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Objective: Due to the difficulties in determining reference intervals with conventional methods, it determines them using modern machine learning methods. Methods: The results of the newborns' inorganic phosphorus, calcium, creatinine, neonatal bilirubin, and urea nitrogen tests, which were studied in the Dokuz Eylül University Central Laboratory for the years 2018-2019-2020, were obtained from the hospital database. The unsupervised machine learning algorithm we developed calculated test-specific age intervals and related reference intervals. Results: It was determined that the unsupervised machine learning method we developed is a new, contemporary alternative to indirect methods for determining reference intervals. With this method, the age ranges in which the test results showed significant variability were found in a high-resolution test-specific manner. Conclusion: Increases in computer processing power, new original artificial intelligence and machine learning-based algorithms, and databases that store large amounts of data offer a contemporary solution for determining reference intervals. In this study, an unsupervised machine learning algorithm solution based on mathematical and statistical foundations, which can determine age ranges, which is the basic step in the calculation of reference intervals, with high resolution is presented. By using the algorithmic method developed in the study, each laboratory will be able to calculate reference intervals suitable for their population and analytical methods in an easy, fast, safe, and economical way.

Abstract The reference intervals (RIs), proposed by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) and the International Union of Pure and Applied Chemistry (IUPAC), were derived for Cd, Hg, Mn and Pb in the blood and urine of the children population living in Kinshasa (n = 200, aged 3–14 years with 97 girls). Levels of metals were measured using coupled plasma mass (ICP-MS). In blood, the proposed RIs [P5-P95 (GM)] were 0.022–1.112 μg/L (0.074), 35.69–144.50 μg/L (71.43), 0.060 to 1.161 μg/L (0.208) and 6.597–15.740 μg/L (9.882) for Cd, Pb, Hg and Mn, respectively. Urinary levels [(P5-P95 (GM)] were 0.082–1.530 μg/L (0.366) for Cd, 1.827–18.500 μg/L (5.458) for Pb, 0.323–1.953 μg/L (0.709) for Hg and 0.070 to 1.703 μg/L (0.186) for Mn. As compared to the CDC updated blood Pb reference value (35 μg/L), Pb levels remain higher of public health concern. Cd and Mn levels were similar to those found in the same city in 2015 and databases involving non-occupationally exposed populations from other countries. Hg levels significantly lower than those found in the same city in 2015, probably due to exclusion criteria of metal exposure applying in the present survey (occupationally exposed to the studied metals, smoking habits, amalgam tooth fillings, fish consumption habit more than one time per week, etc.). These background metal exposures will be useful for future occupational and/or environmental surveys as well as undertaking a reliable regulation of chemical exposure in Kinshasa via a national HBM program.

The western-European hedgehog (Erinaceus europaeus), in expanding its range towards human habitats, faces exposure to contaminants and biological agents, potentially leading to diseases associated with hematological and biochemical changes. As bioindicators of environmental pollution and carriers of zoonotic agents, hedgehogs play a crucial role in One Health studies, emphasizing the need for a comprehensive understanding of their clinical-pathological aspects. Exploring the blood reference values in healthy animals of this species is crucial for understanding and improving their well-being, and identifying possible diseases/pathogens that may affect its conservation and/or impact human health. This review is focused on analyzing the data available in the literature for Erinaceus europaeus blood reference intervals. A comprehensive literature review of the studies published in Europe is performed, highlighting their specificities, and emphasizing the need for continuous research in this field. Our final goal is to provide a crucial tool for assessing the health status of the species, and underscoring the significance of research in this specific domain.

Miranda’s donkey is an endangered, autochthone breed from Northern Portugal. Understanding the physiological and pathological conditions of Miranda’s donkey is crucial for the conservation of the breed. Our study aimed to establish reference intervals (RIs) for blood biochemistry parameters and to evaluate the influence of gender and age on these parameters. Blood samples from 75 clinically healthy animals were analyzed for 21 blood biochemistry parameters using Respons® 920 and Start® 4-Diagnostica-Stago. RIs were calculated according to the ASVCP guidelines, utilizing Reference Advisor software V. 2.1 and the statistical program SPSS version 29 to analyze the effects of gender and age. Significant gender-related differences (p < 0.05) were observed in cholesterol, chlorine, creatinine (CREA), glucose (GLU), sodium, and triglycerides (with higher values in females) and in aspartate aminotransferase, creatine phosphokinase (CK), gamma-glutamyl transferase, potassium, magnesium (Mg), and urea (with higher values in males). Age-related differences (p < 0.05) were noted for alkaline phosphatase, CK, fibrinogen, GLU, and phosphorus (higher in young animals) and for globulin, Mg, and total protein (higher in adults). The RIs described here are invaluable for assessing and monitoring the health status of individual animals and herds. Our study highlights the importance of considering gender and age in the interpretation of biochemical parameters, providing critical insights for the conservation and management of this endangered breed.

This article discusses the reference intervals for serum mast cell tryptase levels in European populations. The authors support the recently proposed normal range of 1-15 μg/L, which includes asymptomatic individuals with the hereditary alpha tryptasemia trait. They summarize reference interval studies from the perspective of laboratory medicine and provide additional sources that support the conclusions of the expert review. The authors also mention the importance of evaluating tryptase levels using each individual's own baseline tryptase. Overall, the article highlights the need for further research on a wider spectrum of international populations. [Extracted from the article]

This document discusses the standardization of pediatric serum phosphate reference intervals in Wales using an indirect data-mining approach. The study was prompted by the need to maintain serum phosphate levels within the age-specific reference interval for children receiving burosumab therapy for X-linked hypophosphataemia (XLH). The researchers used data from the laboratory information management system to establish age-related reference distributions for phosphate levels. The resulting reference intervals were compared to existing guidelines and were found to be significantly lower in the youngest age groups but aligned with adolescents. The study highlights the importance of using locally specific reference intervals and the utility of indirect data-mining methods in establishing these intervals. [Extracted from the article]

IntroductionSubclinical hypothyroidism (SCH) is a common endocrine disorder characterized by elevated thyroid-stimulating hormone (TSH) levels and normal free thyroxine (FT4) levels. The overdiagnosis and overtreatment of SCH in elderly patients have become concerns as TSH levels naturally increase with age. Studies have shown that many elderly patients with SCH can recover without treatment, and the administration of levothyroxine (L-T4) does not improve their prognosis. Therefore, It is necessary to establish age-specific reference ranges for TSH in elderly individuals to aid in clinical decision-making and prevent overdiagnosis.MethodsThis is a multicenter prospective study that focuses on Chinese elderly patients with SCH who have TSH levels below 10 mU/L. After obtaining the informed consent of the patients, their initial diagnosis information will be registered, and they will be asked to fill out questionnaires such as the Montreal Cognitive Assessment-Basic (MoCA-B), Hamilton Depression Scale (HAMD), Hypothyroidism Symptom Questionnaire (SRQ), frail scale(FRAIL), fatigue scale, and EQ-5D. In addition, thyroid function tests, blood lipid analysis, carotid artery ultrasound, and thyroid ultrasound examinations will be conducted. Patients will also be grouped according to FT4 levels, the changes in FT4 and its relationship with TSH can also be described. For patients over 80 years old, a decrease in FT4 will be used as an endpoint event, while for patients between 60-80 years old, TSH levels greater than or equal to 10mIU/L or a decline in FT4 will be used as the endpoint event. The TSH reference intervals of the general and elderly populations will be used to calculate medical costs associated with multiple follow-ups of patients, and a social-economic analysis will also be conducted.DiscussionThis study will prospectively observe elderly patients with SCH who are screened using both age-specific and non-age-specific TSH reference ranges for the elderly population. We will compare the results of elderly patients diagnosed with SCH using different reference ranges and analyze their association with FT4 to identify meaningful SCH patients and reduce over diagnosis and over treatment of elderly SCH.EthicsThe Medical Science Research Ethics Committee of the First Affiliated Hospital of China Medical University approved this study (ID: AF-SOP-07-1.1-01). The results will be published in an open-access journal.Clinical trial registrationhttps://www.chictr.org.cn/, identifier ChiCTR2300070831.

