Accurate Reference Intervals Research Articles

Serum Lipid Profile and Electrolytes Reference Intervals for Apparently Healthy Children and Adolescents in Addis Ababa, Ethiopia.

Accurate reference intervals generated from an apparently healthy population and stratified by crucial variables such as age and gender are required to guarantee appropriate interpretation of test results. Since there were no local reference intervals in the study area, the present study aimed to establish reference intervals on serum lipid profiles and electrolytes for children and adolescents in Addis Ababa. This community-based cross-sectional study was conducted from April to October 2019. Laboratory analysis was performed using the automatic biochemical analyzer Cobas 6000 (c501) from Roche. According to Clinical and Laboratory Standards Institute (CLSI) guidelines, reference intervals for lipid profile and electrolyte tests for apparently healthy children and adolescents were established. We used a non-parametric method to calculate the 2.5th and 97.5th percentiles with a 90% confidence interval. In children, the reference intervals for serum potassium, sodium, chloride, calcium, magnesium, and phosphate in mmol/L were 4.37-5.20, 137-145.50, 101.90-107.90, 2.34-2.70, 0.74-0.97, and 1.42-1.85, respectively; and for total cholesterol, triglycerides, low-density lipoprotein, and high-density lipoprotein, the respective values were 100.76-171.70, 44.16-126.36, 60.60-105.60, and 31.60-53.70 in mg/dL, for both genders. For adolescents, the reference intervals were 4.03-5.58, 137-146, 98.90-120.90, 2.39-2.70, 0.73-0.96, and 0.96-1.80 for serum potassium, sodium, chloride, calcium, magnesium, and phosphate in mmol/L, respectively; and 97.20-189.10, 40.50-143.60, 41.70-120.90, and 21.30-57.0 in mg/dL for total cholesterol, triglycerides, low-density lipoprotein, and high-density lipoprotein, respectively, for both genders. The established reference intervals in the current study revealed that both the lower and upper limits contradicted the manufacturer values as well as the available literature. The study also discovered significant gender differences in reference values for TC, TG, LDL-C, potassium, phosphate, and chloride in the adolescent age groups.

Exchangeable serum copper: Adult and pediatric reference intervals and in vitro stability in a nordic cohort

Wilson disease (WD) is a rare genetic disorder characterized by copper overload, primarily affecting the liver and brain, and the organ damage is believed to be caused by non-ceruloplasmin-bound copper (NCC). Accurate and early diagnosis is important for prognosis. Recently, a method for the measurement of NCC, exchangeable serum copper (CuEXC), was developed and shown to be a promising marker of WD, especially as the fraction of total copper, relative exchangeable copper (REC). This study aimed to validate the CuEXC extraction method and establish reference intervals for CuEXC and REC, as well as to examine short- and long-term stability of CuEXC in serum samples.The adult reference interval for CuEXC was 0.61–1.62 µmol/L and for REC 3.0–9.7 % based on 120 blood donors. Based on 88 children, the reference intervals for CuEXC was 0.45–1.16 µmol/L. The intervals for REC were 1.8–5.8 % for children <10 years and 2.3–8.5 % for children ≥10 years. Regarding stability, CuEXC increased following a logarithmic scale in uncentrifuged serum and exceeded the permissible difference of 10 % after 4 h. With long-term freezing at −20 °C, CuEXC was stable for 1.7 months.In conclusion, reference intervals for CuEXC and REC were established and confirmed to be substantially lower in children. Accurate reference intervals are important to ensure timely diagnosis of WD. Finally, our findings on stability have important implications and highlight the need for standardization of the pre-analytical handling of CuEXC samples in order to obtain comparable results within and between laboratories both for clinical and research use.

