Age-specific Reference Intervals Research Articles

Establishment of gender- and age-related reference intervals for serum uric acid in adults based on big data from Zhejiang Province in China.

This study utilized large-scale health examination data to explore gender- and age-specific reference intervals (RIs) for serum uric acid (UA) using indirect methods and assessed the consistency of different approaches. UA data were collected from a hospital in Zhejiang Province, China. The test set covered January 2019 to December 2023, with a validation set from January to June 2024. Various methods- EP28 nonparametric (EP28-NP), parametric (EP28-P), TMC, refineR, and Kosmic- were used to establish gender- and age-specific RIs. Continuous age-based RIs were derived using the Generalized Additive Model for Location Scale and Shape (GAMLSS). Validation rates were calculated for each method using the validation set. Using EP28-NP as the benchmark, other methods showed similar UA RIs (bias ratios≤0.375, except for one group), with Kosmic, refineR, and TMC yielding slightly higher values than EP28-NP and EP28-P. For males, UA RIs varied by age: 19-42 years (256-537 μmol/L), 43-66 years (235-513 μmol/L) and≥67 years (214-515 μmol/L), with validation rates ranging from 94.05 to 96.50 %. Male continuous RIs declined from ages 20-79 and then gradually increased after age 80. For females, UA RIs were age-dependent: 19-48 years (169-374 μmol/L), 49-74 years (178-405 μmol/L), and≥75 years (186-470 μmol/L), with validation rates ranging from 92.70 to 96.80 %. Female continuous RIs decreased from ages 20-48, then increased significantly from age 49 onward. Three indirect methods and two EP28 methods demonstrated good consistency in establishing UA RIs. Males had higher RIs than females, and RIs showed a non-linear correlation with age.

Attitudes Towards the Management of Congenital Hypothyroidism in Türkiye: National Survey Study.

This study was conducted to assess the perspectives of pediatric endocrinologists in Türkiye on the management of congenital hypothyroidism (CH) and to analyze the potential impact of work environment and professional experience on different attitudes. The members of the Turkish Society for Pediatric Endocrinology and Diabetes were invited to participate in an online survey. An evaluation was made by obtaining survey responses from 95 (19%) of 502 members. Participants' mean age was 42.0±9.6 years, 46.3% of them were working in a university hospital, and 48.6% had >7 years of work experience. When the participants were asked about their approach to a 1-3-week-old neonate whose serum TSH concentration was 6-20 mU/L with a serum-free T4 (FT4) concentration within the age-specific reference interval, 97.7% of the participants preferred to monitor without medication. Only 24% of physicians consider starting treatment immediately if the serum TSH concentration is 20-40 mU/l with a normal FT4 level. While 5.3% of participants preferred dual imaging (ultrasound and scintigraphy), 90.5% requested only thyroid ultrasound for etiological investigation. When considering the discontinuation of levothyroxine in patients with a normal thyroid gland and a low LT4 dose, 28.4% of the participants stated that treatment should be stopped at the earliest at the age of 3 years, 16.8% at 2 years, 5.3% at 1 year, 16.8% at 6 months, and 32.6% at any time if the TSH levels remain low despite the low dosage. Physicians with over 7 years of experience can discontinue medication if TSH is low, even with a lower dose, more frequently than those with less experience (p=0.011). There were no significant differences in the approach of the physicians between employees at university hospitals and other health institutions. Although the attitudes of pediatric endocrinologists working in Türkiye towards the management of CH are generally consistent with the recommendations of international guidelines, their approaches to the treatment for isolated neonatal TSH elevation, thyroid imaging preferences and time to discontinue treatment differ significantly. These different attitudes, which are almost similar among all subgroups by experience and work setting, reflect the differences in local conditions in Türkiye and underline the need for a national consensus on the management of CH.

Reference Intervals (RIs) of the Bone Turnover Markers (BTMs) in Children and Adolescents: A Proposal for Effective Use.

