Albumin and calcium reference interval using healthy individuals and a data-mining approach

Background Harmonization of reference intervals for analytes that have a sound calibration and metrological traceability is a widely recommended practice. The UK Pathology Harmony has recently harmonized reference intervals for calcium and albumin. In this study, we have determined the reference intervals for calcium and albumin on the UK’s most commonly used analytical platforms. Method A prospective reference population of healthy individuals was recruited according to the IFCC CRIDL criteria. A second indirect population was collected from 14 primary care setting and measured in laboratories using various analytical platforms and methods (Roche, Abbott, Beckman and Siemens analytical platforms). Results In total, 299 subjects were recruited; the central 95th centile values for calcium for three out of four analytical platforms were in a close agreement with UK Pathology Harmony reference intervals of 2.2–2.6 mmol/L. Reference intervals of BCG methods from both cohorts and irrespective of analytical platforms were higher for both lower and upper reference limits than those for BCP. In comparison, the indirect study showed an age-related variation. The younger population reference intervals varied by up to 5.7% at the lower reference limit and up to 12% at the upper reference limit compared with Pathology Harmony reference intervals, and the older population showed a variation of up to 14% at both limits. Conclusion While calcium reference intervals can be a subject for harmonization, albumin reference intervals studied showed large variation which is unsupportive of embracing a common reference interval for albumin.

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Choice of Statistical Tools for Outlier Removal Causes Substantial Changes in Analyte Reference Intervals in Healthy Populations

Clinical Chemistry ◽

10.1093/clinchem/hvaa208 ◽

2020 ◽

Vol 66 (12) ◽

pp. 1558-1561 ◽

Cited By ~ 1

Author(s):

Peter E Hickman ◽

Gus Koerbin ◽

Julia M Potter ◽

Nicholas Glasgow ◽

Juleen A Cavanaugh ◽

...

Keyword(s):

Statistical Methods ◽

Population Studies ◽

Large Population ◽

Large Body ◽

Reference Interval ◽

Reference Intervals ◽

Outlier Removal ◽

Reference Limit ◽

Statistical Measures ◽

Upper Reference Limit

Abstract Background Reference intervals are an important aid in medical practice as they provide clinicians a guide as to whether a patient is healthy or diseased. Outlier results in population studies are removed by any of a variety of statistical measures. We have compared several methods of outlier removal and applied them to a large body of analytes from a large population of healthy persons. Methods We used the outlier exclusion criteria of Reed-Dixon and Tukey and calculated reference intervals using nonparametric and Harrell-Davis statistical methods and applied them to a total of 36 different analytes. Results Nine of 36 analytes had a greater than 20% difference in the upper reference limit, and for some the difference was 100% or more. Conclusions For some analytes, great importance is attached to the reference interval. We have shown that different statistical methods for outlier removal can cause large changes to reported reference intervals. So that population studies can be readily compared, common statistical methods should be used for outlier removal.

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Impact of Subgroup Prevalences on Partitioning of Gaussian-distributed Reference Values

Clinical Chemistry ◽

10.1093/clinchem/48.11.1987 ◽

2002 ◽

Vol 48 (11) ◽

pp. 1987-1999 ◽

Cited By ~ 49

Author(s):

Ari Lahti ◽

Per Hyltoft Petersen ◽

James C Boyd

Keyword(s):

Reference Interval ◽

Reference Population ◽

Reference Intervals ◽

Source Population ◽

Distributed Data ◽

New Model ◽

Common Reference ◽

Reference Limits ◽

Partitioning Problem ◽

Analytical Expressions

Abstract Background: The aims of this report were to examine how unequal subgroup prevalences in the source population may affect reference interval partitioning decisions and to develop generally applicable guidelines for partitioning gaussian-distributed data. Methods: We recently proposed a new model for partitioning reference intervals when the underlying data distribution is gaussian. This model is based on controlling the proportions of the subgroup distributions that fall outside each of the common reference limits, using the distances between the reference limits of the subgroup distributions as functions to these proportions. We examine the significance of the unequal prevalence effect for the partitioning problem and quantify it for distance partitioning criteria by deriving analytical expressions to express these criteria as a function of the ratio of prevalences. An application example, illustrating various aspects of the importance of the prevalence effect, is also presented. Results: Dramatic shrinkage of the critical distances between reference limits of the subgroups needed for partitioning was observed as the ratio of prevalences, the larger one divided by the smaller one, was increased from unity. Because of this shrinkage, the same critical distances are not valid for all ratios of prevalences, but specific critical distances should be used for each particular value of this ratio. Although proportion criteria used in determining the need for reference interval partitioning are not dependent on the prevalence effect, this effect should be accounted for when these criteria are being applied by adjusting the sample sizes of the subgroups to make them correspond to the ratio of prevalences. Conclusions: The prevalences of subgroups in the reference population should be known and observed in the calculations for every reference interval study, irrespective of whether distance or proportion criteria are being used to determine the need for reference interval partitioning. We present detailed methods to account for the prevalences when applying each of these types of criteria. Analytical expressions for the distance criteria, to be used when high precision is needed, and approximate distances, to be used in practical work, are derived. General guidelines for partitioning gaussian distributed data are presented. Following these guidelines and using the new model, we suggest that partitioning can be performed more reliably than with any of the earlier models because the new model not only offers an improved correspondence between the critical distances and the critical proportions, but also accounts for the prevalence effect.

