Laboratory Reference Intervals Research Articles

Seasonally adjusted laboratory reference intervals to improve the performance of machine learning models for classification of cardiovascular diseases

BackgroundVariation in laboratory healthcare data due to seasonal changes is a widely accepted phenomenon. Seasonal variation is generally not systematically accounted for in healthcare settings. This study applies a newly developed adjustment method for seasonal variation to analyze the effect seasonality has on machine learning model classification of diagnoses.MethodsMachine learning methods were trained and tested on ~ 22 million unique records from ~ 575,000 unique patients admitted to Danish hospitals. Four machine learning models (adaBoost, decision tree, neural net, and random forest) classifying 35 diseases of the circulatory system (ICD-10 diagnosis codes, chapter IX) were run before and after seasonal adjustment of 23 laboratory reference intervals (RIs). The effect of the adjustment was benchmarked via its contribution to machine learning models trained using hyperparameter optimization and assessed quantitatively using performance metrics (AUROC and AUPRC).ResultsSeasonally adjusted RIs significantly improved cardiovascular disease classification in 24 of the 35 tested cases when using neural net models. Features with the highest average feature importance (via SHAP explainability) across all disease models were sex, C- reactive protein, and estimated glomerular filtration. Classification of diseases of the vessels, such as thrombotic diseases and other atherosclerotic diseases consistently improved after seasonal adjustment.ConclusionsAs data volumes increase and data-driven methods are becoming more advanced, it is essential to improve data quality at the pre-processing level. This study presents a method that makes it feasible to introduce seasonally adjusted RIs into the clinical research space in any disease domain. Seasonally adjusted RIs generally improve diagnoses classification and thus, ought to be considered and adjusted for in clinical decision support methods.

Adult Male Hypogonadism: A Laboratory Medicine Perspective on Its Diagnosis and Management.

Testosterone (T), the principal androgen secreted by the testes, plays an essential role in male health. Male hypogonadism is diagnosed based on a combination of associated clinical signs and symptoms and laboratory confirmation of low circulating T levels. In this review, we have highlighted factors, both biological and analytical, that introduce variation into the measurement of serum T concentrations in men; these need to be considered when requesting T levels and interpreting results. There is an ongoing need for analytical standardisation of T assays and harmonisation of pre- and post-analytical laboratory practices, particularly in relation to the laboratory reference intervals provided to clinicians. Further, there is a need to share with service users the most up-to-date and evidence-based action thresholds for serum T as recommended in the literature. Estimation of free testosterone may be helpful. Causes of secondary hypogonadism should be considered. A comprehensive approach is required in the management of male hypogonadism, including lifestyle modification as well as medication where appropriate. The goal of treatment is the resolution of symptoms as well as the optimisation of metabolic, cardiovascular, and bone health. The advice of an endocrinologist should be sought when there is doubt about the cause and appropriate management of the hypogonadism.

Reference Intervals of Haematological Parameters for Apparently Healthy Adults in Northeast Ethiopia.

Clinical laboratory reference intervals play a vital role in evaluating overall well-being, tracking the progression of diseases, and detecting potential harmful effects and complications. Despite evidence revealing disparities, many African nations currently rely on reference intervals for blood analysis obtained mainly from Western populations. This practice increases the risk of misidentifying and misdiagnosing healthy individuals. The aim of this study was to establish common hematological parameters reference intervals for healthy adults in Northeast Ethiopia. This community-based cross-sectional study consisted of 328 individuals who were presumed to be in good health. To assess their blood-related characteristics, blood samples were collected and analyzed using the advanced Dirui BF-6500 analyzer, along with serological testing. In accordance with guidelines provided by the Clinical and Laboratory Standards Institute, the study employed a non-parametric approach to calculate the medians and 95% confidence intervals. To explore potential variations between males and females, a statistical test known as the Mann-Whitney U-test was used to compare the reference intervals. The established reference intervals were: white blood cells 3.5-11.3×109/L; red blood cells 4.0-6.1×1012/L; hemoglobin 11.2-17.5g/dL; hematocrit 35.4-52.0%; MCV 77.9-93.8fl; MCH 24.7-32.0pg; MCHC 306-349g/L; RDW-CV 12.1-13.8% and platelet 131-391×109/L. The reference values of monocytes, eosinophils, red blood cells, hemoglobin, hematocrit and RDW-CV in males were higher than females, while females had significantly higher platelet counts compared to males. The reference intervals discovered differed from the reference intervals now in use, those mentioned in earlier research in Ethiopia or other African nations, as well as those conducted on Western populations. In the adult demographic of Northeast Ethiopia, specific reference intervals for commonly observed hematological parameters were established, tailored to the local community. Consequently, these reference intervals hold the potential to enhance informed decision-making within this population, by providing valuable guidance when interpreting laboratory test outcomes.