269. Reference Data of Biochemical and Hematology Parameters in Juvenile and Adult Owl Monkeys (Aotus nancymaae) for Biomedical Research

Abstract Background Non-human primates (NHP), including New World monkeys (NWM), are used in varied fields of biomedical research encompassing infectious disease, behavioral sciences and drug and vaccine development. In these studies, normal reference values for biochemical and hematological parameters are often needed for comparison with experimental results. These blood parameters are useful guides in reaching a diagnosis, estimating the prognosis of the disease and monitoring the progress of treatment. Although there are various reports of biochemical and hematologic parameters in Old World monkeys, the range of reference values often differs between NHP species. Despite the importance of NWMs such as Aotus nancymaae in biomedical research, few studies have examined these values and with a limited number of animals only. A. nancymaae is widely used for research and often used to study the principal types of human malaria (P. falciparum and P. vivax). These primates have also been used to study leishmaniasis, schistosomiasis, tuberculosis and various types of enteric infections. Furthermore, in recent years oral challenge models have been developed in A. nancymaae for Campylobacter jejuni, Shigella flexneri, and Enterotoxigenic Escherichia coli (ETEC). However, there is no updated data on biochemical and hematological parameters for A. nancymaae. Therefore, the aim of this study was to provide complete and accurate reference intervals of biochemical and hematological values to assess the health status indices of A. nancymaae housed in a vivarium prior to their use. Methods To characterize these parameters, a total of 1250 blood samples (1003 from juvenile and 247 from adult monkeys) were analyzed between 2007 to 2022. A total of 14 biochemical and 20 hematology parameters were measured. Results A significant change was observed in the values of alkaline phosphatase (ALP), potassium (K+), glucose (GLU), blood urea nitrogen (BUN), creatinine (CRE), hemoglobin (HGB) and lymphocyte (LYM) in relation to sex and age. Conclusion In conclusion, this work establishes a comprehensive and systematic reference of serum biochemical and hematological parameters for A. nancymaae based on a large cohort which can be used to inform and guide future studies utilizing this animal model. Disclosures All Authors: No reported disclosures

A-032 Comparative Serum Free Thyroxine Measurements between Immunoassays and ID-LC/MS/MS Procedure Based on Equilibrium Dialysis

Abstract Background Serum free thyroxine (FT4) measurement is one of the most important clinical laboratory tests for diagnosis and classification of thyroid disorders. Currently serum FT4 is commonly measured with Immunoassays (IAs) in patient care. However, there are concerns about the accuracy of FT4 IAs. A reference measurement procedure (RMP) for FT4 based on well-defined equilibrium dialysis (ED) of serum has been established for standardization of routine FT4 IAs. As FT4 RMP is not intended for routine clinical application, in the current study, we aim to develop a high-throughput routine FT4 method based on ED-isotope dilution liquid chromatography tandem mass spectrometry (ED-ID-LC/MS/MS). FT4 RMP was used as a reference to evaluate the measurement accuracy of our ED-ID-LC/MS/MS method and an IA method, respectively. Methods FT4 in dialysate was isolated from protein-bound T4 in serum by using a commercially available micro-ED plate after 18-h ED. The 13C6 labeled T4 was added into dialysate as an internal standard. FT4 in dialysate was purified with 96-well C18 SPE plate. FT4 in the dialysate samples was analyzed by using LC/MS/MS. The T4 certified primary reference material (IRMM-468) was used for assay calibration. FT4 IA measurement was conducted in clinical analyzers (Roche e411). A set of 40 single donor sera, covering a FT4 concentration range of 11.2–32.1 pmol/L were measured by IA and our ED-ID-LC/MS/MS, respectively. Deming regression analysis was performed to compare the results obtained by these two methods with the reference values assigned by FT4 RMP. Results The described high-throughput method based on ED-ID-LC/MS/MS could simultaneously quantified T4, T3, reverse triiodothyronine (rT3) in the dialysate within 4.5 min. The linear range of the routine FT4 assay covered 1–100 pg/mL. The assay sensitivity allowed detection of 0.3 pg/mL FT4 in serum, which is sufficient for FT4 measurement in clinically relevant ranges including hypothyroid patient samples. The throughput of the ED-ID-LC/MS/MS method could be further improved by application of automated liquid handling system. Deming regression analysis showed good agreement between RMP and the routine ED-ID-LC/MS/MS method with a slope close to 1 (P &amp;gt; 0.05) and an intercept close to 0 (P &amp;gt; 0.05), indicating that the results generated from the platform of high-throughput ED-ID-LC/MS/MS could be tracible to FT4 RMP. However, proportional bias (P &amp;lt; 0.05) with slope of 0.74 and constant bias (P &amp;lt; 0.05) with intercept of 2.6 was observed between RMP and IA tested, indicating calibration bias should be addressed to standardize IA. Conclusion In summary, the accuracy, sensitivity, and throughput of ED-ID-LC/MS/MS method are appropriate for FT4 measurements in clinical laboratories and in large epidemiologic studies to establish accurate reference intervals for FT4. Population data generated by FT4 ED-ID-LC/MS/MS method will support the use of standardized FT4 measurements.