Serum protein electrophoresis has been demonstrated to have utility in diagnostic workup, wellness exams, and prognosis. Agarose gel electrophoresis (AGE) has previously been described for use with serum from Asian elephants (Elephas maximus). As the newer method of capillary zone electrophoresis (CZE) is becoming more commonplace in veterinary diagnostic laboratories, serum samples from Asian elephants were examined using this method. CZE allowed for a reproducible definition of two beta fractions and, overall, showed a low coefficient of variation for fraction quantitation. Preliminary reference intervals were generated using samples primarily from an older population of 22 female elephants. Albumin levels determined by CZE were also compared with those determined by the bromocresol green method on a chemistry analyzer. It was found that the latter method overestimated the level of albumin with a mean positive bias of 11.6% or 0.38 g/dL, thus method-specific reference intervals should be used. Significant negative correlations were observed between A/G ratio determined by CZE and serum amyloid A levels (r = −0.47, p

Background: Hematological parameters vary significantly throughout growth and development due to physiological processes such as fetal‐to‐adult erythropoiesis and puberty. Pediatric age‐ and sex‐specific reference intervals (RIs) are thus essential for appropriate clinical decision‐making. The current study aimed to establish RIs for both common and novel hematology parameters on the Mindray BC‐6800Plus system. Methods: Six hundred and eighty‐seven healthy children and adolescents (30 days to 18 years) were enrolled. Participants were recruited as part of the Canadian Laboratory Initiative on Pediatric Reference Intervals Program upon informed consent or identified from apparently healthy outpatient clinics. Whole blood was collected and assayed for 79 hematology parameters on the BC‐6800Plus system (Mindray). Age‐ and sex‐specific RIs were established as per Clinical and Laboratory Standards Institute EP28‐A3c guidelines. Results: Dynamic reference value distributions were observed for several hematology parameters, including erythrocytes, leukocytes, platelets, reticulocytes, and research‐use‐only markers. Age partitioning was required for 52 parameters, demonstrating changes in infancy and puberty. Sex partitioning was required for 11 erythrocyte parameters (i.e., red blood cell (RBC), hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin concentration, RBC distribution width coefficient of variation, hemoglobin distribution width, macrocyte count, macrocyte percentage, RBC (optical), and reticulocyte production index). Few parameters had undetectable levels in our healthy cohort (i.e., nucleated RBC count and immature granulocyte count). Conclusions: The current study completed hematological profiling for 79 parameters on the BC‐6800Plus system in a healthy cohort of Canadian children and adolescents. These data emphasize the complex biological patterns of hematology parameters in childhood, particularly at the onset of puberty, and support the need for age‐ and sex‐specific RIs for clinical interpretation. [ABSTRACT FROM AUTHOR]

Background: Serum ferritin levels have a clinical application in diagnosing diseases. However, the clinical standard levels and distribution characteristics of serum ferritin based on reference intervals (RIs) in the geriatric Han Chinese population in the East China region have not previously been well reported. This work aimed to investigate the correlation between serum ferritin levels and 14 metabolic markers, analyse the distribution of serum ferritin, and establish serum ferritin RIs for geriatric (> 60 years) individuals in Shanghai. Methods: Four hundred and sixty-nine healthy Chinese Han subjects (age, 61 - 95 years; median, 71 years) were recruited from the Health Examination Center of Shanghai Fourth People's Hospital in 2021. Serum ferritin was measured on a Roche Cobas 8000 e602, and 14 biochemical parameters were measured on a Siemens Atellica CH- 930 to analyse distributions and correlations and to establish serum ferritin RIs for the elderly population in Shanghai. Results: Serum ferritin levels were significantly different between genders (p = 0.06). The established RIs for serum ferritin were 24.44 - 627.09 ng/mL and 48.18 - 554.88 ng/mL in males and females, respectively. Correlation analyses revealed that ferritin levels were correlated with 7 parameters, including body mass index (BMI, p = 0.02), gamma-glutamyl transferase (GGT, p < 0.01), alanine aminotransferase (ALT, p < 0.01), triglycerides (TGs, p < 0.01), high-density lipoprotein (HDL, p < 0.01), total protein (TP, p < 0.01) and prealbumin (PAB, p < 0.01). When the participants were further divided by BMI, aspartate aminotransferase (AST) was an additional variable that was positively correlated only in the overweight/obese group (p = 0.04), while globulin (GLO) was an additional variable that was positively correlated only in the other group (p < 0.01). Conclusions: Nutrition and metabolism may play a great role in the regulation of serum ferritin levels in geriatric individuals in vivo. The RIs established for serum ferritin may provide precise references for further studies on ferritin-related disease in geriatric individuals. [ABSTRACT FROM AUTHOR]

Simple Summary: The Miranda donkey is a Portuguese breed from northern Portugal that is considered endangered. Much research in different scientific areas has been conducted to help in these animals' preservation. Knowledge of hematological reference intervals is important for characterizing the breed, identifying the health status of the animals and helping veterinarians in the diagnosis of diseases and the follow-up of patients. This study aimed to determine the hematological reference intervals for healthy Miranda donkeys and to evaluate the interference of sex and age in these parameters. Only age interfered in the hematological values and should be considered when interpreting the results. The results described here can be used to assess the health of animals and herds, guide the diagnosis of diseases and assist in the selection of healthy animals for reproduction, contributing to the preservation of the breed. The Miranda donkey is an autochthonous Portuguese breed that is considered endangered. Several studies have been carried out on this breed, but to the authors' best knowledge, no studies have been conducted on their clinical pathology. The aims of this study were to determine the hematological reference intervals (RIs) in healthy Miranda donkeys and to estimate the influence of age and sex. Blood samples from 75 clinically healthy animals were analyzed for 22 hematological parameters on the IDEXX ProCyte Dx, an automated hematology analyzer previously validated for the species. The RIs were estimated following the ASVCP guidelines with the Reference Value Advisor software. Regarding sex, no significant differences were found between groups. Regarding age, significant statistical differences (p < 0.05) were observed for red blood cells, red cell distribution width, white blood cells, lymphocytes, monocytes, platelets, plateletcrit (higher mean in young animals), mean corpuscular volume, mean corpuscular haemoglobin, neutrophils and eosinophils (higher mean in adults). The RIs described here can be used to evaluate and monitor the health status of animals and herds, as well as to guide diagnoses or select fit and healthy animals for reproduction, contributing to the preservation of the breed. [ABSTRACT FROM AUTHOR]

Background: Owing to the changes in childbirth policy in China, this work aimed to update the trimester-specific reference intervals (RIs) for Chinese pregnant women with diverse demographics and obstetric history. This study also investigated how advanced maternal age (AMA) (> 35 years old), gravity, and parity influence gestational coagulation parameters. Methods: In this prospective cross-sectional study, five coagulation parameters were measured using assays provided by Roche diagnostics on Cobas t 711: prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (Fib), and D-dimer, and the trimester-specific 2.5th -97.5th and 95th (D-dimer only) percentiles RIs were established accordingly. Linear regressions were undertaken to analyze the association with demographic characteristics and obstetric history for each parameter. Results: 893 eligible pregnant women in different trimesters and at AMA/non-AMA and 275 non-pregnant healthy women were enrolled. For the first, second, and third trimester, respectively, RIs were as follows: APTT (s): 24.8–35.7, 24.6–34.1, and 23.5–34.7; TT (s): 14.4–17.3, 14.1–16.7, and 14.2–17.5; PT (s): 8.30–10.20, 8.00-9.77, and 7.92–9.57; PT-INR: 0.86–1.06, 0.83–1.02, and 0.82–0.98; Fib (g/L): 2.76–4.97, 3.14–5.31, and 3.44–5.93; D-dimer (µg/ml): 0-0.969, 0-2.14, and 0-3.28. No statistically significant differences were observed in TT, D-dimer, and APTT between the AMA and non-AMA women, while PT and PT-INR were shorter and Fib was higher in the AMA group. The association of gravidity and parity with each coagulation parameter is statistically significant (p < 0.05). PT and PT-INR were shortened and D-dimer decreased as gravidity increased. Longer PT and PT-INR, shorter APPT, higher D-Dimer, and lower Fib were associated with increasing parity. Conclusions: This work updated the gestational coagulation profiles of Chinese pregnant women and established trimester-specific RIs accordingly. Establishing specific RIs based on AMA, parity, and gravidity might not be necessary. [ABSTRACT FROM AUTHOR]

It is believed that thyroid function has a significant effect on fertility and fetal development in mammals. So far, however, only few studies have been published about potential effects of the reproductive cycle stage on thyroid hormone concentrations in dogs. Therefore, over the course of 122 pregnant and non-pregnant cycles in healthy bitches, Thyroid stimulating hormone (TSH), free Thyroxine (fT4), total Thyroxine (tT4) and Progesterone (P4) were measured six times to assess the influence of the cycle stage and pregnancy on hormone concentrations. The aim was to evaluate established reference intervals for the thyroid hormones in a female study population. Of the 122 bitches, 98 became pregnant. Blood samples were collected during estrus, three times in pregnancy, during lactation and after weaning, or at equivalent times during and after estrus in non-pregnant dogs. No differences between pregnant and non-pregnant animals in any of the thyroid hormones were found. Hormone concentrations, however, differed significantly between the six samplings (p <.01). TSH initially declined during pregnancy, then rose again. The mean concentration of all dogs exceeded the overall upper reference limit of 0.70 ng/mL during lactation. Concentrations of tT4 and ft4 increased during the first third of pregnancy and then subsequently declined. The overall reference limits for tT4 were 0.47–3.20 μg/dL, and for fT4 4.86–29.60 pmol/L, but the reference intervals varied between the sampling dates. The observed patterns may reflect that maternal tT4 and fT4 seem to have important effects during early pregnancy, including a pronounced negative feedback effect on TSH. The initial increase and subsequent decline of tT4 and fT4 concentrations during the course of pregnancy is in accordance with findings in humans and may support the development of fetal thyroid function. The observed peak of TSH concentrations during lactation suggests that the demand for thyroid hormones in this phase is largest. Even if the underlying causes and mechanisms of thyroid regulation are not fully understood, the results of this study show relevant changes of hormone concentrations in the course of the sexual cycle and pregnancy. In that regard, cycle stage needs to be considered when assessing thyroid function in bitches. • 122 bitches were examined repeatedly throughout pregnancy and lactation. • Stage-dependent reference ranges have been defined. • tT4 and fT4 concentrations were highest during early pregnancy. • The lower reference limits for tT4 and fT4 were lowest during lactation. [ABSTRACT FROM AUTHOR]