Non-parametric Clinical Laboratory Reference Interval Estimation in Volunteer Blood Donors: An Example for Prothrombin Time and Partial Thromboplastin Time

Introduction. To date, there are no reference intervals for prothrombin time (PT) and activated partial thromboplastin time (APTT) based on “normal” Filipino adults. The common practice in most laboratories is to adopt manufacturer provided values or foreign literature even if the importance of establishing or at least verifying laboratory reference intervals has been stressed by Clinical Laboratory Standards Institute (CLSI). Objectives. Here we aim to describe our experience in using a simple non-parametric method to generate reference intervals for PT and APTT, from healthy Filipino volunteer blood donors. Methodology. We used a de novo, a priori non-parametric estimation method following the CLSI guidelines on establishing reference intervals. Results. The non-parametric lower reference limit for PT is 12.55 seconds, with 90% confidence interval of 12.3 to 12.75 seconds. While the non-parametric upper reference limit for PT is 16.15 seconds, with 90% confidence interval of 15.55 to 16.55 seconds. The non-parametric lower reference limit for activated partial thromboplastin time is 26.12 seconds, with 90% confidence interval of 22.95 to 27.1 seconds, and the non-parametric upper reference limit for activated partial thromboplastin time is 37.44 seconds, with 90% confidence interval of 36.75 to 38.65 seconds. The PT and APTT reference intervals were different from foreign sources and manufacturer provided values in terms of interval width and values of the reference limits by 2 to 4 seconds. Conclusion and Recommendations. Estimation of coagulation reference intervals from volunteer health blood donors is doable, simple, and practical. Collaborative multi-center efforts may be done to expand the pool of reference individuals that are included and increase the representativeness of the reference intervals generated. This simple method can also be used to generate reference intervals for other clinical laboratory assays and may also be extended to at least verify reference intervals in special populations like pregnant women, the elderly, and the pediatric population.

Region-specific laboratory reference intervals are important: A systematic review of the data from Africa.

Region-specific laboratory reference intervals (RIs) are important for clinical trials and these data are often sparse in priority areas for research, including Africa. We reviewed data on RIs from Africa to identify gaps in the literature with a systematic review of PubMed for RI studies from Africa published ≥2010. Search focus included clinical analytic chemistry, hematology, immunological parameters and RIs. Data from adults, adolescents, children, pregnant women, and the elderly were included. We excluded manuscripts reporting data from persons with conditions that might preclude clinical trial participation in studies enrolling healthy volunteers. Of 179 identified manuscripts, 80 were included in this review, covering 20 countries with the largest number of studies in Ethiopia (n = 23, 29%). Most studies considered healthy, nonpregnant adults (n = 55, 69%). Nine (11%) studies included pregnant women, 13 (16%) included adolescents and 22 (28%) included children. Recruitment, screening, enrollment procedures and definition of age strata varied across studies. The most common type of RIs reported were hematology (66, 83%); 14 studies (18%) included flow cytometry and/or T cell counts. Other common tests or panels included liver function assays (32, 40%), renal function assays (30, 38%), lipid chemistries (17, 21%) and serum electrolytes (17, 21%). The number of parameters characterized ranged from only one (three studies characterized either CD4+ counts, D-dimer, or hemoglobin), to as many as 40. Statistical methods for calculating RIs varied. 56 (70%) studies compared their results to international RI databases. Though most presented their data side-by-side with international data with little accompanying analysis, nearly all reported deviation from comparator RI data, sometimes with half or more of otherwise healthy participants having an "out of range" result. We found there is limited local RI data available in sub-Saharan Africa. Studies to fill this gap are warranted, including efforts to standardize statistical methods to derive RIs, methods to compare with other RIs, and improve representative participant selection.

Performance Characteristics of DOAC-Remove for Neutralization of the Effects of Apixaban and Rivaroxaban in Lupus Anticoagulant Assays.