Bone turnover markers (BTMs) can provide information on the bone growth of apparently healthy children and adolescents or useful results in the diagnosis and monitoring of the disease condition, comparing them with appropriate reference intervals (RIs). The aim of this study was to establish the RI for the BTM [specific bone alkaline phosphatase (BALP), carboxy-terminal cross-linked collagen type I telopeptide (CTX), N-terminal propeptide pro-collagen type I (PINP), osteocalcin (OC), resistant to acid tartrate phosphatase isoform 5b (TRAcP-5b)] on serum samples from children and adolescents. 202 samples from children and adolescents (ages 1-18 years) (51.48% male), considered apparently healthy. The biomarker was analyzed on automatic immunometric equipment (TGSTA Technogenetics) and the IDS-iSYS automated system kits The RI of the studied parameters was calculated according to CLSI Guideline C28-A3 with stratification by age and sex. Evaluation of the distribution of values and the meaning of the biomarker concentrations were used to calculate general and specific RI for an age group. BTM concentrations vary with pubertal growth. The pattern of change differs for each bone marker. General and age-specific RI were calculated: 1-14 years, 15-18 years for BALP and CTX; 1-13 years, 14-18 years for Oc and PINP and 1-12 years, 13-18 years for TRAcP. Concentrations for biomarker studied vary with age and gender. The proof of concentrations with insignificant changes until puberty led to identification of two groups of RI relating to the covariables (age and sex) for each biomarker.

B-170 Age-Specific reference intervals for ethanolamine plasmalogen species in red blood cells using liquid chromatography tandem mass spectrometry

Abstract Background Plasmalogens are critical membrane structural components that are mainly generated by de novo synthesis starting in peroxisomes. Hence, patients with defects in peroxisome biogenesis (PBD) exhibit markedly reduced plasmalogen levels. Plasmalogen ratios are traditionally measured by gas chromatography-mass spectrometry (GC-MS); however, this method entails a lengthy sample extraction and derivatization and does not report concentrations of individual plasmalogen species. We have developed a robust and easy-to-implement liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify the 18 most abundant ethanolamine plasmalogen (PlsEtn) species in packed red blood cells (RBCs). However, no reference intervals have been published for individual PlsEtn. Here, we describe the establishment of age-specific reference intervals for individual PlsEtn species and their total values (16:0, 18:0, 18:1 species, and total plasmalogens). Methods Plasmalogens were extracted using methanol containing two labeled internal standards, shaking for one hour at room temperature. Chromatographic separation was performed using an Acquity Premier BEH C18 UPLC column with a binary gradient of 5 mM ammonium acetate in water:methanol (15:85) and 5 mM ammonium acetate in methanol. Analysis was performed using a XEVO TQ-XS Mass Spectrometer with Ultra-High Performance Liquid Chromatography (Waters) in multiple reaction monitoring mode. Eighteen PlsEtn species were quantified using four commercially available standards; additionally, totals were calculated for 16:0, 18:0 or 18:1 species, and for total plasmalogens. Reference intervals were established using 376 RBCs from self-reported healthy volunteers and de-identified clinical samples referred for unrelated testing (182 females and 194 males; range 0 to 88 years). Data was analyzed using the R programming language. The study was approved by the Institutional Review Board of the University of Utah. Results Initial age groups were identified using a model-based clustering algorithm followed by iterative Harris-Boyd analysis. Finally, the adjacent groups were merged if their means differed by less than 10%. Once the final age groups were partitioned, data in each individual age group were analyzed using parametric or non-parametric statistics to determine reference intervals (95%, with 90%confidence intervals). PlsEtn species displayed the lowest concentration in the first few months of life, which increased in childhood until adolescence or adulthood (depending on PlsEtn). For most species, the concentrations increased over time reaching a plateau between 18 and 48 years of age, and then starting to decrease. The total values followed the same trend, with neonates showing significantly lower values compared to other age groups. Conclusions We applied a novel statistical approach to identify age groups and determine age-specific reference intervals for 18 individual PlsEtn in RBC and their totals. Lacking previously published data, this study is critical for supporting test implementation in clinical laboratories.

Derivation of Russian-specific reference intervals for complete blood count, iron markers and related vitamins.