Introduction: Immunoassays are the most common method in routine practice for measuring androgens in women. Study’s aim was to establish new population specific indirect reference intervals (RI) for dehydroepiandrostenedione sulphate (DHEAS) and for new androstenedione test available on automated Roche Cobas electrochemiluminescent immunoassay method. Materials and methods: From extracted laboratory records, testosterone, sex hormone binding globulin and follicle-stimulating hormone were used as reference tests to exclude possibly diseased women. After the data selection steps, the study included 3500 subjects for DHEAS and 520 for androstenedione aged 20-45 years. To evaluate the need for age partitioning, we calculated standard deviation ratio and bias ratio. For each hormone, 90% and 95% RIs were calculated with appropriate statistical method. Results: Total age group (20-45 years) 95% RIs were: 2.77-11.50 μmol/L for DHEAS and 2.48-8.89 nmol/L for androstenedione. Age-stratified 95% RIs for DHEAS were: 3.65-12.76 μmol/L (20-25 years); 2.97-11.50 μmol/L (25-35 years) and 2.30-9.83 μmol/L (35-45 years). Age-stratified 95% RIs for androstenedione were: 3.02-9.43 nmol/L (20-30 years) and 2.23-7.75 nmol/L (30-45 years). Conclusion: New RIs for DHEAS were slightly wider for age group 20-25 and 35-45, while the differences in the age group 25-35 years were more pronounced. Androstenedione RI showed significantly higher concentrations than the manufacturer’s. Age-related decrease of androgens should be considered when calculating RIs. We propose population specific, age-stratified RIs for DHEAS and androstenedione on electrochemiluminescent method, which should improve test interpretation in women of reproductive age. [ABSTRACT FROM AUTHOR]

Introduction: COVID-19 and vaccination may affect some parameters of the complete blood count (CBC). The aim of this study was to determine reference intervals (RI) of CBC in healthy population with different COVID-19 and vaccination backgrounds and compare them with those established previously. Materials and methods: A cross-sectional study was conducted in donors who attended the Traumatology Hospital “Dr. Victorio de la Fuente Narváez” (HTVFN) from June to September 2021. Reference intervals were established using the non-parametric method on Sysmex XN-1000. For differences between groups with different COVID-19 and vaccination backgrounds, non-parametric tests were used. Results: The RI were established in 156 men and 128 women. Haemoglobin (Hb), haematocrit (Hct), red blood cells (RBC), platelets (Plt), mean platelets volume (MPV), monocytes and relative neutrophils were higher in men than women (P < 0.001). The percentiles of Hb, Hct, RBC, MPV and relative monocytes showed higher values; Plt, white blood cells (WBC), lymphocytes, monocytes, neutrophils, eosinophils and absolute basophils, the 2.5th was higher and the 97.5th was lower; for lymphocytes and relative neutrophils, both percentiles had a trend toward lower values, compared to previous RI. Differences between groups with different COVID-19 and vaccination backgrounds, in lymphocytes (P = 0.038), neutrophils (P = 0.017) and eosinophils (P = 0.018) in men; Hct (P = 0.014), RDW (P = 0.023) in women and MPV (P = 0.001) in both, were not considered pathological. Conclusions: The RI for the CBC were established in a Mestizo-Mexican population with different COVID-19 and vaccination backgrounds, so should be updated and validated in different hospitals close to the HTVFN that use the same analyser. [ABSTRACT FROM AUTHOR]

Simple Summary: Serum protein electrophoresis (SPE) is a widely used method to determine the concentration of a serum protein fraction in human and veterinary medicine. Serum protein electrophoresis allows the separation of serum proteins into several categories based on their ability to migrate in an electrical field on different supports. Typical migration patterns could be identified in the course of different disorders such as inflammation or neoplasia. However, to be clinically useful, the interpretation of SPE data had to be performed in light of an appropriate method—and species-specific reference intervals (RIs) and for all species, including marine mammals, attention should also be given to the different living environments. In this work, we established the RIs for serum protein fractions evaluated using agarose gel electrophoresis in bottlenose dolphins (Tursiops truncatus) under human care. These data are a new tool for health assessment in dolphins, thus, they may be useful for clinicians to better interpret laboratory data. Serum protein electrophoresis (SPE) is the most used and reliable method to determine the percentage of serum protein subfractions. The interpretation of the kinetics of total proteins and albumin and globulin fractions is receiving increased attention in wild animals, as well as in domestic animals, due to the possibility of identifying typical pathologic patterns. However, the interpretation of these data had to be performed in light of an appropriate method—and species- specific reference intervals (RIs). In marine mammals, as well as other non-domestic species, specific attention should also be given to the different environment (free ranging vs. human managed) and the associated different exposure to environmental stimuli. The aim of this report was to establish RIs for the serum protein fractions evaluated using agarose gel electrophoresis (AGE) in bottlenose dolphins under human care. Peripheral blood samples were collected from 40 bottlenose dolphins during standard veterinary procedures to evaluate their health status. Total protein concentration was determined using the biuret method while AGE was performed using an automated system. A pooled dolphin's serum sample was used to determine the intra-assay and inter-assay imprecision of AGE. The RIs were calculated using an Excel spreadsheet with the Reference Value Advisor set of macroinstructions. The intra and inter-assay imprecisions were 1.2% and 2.5%, respectively, for albumin; 2.9% and 5.7%, respectively, for α-globulins; 3.8% and 4.0%, respectively, for β-globulins; and 3.4% and 4.8%, respectively, for γ-globulins. The total protein, albumin, α-globulin, β-globulin, and γ-globulin concentrations were 65.5 ± 5.4 g/L, 45.5 ± 4.9 g/L, 8.0 ± 1.0 g/L, 5.0 ± 2.0 g/L, and 7.0 ± 2.0 g/L, respectively. We established the RIs for the total protein and serum protein fractions using AGE in bottlenose dolphins under human care. [ABSTRACT FROM AUTHOR]

Indirect methods for reference interval (RI) establishment apply statistical techniques to generate RIs for test result interpretation using stored laboratory data. They present unique advantages relative to traditional direct approaches such as fewer resource requirements; however, there is debate regarding their performance. Herein, we aimed to compare indirect and direct approaches for RI establishment by harnessing data from the Isfahan Cohort Study (ICS). This cohort includes both healthy individuals and those with a history of disease, enabling a direct comparison. Participants were recruited as part of ICS, including 6504 adults aged 34 years and older. Sociodemographic characteristics, anthropometry, blood pressure, various biochemical indices, and hematology parameters were collected. The refineR method was used to establish indirect RIs (before applying exclusion criteria). Direct RIs were calculated using nonparametric methods per CLSI EP28-A3 guidelines (after applying exclusion criteria). Bias ratios were calculated for each parameter to assess significant differences in estimations. Direct and indirect RI estimations for most hematological and biochemical parameters were comparable. Statistically significant bias ratios between methods were observed for the upper limits of total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), hemoglobin (female), and platelet count as well as the lower limits of mean corpuscular hemoglobin (female), mean corpuscular volume, hemoglobin, and hematocrit (female). Data presented indicate RIs derived from direct and indirect approaches are similar, but not identical. Further work should focus on the clinical significance of such differences as well as the investigation of necessary data-cleaning criteria before indirect method application. [ABSTRACT FROM AUTHOR]

Background: The availability of a reliable reference interval is crucial for clinical decision-making. Correctly defined reference intervals for different age groups are currently unavailable for many parameters. Our study aimed to determine the complete blood count reference intervals in our region from newborn to geriatric ages with an indirect method. Methods: The study was carried out at Marmara University Pendik E&R Hospital Biochemistry Laboratory between January 2018 and May 2019 using the laboratory information system data. The complete blood count (CBC) measurements were performed by Unicel DxH 800 Coulter Cellular Analysis System (Beckman Coulter, FL, USA). A total of 14,014,912 test results belonging to infants, children, adolescents, adults, and geriatric ages were collected. We analyzed 22 CBC parameters, and an indirect method was used for reference interval determination. Data were analyzed according to the Clinical and Laboratory Standards Institute (CLSI) C28-A3 guideline for defining, establishing, and verifying reference intervals in the clinical laboratory. Results: We have established reference intervals from newborn to geriatric ages for 22 hematology parameters [hemoglobin (Hb), hematocrit (Hct), red blood cell (RBC), mean red cell volume (MCV), mean red cell hemoglobin (MCH), mean red cell hemoglobin concentration (MCHC), red cell distribution width (RDW), white blood cell (WBC) count, WBC differentials, including percentages and absolute counts, platelet count, platelet distribution width (PDW), mean platelet volume (MPV) and plateletcrit (PCT)]. Conclusions: Our study showed that reference intervals established with data obtained from clinical laboratory databases are comparable to those created using direct methods. [ABSTRACT FROM AUTHOR]