This study established the performance characteristics of DOAC-Remove for neutralization of the effects of rivaroxaban and apixaban in lupus anticoagulant (LAC) testing. Normal donor, LAC control, and patient samples were spiked with rivaroxaban or apixaban to simulate their effects on the dilute Russell's viper venom time (dRVVT), activated partial thromboplastin time (APTT), and dilute prothrombin time (dPT). Anti-Xa activity was measured after spiking and after DOAC-Remove neutralization. Accuracy, complex precision, and reference interval verification were evaluated. DOAC-Remove neutralized rivaroxaban and apixaban concentrations as high as 415 ng/mL and 333 ng/mL, respectively. Percentage positive and negative agreement between the baseline and postneutralization interpretations were 75% or higher for the dRVVT and APTT methods but not for the dPT method. Coefficients of variation (CVs) were 10% or less for all assays except the Staclot-LA delta, which had a standard deviation of 2.5 seconds or CV of 25% or less depending on the level. The laboratory's reference intervals were verified for the dRVVT and APTT assays after DOAC-Remove treatment but not for the dPT assays. DOAC-Remove appears to have acceptable performance characteristics for neutralizing the effects of rivaroxaban and apixaban in the dRVVT and APTT methods but not in the dPT method.

First Estimation of Reference Intervals for Thyroid-Stimulating Hormone and Thyroid Hormones in Slovenian Population

For thyroid function estimation and clinical decision making, use of appropriate reference intervals for thyroid-stimulating hormone (TSH), free thyroxine (fT4) and free triiodothyronine (fT3) is crucial. For each laboratory, establishment of own reference intervals is advised. For the first Slovenian estimation of reference intervals for thyroid hormones a large group of 1722 healthy individuals without thyroid disease was established retrospectively. Hormone analyses were performed on automated analyser Advia Centaur XP Immunoassay System (Siemens Healthineers), which reference intervals for TSH, fT4 and fT3 were 0.55-4.78 mIU/L, 11.5-22.7 pmol/L, and 3.5-6.5 pmol/L, respectively. Statistical analysis followed non-parametric percentile method. Our laboratory reference intervals for TSH, fT4 and fT3 are mostly narrower than intervals given by manufacturer. Median value, lower and upper limit for TSH, fT4 and fT3 were 1.98 (0.59-4.23) mIU/L, 14.5 (11.3-18.8) pmol/L and 4.82 (3.79-6.05) pmol/L, respectively. Most likely, an inclusion of a high number of healthy individuals without thyroid disease was a reason for such results.

Establishing local reference intervals for full blood count and white blood cell differential counts in Cape Town, South Africa.

Accurate laboratory reference intervals (RIs) are essential to differentiate between health and disease. There are variations in haematological indices within populations relating to gender, age, ethnicity and environment. Iron deficiency is common, has a wide range of clinical morbidities and affects red cell indices. Locally derived RIs for full blood count (FBC) parameters are needed for the Western Cape region of South Africa, after the exclusion of iron deficiency. In addition, information regarding the prevalence of iron deficiency in first-time blood donors would inform blood transfusion services regarding policies to screen for and treat iron deficiency. To establish locally derived RIs for FBC and white blood cell (WBC) differential count parameters in healthy adults in the Cape Town area, by including first-time blood donors and excluding those with iron deficiency and thalassaemic indices. These new locally established RIs could update those in use by the local National Health Laboratory Service. A secondary objective was to establish the prevalence of iron deficiency in first-time blood donors. This would inform blood donation policies regarding screening and appropriate iron supplementation in high-risk groups prior to blood donation. This was a prospective, descriptive study with direct convenience sampling. Participants were prospective voluntary blood donors aged between 18 and 60 years, presenting for first-time blood donation. Ethnicity was self-identified. Participants who tested positive for HIV or hepatitis B and/or C viruses were excluded. Prospective participants with iron deficiency, defined by serum ferritin levels below the RI, and those with red cell indices suggestive of an underlying thalassaemia trait were excluded. FBC samples were analysed using a Sysmex XN-1000 cell counter. Statistical non-parametric methods were used to calculate the RIs, according to international guidelines. Of the 774 participants screened, 82 (11%) had iron deficiency and were excluded. Six hundred and sixty-two patients were included for analysis, 409 (62%) female and 253 (38%) male. The majority of the participants, 348 (53%), were between 20 and 29 years of age, with a mean age of 29 years for females and 28 years for males. Participants comprised a mix of the various ethnic groups residing in Western Cape Province. The mean haemoglobin concentration for females was lower than that for males (p<0.0001). There were significant gender differences for total WBC count, absolute neutrophil count and platelet count, with females having higher counts than males. Locally established, population-specific RIs are essential for the accurate interpretation of haematological indices. This study established locally derived gender-specific RIs for the Cape Town region, after exclusion of iron deficiency. These new RIs have implications for the accurate diagnoses of cytopenias, cytoses and other blood count abnormalities. Iron deficiency is common in first-time blood donors, and screening for iron deficiency using point-of-care testing should be considered.