This study aimed to establish reference intervals (RIs) for Russian adults for hematological parameters including related iron markers and vitamins. Sources of variation of reference values (RVs) and needs for secondary exclusion were explored for proper derivations of RIs. Following the harmonized protocol of the IFCC Committee on Reference Intervals and Decision Limits (C-RIDL), 506 healthy Russians (age 18-80; 46% male) were recruited. Complete blood counts (CBC) and leukocyte differentials, iron markers, vitamin B12, and folate were measured by Beckman Coulter's analyzers. Sources of variation were analyzed by multiple regression analysis, and ANOVAs, and the need for partitioning RVs was decided accordingly. Two schemes of excluding latent anemia were compared: (1) latent abnormal values exclusion method (LAVE) based on associations among CBC parameters, or (2) explicit exclusion of individuals with either ferritin or iron below the respective lower limit of the manufacturer. RIs were determined by the parametric method using two-parameter Box-Cox formula. Gender-specific RIs were required for most analytes, while age-specific RIs were set only for ferritin in females. A BMI-related increase in RVs was prominently observed for reticulocyte parameters, hence we chose to exclude individuals with BMI>28 kg/m2 when establishing the RIs. The LAVE method was more effective in excluding individuals with latent anemia, than exclusion based on low ferritin and/or iron values. International comparison revealed that Russian RIs featured a lower side shift of platelet counts. Similar to African countries, Russian RIs for total leukocyte and neutrophil counts were lower compared to most of other countries. RIs for the Russian population for 34 hematological and related parameters were established using up-to-date methods proposed by C-RIDL. Reducing the influences of latent anemia and obesity on RIs was crucial for erythrocyte parameters. Low levels of Russian RIs observed for platelet and neutrophil counts need further investigation.

Defining age-specific reference intervals for biomarkers distinguishing bacterial from viral infection in paediatrics

Differentiating bacterial from viral infections in children is a common clinical challenge. Novel host immune biomarkers have the potential to aid thediagnosis of infection aetiology and identify children who require antibiotics. Data on novel infection biomarkers gender and age-specific correlations, and reference intervals in healthy paediatrics is lacking. This study reports the plasma levels of three novel biomarkers that can aid in the differentiation of bacterial and viral infection in a healthy group of paediatrics. The levels of (Interferon-Gamma Inducible Protein 10 kDa (IP-10), Lipocalin-2 (LCN2) and TNF-Related Apoptosis-Inducing Ligand (TRAIL) were quantified in 199 plasma samples from healthy paediatrics aged 2 to 16 years old from across the UK. Reference intervals (2.5th and 97.5th) were determined, and biomarker levels were examined for sex and age associations. Reference intervals for IP-10, LCN2 and TRAIL for ages 2–16 years were 36.7–168.1 pg/ml, 14.2–123.3 ng/ml, 57.4–71.4 pg/ml respectively. No biomarker showed an association with sex and IP-10 did not show any association with age. TRAIL levels had a weak continuous negative correlation with age and LCN2 levels had a continuous positive correlation with age. Specific cut-offs for LCN2 in two age categories were identified, while TRAIL did not require age partitions. This study provides age-appropriate reference intervals for three biomarkers of infection in healthy children. These findings have the potential to improve the impact of future research on these biomarkers, the accuracy of clinical decision-making in children with infection, paediatric patient care and outcomes, and antimicrobial stewardship.

Age-Specific Reference Intervals for Thyroid-Stimulating Hormones and Free Thyroxine to Optimize Diagnosis of Thyroid Disease.

Background: Thyroid-stimulating hormone (TSH) and subsequent free thyroxine (FT4) concentrations outside the reference interval (RI) are used to diagnose thyroid diseases. Most laboratories do not provide age-specific RIs for TSH and FT4 beyond childhood, although TSH concentrations vary with age. Therefore, we aimed to establish TSH and FT4 age-specific RIs throughout life and aimed to determine whether using these RIs would result in reclassification of thyroid disease diagnoses in adults. Methods: This multicenter retrospective cross-sectional study used big data to determine indirect RIs for TSH and FT4. These RIs were determined by TMC and refineR-analysis, respectively, using four different immunoassay platforms (Roche, Abbott, Siemens, and Beckman Coulter). Retrospective data (2008-2022) from 13 Dutch laboratories for general practitioners and local hospitals were used. RIs were evaluated per manufacturer. Age groups were established from 2 to 20 years by 2-year categories and decade categories between 20 and 100 years. Results: We included totally 7.6 million TSH and 2.2 million FT4 requests. TSH upper reference limits (URLs) and FT4 lower reference limits were higher in early childhood and decreased toward adulthood. In adulthood, TSH URLs increased from 60 years in men, and from 50 years in women, while FT4 URLs increased from 70 years onward. Using adult age-specific RIs resulted in a decrease in diagnoses of subclinical and overt hypothyroidism in women above 50 and men above 60 years in our Roche dataset. Conclusion: This study stressed the known importance of using age-specific RIs for TSH and FT4 in children. This study also showed the clinical relevance of using age-specific RIs for TSH in adulthood to reduce diagnoses of subclinical hypothyroidism in older persons. Therefore, implementation of adult TSH age-specific RIs should be strongly considered. Data are less uniform regarding FT4 age-specific RIs and more research should be performed before implementing these in clinical practice.