Chinese Economic Growth Projections Based on Mixed Data of Carbon Emissions under the COVID-19 Pandemic

Current research on carbon emissions and economic development has tended to apply more homogeneous low-frequency data to construct VAR models with impulse responses, ignoring some of the sample information in high-frequency data. This study constructs a MIDAS model to forecast GDP growth rate based on monthly carbon emission data and quarterly GDP data in the context of the COVID-19 pandemic. The results show that: (1) The MIDAS model has smaller RMSE than the VAR model in short-term forecasting, and provides more stable real-time forecasts and short-term forecasts of quarterly GDP growth rates, which can provide more accurate reference intervals; (2) China’s future macroeconomic growth rate has recently declined due to the impact of the sudden epidemic, but the trend is generally optimistic. By improving urban planning and other methods, the authorities can achieve the two-carbon goal of carbon capping and carbon neutrality at an early date. In the context of the impact of COVID-19 on China’s economic development, we need to strike a balance between ensuring stable economic growth and ecological protection, and build environmentally friendly cities, so as to achieve sustainable economic and ecological development and enhance human well-being.

Radiographic Reference Intervals for Cardiac Size in Common Mynahs (Acridotheres tristis).

Cardiovascular diseases in the common mynah (Acridotheres tristis) often go undiagnosed due to limitations with the physical examination and common concurrent illnesses. The aim of this study was to establish accurate reference intervals for cardiac size based on radiographs for this species. All birds were considered healthy based on physical examination. High-quality ventrodorsal radiographic images were obtained from 34 healthy common mynah birds. The cardiac width (CW), thoracic width, distance between third and fourth ribs, synsacral width, coracoid width, and distance between clavicular bones were evaluated on the ventrodorsal radiographic images. Additionally, the ratio between the CW and these anatomical indices were measured. In order to evaluate the correlation between CW and the radiographic indices, a linear regression model was used. The mean ± SD for CW in the 34 birds was 16.1 ± 0.9 mm (95% confidence interval: 14.1-18 mm). Significant moderate correlation was found for CW with thoracic width (R2 = 0.37; P < 0.001), coracoid width (R2 = 0.25; P = 0.002), and the distance between the third and fourth ribs (R2 = 0.34; P < 0.001). The radiographic reference intervals calculated in this study can be used to evaluate cardiac size in the common mynah bird.

Reference intervals of complete blood count parameters for individuals aged 80 to 89 years in Guizhou, China: A STROBE-compliant retrospective study.