Clinical laboratory reference values in adults in Kisumu County, Western Kenya; hematology, chemistry and CD4.

BackgroundClinical laboratory reference intervals (RIs) are essential for diagnosing and managing patients in routine clinical care as well as establishing eligibility criteria and defining adverse events in clinical trials, but may vary by age, gender, genetics, nutrition and geographic location. It is, therefore, critical to establish region-specific reference values in order to inform clinical decision-making.MethodsWe analyzed data from a prospective observational HIV incidence cohort study in Kombewa, Kenya. Study participants were healthy males and females, aged 18–35 years, without HIV. Median and 95% reference values (2.5th percentile to 97.5th percentile) were calculated for laboratory parameters including hematology, chemistry studies, and CD4 T cell count. Standard Deviation Ratios (SDR) and Bias Ratios (BR) are presented as measures of effect magnitude. Findings were compared with those from the United States and other Kenyan studies.ResultsA total of 299 participants were analyzed with a median age of 24 years (interquartile range: 21–28). Ratio of males to females was 0.9:1. Hemoglobin range (2.5th—97.5th percentiles) was 12.0–17.9 g/dL and 9.5–15.3 g/dL in men and women respectively. In the cohort, MCV range was 59-95fL, WBC 3.7–9.2×103/μL, and platelet 154–401×103/μL. Chemistry values were higher in males; the creatinine RI was 59–103 μmol/L in males vs. 46–76 μmol/L in females (BRUL>.3); and the alanine transferase range was 8.8–45.3 U/L in males vs. 7.5–36.8 U/L in females (SDR>.3). The overall CD4 T cell count RI was 491–1381 cells/μL. Some parameters including hemoglobin, neutrophil, creatinine and ALT varied with that from prior studies in Kenya and the US.ConclusionThis study not only provides clinical reference intervals for a population in Kisumu County but also highlights the variations in comparable settings, accentuating the requirement for region-specific reference values to improve patient care, scientific validity, and quality of clinical trials in Africa.

Low plasma taurine levels in English cocker spaniels diagnosed with dilated cardiomyopathy.

The aims of this study were to evaluate taurine levels in English cocker spaniels with dilated cardiomyopathy and assess their survival time and natural progression of their disease. Retrospective comparison of English cocker spaniels with dilated cardiomyopathy phenotype with and without taurine deficiency at the cardiology department of a UK academic referral centre between 2008 and 2018. Taurine plasma concentration was available in 16 English cocker spaniels with dilated cardiomyopathy phenotype; 13 of 16 had congestive heart failure and three of 16 did not. Taurine concentration was low (<50 μmol/L) in 13 of 16 and normal in three of 16. Deficient dogs received taurine supplementation in addition to conventional cardiac medications. Eight dogs were still alive at the end of this study and eight were dead. MST for all dogs included in the study was 2800 days. Left ventricular systolic function improved and left ventricular dimensions reduced in English cocker spaniels with taurine deficiency following taurine supplementation and conventional cardiac therapy, although similar results were observed in English cocker spaniels with normal taurine concentration on cardiac therapy alone. Based on laboratory reference intervals, low taurine concentrations were common in English cocker spaniels with dilated cardiomyopathy, showing a possible association between dilated cardiomyopathy in English cocker spaniels and taurine deficiency; supplementation with taurine was not curative.

Determination of reference intervals from a laboratory database of an academic clinical research unit in a tertiary care teaching hospital and an audit of out of range values.

