Estimation of Age-specific Reference Intervals for Skewed Data

Summary Objectives: To compare Cole’s LMS method with Wright and Royston’s Exponential-Normal (EN) method for estimating reference intervals and generating smooth centile curves for the body mass index (weight in kg/height in meters squared) measurements of children aged 6 to 13 years. Methods: In the LMS method, the parameters L (the power needed to normalize the data), M (median) and S (coefficient of variation) are modeled as smoothed fits of maximum likelihood estimates. In the Exponential-Normal method, the three parameters mean, standard deviation and skewness are estimated separately using multiple regression techniques. Results: The centiles generated by the LMS and EN methods are close in most of the age groups. The 2.5th and 97.5th quantiles of the interval of the differences between the loss function scores of the LMS and EN methods calculated by bootstrap was found to include zero, indicating that the difference in loss function scores of the two methods is random and not systematic. Conclusions: The two methods are simple to use and generate comparable centile curves.

Download Full-text

Age-Specific Reference Intervals for PT, aPTT, Fibrinogen and Thrombin Time for Parturient Women

Thrombosis and Haemostasis ◽

10.1055/s-0039-1683932 ◽

2019 ◽

Vol 119 (06) ◽

pp. 894-898

Author(s):

Gao-Ming Zhang ◽

Wei Zhang ◽

Guo-Ming Zhang

Keyword(s):

Age Groups ◽

Reference Intervals ◽

Activated Partial Thromboplastin Time ◽

Blood Levels ◽

Specific Reference ◽

Thrombin Time ◽

Healthy Individuals ◽

Medical Decisions ◽

Large Dataset ◽

Upper Limit

Background Parturient women are healthy individuals who require special consideration. Parturient women are considered to be in a hyper-coagulable state. For example, the fibrinogen (FIB) levels are often higher than the upper limit of normal reference intervals (RIs) in parturient women than in non-parturient healthy individuals (2–4 g/L). Objective The aim of this study is to establish the RIs of pro-thrombin time (PT), activated partial thromboplastin time (aPTT), FIB levels and thrombin time (TT) for parturient women. Materials and Methods Blood levels of PT, aPTT, FIB and TT were assayed on an ACL TOP 700 automatic coagulation analyser using plasma samples from 10,472 parturient women. Outlier results were excluded by using Tukey's test. The RIs were calculated by the Clinical and Laboratory Standards Institute C28-A3 guideline. Results The RIs of PT, aPTT, FIB and TT were 8.7 to 12.1 seconds (8.7–12.2 seconds for 16–20 years old, 8.7–12.1 second for 21–25 years old, 8.6–12.0 second for 26–30 years old, 8.7–12.0 second for 31–35 years old, 8.7–12.6 second for 36–40 years old and 8.8–12.2 second for 41 years old), 22.9 to 42.3 seconds, 1.98 to 5.82 g/L and 9.9 to 16.7 seconds, respectively. PT levels were found to be positively associated with aging. Conclusion The above-established age-specific RIs, defined by using a large dataset, may assist clinicians in making accurate medical decisions. This was the first study in which the RIs of PT, aPTT, FIB and TT were established for parturient women in different age groups.

Download Full-text

Age- and sex-specific reference intervals for the serum cystatin C/creatinine ratio in healthy children (0–18 years old)

Journal of International Medical Research ◽

10.1177/0300060519855575 ◽

2019 ◽

Vol 47 (7) ◽

pp. 3151-3159 ◽

Cited By ~ 2

Author(s):

Changjin Liu ◽

Jing Wen ◽

Jialin Xiang ◽

Xuhong Ouyang ◽

Yan Yang ◽

...

