Reference Range Research Articles

Differentiating mixed epithelial and stromal tumor family from predominantly cystic renal cell carcinoma using magnetic resonance imaging-based Bosniak classification system version 2019.

To differentiate mixed epithelial and stromal tumor family (MESTF) of the kidney from predominantly cystic renal cell carcinoma (RCC) using the magnetic resonance imaging (MRI)-based Bosniak classification system version 2019 (v2019). The study included 36 consecutive patients with MESTF and 77 with predominantly cystic RCC who underwent preoperative renal MRI. One radiologist evaluated and documented the clinical and MRI characteristics (age, sex, laterality, R.E.N.A.L. Nephrometry Score [RNS], surgical approach, the signal intensity on T2-weighted imaging, restricted diffusion and enhancement features in corticomedullary phase). Blinded to clinical and pathological information, another two radiologists independently evaluated Bosniak category of all masses. Interobserver agreement based on Bosniak classification system v2019 was measured by the weighted Cohen/Conger's Kappa coefficient. Furthermore, predominantly cystic RCCs and MESTFs were divided into low (categories I, II, and IIF) and high-class (categories III, and IV) tumors. The independent sample t test (Mann-Whitney U test) or Pearson Chi-square test (Fisher's exact probability test) was utilized to compare clinical and imaging characteristics between MESTFs and predominantly cystic RCCs. The performance of the Bosniak classification system v2019 in distinguishing MESTF from predominantly cystic RCC was investigated via receiver operating characteristic curve analysis. MESTF and predominantly cystic RCC groups significantly differed in terms of age, lesion size, RNS, restricted diffusion, and obvious enhancement in corticomedullary phase, but not sex, laterality, surgical approach, and the signal intensity on T2WI. Interobserver agreement was substantially based on the Bosniak classification system v2019. There were 24 low-class tumors and 12 high-class tumors in the MESTF group. Meanwhile, 13 low-class tumors and 64 high-class tumors were observed in the predominantly cystic RCC group. The distribution of low- or high-class tumors significantly differed between the MESTF and predominantly cystic RCC groups. Bosniak classification system v2019 had excellent discrimination (cutoff value = category III), and an area under curve value was 0.81; accuracy, 80.5%; sensitivity, 87.0%; and specificity, 66.7%. The MRI-based Bosniak classification system v2019 can effectively distinguish MESTF from predominantly cystic RCC if category III was used as a cutoff reference.

Reference intervals for knee functions specific to outpatients with knee osteoarthritis: a cross-sectional study.

Reference values (RVs) for knee function tests have been reported in perioperative patients with knee osteoarthritis (KOA); however, such values for practical use in outpatient setting has yet to be determined. Therefore, we aimed to establish the reference intervals (RIs) for outpatients with mild to moderate KOA. This cross-sectional study enrolled 202 outpatients with KOA from 8 Japanese orthopedic clinicsand measured knee extensor/flexor muscle strength (MS) and knee extension/flexion range of motion (ROM). We used multiple regression analysis to evaluate the sources of variation, including sex, age, body mass index, Kellgren-Lawrence (K-L) classification, bilateral KOA, and exercise habits. Magnitude of between-subgroup differences is expressed as standard deviation ratio (SDR) based on a three-level nested analysis of variance, with SDR ≥ 0.4 as the threshold for requiring RIs specific for subgroups. RIs were calculated parametrically using two-parameter Box-Cox formula if Gaussian transformation of RVs was successful, otherwise calculated nonparametrically. Partitioning was required by sex for extensor and flexor MS (SDR = 0.65, 0.57, respectively) and by K-L classification for flexion ROM (SDR = 0.54). RIs were determined parametrically for extensor MS as 0.27-2.09 (male) and 0.27-1.54 (female) Nm/kg and for flexor MS 0.18-1.20 (male) and 0.13-0.79 (female) Nm/kg. On the other hand, RIs for extension and flexion ROM were determined nonparametrically due to discrete nature of their RVs. The RIs determined for extension ROM were -15°-0° and for flexion ROM were 105°-150° (for K-L grade I/II) and 95°-140° (for K-L grade III/IV). The ranges of RIs determined specifically for patients with mild to moderate KOA were in-between those of age-matched healthy controls and pre-surgical KOA patients, both of which we had reported for use in physiotherapeutic management of KOA patients undergone total knee arthroplasty. The newly derived RIs will provide an objective benchmark for physiotherapy targeting outpatients with mild to moderate KOA.