Background: Homocysteine (Hcy) are associated with many age-related diseases. Heterogeneous physiology with aging combined with unresolved assays standardization necessitates the establishment of specific Hcy reference intervals (RIs) applicable to the elderly. This retrospective study aimed to identify Hcy RIs in the elderly aged 60 years and older from a hospital in Jiangsu Province, China. Methods: Data from individuals undergoing routine physical examinations were collected. Hcy were measured on Hitachi 7600 analyzer using hydrolase-based enzymatic cycling method. Outliers were identified by Dixon methods. Age- and gender-specific differences were estimated by nonparametric tests. Factors affected Hcy were assessed using multivariate linear regression. RIs with 90% confidence intervals were determined by nonparametric method. Results: A total of 2594 individuals were included. Hcy levels increased with age (r=0.248, p

Background Reference ranges for bone turnover markers (BTMs) are still lacking in the healthy Chinese population. Aim To establish reference intervals for BTMs and to investigate the correlations between BTMs and bone mineral density (BMD) in Chinese older adults. Subjects and methods A community-based cross-sectional study was conducted among 2511 Chinese subjects aged over 50 yrs residing in Zhenjiang, Southeast China. Reference intervals for BTMs (i.e. procollagen type I N-terminal propeptide, P1NP; β cross-linked C-terminal telopeptide of type I collagen, β-CTX) were calculated as the central 95% range of all measurements in Chinese older adults. Results The reference intervals of P1NP, β-CTX and P1NP/β-CTX were 15.8–119.9 ng/mL, 0.041–0.675 ng/mL and 49.9–1261.5 for females and 13.6–111.4 ng/mL, 0.038–0.627 ng/mL and 41.0–1269.1 for males, respectively. In the multiple linear regression analysis, only β-CTX was negatively associated with BMD after adjusting for age and body mass index (BMI) in both sex-stratified groups (all p

Background: This study aims to establish reference intervals (RIs) for thyroid hormones in the elderly population and analyze their influence on the prevalence of subclinical hypothyroidism. Methods: Thyroid hormone records of subjects who underwent routine health checkup at our hospital between 2018 and 2020 were analyzed. Thyroid stimulating hormone (TSH), total triiodothyronine, total thyroxine, free triiodothyronine (FT3), and free thyroxine (FT4) levels were compared between young and elderly subjects. Thresholds of these thyroid hormones were established for elderly subjects. Results: A total of 22,207 subjects were included. Of them, 2,254 (10.15%) were aged ≥ 65 years. Elderly subjects had higher TSH, and lower FT3 and FT4 levels when compared with young subjects. In the elderly group, the RIs for TSH, FT3 and FT4 were 0.55-5.14 mIU/L, 3.68-5.47 pmol/L, and 12.00-19.87 pmol/L, respectively. The age and sex specific RIs for TSH were 0.56-5.07 mIU/L for men and 0.51-5.25 mIU/L for women. With whole-group RIs and age and sex-specific RIs for elderly people, the prevalence of subclinical hypothyroidism was 9.83% and 6.29% (p < 0.001), respectively. Conclusions: Elderly individuals had higher TSH levels than young individuals. Our study indicated that establishing specific RIs for elderly individuals is needed. This has implications for the diagnosis and management of subclinical hypothyroidism in the elderly population.

Introduction: For interpretation of the most common biochemical markers reference intervals (RIs) are widely considered and reported. Therefore, in this study, we aimed to determine age-specific RIs for some biochemical tests by removing and/or limiting critical gaps including sex, age group, geographical region, measurement device, and type of kits and reagents for routine laboratory biochemical variables in healthy adolescent girls aged 12-19 years.Materials and Methods: In this cross-sectional study a total of 1026 adolescent girl was recruited. According to the study aim, the levels of serum for some routine biochemical tests were measured on a BT-3000 auto-analyzer. On the basis of the non-parametric rank method and by use of CLSI Ep28-A3 guidelines, we determined age-specific RIs, including confidence interval 90%, under specific exclusion criteria.Results: Age partitioning was required for none of the upper and lower limits of biochemical markers. All Serum biochemical tests concentration remained relatively constant throughout the age range. Conclusion: By removing and/or limiting critical gaps involved in reference values of biochemical tests, it has provided an important understanding of metabolic processes and it has facilitated clinical application to track different diseases better

Background: Plasma amyloid-β (Aβ) peptides and tau proteins are promising biomarkers of Alzheimer's disease (AD), not only for predicting Aβ and tau pathology but also for differentiating AD from other neurodegenerative diseases. However, reference intervals for plasma biomarkers of AD in healthy elderly Chinese individuals have not yet been established. Methods: Biomarkers of AD were measured using single-molecule array (Simoa) assays in plasma samples from 193 healthy, cognitively unimpaired Chinese individuals aged 50–89 years. The 95% reference intervals for plasma Aβ42, Aβ40, t-tau, p-tau181, and derived ratios were calculated by using log-transformed parametric methods. Results: Plasma Aβ42, Aβ40, and p-tau181 levels were positively correlated with age, while the Aβ42/Aβ40 ratio was negatively correlated with age. The 95% reference intervals for plasma Aβ42 and Aβ40 were 2.72–11.09 pg/mL and 61.4–303.9 pg/mL, respectively, and the 95% reference intervals for plasma t-tau and p-tau181 were 0.20–3.12 pg/mL and 0.49–3.29 pg/mL, respectively. The 95% reference intervals for the Aβ42/Aβ40 ratio, p-tau181/t-tau ratio, and p-tau181/Aβ42 ratio were 0.022–0.064, 0.38–6.34, and 0.05–0.55, respectively. Conclusion: Reference intervals for plasma biomarkers of AD may assist clinicians in making accurate clinical decisions. [ABSTRACT FROM AUTHOR]

Background: The use of supine reference intervals instead of the corresponding seated reference intervals for seated plasma-free metanephrines (MNs) in pheochromocytoma/paraganglioma (PPGL) screening has been controversial in recent years. Each clinical laboratory should choose the optimal sampling posture and diagnostic strategy according to local conditions. Methods: The reference population consisted of 736 cases aged 14–92 years old and the validation population consisted of 1068 patients aged 8–87 years old. Seated MNs were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the reference intervals and diagnostic cut-off values were established and the diagnostic performance compared with reference intervals established in a supine position. Results: There was no correlation between seated plasma MNs and age (p > 0.05) and there were differences in MNs among the various disease groups (p < 0.05). MNs were different in gender (p < 0.0001). The upper reference limit (URL) established in this study had the same sensitivity (100%) and better specificity (94.6% vs 83.5%) compared with the published age-adjusted supine reference intervals. The proportion of suspected patients with MNs within the URL-2×URL range was lower using seated reference intervals compared to supine intervals (5.3% vs 15.7%). Conclusion: Using the corresponding seated reference intervals for seated plasma MNs can reduce the unnecessary re-examinations of suspected patients with slightly elevated MNs. The cut-off value established by seated plasma MNs has good diagnostic performance in PPGL. Use of seated sampling is an acceptable practice and is more convenient and economical than supine sampling. [ABSTRACT FROM AUTHOR]

Objective: Interpreting laboratory results for transgender individuals who started hormone therapy requires careful consideration, specifically for analytes that have sex-specific reference intervals. In literature, conflicting data exist on the effect of hormone therapy on laboratory parameters. By studying a large cohort, we aim to define what reference category (male or female) is most appropriate to use for the transgender population over the course of gender-affirming therapy. Methods: A total of 2201 people (1178 transgender women and 1023 transgender men) were included in this study. We analyzed hemoglobin (Hb), hematocrit (Ht), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), creatinine, and prolactin, at 3 different time points: pretreatment, during hormone therapy, and after gonadectomy. Results: For transgender women, Hb and Ht levels decrease after initiation of hormone therapy. The concentration of liver enzymes ALT, AST, and ALP decreases whereas the levels of GGT do not change statistically significantly. Creatinine levels decrease whereas prolactin levels rise in transgender women during gender-affirming therapy. For transgender men, Hb and Ht values increase after starting hormone therapy. Liver enzymes and creatinine levels increase statistically significantly as well upon hormone therapy while prolactin concentrations decrease. Overall, reference intervals in transgender people after 1 year on hormone therapy resembled those of their affirmed gender. Conclusions: Generating transgender-specific reference intervals is not essential to correctly interpret laboratory results. As a practical approach, we recommend to use the reference intervals of the affirmed gender from 1 year onwards after starting hormone therapy. [ABSTRACT FROM AUTHOR]

Elevated free T3 (FT3) is an important feature for the early diagnosis of several diseases among which Grave's disease or Allan-Hernon-Dudley syndrome. However, there is a lack of age-adapted reference intervals for plasma thyroid hormones in children. We conducted a study to define reference values of peripheral FT3 in children using a commonly used automated immunoassay. All thyroid function test (TFT) results from our lab collected during 9 months were extracted anonymously, and reference intervals establishment followed recommendations validated by International Federation of Clinical Chemistry (IFCC). We defined five reference intervals covering the whole pediatric period. Overall, 26.1% of peripheral FT3 measured in children with normal TSH are out of the adult reference range, and 22.2% are upper it leading to misinterpretation. In a 9-month old patient with severe neurodevelopmental disorders, a pathological elevated FT3 has been securely interpreted using the newly established interval. The study highlights the poor relevance of adult intervals in pediatric cares, as it confirms that plasmatic FT3 is higher during the whole pediatric period. This work reports useful age-adapted reference intervals for free T3 in pediatrics using a widely used electrochemiluminescent Immunoassay (ECLIA) kit. [ABSTRACT FROM AUTHOR]