Keyword(s):

Cystatin C ◽

Pediatric Population ◽

Age Groups ◽

Serum Markers ◽

Reference Intervals ◽

Specific Reference ◽

Healthy Children ◽

Serum Samples ◽

Serum Cystatin C ◽

Age And Sex

Objective This study aimed to investigate serum levels of the cystatin C (CysC)/creatinine (Cr) ratio and renal serum markers (CysC, Cr, urea, and uric acid [UA]) for different ages and by sex. We also aimed to establish pediatric reference intervals for the serum CysC/Cr ratio. Methods Serum samples were collected from 4765 healthy children (0–18 years old). Serum markers of renal function were measured, and the CysC/Cr ratio of each participant was calculated and statistically analyzed. Results The renal marker CysC did not substantially change after 1 year old. Cr, urea, and UA levels generally increased with age. However, the serum CysC/Cr ratio steadily decreased with age. The CysC/Cr ratio showed significant differences in age among all age groups and varied with sex, except for in the 1 to 6-year-old groups. The overall serum CysC/Cr ratio in girls was higher than that in boys. Conclusion Reference intervals of the serum CysC/Cr ratio in the pediatric population were established. These intervals need to be partitioned by age and sex.

Download Full-text

Differences in Cardiorespiratory Fitness between Chinese and Japanese Children and Adolescents

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph16132316 ◽

2019 ◽

Vol 16 (13) ◽

pp. 2316 ◽

Cited By ~ 1

Author(s):

Xiaofang Yang ◽

Xiaojian Yin ◽

Liu Ji ◽

Ge Song ◽

Huipan Wu ◽

...

Keyword(s):

Primary School ◽

Children And Adolescents ◽

Cardiorespiratory Fitness ◽

Maximal Oxygen Consumption ◽

Age Groups ◽

Japanese Children ◽

Lms Method ◽

The Difference ◽

Run Test ◽

Chinese Girls

Background: This study aimed to compare the difference in cardiorespiratory fitness between Chinese and Japanese children and adolescents. Methods: Participants comprised 9025 children and adolescents aged 7–18 years from China and Japan. Cardiorespiratory fitness (CRF) was measured by performance in the 20 m shuttle run test (20mSRT) and estimated maximal oxygen consumption (VO2max). Differences in CRF between countries were evaluated by t-tests. Centile curves for the 20mSRT and VO2max values were constructed for Chinese and Japanese children and adolescents, respectively, using the Lambda Mu and Sigma (LMS) method. Results: (1) For most of the age groups, the 20mSRT and VO2max performances among Chinese participants were lower than among Japanese participants. (2) Japanese children had the most apparent gains in P10, P50, and P90 VO2max values in primary school; however, they gradually decreased in middle school. For Chinese girls, the P10, P50, and P90 VO2max values decreased gradually with age. (3) The VO2max value among Japanese children increased; however, it decreased or remained flat among Chinese children in primary school. Conclusions: CRF among Chinese participants was lower than among Japanese participants while the VO2max value showed different trends in primary school. Effective measures should be taken to improve CRF among children and adolescents.

Download Full-text

Processing-independent proANP measurement for low concentrations in plasma: reference intervals and effect of body mass index and plasma glucose

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2017-0309 ◽

2017 ◽

Vol 56 (1) ◽

Author(s):

Peter D. Mark ◽

Ingrid Hunter ◽

Dijana Terzic ◽

Jens P. Goetze

Keyword(s):

Body Mass Index ◽

Body Mass ◽

Plasma Glucose ◽

Age Groups ◽

Radioactive Tracer ◽

Reference Intervals ◽

Specific Reference ◽

Regression Analyses ◽

Obesity And Diabetes ◽

Gender Specific

AbstractBackground:Decreased concentrations of pro-atrial-derived natriuretic peptides (proABP) in plasma have been associated with obesity and suggested as a predictor of type 2 diabetes. However, assays for measuring proANP are generally aimed to quantitate higher concentrations of proANP associated with cardiac disease. Therefore, we aimed to measure plasma proANP concentrations in a non-obese Scandinavian reference material and evaluate potential associations of plasma proANP with body mass index (BMI) and plasma glucose, respectively.Methods:We report an optimized processing-independent assay (PIA) for proANP in the lower concentration range. The assay was optimized by raising the amount of radioactive tracer and modifying the mixing ratio of resuspended plasma and buffer. Blood samples from a Scandinavian plasma cohort of 693 healthy subjects were then analyzed and age and gender-specific reference intervals were determined.Results:Simple linear regression analyses of proANP and both BMI and plasma glucose in fasting subjects displayed insignificant associations. Multiple regression analyses supported these findings. However, a higher median plasma concentration of proANP was noted among women <50 years compared to men, whereas no gender-specific differences were seen in other age groups.Conclusions:Our results show that in a healthy non-obese population, BMI and plasma glucose in fasting subjects do not affect plasma proANP concentrations. Our method should be considered for future studies on low proANP concentration studies, e.g. in obesity and diabetes.

