even though the estimated reference intervals are quite coherent. Our theoretical considerations and Monte-Carlo simulations show that overestimating λ can lead to intolerable deviations of the reference interval estimates, whereas λ = 0 produces usually acceptable estimates. For λ close to 1, its estimate has limited influence on the estimate for the reference interval, and with reasonable sample sizes, the uncertainty for the λ -estimate remains quite high. [ABSTRACT FROM AUTHOR]