Background: We preliminarily established the reference intervals for the systemic immune-inflammation index (SII), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and lymphocyte to monocyte ratio (LMR) in healthy adults in Jiangsu region in Eastern China to guide the interpretation and application of these indicators in clinical practice. Methods: In total, 29,947 ostensibly healthy subjects from December 2020 to March 2021 were included in this study. The distributions of the SII, NLR, PLR, and LMR were analyzed using the Kolmogorov-Smirnov test. According to the C28-A3 guidelines, the 2.5th and 97.5th percentiles (P2.5 to P97.5) of the SII, NLR, PLR, and LMR were used to establish the reference intervals based on nonparametric methods. Results: All SII, NLR, PLR, and LMR data were non-normally distributed. The levels of the SII, NLR, PLR, and LMR in healthy adults were significantly different between males and females (all p < 0.05). However, there were no significant differences in the SII, NLR, PLR or LMR among the different age groups, regardless of gender (all p > 0.05). Therefore, the reference intervals for the SII, NLR, PLR, and LMR were established based on the Sysmex testing platform for males (162 x 109/L - 811 x 109/L; 0.89 - 3.26; 63.15 - 191.34; 3.18 - 9.61) and females (165 x 109/L - 792 x 109/L; 0.87 - 3.16; 69.04 - 205.62; 3.46 - 10.96). Conclusions: We have established the reference intervals for SII, NLR, PLR, and LMR in healthy adults based on the Sysmex detection platform and large sample size, which may provide important guidance for its clinical application. [ABSTRACT FROM AUTHOR]

Background: This study aims to establish reference intervals (RIs) for thyroid hormones in the elderly population and analyze their influence on the prevalence of subclinical hypothyroidism. Methods: Thyroid hormone records of subjects who underwent routine health checkup at our hospital between 2018 and 2020 were analyzed. Thyroid stimulating hormone (TSH), total triiodothyronine, total thyroxine, free triiodothyronine (FT3), and free thyroxine (FT4) levels were compared between young and elderly subjects. Thresholds of these thyroid hormones were established for elderly subjects. Results: A total of 22,207 subjects were included. Of them, 2,254 (10.15%) were aged ≥ 65 years. Elderly subjects had higher TSH, and lower FT3 and FT4 levels when compared with young subjects. In the elderly group, the RIs for TSH, FT3 and FT4 were 0.55-5.14 mIU/L, 3.68-5.47 pmol/L, and 12.00-19.87 pmol/L, respectively. The age and sex specific RIs for TSH were 0.56-5.07 mIU/L for men and 0.51-5.25 mIU/L for women. With whole-group RIs and age and sex-specific RIs for elderly people, the prevalence of subclinical hypothyroidism was 9.83% and 6.29% (p < 0.001), respectively. Conclusions: Elderly individuals had higher TSH levels than young individuals. Our study indicated that establishing specific RIs for elderly individuals is needed. This has implications for the diagnosis and management of subclinical hypothyroidism in the elderly population. [ABSTRACT FROM AUTHOR]

Background: The hemogram is the most frequently prescribed laboratory test. It guides the complementary tests essential to the diagnosis and follow-up of the patient. Hematology reference values can be influenced by several parameters such as environmental and genetic factors, rendering it essential to define reference intervals (RIs) for specific populations. This study aimed to determine RIs from a population of healthy adults in Al Hoceima province by following the procedures recommended by the IFCC-CLSI guidelines in 2008 and comparing them to those of similar studies conducted in various countries. Methods: We initially recruited 977 healthy adults from 18 to 60 years old including 255 men and 722 women, who presented themselves at the provincial hospital center of Al Hoceima (Morocco) for health checkups from February 2019 to September 2019. The erythrocyte, leukocyte, and platelet parameters were investigated using hematology analyzer ABX Pentra XL80 HORIBA® (HORIBA ABX SAS, Kyoto, Japan). Results: The results showed that the RIs of the blood count parameters searched were more or less close to the RIs determined in Caucasian populations. Nevertheless, they were low compared to the limits of the RIs published in the literature for certain erythrocyte and platelet parameters. Our RIs were also similar in their majority, except for some parameters, to the RIs published very recently in a study conducted on a Moroccan population in the Tangier-Tetouan region. In addition, our intervals differ in their majority from those published in a study of a Ghanaian population. Conclusions: The differences reported by this preliminary work reinforce the need to establish hemogram RIs specific to the Moroccan population through more extensive studies carried out in different regions of Morocco. These studies should avoid misdiagnosis and allow physicians to interpret hematological tests more specifically. [ABSTRACT FROM AUTHOR]

Schizothorax esocinus, commonly known as snow trout, is one of the main contributors of food and livelihood in the colder zone of Himalayan region. The comprehensive information on its hematological and serum biochemical reference intervals is not reported yet. In the present study an attempt has been made to elucidate the hematological and serum biochemical reference intervals of S. esocinus from River Jhelum using protocols of the American Society of Veterinary Clinical Pathology (ASVCP). Wild fish were sampled over a period of 2 years from the pollution free sites of river Jhelum. Fish blood was harvested through caudal venipuncture and hemato-biochemical analysis performed thereof. Data values from a total of healthy 432 adult fish specimens (216 male, 216 female) were systematically recorded. The reference intervals for hematological and serum biochemical parameters of S. esocinus were established using Reference Value Advisor software v 2.1. RIs for hematological and serum analytes ranged as: hemoglobin (Hb) 78.38-116.35 (g/L); white blood cells (WBC) 10-20 (×109/L); red blood cells (RBC) 1.30-2.15 (×1012/L); packed cell volume 27.00-39.45 (%); total protein 39.21-61.62 (g/L); albumin 8.20-22.02 (g/L); globulin 27.58-49.55 (g/L); glucose 3.25-7.18 (mmol/L); urea 0.96--2.38 (mmol/L); cholesterol 3.80-6.90 (mmol/L). The study also depicted that certain blood measurands were influenced with respect to sex. Significantly (p < 0.05) higher values of Hb, red blood cells count and serum glucose were noted in male as compared to female which, on the other hand, registered higher white blood cells count and serum cholesterol level (Mann Whitney U test, p < 0.05). The work, therefore, provides baseline information on hematological and serum biochemical analytes of this species which holds high commercial importance. RIs reported here can help monitor the health status of fish by improving the use of non-lethal diagnosticmethods in piscine medicine. [ABSTRACT FROM AUTHOR]

Simple Summary: The Western European hedgehog (Erinaceus europaeus) is an insectivorous mammal with a wide geographic distribution. Owing mostly to climate changes and anthropogenic pressures, a considerable number of hedgehogs now live in urban areas close to humans, where they are exposed to contaminants and biological agents that may result in disease with the correspondent hematological and biochemical alterations. Hedgehogs can work as bioindicators to environmental pollution and host multiple zoonotic agents, making them relevant for One Health studies. Thus, it is essential to deepen the knowledge on this species and calculate reference intervals for the usual hematological and biochemical parameters. This would make it possible to recognize the "normal" and identify the "disease". In this study, some significant differences were evident, especially when comparing age groups (juveniles versus adults), showing the relevance of further investigations in this species. The Western European hedgehog (Erinaceus europaeus) can work as a bioindicator of environmental pollution and be a host for multiple zoonotic agents, making it relevant in terms of One Health studies. It is essential to deepen the knowledge on this species and calculate reference intervals (RIs) for the usual hematological and biochemical parameters. For this retrospective study (2017–2022), the archives of the Clinical Pathology Laboratory (LPC) of University of Trás-os-Montes and Alto Douro (UTAD) Veterinary Teaching Hospital were analyzed. Data of hematology, clinical biochemistry, and protein electrophoresis from 37 healthy hedgehogs of the Wild Animal Rehabilitation Center at UTAD, Northern Portugal, were included. It was possible to calculate RIs for almost all of the variables in the study, using Reference Value Advisor V2.1. Moreover, sex and age effects were investigated: alkaline phosphatase (p = 0.012, higher in males); total proteins (p = 0.034, higher in adults); mean cell volume (p = 0.007) and mean corpuscular hemoglobin (p = 0.010) (both higher in juveniles); and red blood cell distribution width (p = 0.021, higher in adults). Our study allowed for the first time to define RIs for a population of hedgehogs in Portugal, having a potentially relevant impact on species conservation and in the human–animal health interface. [ABSTRACT FROM AUTHOR]