Estimation of gestational age-specific reference intervals for coagulation assays in a neonatal intensive care unit using real-world data

BackgroundInterpretation of coagulation testing in neonates currently relies on reference intervals (RIs) defined from older patient cohorts. Direct RI studies are difficult, but indirect estimation may allow us to infer normative neonatal distributions from routinely collected clinical data. ObjectiveAssess the utility of indirect reference interval methods in estimating coagulation reference intervals in critically ill neonates. MethodsWe analyzed first-in-life coagulation testing results from all patients admitted to a level IV neonatal intensive care unit between January 1, 2018, and January 1, 2024. Results obtained after transfusion of any blood product were excluded. Indirect RIs were estimated across gestational age groups using refineR and compared with currently reported intervals for patients less than 1 year of age. ResultsProthrombin times (PTs) and international normalized ratios (INRs) were available for 1128 neonates, while activated partial thromboplastin times (APTTs) were available for 790 neonates. The indirect RI was 10 to 25 seconds in preterm, 10 to 22 seconds in term, and 10 to 24 seconds in all neonates for PT; 0.7 to 2.1 in preterm, 0.8 to 1.8 in term, and 0.8 to 1.9 in all neonates for INR; and 25 to 68 seconds in preterm, 25 to 58 seconds in term, and 25 to 62 seconds in all neonates for APTT. Compared with our current intervals, the indirect RIs would flag 58% fewer PT, 43% fewer INR, and 17% fewer APTT results as abnormal. ConclusionIndirectly estimated RIs in neonates admitted to intensive care show substantial divergence from current, first-year-of-life RIs, leading to an abundance of abnormal flags. The associations between these flags and provider behavior, transfusion practice, or clinical outcomes are areas of future exploration.

Sex- and age-based reference intervals for capillary complete blood count parameters among urban preschoolers in southeast China based on a large community population

Background and aimPediatricians commonly use the complete blood count (CBC) of capillary blood to evaluate health status, guide diagnoses, and determine treatment strategies. This study aimed to establish sex- and age-specific reference intervals (RIs) for 23 capillary CBC parameters for urban preschoolers in Fuzhou, Southeast China. Materials and methodsCapillary blood CBC data of 18,369 healthy preschoolers who underwent annual physical examinations at Fujian Maternity and Child Health Hospital between January 01, 2022, and November 31, 2023, were analyzed retrospectively. To fully validate the new RIs, the data of all apparently healthy children within the same age cohort at the same institution were comprehensively analyzed in December 2023. The new RIs were assessed by comparing them with the RIs currently used in laboratories and those obtained from different regions, sample types, or methodologies. ResultsDynamic temporal changes that differ between males and females were observed in the blood system of 3-7-year-old children in this region. The new sex- and age-specific RIs for capillary CBC parameters were feasible to guide clinical decision-making in the local region. ConclusionsOur findings demonstrated the importance of establishing sex- and age-specific RIs for each region and underscored the necessity of continuous adjustment of clinical Rls based on statistical rules and clinical responses.

Sex- and age-specific reference intervals of 16 steroid metabolites quantified simultaneously by LC-MS/MS in sera from 2458 healthy subjects aged 0 to 77 years