Point-of-care viscoelastic coagulation monitor parameters in Amazon parrots (Amazona spp.).

To evaluate the feasibility of the point-of-care viscoelastic coagulation monitor (VCM) in Amazon parrots (Amazona spp.) and describe the parameters with fresh whole-blood samples in healthy Amazon parrots. A total of 18 Amazon parrots were enrolled. Physical examinations, a CBC, and a biochemistry profile, including bile acids, were performed on all parrots. VCM tracings were obtained at the time of venipuncture for baseline laboratory work. The median clot time was 2102seconds (range: 38.6-3599s), median clot formation time was 929seconds (range: 21.4-1711s), median alpha angle was 20 (range: 6-67), and the median maximum clot formation was 8.5 (range: 0-36). The median lysis index at 30minutes (LI30) was 100 (range: 98-100), and the median lysis index at 45minutes (LI45) was 100 (range: 90-100). Of 18 samples, alpha angles were not reported in 7 samples, LI30 was not reported in 10 samples, and LI45 was not reported in 12 samples. Of the qualitative curves, 6 reflected normal mammalian curves, and the remainder were consistent with a hypocoaguable state. The results were markedly variable, with the majority of VCM tracings being hypocoagulable in comparison with reference intervals established for dogs and cats. Using these protocols, the VCM is not reliable in Amazon parrots. Future areas of investigation include altering the temperature during sample analysis, the use of activators, or an exchange of clotting reagents for an extrinsic pathway activator, which may contribute to the success of this device in avian species.

Enhanced patient-based real-time quality control using the graph-based anomaly detection.

Patient-based real-time quality control (PBRTQC) is an alternative tool for laboratories that has gained increasing attention. Despite the progress made by using various algorithms, the problems of data volume imbalance between in-control and out-of-control results, as well as the issue of variation remain challenges. We propose a novel integrated framework using anomaly detection and graph neural network, combining clinical variables and statistical algorithms, to improve the error detection performance of patient-based quality control. The testing results of three representative analytes (sodium, potassium, and calcium) and eight independent variables of patients (test date, time, gender, age, department, patient type, and reference interval limits) were collected. Graph-based anomaly detection network was modeled and used to generate control limits. Proportional and random errors were simulated for performance evaluation. Five mainstream PBRTQC statistical algorithms were chosen for comparison. The framework of a patient-based graph anomaly detection network for real-time quality control (PGADQC) was established and proven feasible for error detection. Compared with classic PBRTQC, the PGADQC showed a more balanced performance for both positive and negative biases. For different analytes, the average number of patient samples until error detection (ANPed) of PGADQC decreased variably, and reductions could reach up to approximately 95 % at a small bias of 0.02 taking calcium as an example. The PGADQC is an effective framework for patient-based quality control, integrating statistical and artificial intelligence algorithms. It improves error detection in a data-driven fashion and provides a new approach for PBRTQC from the data science perspective.

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

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

Normative data for insulin-like growth factor-1 (IGF-1) in healthy children and adolescents from India.

Serum IGF-1 is an important biochemical tool to diagnose and monitor GH-related disorders. However, ethnic-specific Indian data following consensus criteria for the establishment of normative data, are not available. Our objective was to generate chronological age (CA)-, bone age (BA)- and Tanner stage-specific normative data for IGF-1 in healthy Indian children and adolescents. A cross-sectional epidemiological study was conducted in schools and the community, which enrolled apparently healthy children and adolescents with robust exclusion criteria. The outcome measure was serum IGF-1 assessed using an electro-chemiluminescence immunoassay (ECLIA). The 2.5th, 5th, 10th, 25th, 50th (median), 75th, 90th, 95th, and 97.5th centiles for IGF-1 were estimated using generalized additive models. We recruited 2226 apparently healthy participants and following exclusion, 1948 (1006 boys, 942 girls) were included in the final analysis. Girls had median IGF-1 peak at CA of 13 years (321.7 ng/mL), BA of 14 years (350.2 ng/mL) and Tanner stage IV (345 ng/mL), while boys had median IGF-1 peak at CA of 15 years (318.9 ng/mL) BA of 15 years (340.6 ng/mL) and Tanner stage III (304.8 ng/mL). Girls had earlier rise, peak and higher IGF-1 values. The reference interval (2.5th-97.5th percentile) was broader during peri-pubertal ages, indicating a higher physiological variability. This study provides ethnicity-specific normative data on serum IGF-1 and will improve the diagnostic utility of IGF-1 in the evaluation and management of growth disorders in Indian children and adolescents.