The reference intervals (RIs), proposed by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) and the International Union of Pure and Applied Chemistry (IUPAC), were derived for Cd, Hg, Mn and Pb in the blood and urine of the children population living in Kinshasa (n = 200, aged 3–14 years with 97 girls). Levels of metals were measured using coupled plasma mass (ICP-MS). In blood, the proposed RIs [P5-P95 (GM)] were 0.022–1.112 μg/L (0.074), 35.69–144.50 μg/L (71.43), 0.060 to 1.161 μg/L (0.208) and 6.597–15.740 μg/L (9.882) for Cd, Pb, Hg and Mn, respectively. Urinary levels [(P5-P95 (GM)] were 0.082–1.530 μg/L (0.366) for Cd, 1.827–18.500 μg/L (5.458) for Pb, 0.323–1.953 μg/L (0.709) for Hg and 0.070 to 1.703 μg/L (0.186) for Mn. As compared to the CDC updated blood Pb reference value (35 μg/L), Pb levels remain higher of public health concern. Cd and Mn levels were similar to those found in the same city in 2015 and databases involving non-occupationally exposed populations from other countries. Hg levels significantly lower than those found in the same city in 2015, probably due to exclusion criteria of metal exposure applying in the present survey (occupationally exposed to the studied metals, smoking habits, amalgam tooth fillings, fish consumption habit more than one time per week, etc.). These background metal exposures will be useful for future occupational and/or environmental surveys as well as undertaking a reliable regulation of chemical exposure in Kinshasa via a national HBM program. [ABSTRACT FROM AUTHOR]

• First established reference intervals for estradiol using a UHPLC-MS/MS-based method in South Korea. • Serum samples from 634 pediatric patients, including neonates, infants, children, and adolescents. • The highly analytical sensitive UHPLC-MS/MS method was useful for estradiol determination in children. Ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC–MS/MS) is a reliable and accurate method for measuring steroid hormone levels. There is an increasing need for sensitive and precise methods to measure estradiol in pediatric patients. Here, we established reference intervals for estradiol in healthy children using a UHPLC–MS/MS-based method for the first time in South Korea. Serum estradiol was measured using a Sciex Triple QuadTM 6500 + UHPLC–MS/MS (Sciex, Framingham, MA, USA). Reference intervals for estradiol were established according to the CLSI document EP28-A3c:2008. The reference intervals were validated using serum samples from 634 pediatric patients, including neonates, children, and adolescents. Among them, 389 specimens were used in analysis of the specimen acceptance time. Statistical analysis was performed using MedCalc (MedCalc, Ostend, Belgium) and Analyse–it (Analyse–it Software Ltd., Leeds, United Kingdom) software. Reference intervals for boys (n = 297) were <16.6, <7.3, <19.0, <30.5, 7.6–96.5, and 10.6–134.4 pmol/L among those aged <1, 1–5, 6–9, 10–11, 12–14, and 15–17 years, respectively. Reference intervals for girls (n = 337) were <114.7, <24.2, <34.8, 8.0–177.0, 10.4–480.5, and 9.1–486.7 pmol/L among those aged <1, 1–5, 6–9, 10–11, 12–14, and 15–17 years, respectively. Overall, there was no effect of specimen acceptance time on estradiol measurements in boys or girls, except for that in the group aged 10–11 years. The reference intervals for healthy children were validated using a UHPLC–MS/MS-based method. The highly analytical sensitive UHPLC–MS/MS method may be useful for estradiol determination in pediatric patients. [ABSTRACT FROM AUTHOR]

Therefore, we reaffirm our proposed panhaemocytometric approach to COVID-19, where analysis of multi-lineage population data may serve as an adjunct to the diagnosis and monitoring of patients with severe COVID-19. Keywords: cell population data; COVID-19; haematology; haemocytometry; reference intervals; SARS-CoV-2; Sysmex XN analyser EN cell population data COVID-19 haematology haemocytometry reference intervals SARS-CoV-2 Sysmex XN analyser e43 e47 5 01/30/23 20230301 NES 230301 To the Editor, The SARS-CoV-2-associated COVID-19 pandemic remains a global concern, with more than 629 million confirmed cases of COVID-19 - including 6.5 million deaths - reported to the World Health Organisation as of November 2022 [[1]]. We previously reported SARS-CoV-2-associated haemocytometric changes on Sysmex XN-series analysers (Sysmex, Kobe, Japan), where cell population data (CPD) parameters distinguished between patients with and without COVID-19 [[2]]. [Extracted from the article]

Reference intervals are established either by direct or indirect approaches. Whereas the definition of direct is well established, the definition of indirect is still a matter of debate. In this paper, a general definition that covers all indirect models presently in use is proposed. With the upcoming popularity of indirect models, it has become evident that further partitioning strategies are required to minimize the risk of patients' false classifications. With indirect methods, such partitions are much easier to execute than with direct methods. The authors believe that the future of reference interval estimation belongs to indirect models with big data pools either from one laboratory or combined from several regional centres (if necessary). Independent of the approach applied, the quality assurance of the pre-analytical and analytical phase, considering biological variables and other confounding factors, is essential. [ABSTRACT FROM AUTHOR]

Conventionally, reference intervals are established by direct methods, which require a well-characterized, obviously healthy study population. This elaborate approach is time consuming, costly and has rarely been applied to steroid hormones measured by mass spectrometry. In this feasibility study, we investigate whether indirect methods based on routine laboratory results can be used to verify reference intervals from external sources. A total of 11,259 serum samples were used to quantify 13 steroid hormones by mass spectrometry. For indirect estimation of reference intervals, we applied a "modified Hoffmann approach", and verified the results with a more sophisticated statistical method (refineR). We compared our results with those of four recent studies using direct approaches. We evaluated a total of 81 sex- and age-specific reference intervals, for which at least 120 measurements were available. The overall agreement between indirectly and directly determined reference intervals was surprisingly good as nearly every fourth reference limit could be confirmed by narrow tolerance limits. Furthermore, lower reference limits could be provided for some low concentrated hormones by the indirect method. In cases of substantial deviations, our results matched the underlying data better than reference intervals from external studies. Our study shows for the first time that indirect methods are a valuable tool to verify existing reference intervals for steroid hormones. A simple "modified Hoffmann approach" based on the general assumption of a normal or lognormal distribution model is sufficient for screening purposes, while the refineR algorithm may be used for a more detailed analysis. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective: The objective of this study was to determine the serum thyroid-stimulating hormone (TSH) concentration reference intervals (RIs) of healthy children aged 1 to 10 years of both sexes, living in the Central Region of Brazil. Subjects and methods: 1,735 children [869 (50.1%) female; 866 (49.9%) male] enrolled in the morning shift of 47 pre- and 83 public elementary schools in the municipality of Cuiabá, Mato Grosso, were studied by gathering anthropometric and social data and their medical history. A blood sample was collected from each child to determine the TSH concentration using the electrochemiluminescence method on a Cobas® 6000 modular analyzer (Analyzer series, Roche Diagnostics). Results: The RIs were determined using the 2.5 and 97.5 percentile and the mean ± 2 standard deviations methods. After identifying the homoscedastic groups by age and sex, outliers higher or lower than three standard deviations were excluded. The distribution of serum TSH concentrations showed no significant age or sex differences. Based on the percentile method, TSH RI ranged from 0.93 to 5.86 μIU/mL. Based on the mean ± 2 standard deviations, TSH RI ranged from 0.30 to 5.29 μIU/mL. Conclusion: The normal serum TSH concentration of the Brazilian children evaluated in this study differ from those of populations from other countries. Other regional population studies may validate the RIs found in this study and enable its safer use in pediatric clinical practice.

Objectives. To determine the ferritin inter-assay differences between three “Conformité Européenne” (CE) marked tests, the impact on reference intervals (RI), and the proportion of individuals with iron deficiency (ID), we used plasma and serum from healthy blood donors (HBD) recruited in three different Switzerland regions. Design and Methods. Heparinized plasma and serum from HBD were obtained from three different transfusion centers in Switzerland (Fribourg, Geneva, and Neuchatel). One hundred forty samples were recruited per center and per matrix, with a gender ratio of 50%, for a total of 420 HBD samples available per matrix. On both matrices, ferritin concentrations were quantified by three different laboratories using electrochemiluminescence (ECL), latex immunoturbidimetric assay (LIA), and luminescent oxygen channeling immunoassay (LOCI) assays, respectively. The degree of agreement between matrices and between the three sites/methods was assessed by Passing–Bablok and we evaluated the proportion of individuals deemed to have ID per method. Results. Overall, no difference between serum and heparinized plasma ferritin values was observed according to Passing–Bablok analyses (proportional bias range: 1.0–3.0%; maximum constant bias: 1.84 µg/L). Significant median ferritin differences (p < 0.001 according to Kruskal–Wallis test) were observed between the three methods (i.e., 83.6 µg/L, 103.5 µg/L, and 62.1 µg/L for ECL, LIA, and LOCI in heparinized plasma, respectively), with proportional bias varying significantly between ±16% and ±32% on serum and from ±14% to ±35% on plasma with no sign of gender-related differences. Affecting the lower end of RI, the proportion of ID per method substantially varied between 4.76% (20/420) for ECL, 2.86% (12/420) for LIA, and 9.05% (38/420) for LOCI. Conclusions. Serum and heparinized plasma are exchangeable for ferritin assessment. However, the order of magnitude of ferritin differences across methods and HBD recruitment sites could lead to diagnostic errors if uniform RI were considered. Challenging the recently proposed use of uniform ferritin thresholds, our results highlight the importance of method- and region-specific RI for ferritin due to insufficient inter-assay harmonization. Failing to do so significantly impacts ID diagnosis.