Background:Abnormal laboratory values are a common reason for the exclusion of participants in clinical studies, increasing the recruitment time and cost during conduct. The use of sample-specific reference intervals (RIs) may help to address this issue. Hence, the present study derived site-specific RIs using the department laboratory database and compare the proportion of “out of range” (OOR) values between the new and the old RIs used by the trial site.Methods:Institutional ethics committee approval was obtained. Data for hematology and biochemistry parameters were analyzed. Normality was assessed and RIs computed using nonparametric method. Data were partitioned for gender and descriptive statistics applied for demographics. The OOR values based on new RIs were compared with old RIs using Chi-squared tests. Between gender OOR proportions compared using Chi-squared test (significance at P< 0.05). Post hoc analysis was performed with Beasley's technique.Results:Data of 601 participants were analyzed. The median (Inter Quartile Range) age was 22 (47) years and 64.72% were male. New RIs for key parameters were: Haemoglobin (9.3–16.5 g/dl), alanine aminotransferase (11.4–47.74 U/I), aspartate aminotransferase (8.8–58 U/I), total bilirubin (0.27–1.4 mg/dl), and creatinine (0.59–1.36 mg/dl). Post partitioning, the RI for hemoglobin (g/dl) was lower (8.72–15.72) in females. The proportion of OOR values were lower with new RIs relative to old laboratory RIs (P < 0.0001).Conclusion:A reduction in the proportion of OORs and a change in the upper and lower bound laboratory intervals with new RIs emphasize the need for sample-specific ranges to prevent unnecessary exclusions of volunteers from trials.

Recognizing Laboratory Medicine's Collaborative Role in Identifying and Eliminating Health Disparities.

A health disparity is a health outcome that presents in a lesser or greater extent between populations. Health disparities in diseases are products of complex interactions between social, economic, and to a lesser extent, biological factors and can be mediated by structural racism and discriminatory policies. The objective of this review is to understand how both laboratorians and nonlaboratorians think about the relationship between laboratory medicine and health disparities and to highlight ways in which laboratory medicine can play a role in eliminating health disparities. We developed an electronic survey from which we selected the top responses reported by the 215 participants to frame a discussion around why laboratorians perceive health disparities exists, and how they can reduce health disparities. We found that both laboratorians and nonlaboratorians feel that laboratory medicine can and should play a role in reducing health disparities using many tools already in use in the clinical laboratory. The skills of laboratory workers in data generation, the establishment of reference ranges, control over the presentation of laboratory results, generation of test menus, and the development of novel diagnostics may impact health disparities. Laboratorians' responses in our survey indicated that they felt that they could reduce health disparities by using laboratory data to proactively track in cooperation with healthcare providers individuals with chronic conditions to prevent acute events, ensuring gender and ethnic diversity in new clinical trials, including appropriate curriculum in laboratory medicine training, using equations and reference intervals based on physiological differences and participating in unconscious bias training.

Reference interval determination of venous blood gas, hematologic, and biochemical parameters in healthy sedated, neutered ferrets (Mustela putorius furo)

The purpose of this study was to determine reference ranges for the Nova tabletop blood gas analyzer laboratory parameters in ferrets. Blood was collected from 40 clinically healthy ferrets, ranging in age from 1 to 5 years old (28 neutered males, 12 spayed females). The evaluated parameters were measured using whole blood and included hematologic (hematocrit, hemoglobin), biochemical (lactate, glucose, Na+, K+, iCa++, iMg++, Cl−, BUN/Urea, creatinine, tCO2, anion gap), and blood gas values (pH, PCO2, PO2, SO2%, BEecf, BEb, HCO3−). Laboratory reference intervals were established for 20 hematologic, biochemical, and blood gas values. The reference intervals are as follows: pH 7.274–7.415, PCO2 35.2–59.1 mm Hg, PO2 30.0–69.2 mm Hg, SO2 55.3–93.3%, Hematocrit 33–57%, Hemoglobin 11.0–18.9 g/dL, Na 147.4–154.8 mmol/L, K 3.81–5.37 mmol/L, Cl 109.2–119.3 mmol/L, iCa 1.14–1.35 mmol/L, iMg 0.44–0.66 mmol/L, Glu 74–152 mmol/L, Lac 0.3–1.5 mmol/L, BUN 10–33 mg/dL, Cr 0.4–0.9 mg/dL, TCO2 22.6–31.6 mmol/L, Anion gap 7.8–14.9 mmol/L, BEecf −5.2 to 3.8 mmol/L, BEb −3.9 to 3.5 mmol/L, HCO3− 21.3–30.0 mmol/L. Results varied slightly from previously established values in ferrets and include reference intervals for blood gas analytes that have not been previously reported. The reference intervals provided in this manuscript will aid veterinarians in the evaluation of acid–base balance of ferrets.

Comprehensive laboratory reference intervals for routine biochemical markers and pro-oxidant-antioxidant balance (PAB) in male adults.

