Reference Range Research Articles

Harmonized Tubular Maximum Phosphate Reabsorption per Glomerular Filtration Rate (TmP/GFR) reporting in adults and children in Australia and New Zealand

Abstract Tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR) is a key diagnostic test for renal phosphate wasting. However, there is a lack of international consensus regarding the reporting of age-related reference intervals. The TmP/GFR Harmonization Working Group, formed by The Australasian Association for Clinical Biochemistry and Laboratory Medicine and The Australian and New Zealand Bone and Mineral Society, aimed to evaluate analytical differences amongst commercial creatinine and phosphate assays, harmonize age-specific cut-offs and compare the ANZBMS TmP/GFR online calculator with existing products. A total of 11 360 results from The Royal College of Pathologists of Australasia Quality Assurance Programs were analyzed to assess creatinine and phosphate assay performance amongst five In Vitro Diagnostic (IVD) companies. Ortho-Clinical Diagnostics analyzers had a positive bias of up to 32% for serum phosphate and up to 29% for TmP/GFR. The other IVD companies produced comparable results and are suitable for harmonized reference intervals. To date, the AACB-ANZBMS TmP/GFR online calculator is the only validated Isotope Dilution Mass Spectrometry-creatinine aligned tool which caters for both pediatric and adult individuals, providing automatic interpretive comments to aid clinicians managing patients with hypophosphatemia.

Serum Transcobalamin Concentration in Cats—Method Validation and Evaluation in Chronic Enteropathies and Other Conditions

Hypocobalaminemia is common in cats with chronic enteropathy (FCE). However, the disruptions in cobalamin metabolism are not fully understood and may vary across species. Cobalamin is distributed to target tissues via binding to transcobalamin (TC) in blood, which has not been evaluated in cats. Thus, an in-house sandwich-ELISA was established to evaluate serum total TC concentrations in cats with FCE. Surplus sera served to analytically validate the assay, and serum TC concentrations were compared among cats with FCE and other diseases (gastrointestinal neoplasia, cholangiohepatopathy, and other neoplastic or non-neoplastic conditions) and healthy controls. Observed-to-expected ratios for serial dilutions ranged from 72.4 to 145.6% and were 75.1–126.7% for spiking-and-recovery. Intra- and inter-assay variability was <17.7% and <17.2% and the preliminary reference interval for feline serum TC was <160–2795 aU/L (lower detection limit: 160 aU/L). Serum TC levels were significantly decreased (p = 0.0067) but not correlated with paired cobalamin concentrations in FCE. Hypertranscobalaminemia predominated with hypercobalaminemia, reaching the highest levels in advanced-stage chronic kidney disease (CKD) cases. TC variations in cobalamin deficiency states with FCE may be linked to inflammation or autoantibodies. This and possible links between serum TC variation in FCE, intracellular cobalamin availability, response to supplementation, and concurrent CKD require further exploration.

Comparison of the effectiveness of drug therapy and non-drug technology of post-COVID rehabilitation of workers with intensive computer load

Currently, there is sufficient evidence of the importance and clinical effectiveness of non-drug therapy. The scientific discussion on the priority of the clinical application of pharmacological and non-pharmacological methods of rehabilitation of patients with mononeuropathies has acquired particular importance against the background of neurological post-COVID complications in patients with COVID-19. The study aims to compare the effectiveness of drug therapy and non–drug technology of post-covid rehabilitation of workers with intensive computer workload based on the study of clinical and laboratory parameters. Scientists have conducted a survey of two groups of workers with intensive computer workload who underwent rehabilitation after COVID-19 with the use of drug therapy and non-drug technologies, including balneotherapy, drinking narcotherapy, aerosol inhalations, low-frequency magnetic therapy. The authors have evaluated the effectiveness of therapy based on the results of studies of asthenization, degree of fatigue, latent coronary insufficiency, the state of the blood microcirculation system, immune status, the state of the POL-AOSIS system and endogenous intoxication of patients. Asthenization, the degree of fatigue, and latent coronary insufficiency decreased in the majority of the examined patients after post-COVID non-drug measures. Whereas in patients of the drug group, a decrease in these indicators was noted in a small number of examined patients. The indicators of the immune status of patients after non-drug therapy returned to normal, after drug therapy they only approached the limits of the norm, but did not reach it. After the treatment, the indicators of lipid peroxidation in the group of patients undergoing post-COVID rehabilitation using non-drug technologies decreased more significantly than in the group receiving drug treatment. The content of the antioxidant enzymes catalase and ceruloplasmin and the fat-soluble antioxidant α-tocopherol after treatment increases in both groups, but in the group of drug treatment they do not reach the lower limit of the reference intervals. The decrease in the content of medium-molecular peptides is more pronounced when using non-drug technologies. The application of the proposed non-drug technology for the rehabilitation of patients with post-COVID syndrome who are subjected to intense computer loads during work showed a significantly more pronounced normalization of asthenization, fatigue, latent coronary insufficiency and the state of the blood microcirculation system, immune status, the state of the POL-AOSIS system and endogenous intoxication of patients. The data obtained indicate a high therapeutic effect of the use of non-drug technology. Limitations. The surveyed groups included only persons permanently registered in Kislovodsk. Ethics. The research was conducted in accordance with the principles of biomedical ethics and approved by the local Ethics Committee of the Izmerov Research Institute of Occupation Health, Moscow (Protocol No. 4 dated 04/14/2021). Each participant of the study submitted a voluntary written informed consent signed by him after explaining to him the potential risks and benefits.