The reference intervals of complete blood count (CBC) parameters were commonly based on healthy individuals aged 20 to 79 years. However, these values are not optimal for correct clinical diagnosis in older individuals (e.g., 80–89 years). Although the reference intervals for this age group have been reported in China, there is no population-based report in Guizhou province. A total of 481 healthy adults (238 males and 243 females) aged 80 to 89 years were recruited from Affiliated Hospital of Zunyi Medical University in Guizhou. The CBC parameters were detected by Sysmex XN-9000 automatic hematology analyzer. The reference intervals of the components were analyzed according to the guidelines of International Federation of Clinical Chemistry. This study reported the reference intervals of CBC parameters. There were significant differences were examined in some reference intervals between the different gender groups, especially for RBC-related parameters. Compared with national standards, the most of all conventional reference intervals for CBC parameters were decreased. The present study provided the local reference intervals of CBC parameters for individuals aged 80 to 89 years in Guizhou, China. Some of our results were sex-specific, and most of our results show lower values while comparing with commonly used reference intervals in China. Therefore, more attentions should be paid to these differences, and accurate reference intervals will facilitate clinical diagnosis and decision-making in these populations.

Establishing laboratory-specific reference intervals for TSH and fT4 by use of the indirect Hoffman method.

The results of examinations of laboratory parameters are the basis of appropriate medical decisions. The availability of reliable and accurate reference intervals (RIs) for each laboratory parameter is an integral part of its appropriate interpretation. Each medical laboratory should confirm their RIs. Up-to-date reference intervals for thyroid function hormones are still a matter of ongoing controversy. The aim of the study was the application of the indirect Hoffman method to determine RIs for TSH and fT4 based on the large data pools stored in laboratory information systems and the comparison of these RIs to generally used RIs. The TSH and fT4 routine examination results of hospitalized and outpatient populations were collected over five years (2015-2019), and reference limits were established by the improved Hoffmann method after the exclusion of outliers. Comparative verification of established RIs was conducted with the RIs values provided by test manufacturers and literature data. Various RIs were observed in different age groups in the examined populations. For TSH, RIs varied between different age groups, with a narrower range of RIs in the studied adult population and a shift of both reference boundaries toward higher values in comparison to manufacturers' data among children. RIs estimated for fT4 were very similar to the manufacturer and literature data. Thyroid hormone levels change during a person's lifetime and vary between sexes, but this difference does not always influence the clinical interpretation of laboratory results in the context of RIs. The use of indirect methods is justified due to the ease and low cost of their application.

Pediatric Reference Intervals for Point-of-Care Random Glucose in Healthy Children and Adolescents.

Glucose testing at the point-of-care (POC) is routinely used in the diagnosis, prognosis, and monitoring of diabetic states and other clinical conditions. Accurate reference intervals (RIs) are essential in appropriate clinical decision-making. In this study, RIs were established for random glucose (whole blood) in the Canadian Laboratory Initiative on Pediatric Reference (CALIPER) cohort using 2 POC instruments: the Nova Biomedical StatStrip (handheld glucometer) and Radiometer ABL90 FLEX Plus (benchtop instrument). An analytical comparison was also completed between the 2 POC systems and a laboratory-based analyzer (Ortho Vitros 5600). Approximately 400 healthy children and adolescents (birth to 18 years) were recruited with informed consent from community schools or clinics providing care to metabolically stable/healthy children. Random venous samples were collected and run sequentially on the Nova Biomedical StatStrip (whole blood), Radiometer ABL90 FLEX Plus (whole blood), and Ortho Vitros 5600 (serum). RIs and method comparisons between analytical platforms were completed according to CLSI guidelines. Significantly different glucose concentrations were observed in infancy, requiring age-specific partitioning (0-<1 month, 1-<6 months, 6 months-<19 years) on all platforms. Excellent concordance was observed between POC platforms (Pearson r > 0.90), with a small negative bias. Good comparability was observed between POC and laboratory-based platforms (Pearson r > 0.80). This study established comprehensive pediatric RIs for random glucose (whole blood) on modern POC systems in the CALIPER cohort for the first time. Results demonstrate excellent concordance in glucose values between POC systems and good comparability with a laboratory-based analyzer. These data will assist in more accurate clinical decision-making in pediatric healthcare institutions.

Reference Intervals for Total T4 and Free T4 in Cynomolgus Macaques (Macaca fascicularis) and Rhesus Macaques (Macaca mulatta).