BackgroundReference values of biochemical markers are influenced by various parameters including age, sex, region, and lifestyle. Hence, we aimed to determine age‐ and BMI‐specific reference intervals (RIs) for important clinical biomarkers in a healthy adult male population from northeastern Iran. This is also the first study to investigate reference values for pro‐oxidant‐antioxidant balance (PAB).MethodsSeven hundred and twenty (720) healthy men, aged 20‐60 years, were recruited from Sarakhs in the northeast region of Iran. Reference values for lipid profiles (total cholesterol, triglyceride, HDL‐C and LDL‐C), fasting blood glucose, inflammatory factors (hs‐CRP and PAB), minerals (zinc and copper), uric acid, and blood pressure were measured and statistically analyzed to establish accurate age‐ and BMI‐specific RIs in alignment with CLSI Ep28‐A3 guidelines.ResultsRIs for lipid profiles, inflammatory factors, minerals, and uric acid required no age partitioning with the exception of fasting blood glucose and blood pressure, which demonstrated significantly higher values in subjects aged 50 years and older. Among these biomarkers, only uric acid, blood pressure, and triglycerides demonstrated statistically significant increases in reference value concentrations with increasing BMI.ConclusionIn this study, age‐ and BMI‐specific RIs for several biochemical markers were determined in healthy adult Iranian men. Partitioning by age and BMI was only required for a few analytes with most demonstrating no statistically significant changes with these covariates. These data can be useful to monitor various diseases in male adults with varying BMI in this region and others.

Haematological, serum biochemical and electrophoretic data on healthy captive Egyptian fruit bats (Rousettus aegyptiacus).

Bats play a key role as reservoir hosts of many emerging viral diseases with zoonotic potential. However, little is known about the laboratory reference intervals (RIs) of bats, especially Egyptian fruit bats (Rousettus aegyptiacus). The aim of this study was to obtain haematological, biochemical and electrophoretic RIs from captive fruit bats. Blood was collected from 21 R. aegyptiacus (11 females and 10 males). Complete blood cell count was performed using an impedance cell counter followed by the morphologic analysis of blood smears. Clinical biochemistry was performed with an automated spectrophotometer and agarose gel electrophoresis was carried out with an automated instrument. Reference intervals were determined using the Reference Value Advisor V2.1, following the American Society for Veterinary Clinical Pathology guidelines. Possible differences related to sex or sexual maturity were also investigated. The RIs for most of the analytes investigated were similar to those of other types of bats and other mammalian species. Haematology revealed mild polychromasia and slightly lower haematocrit, haemoglobin, leukocyte and lymphocyte counts compared to other bats. Glucose levels varied possibly due to stress, the anaesthetic protocol and fasting time. Creatine kinase was higher, while triglycerides were lower compared with domestic mammals and other bats. No sex- or age-related differences were found. Serum protein electrophoresis showed five fractions (albumin, α-, β1-, β2- and γ-globulins). The values recorded in this study could be helpful as a reference biological dataset to monitor the health status of wild and captive R. aegyptiacus and, possibly, of other Chiroptera.

Establishing Simultaneous T Cell Receptor Excision Circles (TREC) and K-Deleting Recombination Excision Circles (KREC) Quantification Assays and Laboratory Reference Intervals in Healthy Individuals of Different Age Groups in Hong Kong.

The clinical experience gathered throughout the years has raised awareness of primary immunodeficiency diseases (PIDD). T cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC) assays for thymic and bone marrow outputs measurement have been widely implemented in newborn screening (NBS) programs for Severe Combined Immunodeficiency. The potential applications of combined TREC and KREC assay in PIDD diagnosis and immune reconstitution monitoring in non-neonatal patients have been suggested. Given that ethnicity, gender, and age can contribute to variations in immunity, defining the reference intervals of TREC and KREC levels in the local population is crucial for setting up cut-offs for PIDD diagnosis. In this retrospective study, 479 healthy Chinese sibling donors (240 males and 239 females; age range: 1 month−74 years) from Hong Kong were tested for TREC and KREC levels using a simultaneous quantitative real-time PCR assay. Age-specific 5th–95th percentile reference intervals of TREC and KREC levels (expressed in copies per μL blood and copies per 106 cells) were established in both pediatric and adult age groups. Significant inverse correlations between age and both TREC and KREC levels were observed in the pediatric age group. A significant higher KREC level was observed in females than males after 9–12 years of age but not for TREC. Low TREC or KREC levels were detected in patients diagnosed with mild or severe PIDD. This assay with the established local reference intervals would allow accurate diagnosis of PIDD, and potentially monitoring immune reconstitution following haematopoietic stem cell transplantation or highly active anti-retroviral therapy in the future.

Establishment of reference intervals of biochemical analytes for healthy Chinese volunteers during the screening process in clinical pharmacology trials.