Arginine Vasopressin Deficiency Heralding Rosai-Dorfman Disease With Neurological Manifestations

Abstract Rosai-Dorfman disease (RDD) is a rare heterogeneous disorder of non–Langerhans cell histiocytosis. The patient is a 24-year-old woman who presented with a 1-month history of polydipsia, polyuria, and 25-lb (11.3-kg) weight loss over 6 months and was found to have significantly elevated 24-hour urine volume (8.4 L). Prior to completion of the work-up for her presenting symptoms, she returned with a new complaint of disabling back pain and bilateral lower-extremity numbness with weakness refractory to conservative treatment. Magnetic resonance imaging (MRI) showed a prominent T2 to T4 stenosis from a soft tissue mass. Due to progressive pain and accelerating neurological symptoms, she was admitted for surgical debulking and biopsy. In the 10 hours she was unable to drink fluids surrounding her procedure, her serum sodium climbed to 160 mmol/L (reference interval, 137-145 mEq/L; [137-145 mmol/L]). Urine testing and desmopressin challenge revealed arginine vasopressin deficiency (AVP-D), formerly known as central diabetes insipidus. Pituitary MRI showed a mildly enlarged pituitary gland with loss of normal posterior pituitary signal supporting the diagnosis. Epidural mass pathology showed predominant histiocytes indicating RDD. This case highlights the diverse clinical manifestations of RDD and is an unusual instance of RDD linked with AVP-D and neurological involvement.

Redivision of reference intervals of the red blood cell distribution width in a healthy Chinese population based on natural geographic environment

Revealing the spatial distribution and regional differences of red blood cell distribution width (RDW) reference values in the healthy Chinese population is important for the monitoring, diagnosis and prevention of the top chronic diseases in the disease spectrum in China. Medical indicator data were matched with geographical data and environmental pollution data to predict RDW reference values for the whole region of China using ridge regression analysis, support vector machine and BP neural network. Taylor diagrams and assignment methods were used to select the optimal model, and the spatial distribution was mapped according to the prediction results of the optimal model, and the intervals of RDW reference values for different age groups of healthy people in China were redefined. It was suggested that the reference values of RDW in the young and middle-aged groups in China were divided into low-value areas in the north (12.31,12.80) and high-value areas in the south (12.80,13.18); the reference values of RDW in the elderly group were divided into low-value areas in the north (11.28,12.60) and high-value areas in the south (12.60,13.91).In turn, it can provide a more accurate reference basis in the monitoring, diagnosis and prevention of chronic diseases at the top of the disease spectrum.

Serum Glutamate dehydrogenase activity enables sensitive and specific diagnosis of hepatocellular injury in humans.