BackgroundReference intervals covering the whole life span for all the metabolites in the steroid hormone biosynthesis quantified by sensitive and robust analytical methods are sparse or not existing. ObjectiveTo develop a state-of-the-art LC-MS/MS method for simultaneous quantification of multiple steroid metabolites and to establish detailed sex- and age-specific reference intervals for 16 steroid metabolites. Materials and methodAn isotope diluted LC-MS/MS method was developed for simultaneous quantitation of 16 steroid hormones. Serum samples from cross-sectional cohorts of healthy infants, children, adolescents, and adults aged 0.17 months to 77 years (n = 2458) were analysed. ResultsWith this novel, specific, and sensitive LC-MS/MS method, it was possible to quantify progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, androstenedione, testosterone, dihydrotestosterone, 11-deoxycorticosterone, corticosterone, 11-deoxycortisol, cortisol, and cortisone in ≥90 % of the samples, while estrone sulfate, aldosterone and dehydroepiandrosterone were quantified in 77 %, 75 % and 60 % of the samples, respectively. 21-deoxycortisol was only detectable in 2.5 % of samples from healthy subjects. Sex- and age-dependent fluctuations observed in minipuberty, puberty and adulthood including the menopausal transition were modelled. This enabled us to establish valid reference intervals from birth to late adult life for both males and females. ConclusionDetailed sex- and age-specific reference intervals of multiple, simultaneously quantified steroid metabolites by a novel and specific LC-MS/MS method provides a valuable tool for clinical practice and for future research.

Gestational Age-specific Reference Intervals for Androgens in Pregnancy.

Androgen could impact cervical remodeling during pregnancy, and a higher level is associated with adverse pregnancy outcomes. A population-based gestation age-specific reference interval of total testosterone (TT), androstenedione (A4), and 17-hydroxyprogesterone (17-OHP) can help to diagnose maternal hyperandrogenism. We enrolled 600 healthy Chinese women to obtain longitudinal serum samples across gestation. The serum androgen profile was measured by liquid chromatography-tandem mass spectrometry. The equations for medians of TT, A4, and 17-OHP were generated by MedCal, and the variances adjusted for 2-level modeling were generated by MLwiN, a system for the specification and analysis of a range of multilevel models. A4 and TT levels increased across the gestation, and they closely correlated with each other (R = .90, P = <.001), whereas the 17-OHP level decreased from the 5th gestational week to the 16th gestational week and then increased afterward toward the end of pregnancy. Women diagnosed with preeclampsia (PE) were found to have a significantly higher level of A4, TT, and 17-OHP when compared with non-PE cases with P≤ .01, whereas mothers carrying male vs female fetuses have comparable levels of A4, TT, and 17-OHP. The study highlights a methodology for constructing gestational age-specific TT, A4, and 17-OHP levels to provide a better interpretation of results in a cohort of healthy Chinese women. The observation in PE supports previous findings, and the higher levels of TT, A4, and 17-OHP were observed before the onset of PE.

Patient-derived reference intervals for alkaline phosphatase to support appropriate utility for isoenzymes determinations and hypophosphatasia.

Appropriate age- and sex-specific reference intervals for alkaline phosphatase (ALP) are essential to identify patients with hypophosphatasia (low ALP) and to avoid unnecessary ALP isoenzymes analysis (elevated ALP). This study used patient ALP historical data to statistically derive sex- and age-specific reference intervals. The ALP values reported as part of clinical management during an 18 month period (from July 2021 to March 2023) were obtained. Following logarithmic transformation of ALP data and repeated removal of outliers, cumulative frequency plots were generated using a modified Hoffmann approach to derive age- and sex-specific reference intervals. Age-specific ALP reference intervals ranged from 110 to 250 and 120 to 295 U/L for males and females <15 days old, 80 to 400 and 90 to 380 U/L for males and females 15 days to 1 year old, 105 to 280 and 90 to 290 U/L for males and females 1 to 10 years old, 75 to 300 and 90 to 300 U/L for males and females 10 to 13 years old, 80 to 300 and 60 to 175 U/L for males and females 13 to 15 years old, 55 to 150 and 60 to 180 U/L for males and females 15 to 18 years old, and 55 to 140 and 60 to 147 U/L for male and female adults, respectively (>18 years old). By applying derived ranges, a retrospective review of ALP isoenzymes would eliminate 24.5% of requests. Additionally, 9 neonates would have required investigation for possible hypophosphatasia.

Establishing reference intervals for common hematology test parameters from apparently healthy geriatrics in Asella town, Southeast Ethiopia, 2020: a community-based cross-sectional study.