Laboratory reference intervals (RIs) play a key role in clinical pharmacology trials, both in the screening process and in evaluating drug safety. However, RIs tend to be confined to the general population, and data about RIs for the trial population are limited. The purpose of this study was to determine appropriate RIs for use when screening a defined special subgroup of a healthy Chinese population in clinical pharmacology trials. A total of 773 healthy Chinese volunteers (552 men and 221 women) who sought to participate in clinical pharmacology trials were included in this study. Sixteen different biochemical analytes were measured by a Beckman Coulter Unicel DxC 800 automatic analyzer. RIs were partitioned by gender using Harris and Boyd's method and calculated using a non-parametric method. The RIs of 16 biochemical analytes for healthy Chinese volunteers during the screening process in clinical pharmacology trials are reported in this study. Noticeable differences between the RIs in this study and RIs provided by our laboratory or existing literature were also observed. Compared to our institutional RIs, the newly established RIs were more applicable to the current trial population. The RIs in this study can serve as a powerful clinical tool during the screening process in clinical pharmacology trials. However, these RIs should be re-verified if any condition changes. The results also emphasize the importance re-establishing RIs which are more applicable to local trial populations.

Community based reference interval of selected clinical chemistry parameters among apparently healthy Adolescents in Mekelle City, Tigrai, Northern Ethiopia.

Locally established clinical laboratory reference intervals (RIs) are required to interpret laboratory test results for screening, diagnosis and prognosis. The objective of this study was establishing reference interval of clinical chemistry parameters among apparently healthy adolescents aged between 12 and 17 years in Mekelle, Tigrai, northern part of Ethiopia. Community based cross sectional study was employed from December 2018 to March 2019 in Mekelle city among 172 males and 172 females based on Multi stage sampling technique. Blood samples were tested for Fasting blood sugar (FBS), alanine aminino transferase (ALT), aspartate amino transferase (AST), alkaline phosphatase (ALP), Creatinine, urea, total protein, albumin (ALB), direct and indirect bilirubin (BIL.D and BIL.T) using 25 Bio system clinical chemistry analyzer. Results were analyzed using SPSS version 23 software and based on the Clinical Laboratory Standard Institute (CLSI)/ International Federation of Clinical Chemistry (IFCC) C 28-A3 Guideline which defines the reference interval as the 95% central range of 2.5th and 97.5th percentiles. Mann Whitney U test, descriptive statistics and box and whisker were statistical tools used for analysis. This study observed statistically significant differences between males and females in ALP, ALT, AST, Urea and Creatinine Reference intervals. The established reference intervals for males and females, respectively, were: ALP (U/L) 79.48-492.12 versus 63.56-253.34, ALT (U/L) 4.54-23.69 versus 5.1-20.03, AST 15.7-39.1 versus 13.3-28.5, Urea (mg/dL) 9.33-24.99 versus 7.43-23.11, and Creatinine (mg/dL) 0.393-0.957 versus 0.301-0.846. The combined RIs for Total Protein (g/dL) was 6.08-7.85, ALB (g/dL) 4.42-5.46, FBS(mg/dL) 65-110, BIL.D (mg/dL) 0.033-0.532, and BIL.T (mg/dL) 0.106-0.812. The result showed marked difference among sex and with the company derived values for selected clinical chemistry parameters. Thus, use of age and sex specific locally established reference intervals for clinical chemistry parameters is recommended.

A Comparison of Complete Blood Count Reference Intervals in Healthy Elderly Versus Younger Korean Adults: A Large Population Study