Download Full-text

Study of the Total Serum Concentration of Serrum Ionized Magnesium in Children and Adolescents from Sibiu Area

Revista de Chimie ◽

10.37358/rc.18.12.6756 ◽

2019 ◽

Vol 69 (12) ◽

pp. 3389-3392 ◽

Cited By ~ 3

Author(s):

Elisabeta Antonescu ◽

Gabriela Bota ◽

Bogdan Serb ◽

Diter Atasie ◽

Cristina Dahm Tataru ◽

...

Keyword(s):

Children And Adolescents ◽

Reference Range ◽

Serum Magnesium ◽

Age Groups ◽

Reference Intervals ◽

Magnesium Concentration ◽

Total Serum ◽

Reference Ranges ◽

Insulin Metabolism ◽

The Difference

Magnesium is an essential nutrient for the living organisms and plays an important part in the prevention and treatment of many diseases. It is an enzymatic cofactor for more than 300 reactions. Magnesium is essential for regulating blood pressure, muscle contraction, cardiac excitability, insulin metabolism, vasomotor tonus. Studying the way in which serum magnesium concentration varies in children and adolescents in the Sibiu area according to the reference intervals we especially set for this area. The study is a retrospective one, using approximately 4900 data from the archives of the Medical Analysis Laboratory within the Sibiu Pediatric Clinical Hospital. Serum magnesium was dosed using the Konelab Prime 30i analyser. The data from the literature was used to compare the results. The reference ranges obtained in the current study were similar to the literature studied. The percentage of patients with magnesium concentration outside the reference ranges was roughly equal for all age groups. The difference was between 1 month and 2 year-old children with very few deviations from the reference range. The results of our study reflect more accurately the real reference range for the population in the Sibiu area, helping clinicians to establish a diagnosis as quickly and accurate as possible. These results were not significantly different from the literature studied.

Download Full-text

Immunoglobulin G (IgG) and IgG subclass reference intervals in children, using Optilite® reagents

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2018-0001 ◽

2018 ◽

Vol 56 (8) ◽

pp. 1319-1327 ◽

Cited By ~ 2

Author(s):

Olivier Grunewald ◽

Benjamin Lopez ◽

Séverine Brabant ◽

Stéphanie Rogeau ◽

Antoine Deschildre ◽

...

Keyword(s):

Immunoglobulin G ◽

Age Groups ◽

Reference Intervals ◽

Igg Subclasses ◽

Specific Reference ◽

Igg Subclass ◽

Serum Samples ◽

Gender Specific Differences ◽

Specific Igg ◽

Changes Over Time

Abstract Background: Immunoglobulin G (IgG) and IgG subclass assays are indicated in patients with suspected primary immunodeficiency (PID). Commercially available assays for IgG subclass determination are calibrated against various preparations, and so specific reference values are required for each of them. Using Optilite® reagents from The Binding Site Group Ltd., we sought to determine the pediatric IgG and IgG subclass reference intervals with respect to the ERM-DA470k certified reference material. Methods: Levels of IgG and IgG subclasses were analyzed in serum samples collected from a large cohort of PID-free children and adolescents. Reference intervals were calculated for previously published age groups (6–12 months, 12–18 months, 18 months–2 years, 2–3 years, 3–4 years, 4–6 years, 6–9 years, 9–12 years and 12–18 years), according to the Clinical and Laboratory Standards Institute’s C28-A3c protocol. Results: A total of 456 serum samples were analyzed. The correlation between the total IgG and the sum of the IgG subclasses was good (r2=0.96). No statistically significant gender-specific differences were observed. Our results for the changes over time in IgG and IgG subclass levels are consistent with previous reports. The differences between our lower/upper reference limits and those in the literature are probably due to variations in calibration. Conclusions: Our present results provide a reliable basis for the diagnosis of PIDs in childhood and for the accreditation of laboratories using Optilite® immunoturbidimetric reagents for IgG subclass measurement. Laboratory scientists and clinicians should be aware of the need for manufacturer-specific IgG subclass reference intervals.