Serum activities of alanine- and aspartate- aminotransferases (ALT and AST) are considered the "gold standard" biomarkers of hepatocyte injury in clinical practice and drug development. However, due to expression of ALT and AST in myocytes, the diagnosis of hepatocellular injury in patients with underlying muscle diseases, including drug-induced muscle injury, is severely limited. Thus, we proposed glutamate dehydrogenase (GLDH) as a liver-specific alternative to serum ALT and AST. In fact, our exploratory studies showed that GLDH has comparable performance to ALT for detecting hepatocyte injury without interference from concomitant muscle injury. Here, we report the results of studies confirming the reference intervals in a healthy human population and sensitivity and specificity of GLDH for detection of hepatocyte injury in human subjects. In human subjects, we could not perform liver biopsies due to ethical reasons, we also confirmed the relationship of GLDH and histopathologic lesions using 32 model toxicants in rats. Furthermore, we have shown that injury to tissues that are known to express appreciable levels of GLDH does not affect serum GLDH measurements, indicating excellent liver specificity of serum GLDH. Finally, we observed faster elimination of GLDH than ALT in humans, indicating that decreasing GLDH values could be considered an early sign of recovery. This study provides comprehensive evidence of excellent sensitivity and liver specificity of GLDH for diagnosis of hepatocellular injury, including evaluation of reference intervals that is essential for interpretation of serum GLDH in human subjects.

Disseminated Neospora caninum Encephalomyelitis and Myositis in a 3-Month-Old Cane Corso Puppy

We present a case of fatal disseminated neosporosis in a 3-month-old Cane Corso puppy. The puppy presented to the Purdue Veterinary Hospital emergency service with a 1-week history of progressive left hindlimb lameness. On presentation, the puppy was nonambulatory paraparetic. Signs progressed over two days to nonambulatory tetraparesis, and decreased to absent limb reflexes, cranial nerve deficits, and dull mentation. Blood work showed eosinophilia, elevated ALT, and extremely elevated creatine kinase at 36,000 IU/L (reference interval 22–491 IU/L). Two days after diagnostics were performed, the puppy experienced acute cardiac arrest, and the body was submitted for necropsy. At necropsy, skeletal muscle in all four limbs was diffusely pale tan. Tan streaks were disseminated through the diaphragm, abdominal wall, and myocardium. Histologically, Skeletal myocytes and cardiomyocytes were frequently degenerative, with abundant lymphohistiocytic inflammation and fibrosis. White matter within the brain and spinal cord was inflamed and contained frequent dilated myelin sheaths and spheroids. A few protozoal cysts were within the brain and skeletal myocytes. Antemortem antibody titers were positive for IgG against Neospora caninum (dilution titer of 1:4096, baseline 1:32), confirming protozoal cysts as Neospora caninum. Disseminated neosporosis is an uncommon but important clinical differential for ascending paresis in young dogs.

Reference Interval for Calcium among Libyan Healthy Individuals

The goal of this study was to determine the reference intervals (RIs) of calcium levels (Ca) in the blood of Libyan individuals. Blood samples were obtained from 120 healthy males and females through aseptic venipuncture. Informed consent was obtained prior to sample collection. Serum was extracted from the centrifuged samples and analyzed spectrophotometrically to determine calcium concentrations. The non-parametric percentile method was applied to establish the RIs of calcium, results showed the reference period is 7.8- 10.1 mg/dl. The study establishes RIs for serum calcium concentration between 7.8 mg/dl and 10.1 mg/dl in the Libyan population. These findings underscore the importance of developing geographically specific RIs, as RIs derived from manufacturer's kits or other populations may not accurately reflect the unique characteristics of the Libyan population. The RIs identified in this study are more relevant and appropriate for the Libyan context.

Hematologic and biochemical reference values for anesthetized juvenile German crossbred farm pigs

Juvenile crossbred pigs are widely used for acute and chronic animal testing due to their anatomical and physiological resemblance to humans. They are particularly prevalent in preclinical cardiovascular research, including studies investigating extracorporeal resuscitation and mechanical circulatory support devices. However, the availability of comprehensive laboratory reference values is limited. In a single-center study at the University Medical Center Freiburg, Germany, the hematologic and biochemical laboratory values of anesthetized healthy juvenile German crossbred farm pigs were determined. Blood samples were collected at the beginning of surgical procedures, either arterially or venously. Females and males were compared, and correlation with body weight was assessed. In total, 268 animals (weight 57.8 ± 12.4 kg) were included, thereof 180 castrated males (55.2 ± 7.7 kg) and 79 females (63.6 ± 18.3 kg). There were significant differences between males and females in 11 of 45 parameters and a moderate correlation between body weight and creatinine (R = 0.41, p < 0.001). The reference intervals and insights into sex and body weight correlations enhance the utility of healthy juvenile German crossbred farm pigs in translational research, providing a robust reference for future studies.