Defining Trimester-Specific Reference Intervals for Thyroid Hormones: Insights from a Bulgarian Monocenter Study

Defining Trimester-Specific Reference Intervals for Thyroid Hormones: Insights from a Bulgarian Monocenter Study

Dynamic mirroring: unveiling the role of digital twins, artificial intelligence and synthetic data for personalized medicine in laboratory medicine.

In recent years, the integration of technological advancements and digitalization into healthcare has brought about a remarkable transformation in care delivery and patient management. Among these advancements, the concept of digital twins (DTs) has recently gained attention as a tool with substantial transformative potential in different clinical contexts. DTs are virtual representations of a physical entity (e.g., a patient or an organ) or systems (e.g., hospital wards, including laboratories), continuously updated with real-time data to mirror its real-world counterpart. DTs can be utilized to monitor and customize health care by simulating an individual's health status based on information from wearables, medical devices, diagnostic tests, and electronic health records. In addition, DTs can be used to define personalized treatment plans. In this study, we focused on some possible applications of DTs in laboratory medicine when used with AI and synthetic data obtained by generative AI. The first point discussed how biological variation (BV) application could be tailored to individuals, considering population-derived BV data on laboratory parameters and circadian or ultradian variations. Another application could be enhancing the interpretation of tumor markers in advanced cancer therapy and treatments. Furthermore, DTs applications might derive personalized reference intervals, also considering BV data or they can be used to improve test results interpretation. DT's widespread adoption in healthcare is not imminent, but it is not far off. This technology will likely offer innovative and definitive solutions for dynamically evaluating treatments and more precise diagnoses for personalized medicine.

Preliminary Results of Variation in Plasma N-acetyl-beta-D-glucosaminidase Concentration Among Bearded Dragons (Pogona vitticeps), Corn Snakes (Pantherophis guttatus), and Wood Turtles (Glyptemys insculpta)

Abstract N-acetyl-beta-D-glucosaminidase (NAG) is a lysosomal enzyme found in renal tubular epithelial cells whose concentration can be measured in blood as a possible diagnostic tool to monitor renal disease; however, no reference values are currently available in reptiles. This study investigated the presence of plasma NAG concentrations in 3 reptile species. Blood samples were obtained from clinically healthy bearded dragons (Pogona vitticeps; n = 13), corn snakes (Pantherophis guttatus; n = 9) and wood turtles (Glyptemys insculpta; n = 13). To further assess renal health, a biochemistry panel was performed for all animals, and renal biopsies were collected from the bearded dragons and snakes, but not from the turtles. Biopsies were not taken from wood turtles to limit the risk associated with anesthetizing an endangered species. Of the 35 animals sampled, 29 were considered healthy and included in the study. Plasma NAG concentrations in the wood turtles were significantly lower than in the corn snakes (P = 0.004) and plasma NAG concentrations in the corn snakes were significantly higher than in bearded dragons (P = 0.038). Wood turtles had the lowest NAG concentrations, followed by bearded dragons and corn snakes. In conclusion, NAG reference intervals should be established for each reptile species and analyte validation is needed for this assay in reptiles. Further research is needed to establish NAG reliability as a diagnostic tool in reptiles.

Complete Blood Count Reference Intervals for Children Aged Less Than 1 to 12 Years in the Northern Region of Ghana.