Abstract Background Leptin is a peptide hormone secreted by adipose tissue and is an important determinant of obesity and its complications. The purpose of this study was to establish sex- and body mass index (BMI)-specific reference intervals for serum leptin in a Chinese population and investigate the factors influencing leptin concentrations. Methods Fasting serum leptin levels were assayed in 469 men and 773 women from randomly sampled Chinese residents. Blood glucose, insulin, hemoglobin A1c (HbA1c), liver enzymes, blood lipid profiles, creatinine, and uric acid (UA) levels were measured. Pearson’s correlation coefficient and multiple linear regression analyses were used to estimate the relationship between serum leptin level and other variables. The reference intervals were determined by the 2.5th and 97.5th percentiles. Results The mean ± standard deviation serum leptin level was much higher in women (20.92 ± 12.96 ng/mL) than in men (6.45 ± 5.53 ng/mL). The reference interval of serum leptin was 0.33–19.85 ng/mL in men and 3.60–54.86 ng/mL in women. The specific reference intervals of serum leptin in men with BMI of 20 to 90 cm), and metabolic syndrome were found in men, and significantly higher levels of HOMA-IR, UA and a higher proportion of central obesity (WC > 85 cm) were found in women. Conclusion This is the first study to establish sex- and BMI-specific reference intervals of leptin for both sexes in a large Chinese population. Serum concentration of leptin was predicted by BMI, HOMA-IR, UA in women, and TG in men.

Abstract Background Reference intervals represent the expected range of physiological test results in a healthy population and are essential to support medical decision making. Particularly in the context of pediatric reference intervals, where recruitment regulations make prospective studies challenging to conduct, indirect estimation strategies are becoming increasingly important. Established indirect methods enable robust identification of the distribution of “healthy” samples from laboratory databases, which include unlabeled pathologic cases, but are currently severely limited when adjusting for essential patient characteristics such as age. Here, we propose the use of mixture density networks (MDN) to overcome this problem and model all parameters of the mixture distribution in a single step. Results Estimated reference intervals from varying settings with simulated data demonstrate the ability to accurately estimate latent distributions from unlabeled data using different implementations of MDNs. Comparing the performance with alternative estimation approaches further highlights the importance of modeling the mixture component weights as a function of the input in order to avoid biased estimates for all other parameters and the resulting reference intervals. We also provide a strategy to generate partially customized starting weights to improve proper identification of the latent components. Finally, the application on real-world hemoglobin samples provides results in line with current gold standard approaches, but also suggests further investigations with respect to adequate regularization strategies in order to prevent overfitting the data. Conclusions Mixture density networks provide a promising approach capable of extracting the distribution of healthy samples from unlabeled laboratory databases while simultaneously and explicitly estimating all parameters and component weights as non-linear functions of the covariate(s), thereby allowing the estimation of age-dependent reference intervals in a single step. Further studies on model regularization and asymmetric component distributions are warranted to consolidate our findings and expand the scope of applications.

Reference interval limits for cancer biomarkers in geriatrics are rare because priority is given to the development of reference interval limits for those in the age range of 18–60 years, which are normally used for clinical trials study. The aim of this study was therefore to develop gender and age-specific reference interval limits for cancer markers CA19-9, CEA, CA 15-3, CA 125, and PSA for adults and geriatrics in Taita-Taveta County, Kenya, using the CLSI CA28-A3 guideline. This prospective cross-sectional study involved 244 healthy referents, including 124 females and 120 males of ages 50–95, between May 2015 and December 2017 at the Department of Clinical Chemistry of Moi Subcounty Hospital, Voi, Kenya. Serum CA 19-9, CEA, CA 15-3, CA 125, and PSA of the 244 referents were measured using a well-calibrated, quality controlled Clinical Chemistry AutoAnalyzer. Gender differences in the measured values of the biomarkers were assessed using the Mann-Whitney U test, while age differences were assessed using the Kruskal-Wallis H test followed by the Mann-Whitney U test with an adjusted significant ρ-value of less than 0.0167. Reference interval limits for the measured cancer biomarkers were expressed in terms of medians and ranged between 2.5 and 97.5 percentiles. The established 95% reference interval limits were: 0-58 U/mL males and 0-42.8 U/mL females for CA 19–9, 0–7 ng/mL for CEA, 0-56.9 U/mL for CA 15–3, 0–25 ng/mL for CA 125, and 0–6.8 ng/mL for PSA. Gender-related biomarker values were developed for CA 19-9 adults and geriatrics (60–70 years), CEA for geriatrics (60–70 years), and CA 15-3 for adults. Age-related biomarker values were developed for CA 19–9 males and not for females. In conclusion, gender-related 95% reference interval limits were developed for CA 19-9, CEA, CA 15-3, CA 125, and PSA, and age-related 95% reference interval limits were established for CA 19-9. CA 19-9 decreased from adulthood to the early elderly and increased in the more elderly population. These developed reference interval limits for these biomarkers, which differed from those reported in previous literature, could be adopted for use in Taita-Taveta County, Kenya, for better medical care. Doi: 10.28991/SciMedJ-2022-04-02-04 Full Text: PDF

الملخص: أهداف البحث: الفترات المرجعية للمتممة 3 والمتممة 4 نادرة، خاصة بالطرق غير المباشرة. تهدف هذه الدراسة إلى إنشاء فترات مرجعية إقليمية للمتممة 3 والمتممة 4 باستخدام الطريقة غير المباشرة بالأساليب الإحصائية المناسبة. طرق البحث: تم تضمين 12313 نقطة بيانات للمتممة 3 و 12125 نقطة بيانات للمتممة 4 من قاعدة بيانات المستشفى الأول بجامعة جيلين في الصين، وتم توحيدها بواسطة الأساليب الإحصائية. تم استخدام معاملات التجانف - الوسيط – معامل التفاوت لتحديد القيمة الحرجة للعمر، مع اختبار ''زي'' اللاحق لمقارنة الاختلافات. تم استخدام الطريقة غير المتثابتة لإنشاء الفترات المرجعية. النتائج: لم تظهر التراكيز للمتممة 3 والمتممة 4 فروقا ذات دلالة احصائية مع الجنس وأظهرت ارتباطا ضعيفا مع العمر. كما لم يتم العثور على فروق ذات دلالة إحصائية بعد حساب قيمة ''زي'' للنقاط العمرية على المنحنيات المستخدمة. كانت الفترات المرجعية للمتممة 3 هو 0,83-1,58 جم/لتر وللمتممة 4 هو 0.15-0.40 جم/لتر. اجتازت الفترات المرجعية جميع أدوات التحقق. الاستنتاجات: تم إنشاء الفترات المرجعية المناسبة للمتممة 3 وللمتممة 4 للسكان المحليين وستفيد في التشخيص السريري. تم إثبات جدوى وعملية الطريقة غير المباشرة. Abstract: Objective: The establishment of reference intervals (RIs) for complement 3 (C3) and complement 4 (C4) is rare, especially by indirect methods. Therefore, this study aims to establish regional RIs for C3 and C4 by an indirect method, using relevant statistical methods. Methods: Total of 12,313 data points for C3 and 12,125 data points for C4 were obtained from the First Hospital of Jilin University's database in China and standardised using the Tukey and Box–Cox statistical methods. The coefficients of the skewness-median-coefficient of variation curves (LMS) were used to determine the critical value for age, and a subsequent z test used to compare the differences. A non-parametric method was used to establish the RIs. Results: The C3 and C4 concentrations showed no significant differences by sex, and a weak correlation with age. No significant difference was found after calculating the z value for the age points on the LMS curves. The RIs for C3 and C4 were 0.83–1.58 g/L and 0.15–0.40 g/L, respectively. The RIs all passed verification. Conclusion: Suitable RIs for C3 and C4 were established for the local population, and will benefit clinical diagnosis. The feasibility and practicability of the indirect method were demonstrated.

Abstract Aims The aim of this study was to establish age‐specific and sex‐specific cut‐off values for N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) and high‐sensitivity troponin T (hs‐troponin T) in healthy subjects and assess cardiac biomarkers as screening tools for subclinical heart failure (HF) in a general population. Methods and results Altogether, 1936 participants were randomly selected from the general population Tromsø 7 study in Northern Norway. Diagnostic accuracy (sensitivity, specificity, and negative and positive predictive value) of cardiac markers for echocardiographically defined subclinical HF was evaluated. The receiver‐operating characteristic analysis showed that areas under the curve were relatively low (under 0.75) for both NT‐proBNP and hs‐troponin T, suggesting that the diagnostic accuracy of these biomarkers for subclinical HF was not excellent, especially for mild forms of HF and younger age group 40–49 years. Sex‐specific and age‐specific cut‐offs for hs‐troponin T (99th percentiles) and NT‐proBNP (97.5th percentiles) were established in healthy subjects from the same general population. The sex‐specific and age‐specific cut‐offs for NT‐proBNP had higher specificity for subclinical HF compared with the previously established single cut‐off 125 pg/mL. Age‐specific cut‐off for hs‐troponin T (18 ng/L) for men ≥60 years had also higher specificity than the single cut‐off 14 ng/L. These cut‐offs had high specificity, but low sensitivity, that makes hs‐troponin T and NT‐proBNP good biomarkers to rule in HF in case of a positive test, but not good enough to rule out all unrecognized HF due to false negative results. Conclusions N‐terminal pro‐brain natriuretic peptide and hs‐troponin T are suboptimal screening tools for subclinical HF in a general population due to low sensitivity.