Thyroid diseases, associated with either increased or decreased concentrations of circulating thyroid hormones, are prevalent in both human and veterinary populations. Hypothyroidism is a differential diagnosis for many medical problems as the disease presents with nonspecific clinical signs that can include lethargy, weight gain, cold intolerance, and dermatologic manifestations such as alopecia. Alopecia is a frequently reported problem in captive nonhuman primates (NHP), and hypothyroidism is considered to be a differential diagnosis. However, thyroid function test results in NHP using total T4 (TT4) and free T4 (FT4) assays are difficult to interpret without accurate reference intervals (RI) for comparison. As a consequence, hypothyroidism may be underdiagnosed in these species. The objective of this study was to establish RI for TT4 and FT4 in healthy populations of cynomolgus macaques ( n = 133; age range 2.6 to 24.7 y) and rhesus macaques ( n = 172; age range 0.8 to 31.0 y). Serum samples were collected across a 14-y period during routine anesthetic events in clinically healthy animals, and TT4 and FT4 concentrations were measured using commercially available immunoassays. The RI established for TT4 and FT4 were 5.1 to 14.9 ug/dL and 0.48 to 1.17 ng/dL for cynomolgus macaques, and 3.9 to 14.7 ug/dL and 0.36 to 1.12 ng/dL for rhesus macaques. Significant differences in thyroid hormone concentrations were found between Indian and Chinese origin rhesus, and between Mauritian and other origin cynomolgus. In addition, juvenile and subadult rhesus exhibited significantly higher FT4 and TT4 concentrations than did older animals. Individual RI were established for subgroups with adequately different thyroid hormone concentrations. These results will allow a more thorough diagnostic evaluation of cynomolgus and rhesus macaques with clinical signs consistent with thyroid disease and will ultimately be a refinement in NHP medicine.

Indirect Reference Intervals: Harnessing the Power of Stored Laboratory Data.

Reference intervals are relied upon by clinicians when interpreting their patients' test results. Therefore, laboratorians directly contribute to patient care when they report accurate reference intervals. The traditional approach to establishing reference intervals is to perform a study on healthy volunteers. However, the practical aspects of the staff time and cost required to perform these studies make this approach difficult for clinical laboratories to routinely use. Indirect methods for deriving reference intervals, which utilise patient results stored in the laboratory's database, provide an alternative approach that is quick and inexpensive to perform. Additionally, because large amounts of patient data can be used, the approach can provide more detailed reference interval information when multiple partitions are required, such as with different age-groups. However, if the indirect approach is to be used to derive accurate reference intervals, several considerations need to be addressed. The laboratorian must assess whether the assay and patient population were stable over the study period, whether data 'clean-up' steps should be used prior to data analysis and, often, how the distribution of values from healthy individuals should be modelled. The assumptions and potential pitfalls of the particular indirect technique chosen for data analysis also need to be considered. A comprehensive understanding of all aspects of the indirect approach to establishing reference intervals allows the laboratorian to harness the power of the data stored in their laboratory database and ensure the reference intervals they report are accurate.

Indirect Reference Intervals: Harnessing the Power of Stored Laboratory Data

Reference intervals are relied upon by clinicians when interpreting their patients’ test results. Therefore, laboratorians directly contribute to patient care when they report accurate reference intervals. The traditional approach to establishing reference intervals is to perform a study on healthy volunteers. However, the practical aspects of the staff time and cost required to perform these studies make this approach difficult for clinical laboratories to routinely use. Indirect methods for deriving reference intervals, which utilise patient results stored in the laboratory’s database, provide an alternative approach that is quick and inexpensive to perform. Additionally, because large amounts of patient data can be used, the approach can provide more detailed reference interval information when multiple partitions are required, such as with different age-groups. However, if the indirect approach is to be used to derive accurate reference intervals, several considerations need to be addressed. The laboratorian must assess whether the assay and patient population were stable over the study period, whether data ‘clean-up’ steps should be used prior to data analysis and, often, how the distribution of values from healthy individuals should be modelled. The assumptions and potential pitfalls of the particular indirect technique chosen for data analysis also need to be considered. A comprehensive understanding of all aspects of the indirect approach to establishing reference intervals allows the laboratorian to harness the power of the data stored in their laboratory database and ensure the reference intervals they report are accurate.