Reliable laboratory diagnostic results are key for evaluating and improving children's health. To interpret these results, child-specific reference intervals (RIs), which account for constant biological changes and physiological development with sex and age, are required, as recommended by the Clinical and Laboratory Standards Institute (CLSI). This study presents age- and sex-specific reference intervals for complete blood count (CBC) parameters in children (<1-12 years old) in the Northern Region of Ghana. In this cross-sectional study, 600 healthy children from randomly sampled schools in Tamale (the Northern Region) were recruited and screened. Data from 388 eligible children were used to nonparametrically determine the reference intervals of CBC parameters at the 2.5th and 97.5th percentiles. The CBC reference intervals were compared for variations in sex and age groups using the Wilcoxon rank-sum test. There were no statistically significant differences in most CBC parameters by sex (RBC, Hb, HCT, MCH, RDW (CV/SD), WBC, LYM#, MON#(%) NEU#(%), EOS#(%), and BAS#(%); p > 0.05) and age group (RBC, MCV, RDW (CV/SD), WBC, LYM#, MON#(%) NEU#(%), EOS#(%), and BAS%; p > 0.05). However, there were observable differences between this locally established CBC reference interval and that used for children at Tamale Teaching Hospital (manufacturer's RIs). This study emphasises the importance of determining reference intervals representative of the local child population and incorporating them into the current reporting system of laboratories in the Northern Region to ensure the provision of effective and efficient healthcare services.

Establishment of dry-chemistry-based reference intervals of routine liver function tests for the adult population of Gandaki Province, Nepal.

Every clinical laboratory should ideally establish its own population-specific reference intervals (RIs) to promote precision and evidence-based medicine. However, clinical laboratories in Nepal find it easier to follow external RIs than establish their own, leading to a lack of RIs specific to the local population. This study thus aimed to establish RIs of routine LFTs for the adult population of Gandaki Province, Nepal, and compare them with the current RIs used by our laboratory. We established the dry-chemistry-based reference intervals of 11 common LFT parameters for the adult population of Gandaki Province, Nepal using the direct priori-based method. The combined and sex-specific 95% double-sided RIs of total protein, albumin, globulin, A/G ratio, bilirubin, aspartate aminotransaminase (AST), alanine aminotransaminase (ALT), AST/ALT ratio, and alkaline phosphatase (ALP) were established using non-parametric percentile method. The new RIs were also compared with the currently used RIs that were adopted from the reagent kit inserts. The newly established RIs for each LFT were: Total proteins: 68.0-69.0g/L, albumin: 39.0-52.0g/L; globulin: 27.0-42.0g/L; A/G ratio: 1.1-1.8; total bilirubin: 5.13-25.65μmol/L (0.30-1.50mg/dl); unconjugated bilirubin: 1.71-17.10μmol/L (0.10-1.00mg/dl); conjugated bilirubin: 0.00-10.26 μmol/L (0.00-0.60mg/dl); AST: 20.0-43.2U/L; ALT: 11.0-53.0 U/L; AST/ALT ratio: 0.7-2.1; ALP: 42.0-135.4U/L. The RIs of albumin, globulin, A/G ratio, AST, ALT, and AST/ALT ratio differed significantly (p < 0.05) between males and females. Moreover, calculated out-of-range values showed that up to 4-40% of apparently healthy adults were classified as having abnormal test results based on current RIs. The newly established RIs fulfil the need for population and platform-specific RIs for the adult population of Gandaki Province of Nepal and bring more conformity and accuracy in interpreting the LFT results, diagnosis of hepatobiliary diseases, clinical decision-making, monitoring the success of therapy and future liver specific biomedical researches within the Gandaki Province of Nepal.