Background: The use of laboratory reference intervals based on younger populations is of questionable validity in older populations. We established reference intervals for 16 complete blood count (CBC) parameters in healthy elderly Koreans aged ≥60 years and compared them to those of individuals aged 20-59 years.Methods: Among 64,532 individuals (39,609 men and 24,923 women) aged ≥20 years who underwent medical check-ups, 8,151 healthy subjects (12.6%, 5,270 men and 2,881 women, including 675 and 511, respectively, who were ≥60 years of age) were enrolled based on stringent criteria including laboratory, imaging, and endoscopy results; previous medical history; and medication history. CBC parameters were measured using an Advia2120i instrument. The difference between 2 age groups in subjects of each sex was compared using the Mann-Whitney U-test. P-values <0.05 were considered statistically significant. The reference intervals for measured CBC parameters were established according to a nonparametric method based on the CLSI EP28A-3C in each subgroup. The 90% confidence intervals for the upper and lower limits of each reference interval were calculated; the Reed method was used to remove extreme outliers. The Harris and Boyd method was used to determine the necessity of separating the reference intervals for different age groups within each sex group. To identify reference intervals in different age groups in individuals aged 60 years and over, such individuals of each sex were subdivided into 5 age subgroups with 5-year age interval: since the sizes of 4 of these subgroups were not sufficiently large, we used the Robust method.Results: A statistical difference in the medians of the following parameters were observed between the <60- and ≥60-year age groups: RBC, Hb, hematocrit (Hct), basophils, and platelets in men aged <60 years were higher than those in men aged ≥60 years; furthermore, MCV, MCH, and RDW in men aged ≥60 years were higher than those in men aged <60 years. Neutrophils in women aged <60 years were higher than in those aged ≥60 years. Hb, Hct, MCV, MCH, MCHC, lymphocytes, and basophils in women aged ≥60 years were higher than in those aged <60 years. Separate reference intervals were required only for RDW and MCH in women ≥60 from those < 60 years of age. Men aged ≥60 years versus those <60 years did not require separate reference intervals for any of the 16 measured parameters. In subjects aged ≥60 years, RBC, Hb, Hct, MCV, MCH, MCHC, RDW, WBC, neutrophils, monocytes, eosinophils, MPV, and PDW were higher in men than in women, while the opposite was true for lymphocytes and platelets. Partitioning of reference intervals by sex was required for RBC, Hb, Hct, MCH, monocytes, and eosinophils. In men, median values and the lower limits of the reference intervals for RBC, Hb, and Hct tended to decrease with advancing age. The upper and lower limits of reference intervals for WBC, neutrophils, lymphocytes, and MPV also showed increasing and decreasing tendencies, respectively, widening the reference intervals as the subjects aged (except in the 70-74-year-old group for men). Among women, the lower limits of the reference intervals for RBC, Hb, and Hct showed a tendency to decrease with increasing age for those >70 years of age; however, the median values did not show such a tendency. The reference interval for PDW narrowed as women aged. Separate reference intervals were required among men for MCH and eosinophils in the 70-74-year group, and for basophils in the 65-69-year group. Among women, separate reference intervals were required for MCV in the 65-69-year group; for MCH in the 60-64, 65-69, and ≥75-years groups; and for RDW in all the 4 elderly age subgroups.Conclusion: Healthy elderly Koreans can use the same reference intervals as younger populations. Thus, abnormal CBC results may not necessarily be attributable to physiologic changes but possible underlying diseases that should be investigated. DisclosuresNo relevant conflicts of interest to declare.

A multicenter study of reference intervals for 15 laboratory parameters in Chinese children

Objective: To establish comprehensive laboratory reference intervals for Chinese children. Methods: This was a cross-sectional multicenter study. From June 2013 to December 2014, eligible healthy children aged from 6-month to 17-year were enrolled from 20 medical centers with informed consent. They were assessed by physical examination, questionnaire survey and abdominal ultrasound for eligibility. Fasting blood samples were collected and delivered to central laboratory. Measurements of 15 clinical laboratory parameters were performed, including estradiol (E2), testosterone(T), luteinizing hormone(LH), follicle-stimulating hormone(FSH), alanine transaminase(ALT), serum creatinine(Scr), cystatin C, immunoglobulin A(IgA), immunoglobulin G(IgG), immunoglobulin M(IgM), complement (C3, C4), alkaline phosphatase(ALP), uric acid(UA) and creatine kinase(CK). Reference intervals were established according to central 95% confidence intervals for reference population, stratified by age and sex. Results: In total, 2 259 children were enrolled. Finally, 1 648 children were eligible for this study, including 830 boys and 818 girls, at a mean age of 7.4 years. Age- and sex- specific reference intervals have been established for the parameters. Reference intervals of sex hormones increased gradually with age. Concentrations of ALT, cystatin C, ALP and CK were higher in children under 2 years old. Serum levels of sex hormones, creatinine, immunoglobin, CK, ALP and urea increased rapidly in adolescence, with significant sex difference. In addition, reference intervals were variable depending on assay methods. Concentrations of ALT detected by reagents with pyridoxal 5'-phosphate(PLP) were higher than those detected by reagents without PLP. Compared with enzymatic method, Jaffe assay always got higher results of serum creatinine, especially in children younger than 9 years old. Conclusion: This study established age- and sex- specific reference intervals, for 15 clinical laboratory parameters based on defined healthy children.