Biological variation and analytical performance specification study of erythrocyte and related parameters

Objective: To study biological variation (BV) and analytical performance specifications (APS) of 15 erythrocyte and related parameters. Methods: Sixty healthy participants from Beijing Hospital were prospectively recruited for the study, from July to December, 2023, including 30 males [aged (41.3±11.9) years] and 30 females [aged (40.3±12.4) years]. The study was designed based on the Biological Variation Data Critical Appraisal Checklist and the characteristics of erythrocyte detection. Whole blood samples were collected 10 times at 2-week intervals during 20 weeks. All samples were tested in duplicate using Mindray BC-7500 hematology analyzer and its accompanying reagents. Within-subject biological variation (CVI) and between-subject biological variation (CVG) were estimated by the nested ANOVA method. The BV data in this study were compared with the BV data of the European Database of Biological Variation. APS, reference change value (RCV) and index of individuality (II) were calculated. Results: The CVI for 15 parameters ranged from 0.49% to 86.46%, and the CVI data for red cell distribution width (RDW)-CV, RDW-SD, reticulocyte (RET) percentage, RET count, reticulocyte hemoglobin content (RHE), medium fluorescence reticulocyte (MFR) and high fluorescence reticulocyte (HFR) were significantly higher in females than in males (all P<0.05). The CVG ranged from 1.27% to 100.79%, and the CVG data for HFR were significantly different between genders (P<0.05). The CVI data for red blood cell (RBC), hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC) and RHE in this study were lower than those recommended by the European database. The derived indicators of most parameters were influenced by gender. The II values for all parameters were<1.4, where the II values of MCHC and HFR were between 0.6 and 1.4; the II values for the remaining 13 parameters were<0.6. Conclusions: A BV study protocol for erythrocyte parameters is designed. When the reference intervals differ between genders, BV data should be calculated separately and the lower BV data are recommended for calculating APS; the RCV should be set separately for each gender.

Interpretation of reference intervals and clinical decision limits

Reference intervals (RI) and clinical decision limits (CDL) are an important part of th e medical information needed to interpret the results of a laboratory tests. The emphasis is on the need to distinguish between the two concepts. RI allows to assess the compliance of the patient’s result with the values detected in a healthy population with a certain probability. CDL is associated with specific diseases and medical risks and may be more significant for clinical decision-making than RI. When interpreting RI and CDL, it is necessary to take into account the possibility of divergence of results on different analytical systems as a potential source of erroneous medical decisions.

Reference TSH intervals in children and adolescents

The determination of thyroid-stimulating hormone (TSH) is a reliable test in the diagnosis of thyroid dysfunction. When interpreting the results of quantitative studies, clinicians and laboratory specialists most often resort to assessing the compliance of the result with reference intervals (RI). At the same time, each laboratory must determine them for the analytes being measured itself, based on the characteristics of the examined contingent, the characteristics of the analytical systems used, achieving the necessary diagnostic effectiveness of the methodology, and its own practical and economic capabilities. A retrospective analysis of TSH results obtained from patients under the age of 19 years was performed for 54970 patients without hypothyroidism, thyrotoxicosis and pituitary disorders. For this work, reagent kits “Roche Cobas”, “Mindray” and “Beckman Coulter” (ICLA) were used. As a result, RI was established for the study of TSH for three sets of reagents with appropriate equipment and for four age groups: 1 day – 6 months, 6 months – 7 years, 7–14 years, 14–19 years. This makes it possible to use RI as a screening for possible developmental pathology in childhood and to determine the limits of clinical decisions.

Echocardiographic estimates of stroke volume in healthy dogs: Comparability, reference intervals, and reproducibility