Novel standardized indexes of brainstem auditory evoked potentials for predicting hearing preservation in vestibular schwannomas

Hearing preservation (HP) during vestibular schwannomas (VSs) surgery poses a significant challenge. Although brainstem auditory evoked potentials (BAEPs) on the affected side are commonly employed to monitor cochlear nerve function, their low signal-to-noise ratio (SNR) renders them susceptible to interferences, compromising their reliability. We retrospectively analyzed the data of patients who underwent tumor resection, while binaural brainstem auditory evoked potentials (BAEPs) were simultaneously recorded during surgery. To standardize BAEPs on the affected side, we incorporated the synchronous healthy side as a reference (interval between affected and healthy side ≤ 3 min). A total of 127 patients were enrolled. Comparison of the raw BAEPs data pre- and post-tumor resection revealed that neither V-wave amplitude (Am-V) nor latency (La-V) could serve as reliable predictors of HP simultaneously. However, following standardization, V-wave latency (STIAS-La-V) and amplitude (STIAS-Am-V) emerged as stable predictors of HP. Furthermore, the intraoperative difference in V-wave amplitude (D-Am-V) predicted postoperative HP in patients with preoperative HP and remained predictive after standardization. The utilization of intraoperative synchronous healthy side BAEPs as a reference to eliminate interferences proves to be an effective approach in enhancing the reliability of BAEPs for predicting HP in VSs patients.

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

Exploring Appropriate Reference Intervals and Clinical Decision Limits for Glucose-6-Phosphate Dehydrogenase Activity in Individuals From Guangzhou, China.

Quantitative detection of glucose-6-phosphate dehydrogenase (G6PD) is commonly done to screen for G6PD deficiency. However, current reference intervals (RIs) of G6PD are unsuitable for evaluating G6PD-activity levels with local populations or associating G6PD variants with hemolysis risk to aid clinical decision-making. We explored appropriate RIs and clinical decision limits (CDLs) for G6PD activity in individuals from Guangzhou, China. We enrolled 5,852 unrelated individuals between 2020 and 2022 and screened their samples in quantitative assays for G6PD activity. We conducted further investigations, including G6PD genotyping, thalassemia genotyping, follow-up analysis, and statistical analysis, for different groups. In Guangzhou, the RIs for the G6PD activities were 11.20-20.04 U/g Hb in male and 12.29-23.16 U/g Hb in female. The adjusted male median and normal male median (NMM) values were 15.47 U/g Hb and 15.51 U/g Hb, respectively. A threshold of 45% of the NMM could be used as a CDL to estimate the probability of G6PD variants. Our results revealed high hemolysis-risk CDLs (male: <10% of the NMM, female: <30% of the NMM), medium hemolysis-risk CDLs (male: 10%-45% of the NMM, female: 30%-79% of the NMM), and low hemolysis-risk CDLs (male: ≥ 45% of the NMM, female: ≥ 79% of the NMM). Collectively, our findings contribute to a more accurate evaluation of G6PD-activity levels within the local population and provide valuable insights for clinical decision-making. Specifically, identifying threshold values for G6PD variants and hemolysis risk enables improved prediction and management of G6PD deficiency, ultimately enhancing patient care and treatment outcomes.

Are shortened aPTT values always to be attributed only to preanalytical problems?

It has been recognized that shortened activated partial thromboplastin time (aPTT) may be caused by various preanalytical conditions. As coagulation Factor VIII is included in the invitro intrinsic coagulation cascade measured by aPTT, we hypothesized that the shortened aPTT could be a result of elevated FVIII activity. We aimed to inspect the connection of elevated FVIII with shortened aPTT, and the possible effect inflammation has on routine laboratory parameters. 40 patients from various hospital departments with aPTT measurement below the lower limit of the reference interval (<23.0 s) were included in the study. To compare the obtained results with aPTT measurements in the non-inflammatory state, samples from 25 volunteers (laboratory personnel) were collected. White blood cell count, C-reactive protein, aPTT, and FVIII values were measured in the control group. Only two samples among 40 patients with shortened aPTT (5 %) were clotted. Out of the remaining 38, 26 had FVIII activity above 150 % (upper limit of a reference interval), median value of 194 % (IQR: 143-243 %). Seven samples in the control group had shortened aPTT results (36 %). However, all coagulation samples were clot and hemolysis-free. Multiple regression identified only FVIII activity as an independent variable in predicting aPTT values (p=0.001). Our results support the thesis that shortened aPTT is rarely a consequence of preanalytical problems. Elevated FVIII activity causes shortened aPTT, not only in theinflammatory state but also in individuals with concentration of inflammatory markers within reference intervals.