Download Full-text

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

PLoS ONE ◽

10.1371/journal.pone.0261715 ◽

2022 ◽

Vol 17 (1) ◽

pp. e0261715

Author(s):

Sylwia Płaczkowska ◽

Małgorzata Terpińska ◽

Agnieszka Piwowar

Keyword(s):

Low Cost ◽

Adult Population ◽

Age Groups ◽

Large Data ◽

Reference Intervals ◽

Medical Laboratory ◽

Specific Reference ◽

Medical Decisions ◽

Indirect Methods ◽

Laboratory Information Systems

Background 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. Material and methods 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. Results 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. Conclusion 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.

Download Full-text

SUN-LB46 Differences in IGF-I Concentrations Between European and US Populations - Consequences for Reference Intervals

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.2165 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Martin Bidlingmaier ◽

Andre Valcour ◽

Kelly Y Chun ◽

Katharina Schilbach ◽

Tim Kühnle ◽

...

Keyword(s):

Routine Data ◽

Reference Intervals ◽

Striking Difference ◽

Specific Reference ◽

Original Publication ◽

Clin Pathol ◽

Assay Performance ◽

The Us ◽

Igf I ◽

The Difference

Abstract Background: IGF-I is the most widely used biomarker for management of GH related diseases. Reproducible assays and method-specific reference intervals (RIs) are crucial determinants of its clinical utility. Assay validation and RIs based on >15,000 subjects were published for the IDS iSYS IGF-I assay (J Clin Endocrinol Metab 2014). We now analyzed distribution of IGF-I results obtained in routine samples analyzed by accredited laboratories in the US and Europe, all using the IDS iSYS assay. Methods: All results from routine IGF-I measurements during the past 5 years in 4 laboratories were included (US lab n=778,173 males/710,752 females; European labs (Germany/Belgium, n=23,220 males/40,183 females). Assay performance across laboratories was confirmed through proficiency testing schemes and exchange of patient samples. We constructed RIs adjusted for age/sex from European and US cohorts separately using a modified Hoffmann approach (Am J Clin Pathol 2015), and compared to the originally published RIs (n=6697 males/8317 females, adults from Europe). A subset of US samples was used to compare IGF-I between regions with lower (Colorado) and higher (Alabama) mean body mass index (BMI). Results: Lower limits (LLs) of RIs calculated from routine results are superimposable to LLs from the original publication for all ages and sexes, regardless whether IGF-I results were from Europe or the US. For groups with sufficient n, upper limits (ULs) of RIs calculated from European routine data were also not statistically different from the originally published central 95%. However, a striking difference exists in calculated ULs from data of European and US origin: For ages 10-18 years, calculated UL on average was 149.3 ng/mL (34.6%) higher in boys and 94.9 ng/mL (19.8%) in girls from the US. In adults (19-95 years), calculated UL on average was 45 ng/mL (20.3%) higher in males and 29.7 ng/mL (13.8%) in females from the US. Within the US, mean IGF-I was significantly higher in samples from Colorado (lower mean BMI) than in Alabama (p<0.0001) across age- and sex groups, although the difference between the two states was smaller than between each of them and Europe. Conclusion: This study provides evidence that in sufficiently large datasets, both, direct sampling (as in the original publication) and the indirect Hoffmann algorithms provide statistically comparable RI limits and may be considered as accurate representation of results distribution in the disease-free populations. More importantly, we demonstrate that even with tight cross-correlation and continuous monitoring of IGF-I assay performance RIs generated in different populations can be different. Notably, in our extremely large study, the difference between Europe and the US was clinically relevant only at the UL. Although our study cannot reveal the cause of the difference, we suggest using adapted RIs for the US.