Reference intervals for canine hematologic analytes using Siemens Advia 120

Hematologic investigation is essential for the evaluation of health status of companion animals. Appropriate and accurate reference intervals (RIs) are required for the interpretation of laboratory results. Thus, the primary aim of the present study was to establish canine complete blood count (CBC) RIs using Advia 120, a widely used in veterinary medicine automated hematology analyzer. Additional objectives were to evaluate sex as a partitioning factor of RIs and to investigate the effect that breed size has on CBC RIs. Reference individuals were selected by indirect sampling method from the medical records of a veterinary teaching hospital. The reference population comprised 284 adult dogs of both sexes and various breeds. The reference individuals were allocated into 3 groups based on breed size (small-sized, medium-sized and large-sized breeds). Complete blood count results from the dogs that met the inclusion criteria were used for the nonparametric calculation of RIs. Statistical and nonstatistical criteria were employed in order to decide whether sex-specific RIs are needed. Depending on the data distributions, mean or median comparisons were used to determine the effect of breed size and lifestyle on CBC results. Nine outliers were detected based on CBC results. The estimated RIs were generally comparable to those previously reported in the literature. Sex-dependent partitioning of RIs was indicated by the statistical criteria for a few analytes. From a clinicopathologic point of view though, sex-dependent partitioning of RIs is questioned and seems not to be required. Breed size appears to have an effect on CBC RIs. The RIs determined in the present study can be used as a guide for the interpretation of CBC results in dogs and can potentially be adopted by veterinary laboratories using Advia 120. Finally, based on the results of this study, breed size should probably be considered when interpreting CBC results.

Algorithm on age partitioning for estimation of reference intervals using clinical laboratory database exemplified with plasma creatinine.

We describe an algorithm to determine age-partitioned reference intervals (RIs) exemplified for creatinine using data collection from the clinical laboratory database. The data were acquired from the test results of creatinine of 164,710 outpatients aged <18 years in Beijing Children's Hospital laboratories' databases between January 2016 and December 2016. The tendency of serum creatinine with age was examined visually using box plot by gender first. The age subgroup was divided automatically by the decision tree method. Subsequently, the statistical tests of the difference between subgroups were performed by Harris-Boyd and Lahti methods. A total of 136,546 samples after data cleaning were analyzed to explore the partition of age group for serum creatinine from birth to 17 years old. The suggested age partitioning of RIs for creatinine by the decision tree method were for eight subgroups. The difference between age subgroups was demonstrated to be statistically significant by Harris-Boyd and Lahti methods. In addition, the results of age partitioning for RIs estimation were similar to the suggested age partitioning by the Canadian Laboratory Initiative in Pediatric Reference Intervals study. Lastly, a suggested algorithm was developed to provide potential methodological considerations on age partitioning for RIs estimation. Appropriate age partitioning is very important for establishing more accurate RIs. The procedure to explore the age partitioning using clinical laboratory data was developed and evaluated in this study, and will provide more opinions for designing research on establishment of RIs.

Advances in pediatric reference intervals: from discrete to continuous

The clinical utility of laboratory tests largely relies on availability of normative ranges (i.e., reference intervals) to enable objective interpretation and clinical decision making. Establishing accurate reference intervals is often beyond the capabilities of individual laboratories, requiring recruitment of a sufficiently large, healthy reference population, which becomes even more challenging in the pediatric population.

Pediatric reference intervals for 29 Ortho VITROS 5600 immunoassays using the CALIPER cohort of healthy children and adolescents.