Specimen type validation and establishment of normal cytokine reference intervals in cerebrospinal fluid

Cerebrospinal fluid (CSF) is a critical body fluid to examine in attempts to discover potential biomarkers for neuroinflammatory and other disorders of the central nervous system (CNS). Serum and/or plasma cytokine levels have been associated with a variety of inflammatory conditions, and some have been shown to be actionable therapeutic targets. Less is known, however, about cytokine levels in CSF. Serum and plasma cytokine testing is widely available in clinical and research laboratories, but cytokine testing in CSF is extremely limited and if performed, accompanied by a disclaimer that it is an unvalidated specimen type. In this study, we validate CSF as a suitable specimen type and determine normal reference intervals for multiple cytokines as well as a soluble cytokine receptor. CSF was validated as a specimen type for testing using a laboratory developed multiplexed cytokine assay previously validated to measure 13 cytokines/markers in serum and plasma. Performance parameters including specimen dilution, specimen interference, linearity and precision were examined. Reference intervals were established using 197 normal and control CSF specimens by non-parametric quantile-based methods. CSF cytokine analysis demonstrated within and between run precision of <10% and < 20% CV, respectively and linearity of ±15% for all analytes throughout the analytical measurement range of the assay. Reference intervals for the 13 cytokines/markers were established from 197 normal and control CSF specimens (78 Male; mean 44.8 y ± 21.7 SD, 119 Female; mean 42.8 y ± 20.3 SD). Cytokine concentrations in CSF from normal donors and controls were less than the lower limit of quantitation of our assay for 6 of the 13 measured cytokines/markers. The chemokine IL8 demonstrated the highest concentration of all analytes measured. CSF demonstrated acceptable performance as a specimen type in our multiplexed cytokine assay. By validating CSF as a specimen type and establishing normal reference intervals for cytokine concentrations in CSF, their potential as biomarkers for infectious, autoimmune and other inflammatory CNS disorders can be more appropriately investigated.

Creatine kinase serum levels in children revisited: New reference intervals from a large cohort of healthy children and adolescents

BackgroundCreatine Kinase (CK) has become increasingly important in pediatrics as a commonly used laboratory screening parameter for neuromuscular diseases. Recent research suggests that hyperCKemia in children is not always associated with pathology and can occur due to several reasons. Little is known of various clinical factors that may influence CK throughout child development. ObjectiveThis study aimed to establish reliable age- and sex-specific reference ranges for serum CK levels in healthy infants, children, and adolescents. In addition, the effect of puberty, oral contraceptive (OC) use as well as steroid hormones on CK was examined. Materials and methodsThe data was collected from subjects of the longitudinal population-based “LIFE Child”-cohort between 2011 and 2016 in Leipzig, Germany. 5238 blood samples of 2707 healthy children, aged between 0.14 months and 18 years, were analyzed. ResultsSerum CK levels raised during the first year of life, peaking shortly after age one (P50girls = 2.7 µkat/L, P50boys = 2.90 µkat/L). There was a pronounced difference in the 97.5th percentile between boys and girls during adolescence with its maximum at age 18 (P97.5girls = 5.74 µkat/L, P97.5boys14.48 µkat/L). Also, mean CK serum levels were significantly higher in boys (bboys = 0.29, pboys < 0.001). Intake of oral contraceptives (OC), extreme underweight, underweight and obesity revealed a significant inverse correlation with CK serum levels. ConclusionAge, sex, OC intake and weight status affect serum CK levels, particularly during infancy and puberty. We recommend the use of age- and sex-specific reference values for CK serum levels to assess the clinical relevance of measurements.

Applying indirect reference interval method for the reference interval appropriateness assessment: A retrospective study from a medical center

Applying indirect reference interval method for the reference interval appropriateness assessment: A retrospective study from a medical center

Determination of reference intervals for magnesium, manganese and molybdenum by ICP-MS in different age and sex groups

Determination of reference intervals for magnesium, manganese and molybdenum by ICP-MS in different age and sex groups

Establishing population-specific reference intervals for AMH & enhancing its use as a diagnostic marker in PCOS

Establishing population-specific reference intervals for AMH & enhancing its use as a diagnostic marker in PCOS