Download Full-text

Determination of new hematologic reference intervals for sows with optimal reproductive performance, according to reproductive stage, parity and body condition: A cohort study

10.21203/rs.3.rs-317100/v1 ◽

2021 ◽

Author(s):

Carolina Baeza ◽

Paula Gädicke ◽

Álvaro Ruiz

Keyword(s):

Cohort Study ◽

Body Condition ◽

Reproductive Cycle ◽

Reproductive Performance ◽

Repeated Measures ◽

Reference Intervals ◽

The Body ◽

Reproductive Stage ◽

Hematological Parameter ◽

Specific Reference

Abstract Background. Inappropriate feeding and reproductive management according to strategies in sow's reproductive efficiency produce important consequences on sow metabolism. The metabolic alterations can increase mortality and reduce fertility, productivity and lifespan of sows within a farm, decreasing herd output. In according to that, this research aimed to determine the effect of reproductive stage, parity and body condition on hematological parameters of intensive-production sows and also to establish new and representative hematological Reference Intervals for each stage of the reproductive cycle in Chilean sows of optimal reproductive performance. In order to that, a cohort study in 307 healthy sows from two farms was performed. Serial hemograms were obtained and sows were monitored at weaning, prior to artificial insemination, at 35, 60 and 90 days of gestation, and subsequent weaning. Results were analyzed by Repeated-Measures of Anova and Tukey Test to establish differences between times and by the Kruskall-Wallis Test, or Simple Anova Test, to determine differences within times caused by the body condition (BC) or sow age. Results: Significant differences were found in most factors during gestation (P=0,00). At each time frame considered, there was an effect of parity. The sow`s parity history, their BC and the farm`s infrastructure and environment were all relevant factors in each hematological parameter. Additionally, statistically significant differences in almost all the evaluated indicators were contrasted with reference IRs (P=0,00). Hematological indicators supported the interaction between BC and parity in some sows. ConclusionsThis study showed the need of not only specific reference intervals for high-production sows, but also highlights the relevance of considering the different stages of sows´s reproductive cycle. Consideration of sow’s physiological stage and parity, along with body condition appear to be highly relevant to get appropriate hematologic reference intervals.

Download Full-text

Mining of hospital laboratory information systems: a model study defining age- and gender-specific reference intervals and trajectories for plasma creatinine in a pediatric population

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2014-0949 ◽

2015 ◽

Vol 53 (10) ◽

Cited By ~ 9

Author(s):

Karen Søeby ◽

Peter Bjødstrup Jensen ◽

Thomas Werge ◽

Steen Sørensen

Keyword(s):

Pediatric Population ◽

Laboratory Data ◽

Age Groups ◽

Reference Intervals ◽

Repeated Measurements ◽

Plasma Creatinine ◽

Specific Reference ◽

Healthy Population ◽

Hospital Laboratory ◽

Gender And Age

AbstractThe knowledge of physiological fluctuation and variation of even commonly used biochemical quantities in extreme age groups and during development is sparse. This challenges the clinical interpretation and utility of laboratory tests in these age groups. To explore the utility of hospital laboratory data as a source of information, we analyzed enzymatic plasma creatinine as a model analyte in two large pediatric hospital samples.Plasma creatinine measurements from 9700 children aged 0–18 years were obtained from hospital laboratory databases and partitioned into high-resolution gender- and age-groups. Normal probability plots were used to deduce parameters of the normal distributions from healthy creatinine values in the mixed hospital datasets. Furthermore, temporal trajectories were generated from repeated measurements to examine developmental patterns in periods of changing creatinine levels.Creatinine shows great age dependence from birth throughout childhood. We computed and replicated 95% reference intervals in narrow gender and age bins and showed them to be comparable to those determined in healthy population studies. We identified pronounced transitions in creatinine levels at different time points after birth and around the early teens, which challenges the establishment and usefulness of reference intervals in those age groups.The study documents that hospital laboratory data may inform on the developmental aspects of creatinine, on periods with pronounced heterogeneity and valid reference intervals. Furthermore, part of the heterogeneity in creatinine distribution is likely due to differences in biological and chronological age of children and should be considered when using age-specific reference intervals.

Download Full-text