Schizothorax esocinus, commonly known as snow trout, is one of the main contributors of food and livelihood in the colder zone of Himalayan region. The comprehensive information on its hematological and serum biochemical reference intervals is not reported yet. In the present study an attempt has been made to elucidate the hematological and serum biochemical reference intervals of S. esocinus from River Jhelum using protocols of the American Society of Veterinary Clinical Pathology (ASVCP). Wild fish were sampled over a period of 2 years from the pollution free sites of river Jhelum. Fish blood was harvested through caudal venipuncture and hemato-biochemical analysis performed thereof. Data values from a total of healthy 432 adult fish specimens (216 male, 216 female) were systematically recorded. The reference intervals for hematological and serum biochemical parameters of S. esocinus were established using Reference Value Advisor software v 2.1. RIs for hematological and serum analytes ranged as: hemoglobin (Hb) 78.38–116.35 (g/L); white blood cells (WBC) 10–20 (×109/L); red blood cells (RBC) 1.30–2.15 (×1012/L); packed cell volume 27.00–39.45 (%); total protein 39.21–61.62 (g/L); albumin 8.20–22.02 (g/L); globulin 27.58–49.55 (g/L); glucose 3.25–7.18 (mmol/L); urea 0.96—2.38 (mmol/L); cholesterol 3.80–6.90 (mmol/L). The study also depicted that certain blood measurands were influenced with respect to sex. Significantly (p < 0.05) higher values of Hb, red blood cells count and serum glucose were noted in male as compared to female which, on the other hand, registered higher white blood cells count and serum cholesterol level (Mann Whitney U test, p < 0.05). The work, therefore, provides baseline information on hematological and serum biochemical analytes of this species which holds high commercial importance. RIs reported here can help monitor the health status of fish by improving the use of non-lethal diagnostic methods in piscine medicine.

Background: Erythrocyte parameter analysis is the important means for diagnosis and treatment of hematological diseases, which are essential for screening of thalassemia in southern China combined with hemoglobin electrophoresis analysis. But little is known regarding the reference intervals (RIs) in healthy pediatrics in these two areas. Methods: 95% RIs of erythrocyte parameters were calculated from 853 healthy preschoolers, aged from 1 days to <6 years, according to the C28‐A3C guidelines of the Institute of Clinical and Laboratory Standards. To express the magnitude of sex and age variation, standard deviation ratio (SDR) was calculated using ANOVA. Concurrently, we selected 3814 thalassemia carriers as carriers group and drew receiver operating characteristic (ROC) curves to establish the optimal cut‐off values of hemoglobin electrophoresis parameters, which were used as the upper/lower limits of RIs to efficiently screen thalassemia. Results: All parameters except red blood cell (RBC) required age partitioning, confirmed by SDRage above.4. There was no need for sex partitioning on all parameters, confirmed by SDRsex below.4. The optimal cut‐off value of Hemoglobin A2 (Hb A2) in the four subgroups was <7.8% (Hb A), 2.3%–3.2%, 2.5%–3.6% and 2.6%–3.6%, respectively. Conclusion: In this study, the establishment of RIs improved the diagnostic efficiency of hematological disease (especially thalassaemia) for children in Guangxi. It provides reliable hematological references for the identification and diagnosis, treatment monitoring, and health screening of children's clinical diseases. [ABSTRACT FROM AUTHOR]

Reference ranges for bone turnover markers (BTMs) are still lacking in the healthy Chinese population. To establish reference intervals for BTMs and to investigate the correlations between BTMs and bone mineral density (BMD) in Chinese older adults. A community-based cross-sectional study was conducted among 2511 Chinese subjects aged over 50 yrs residing in Zhenjiang, Southeast China. Reference intervals for BTMs (i.e. procollagen type I N-terminal propeptide, P1NP; β cross-linked C-terminal telopeptide of type I collagen, β-CTX) were calculated as the central 95% range of all measurements in Chinese older adults. The reference intervals of P1NP, β-CTX and P1NP/β-CTX were 15.8–119.9 ng/mL, 0.041–0.675 ng/mL and 49.9–1261.5 for females and 13.6–111.4 ng/mL, 0.038–0.627 ng/mL and 41.0–1269.1 for males, respectively. In the multiple linear regression analysis, only β-CTX was negatively associated with BMD after adjusting for age and body mass index (BMI) in both sex-stratified groups (all p <.05). This study established age- and sex-specific reference intervals for BTMs in a large sample of healthy Chinese participants ≥ 50 and < 80 years of age and explored the correlations between BTMs and BMD, which provides an effective reference for the assessment of bone turnover in the clinical practice of osteoporosis. [ABSTRACT FROM AUTHOR]

Simple Summary: We explored the effect of age, gender, weight-for-height indices, sedation protocol, and housing conditions on the hematologic and serum biochemical values of captive rhesus and cynomolgus macaques. Several blood parameters demonstrated significant and clinically relevant changes in relation to the investigated variables. The results will provide veterinarians and researchers with important reference intervals for evaluating experimental results and health control from rhesus and cynomolgus macaques. Several physiological characteristics and housing conditions are known to affect hematologic and serum biochemical values in macaques. However, the studies that have been conducted either report values calculated based on a small number of animals, were designed specifically to document the effect of a particular condition on the normal range of hematologic and serum biochemical values, or used parametric assumptions to calculate hematologic and serum biochemical reference intervals. We conducted a retrospective longitudinal cohort study to estimate reference intervals for hematologic and serum biochemical values in clinically healthy macaques based on observed percentiles without parametric assumptions. Data were obtained as part of the Biomedical Primate Research Centre (Rijswijk, The Netherlands) health monitoring program between 2018 and 2021. In total, 4009 blood samples from 1475 macaques were analyzed with a maximum of one repeat per year per animal. Data were established by species, gender, age, weight-for-height indices, pregnancy, sedation protocol, and housing conditions. Most of the parameters profoundly affected just some hematologic and serum biochemical values. A significant glucose difference was observed between the ketamine and ketamine-medetomidine sedation protocols. The results emphasize the importance of establishing uniform experimental groups with validated animal husbandry and housing conditions to improve the reproducibility of the experiments. [ABSTRACT FROM AUTHOR]

Red blood cell parameters are frequently used biomarkers when assessing clinical status in newborns and in early childhood. Cell counts, amounts, and concentrations of these parameters change through gestation and after birth. Robust age-specific reference intervals are needed to optimize clinical decision making. The Copenhagen Baby Heart Study (CBHS) and the COMPARE study are prospective cohort studies including red blood cell parameters from 7,938 umbilical cord blood samples and 295 parallel venous blood samples from newborns with follow-up at two and at 14–16 months after birth. For venous blood at birth, reference intervals for hemoglobin, erythrocytes, and hematocrit were 145–224 g/L, 4.1–6.4 × 1012/L, and 0.44–0.64, respectively. Hemoglobin, erythrocytes, and hematocrit were lower at birth in children delivered by prelabor cesarean section compared to vaginal delivery. Conversion algorithms based on term newborns were: venous hemoglobin=(umbilical cord hemoglobin˗86.4)/0.39; venous erythrocytes=(umbilical cord erythrocytes-2.20)/0.44; and venous hematocrit=(umbilical cord hematocrit-0.24)/0.45. This study presents new reference intervals for red blood cell parameters in early childhood, describes the impact of delivery mode, and provide exact functions for converting umbilical cord to venous blood measurements for term newborns. These findings may improve clinical decision making within neonatology and infancy and enhance our clinical understanding of red blood cell parameters for health and diseases in early life. [ABSTRACT FROM AUTHOR]

The aim of this study was to harmonize the criteria for the Bhattacharya indirect method Microsoft Excel Spreadsheet for reference intervals calculation to reduce between-user variability and use these criteria to calculate and evaluate reference intervals for eight analytes in two different years. Anonymized laboratory test results from outpatients were extracted from January 1st 2018 to December 31st 2019. To assure data quality, we examined the monthly results from an external quality control program. Reference intervals were determined by the Bhattacharya method with the St Vincent's hospital Spreadsheet firstly using original criteria and then using additional harmonized criteria defined in this study. Consensus reference intervals using the additional harmonized criteria were calculated as the mean of four users' lower and upper reference interval results. To further test the operation criteria and robustness of the obtained reference intervals, an external user validated the Spreadsheet procedure. The extracted test results for all selected laboratory tests fulfilled the quality criteria and were included in the present study. Differences between users in calculated reference intervals were frequent when using the Spreadsheet. Therefore, additional criteria for the Spreadsheet were proposed and applied by independent users, such as: to set central bin as the mean of all the data, bin size as small as possible, at least three consecutive bins and a high proportion of bins within the curve. The proposed criteria contributed to the harmonization of reference interval calculation between users of the Bhattacharya indirect method Spreadsheet. [ABSTRACT FROM AUTHOR]