Accurate reference intervals (RIs) based on a healthy pediatric population are essential for pediatric test result interpretation. The CALIPER project has recruited a large healthy cohort and completed a series of a priori studies to address gaps in pediatric RIs. As immunoassays from different manufacturers for endocrine and special chemistry markers are not standardized and show marked intermethod differences, direct RI studies are needed for each major analytical platform. Here, we report age- and sex-specific pediatric RIs for 29 immunoassays on the Ortho Clinical Diagnostics (Ortho) VITROS® 5600 analyzer. Health information and blood samples were collected from healthy pediatric subjects. Using the Ortho VITROS 5600 Integrated System MicroWell Technology, 29 biomarkers were measured. Analyte concentrations were partitioned by age and sex according to the Harris and Boyd method. After removing outliers, age- and sex-specific RIs and corresponding 90% confidence intervals were calculated according to CLSI guidelines. All analytes required age partitioning except β-human chorionic gonadotropin (β-hCG), cancer antigen 15-3 (CA15-3), rubella immunoglobulin G (rubella IgG), and vitamin D. Several analytes including estradiol, progesterone, testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), free triiodothyronine (FT3), total triiodothyronine (TT3), total thyroxine (TT4), thyroid uptake, ferritin, intact parathyroid hormone (iPTH), total prostate-specific antigen (tPSA), free prostate-specific antigen (fPSA), cancer antigen 125 (CA125), creatine kinase MB (CK-MB), and myoglobin showed sex differences, observed mostly with the onset of puberty. Complex reference value trends were observed across the pediatric age range for several biomarkers examined on Ortho VITROS immunoassays. The availability of VITROS immunoassay RIs will enable accurate laboratory test interpretation and diagnosis for the pediatric population. As recommended by the CLSI EP28-A3c guidelines, implementation of these RIs should be validated for each laboratory's local pediatric population.

SENIORLAB: a prospective observational study investigating laboratory parameters and their reference intervals in the elderly.

Background:In clinical practice, laboratory results are often important for making diagnostic, therapeutic, and prognostic decisions. Interpreting individual results relies on accurate reference intervals and decision limits. Despite the considerable amount of resources in clinical medicine spent on elderly patients, accurate reference intervals for the elderly are rarely available. The SENIORLAB study set out to determine reference intervals in the elderly by investigating a large variety of laboratory parameters in clinical chemistry, hematology, and immunology.Methods/design:The SENIORLAB study is an observational, prospective cohort study. Subjectively healthy residents of Switzerland aged 60 years and older were included for baseline examination (n = 1467), where anthropometric measurements were taken, medical history was reviewed, and a fasting blood sample was drawn under optimal preanalytical conditions. More than 110 laboratory parameters were measured, and a biobank was set up. The study participants are followed up every 3 to 5 years for quality of life, morbidity, and mortality. The primary aim is to evaluate different laboratory parameters at age-related reference intervals. The secondary aims of this study include the following: identify associations between different parameters, identify diagnostic characteristics to diagnose different circumstances, identify the prevalence of occult disease in subjectively healthy individuals, and identify the prognostic factors for the investigated outcomes, including mortality.Discussion:To obtain better grounds to justify clinical decisions, specific reference intervals for laboratory parameters of the elderly are needed. Reference intervals are obtained from healthy individuals. A major obstacle when obtaining reference intervals in the elderly is the definition of health in seniors because individuals without any medical condition and any medication are rare in older adulthood. Reference intervals obtained from such individuals cannot be considered representative for seniors in a status of age-specific normal health. In addition to the established methods for determining reference intervals, this longitudinal study utilizes a unique approach, in that survival and long-term well-being are taken as indicators of health in seniors. This approach is expected to provide robust and representative reference intervals that are obtained from an adequate reference population and not a collective of highly selected individuals.Trial registration:The present study was registered under International Standard Randomized Controlled Trial Number registry: ISRCTN53778569.

Reference intervals: current status, recent developments and future considerations.