Reference intervals are an important method tool for identifying abnormal laboratory test results. Complete blood count reference values are useful to interpret complete blood count (CBC) results and make clinical decisions, but these values have not been established for geriatrics in Asella town. Therefore, this study aimed to establish reference intervals (RIs) for complete blood count (CBC) parameters from geriatric participants/subjects in Asella town, Southeast Ethiopia. A community-based cross-sectional study was conducted from December 2019 to May 2020. An interviewer-administered questionnaire was used to collect data on sociodemography and other characteristics from 342 eligible geriatric participants. Weight, height, and vital signs were measured, and 8 mL of blood sample was collected. Screening tests such as HIV, HBsAg, HCV, syphilis, stool examination, and urinalysis were performed. The hematological parameter was measured using a Sysmex kx-21 hematology analyzer. The data were analyzed using SPSS version 21 software. The non-parametric independent Kruskal-Wallis test and Wilcoxon rank-sum test (Mann-Whitney U test) were used to compare the parameters between age groups and genders. The 97.5 and 2.5th percentile were the upper and lower reference limit for the population. According to the study's findings, the reference intervals of red blood cell, white blood cell, platelet count, hemoglobin (HGB), and hematocrit (HCT) in male geriatrics were 3.8-5.85 × 1012/L, 3.1-9.66 × 109/L, 115.8-353 × 109/L, 12.4-17.76 g/dL, and 35.06-50.2%, respectively. The respective values for women were 3.94-5.48 × 1012/L, 3.13-8.4 × 109/L, 137.5-406 × 109/L, 12.5-16.4 g/dL, and 36.09-48.2%. Most of the hematological parameters showed significant differences between the two genders (p value <0.05). Accurate gender and age-specific reference intervals are crucial in managing patient health. The current study offers essential CBC hematological parameters that can assist clinicians in interpreting laboratory results and can improve healthcare quality in the geriatric population. Therefore, it is more relevant to use the current RIs in the geriatric set-up.

Age-specific reference intervals for TSH and FT4 to optimize diagnosis of thyroid disease

Age-specific reference intervals for TSH and FT4 to optimize diagnosis of thyroid disease

Reference intervals of circulating secretoneurin concentrations determined in a large cohort of community dwellers: the HUNT study.

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

Analysis of Serum Free Thyroxine Concentrations in Healthy Term Neonates Underlines Need for Local and Laboratory-Specific Reference Interval: A Systematic Review and Meta-Analysis of Individual Participant Data.

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

Quantitative anatomy of the extensor digiti minimi muscle in the growing human fetus.

Introduction Age-specific reference intervals for the extensor digiti minimi muscle (EDMM) in the human fetus may be relevant in the detailed evaluation of the musculoskeletal systems with potential relevant aspects for surgical treatment. The aim of the study was to examine the age-specific reference intervals and growth dynamics of the EDMM in relation to its length, width, projection surface area and volume. Material and methods The examined material included 70 human formalin-fixed fetuses of both sexes (37♀, 33♂) aged from 17 to 29 weeks. With the use of anatomical dissection every EDMM was visualized, recorded in a form of JPG formats and analyzed by the digital image analysis system and statistical methods. Results No variability of the EDMM was found. All the morphometric parameters of the EDMM revealed neither sex nor laterality differences. With fetal age most linear parameters of the EDMM concerning its examined lengths and widths increased in accordance with natural logarithmic functions. The only two exceptions to this referred to the belly width of EDMM measured at its mid-length and the tendon width of EDMM measured proximal to the extensor retinaculum of wrist, which both followed square root functions. The projection surface areas of the EDMM followed natural logarithmic functions, while the volumetric growth of the EDMM was proportionate to fetal age. Conclusions The variability of the EDMM in the human fetus is minimal. The morphometric data of the EDMM represents age-specific reference intervals of clinical significance. Morphometric parameters of the EDMM reveal neither sex nor laterality differences. The EDMM displays three different growth dynamics: from gradual growth deceleration according to both natural logarithmic functions (total length of the muscle and its tendons, belly length, tendon lengths, belly width at its origin, tendon width at its insertion, and projection surface areas) and square root functions (belly width at its mid-length and tendon width in the pre-retinacular segment) to a proportionate growth (total volume).

Quantitative study of the popliteal fossa in the human fetus.