Introduction/Objectives: To compare estimates of stroke volume (SV) from different anatomic sites and to generate reference intervals for indices such as shunt volume (ShuntVol) or regurgitant volume (RegVol) in a large sample of healthy dogs. Animals, Materials and MethodsNinety healthy dogs underwent an echocardiogram where SV was assessed at the level of the pulmonary valve (SVPV), aortic valve (SVAV), mitral valve (SVMV), and left ventricle using the difference in end-diastolic volume and end-systolic volume from a right parasternal long-axis four-chamber view (SVLV_RPLx) and left apical four-chamber view (SVLV_Ap4Ch). Eight dogs underwent repeated echocardiograms by the same operator on three different days and by three different operators on the same day. Bland-Altman plots and 95% reference intervals were generated. Reproducibility was described using coefficients of variation (CV) and reproducibility coefficients. ResultsMean difference (95% limits of agreement) for ShuntVol (SVPV-SVAV), RegVolLV_RPLx (SVLV_RPLx-SVAV), RegVolLV_Ap4Ch (SVLV_Ap4Ch-SVAV), and RegVolMV (SVMV-SVAV) were: -0.14 (-0.72, 0.44), -0.05 (-0.59, 0.48), -0.16 (-0.71, 0.39), and 0.12 (-0.76, 1.00) mL/kg, respectively. All but RegVolLV_RPLx showed significant (P<0.01) fixed bias. Reference intervals for ShuntVol, RegVolLV_RPLx, RegVolLV_Ap4Ch, and RegVolMV were: -0.85-0.64, -0.65-0.58, -0.77-0.52, and -0.91-1.06 mL/kg, respectively. Intra-operator and inter-operator CVs were lowest for SVAV, and highest for SVMV and SVLV_AP4Ch, respectively. ConclusionsEchocardiographic estimates of SV are not interchangeable and can exhibit wide limits of agreement. Reference intervals help provide a frame of reference to assess disease severity in dogs with a shunting lesion (ShuntVol) and mitral regurgitation (RegVol).

Glycated albumin in pregnancy correlates negatively with body mass index and contributes to the risk of gestational diabetes mellitus

ObjectivesThe 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). Designand 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. ResultsThe 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. ConclusionGA 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.

Suspicious of Acute Kidney Graft Rejection: Tacrolimus Pharmacokinetics Under Methylprednisolone Therapy.

Acute rejection remains one of the main complications in the first months after transplantation and may influence long-term outcomes. Tacrolimus has proven its usefulness in solid organ transplants and its monitoring through the application of pharmacokinetic concepts to optimize individual drug therapy. This research proposes to evaluate the tacrolimus pharmacokinetic parameters in patients suspected of acute kidney graft rejection under methylprednisolone pulse therapy. Eleven adult tacrolimus-treated renal recipients were selected from a prospective, single-arm, single-center cohort study, with suspicion of acute rejection although in use of methylprednisolone pulses therapy. They were followed up for three months posttransplantation, being tacrolimus trough serum concentrations determined using a chemiluminescent magnetic immunoassay, and pharmacokinetic parameters were estimated by using a nonlinear mixed-effects model implemented by Monolix 2020R1. A tacrolimus trough serum concentration range of 8 to 12 ng.mL-1 was considered therapeutic. Six patients showed acute cellular rejection, and two of them in addition had an antibody- mediated rejection. Tacrolimus trough serum concentration was below the reference range in eight patients. Most patients showed a high tacrolimus concentration intrapatient and pharmacokinetic parameters variability. The obtained pharmacokinetics parameters helped in understanding the kidney recipient patients' tacrolimus behavior, assisting in the improvement of individual drug therapy and reducing the risk of acute rejection episodes.

Age-dependent haemogram and sex-dependent serum biochemistry values in semi-feral Konik horses.

Semi-feral, free-roaming Konik polski horses are used in some European countries for preserving semi-open pasture landscapes. The estimation of their health status is still limited by insufficient data on various blood parameters. Therefore, our study aimed at the sex- and age-dependent analysis of haemogram and selected biochemistry parameters in healthy, semi-feral Koniks. In order to reach this aim, we took blood samples from 53 female and 18 male (8 uncastrated, 10 castrated) Koniks living in two Middle German nature reserves. They were of different age (9-266 months) and without signs of illness. Blood samples were analysed by an accredited laboratory. We identified age- but not sex-dependent changes in the white blood cell count (WBC). Higher age mainly caused a decrease in lymphocytes. Therefore, WBC correlated negatively and granulocyte-to-lymphocyte ratio positively with increasing age. Serum values of selected biochemical parameters did not depend on age but showed some sex-related differences. In this regard, serum total protein, triglyceride and the enzymatic activities of alkaline phosphatase, aspartate transaminase and g-glutamyltransferase were higher in males than females. However, the sex dependency of these enzymatic activities was restricted to uncastrated males. They also showed higher serum values for calcium and selenium than castrated males or all females. As far as the respective group sizes permitted, we then calculated age- or sex-dependent reference interval values for all parameters analysed. These values improve now the estimation of the health status of semi-feral, free-roaming Konik horses and provide a stable basis for future studies.