Reliable and accurate reference intervals (RIs) for laboratory analyses are an integral part of the process of correct interpretation of clinical laboratory test results. RIs given in laboratory reports have an important role in aiding the clinician in interpreting test results in reference to values for healthy populations. Since the 1980s, the International Federation of Clinical Chemistry (IFCC) has been proactive in establishing recommendations to clarify the true significance of the term ‘RIs, to select the appropriate reference population and statistically analyse the data. The C28-A3 guideline published by the Clinical and Laboratory Standards Institute (CLSI) and IFCC is still the most widely-used source of reference in this area. In recent years, protocols additional to the Guideline have been published by the IFCC, Committee on Reference Intervals and Decision Limits (C-RIDL), including all details of multicenter studies on RIs to meet the requirements in this area. Multicentric RIs studies are the most important development in the area of RIs. Recently, the C-RIDL has performed many multicentric studies to obtain common RIs. Confusion of RIs and clinical decision limits (CDLs) remains an issue and pediatric and geriatric age groups are a significant problem. For future studies of RIs, the genetic effect would seem to be the most challenging area. The aim of the review is to present the current theory and practice of RIs, with special emphasis given to multicenter RIs studies, RIs studies for pediatric and geriatric age groups, clinical decision limits and partitioning by genetic effects on RIs.

Complex Biological Pattern of Fertility Hormones in Children and Adolescents: A Study of Healthy Children from the CALIPER Cohort and Establishment of Pediatric Reference Intervals

Pediatric endocrinopathies are commonly diagnosed and monitored by measuring hormones of the hypothalamic-pituitary-gonadal axis. Because growth and development can markedly influence normal circulating concentrations of fertility hormones, accurate reference intervals established on the basis of a healthy, nonhospitalized pediatric population and that reflect age-, gender-, and pubertal stage-specific changes are essential for test result interpretation. Healthy children and adolescents (n = 1234) were recruited from a multiethnic population as part of the CALIPER study. After written informed parental consent was obtained, participants filled out a questionnaire including demographic and pubertal development information (assessed by self-reported Tanner stage) and provided a blood sample. We measured 7 fertility hormones including estradiol, testosterone (second generation), progesterone, sex hormone-binding globulin, prolactin, follicle-stimulating hormone, and luteinizing hormone by use of the Abbott Architect i2000 analyzer. We then used these data to calculate age-, gender-, and Tanner stage-specific reference intervals according to Clinical Laboratory Standards Institute C28-A3 guidelines. We observed a complex pattern of change in each analyte concentration from the neonatal period to adolescence. Consequently, many age and sex partitions were required to cover the changes in most fertility hormones over this period. An exception to this was prolactin, for which no sex partition and only 3 age partitions were necessary. This comprehensive database of pediatric reference intervals for fertility hormones will be of global benefit and should lead to improved diagnosis of pediatric endocrinopathies. The new database will need to be validated in local populations and for other immunoassay platforms as recommended by the Clinical Laboratory Standards Institute.

Investigation of hypercalcemia

Hypercalcemia is a relatively common clinical finding. Primary hyperparathyroidism, hypercalcemia associated with malignancy and chronic renal failure (with calcium and vitamin D metabolite treatment or tertiary hyperparathyroidism) are the most common causes. Less common causes of hypercalcemia include vitamin D-related (granulomatous diseases, lymphoma, vitamin D intoxication), other endocrine (thyrotoxicosis), medications (milk-alkali, thiazides, lithium) and other causes (immobilization, familial hypocalciuric hypercalcemia). The clinical laboratory is central to the diagnosis and differential diagnosis of hypercalcemia. Its role has expanded from measuring routine chemistry tests such as total calcium, phosphate, creatinine and alkaline phosphate to include quantification of ionized calcium, parathyroid hormone (PTH) and vitamin D metabolites. In spite of this progress, the diagnosis and differential diagnosis of hypercalcemia can be significantly improved by: 1) increasing the availability and utilization of ionized calcium since total and corrected calcium are often inaccurate; 2) establishing more accurate reference intervals for parathyroid hormone by excluding individuals who are vitamin D insufficient or deficient; and 3) harmonizing intact PTH immunoassays.