The popliteal fossa presents an extensive diamond-shaped topographical element on the posterior aspect of the knee. With the use of classical anatomical dissection, digital image analysis of NIS Elements AR 3.0 and statistics we morphometrically analyzed the size of the popliteal fossa in human fetuses aged 17-29 weeks of gestation. Morphometric parameters of the popliteal fossa increased logarithmically with fetal age: y = -44.421 + 24.301 × ln (Age) for length of superomedial boundary, y = -41.379 + 22.777 × ln (Age) for length of superolateral boundary, y = -39.019 + 20.981 × ln (Age) for inferomedial boundary, y = -37.547 + 20.319 × ln (Age), for length of inferolateral boundary, y = -28.915 + 15.822 × ln (Age) for transverse diameter, y = -69.790 + 38.73 × ln (Age) for vertical diameter and y = -485.631 + 240.844 × ln (Age) for projection surface area. Out of the four angles of the popliteal fossa the medial one was greatest, the inferior one the smallest, while the lateral one was somewhat smaller than the medial one and approximately three times greater than the superior one, with no difference with fetal age. In terms of morphometric parameters the popliteal fossa in the human fetus displays neither male-female nor right-left differences. In the popliteal fossa, growth patterns of its four boundaries, vertical and transverse diameters, and projection surface area all follow natural logarithmic functions. All the morphometric data is considered age-specific reference intervals, which may be conducive in the diagnostics of congenital abnormalities in the human fetus.

Serum symmetric dimethylarginine in older dogs: Reference interval and comparison of a gold standard method with the ELISA.

Serum symmetric dimethylarginine (SDMA) is used to screen for renal dysfunction in dogs. The gold standard technique for measuring SDMA, liquid chromatography-tandem mass spectrometry (LC-MS/MS) is not widely available. Age-specific reference intervals for SDMA in older dogs are lacking. Prospective study in older dogs to validate a commercially available LC-MS/MS method for SDMA, compare SDMA concentrations with concentrations measured using ELISA and obtain a reference interval (RI) for older dogs using both methods. Client-owned older dogs undergoing health screening. The LC-MS/MS method was analytically validated (limit of detection, precision, and linearity). Serum was sent cooled overnight for ELISA or was frozen at -80°C until batch analysis using LC-MS/MS. Results of LC-MS/MS and ELISA were compared and RIs for older dogs were calculated according to international guidelines. The LC-MS/MS method showed good linearity (r2 = .99) and precision (coefficient of variation <10%), with a laboratory RI between 8.0 and 14.0 μg/dL. Paired measurements were available from 118 different dogs. Median SDMA concentration were 9.4 (range, 5.0-21.2) using LC-MS/MS and 12.0 (range, 5.0-22.0) μg/dL using ELISA. Both methods significantly differed with a mean difference of 2.2 μg/dL. The RI for older dogs for LC-MS/MS was 4.4-15.0 μg/dL, and for ELISA was 6.4-17.4 μg/dL. The ELISA provided significantly higher SDMA concentrations compared to the validated LC-MS/MS method, indicating the need for device- or assay-specific RI. The obtained age-specific RI for SDMA is considerably higher in older dogs compared to the general laboratory RI.

Age-specific Reference Intervals of Abbott Intact PTH-Potential Impacts on Clinical Care.

PTH assays are not standardized; therefore, method-specific PTH reference intervals are required for interpretation of results. PTH increases with age in adults but age-related reference intervals for the Abbott intact PTH (iPTH) assay are not available. Deidentified serum PTH results from September 2015 to November 2022 were retrieved from the laboratory information system of a laboratory serving a cosmopolitan population in central-west England for individuals aged 18 years and older if the estimated glomerular filtration rate was ≥60 mL/min, serum 25-hydroxyvitamin D was >50 nmol/L, and serum albumin-adjusted calcium and serum phosphate were within reference intervals. Age-specific reference intervals for Abbott iPTH were derived by an indirect method using the refineR algorithm. PTH increased with age and correlated with age when controlled for 25-hydroxyvitamin D, estimated glomerular filtration rate, and adjusted calcium (r = 0.093, P < .001). The iPTH age-specific reference intervals for 4 age partitions of 18 to 45 years, 46 to 60 years, 61 to 80 years, and 81 to 95 years were 1.6 to 8.6 pmol/L, 1.8 to 9.5 pmol/L, 2.0 to 11.3 pmol/L, and 2.3 to 12.3 pmol/L, respectively. PTH was higher in women compared with men (P < .001). Sex-specific age-related reference intervals could not be derived because of the limited sample size. Age-specific Abbott iPTH reference intervals were derived. Application of age-specific reference intervals will impact the diagnosis and management of normocalcemic hyperparathyroidism, based on current definitions, and secondary hyperparathyroidism. Additional studies are required to clarify the effect of sex and ethnicity on PTH.