Morphometric Evaluation of the Thoracic and Lumbar Vertebral Canal and Spinal Cord Using Computed Tomography in Healthy Korean Shorthair Cats.

This study aimed to evaluate the spinal morphometry of the thoracic and lumbar regions in normal Korean Shorthair cats using computed tomography (CT) and to investigate the relationship with variables such as sex, age and body weight. Fifteen clinically healthy Korean Shorthair cats (eight males, seven females) from Seoul National University Veterinary Medical Teaching Hospital were included in this retrospective study. Measurements of the height, width and area of the vertebral canal and spinal cord on CT images were taken at the cranial, middle and caudal points of the thoracic and lumbar vertebrae by three observers, and the ratios of the spinal cord area to the vertebral canal area were calculated. The significance of the differences in measurements between sexes and correlations with age and body weight were analysed. The mean age of the cats was 7 years (range: 2-12 years), with a mean weight of 5.27 kg (range: 2.6-8.3 kg). The height, width and area of the vertebral canal and spinal cord were significantly greater in males than in females (p < 0.05). The ratios of the spinal cord area to the vertebral canal area showed no significant difference between sexes (p > 0.05), and no significant correlations were found between the ratios of the spinal cord area to the vertebral canal area and age or body weight. This study provides useful reference intervals for spinal morphometry in the thoracic and lumbar regions of healthy Korean Shorthair cats and investigate the relationship with variables such as sex, age and body weight. This anatomical information may assist in the diagnosis and prognosis of thoracic, lumbar vertebral and spinal cord diseases using CT.

Application of composite reference intervals in the diagnosis of subclinical hypothyroidism in the elderly: a retrospective study.

Thyroid stimulating hormone releasing hormone (TSH) is a key indicator for diagnosing subclinical hypothyroidism (SCH). We evaluated factors affecting TSH levels in elderly SCH, establishing a composite reference interval, and comparing it with traditional one in diagnosis. We collected data on patients aged ≥60 undergoing physical examinations in Chengdu, screening the influencing factors associated with TSH. Then, a two-dimensional composite reference interval was established for TSH and FT4, and the differences between the new and traditional diagnosing methods were compared. The incidence of subclinical thyroid dysfunction was about 14%, with SCH accounting for 97%. Regression analysis found that TSH levels increase as FT4 and uric acid levels decrease. Compared with the two-dimensional composite reference interval, the traditional one has a higher incidence rate of SCH. Compared with the two-dimensional composite reference interval, the traditional one is more likely to overestimate the incidence rate of SCH, leading to excessive diagnosis and treatment.

Reference values for plasma and urine trace elements in a Swiss population-based cohort.

Trace elements (TEs) are ubiquitous. TE concentrations vary among individuals and countries, depending on factors such as living area, workplaces and diet. Deficit or excessive TEs concentrations have consequences on the proper functioning of human organism so their biomonitoring is important. The aim of this project was to provide reference values for TEs concentrations in the Swiss population. The 1,078 participants to the SKiPOGH cohort included in this study were aged 18-90 years. Their 24-h urine and/or plasma samples were analyzed by inductively coupled plasma mass spectrometry (ICP-MS) to determine 24 TEs concentrations: Ag, Al, As, Be, Bi, Cd, Co, Cr, Cu, Hg, I, Li, Mn, Mo, Ni, Pb, Pd, Pt, Sb, Se, Sn, Tl, V and Zn. Statistical tests were performed to evaluate the influence of covariates (sex, age, BMI, smoking) on these results. Reference intervals for the Swiss adult population were also defined. TEs concentrations were obtained for respectively 994 and 903 persons in plasma and urine matrices. It was possible to define percentiles of interest (P50 and P95) for almost all the TEs. Differences in TEs distribution between men and women were noticed in both matrices; age was also a cofactor. This first Swiss biomonitoring of a large TEs-panel offers reference values in plasma and in urine for the Swiss population. The results obtained in this study were generally in line with clinical recommendations and comparable to levels reported in other population-based surveys.

Estimating reference intervals from an IPD meta-analysis using quantile regression

BackgroundReference 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.MethodsWith 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.ResultsWe 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. ConclusionWe 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.