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Urine soluble CD163 (sCD163) as biomarker in glomerulonephritis: stability, reference interval and diagnostic performance

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2020-0466 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Anne J. Nielsen ◽

Marlene C. Nielsen ◽

Henrik Birn ◽

Per Ivarsen ◽

Holger J. Møller ◽

...

Keyword(s):

Crescentic Glomerulonephritis ◽

Reference Interval ◽

Enzyme Linked Immunosorbent Assay ◽

Healthy Individuals ◽

Reference Limit ◽

Urine Albumin ◽

Analytical Stability ◽

Different Types ◽

Upper Reference Limit ◽

Better Than

AbstractObjectivesSoluble (s) CD163 is a well-established macrophage biomarker, and recent data suggests urine sCD163 to reflect disease activity in crescentic glomerulonephritis (GN). Other types of GN may also be associated with glomerular inflammation but the potential usefulness of urine sCD163 as a general biomarker of GN remains unaddressed.MethodsAn in-house sCD163 enzyme-linked immunosorbent assay (ELISA) was validated for urinary use and compared to a frequently used commercial ELISA. The pre-analytical stability of urine sCD163 was assessed and a reference interval was established according to the CLSI guidelines using specimens from 253 healthy individuals. Urine samples from 64 patients with different types of renal disorders were also analysed.ResultsUrine sCD163 was highly stable during storage. An upper reference limit of 5.1 μg/L (1.9 μg/mmol, normalised to creatinine) was established using the in-house ELISA. Urine sCD163 was generally increased in GN patients (3.9 μg/mmol, p<0.0001, AUROC=0.97) and decreased upon treatment, but did not perform better than urine albumin (AUROC=1.00). Patients with proliferative GN had higher urine sCD163/albumin (p=0.0001) ratio. The commercial assay had a higher detection limit, and patient levels were 4–6 times lower than in the in-house assay.ConclusionsUrine sCD163 is a stable biomarker that can be measured with acceptable accuracy using our in-house ELISA. Its pre-analytical characteristics makes it a reliable biomarker and our findings point towards the use of urine sCD163 as a biomarker of specific subtypes of GN.

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RIA for Serum Holo-Transcobalamin: Method Evaluation in the Clinical Laboratory and Reference Interval

Clinical Chemistry ◽

10.1373/49.3.455 ◽

2003 ◽

Vol 49 (3) ◽

pp. 455-462 ◽

Cited By ~ 40

Author(s):

Saila Loikas ◽

Minna Löppönen ◽

Pauli Suominen ◽

Jan Møller ◽

Kerttu Irjala ◽

...

Keyword(s):

Biochemical Markers ◽

Methylmalonic Acid ◽

Clinical Laboratory ◽

Reference Interval ◽

Reference Population ◽

Reference Intervals ◽

Method Evaluation ◽

Elderly Individuals ◽

Reference Limit ◽

Total Homocysteine

Abstract Background: Decreased serum holo-transcobalamin (holoTC) could be the earliest marker of cobalamin (Cbl) deficiency, but there has been no method suitable for routine use. We evaluated a new commercial holoTC RIA, determined reference values, and assessed holoTC concentrations in relation to other biochemical markers of Cbl deficiency. Methods: The reference population consisted of 303 individuals 22–88 years of age, without disease or medication affecting Cbl or homocysteine metabolism. In elderly individuals (≥65 years), normal Cbl status was further confirmed by total homocysteine (tHcy; <19 μmol/L) and methylmalonic acid (MMA; <0.28 μmol/L) concentrations within established reference intervals. HoloTC in Cbl deficiency was studied in a population of 107 elderly individuals with normal renal function. The Cbl deficiency was graded as potential (total Cbl ≤150 pmol/L or tHcy ≥19 μmol/L), possible (total Cbl ≤150 pmol/L and either tHcy ≥19 μmol/L or MMA ≥0.45 μmol/L), and probable (tHcy ≥19 μmol/L and MMA ≥0.45 μmol/L). Results: The intra- and between-assay imprecision (CV) for the holoTC RIA were 4–7% and 6–8%, respectively. A 95% central reference interval for serum holoTC was 37–171 pmol/L. All participants (n = 16) with probable Cbl deficiency, 86% of those with possible, and 30% of those with potential Cbl deficiency had holoTC below the reference limit (<37 pmol/L). The holoTC correlated with total Cbl (rs = 0.80; P <0.0001) and inversely with MMA (rs = −0.52; P <0.0001). HoloTC concentrations were significantly (P = 0.01) higher in women than in men. Conclusions: The new holoTC RIA is precise and simple to perform. Low holoTC is found in individuals with biochemical signs of Cbl deficiency, but the sensitivity and specificity of low holoTC in diagnosis of Cbl deficiency need to be further evaluated.

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Clinical and analytical evaluation of kits for measurement of creatine kinase isoenzyme MB.

Clinical Chemistry ◽

10.1093/clinchem/32.1.186 ◽

1986 ◽

Vol 32 (1) ◽

pp. 186-191 ◽

Cited By ~ 12

Author(s):

T R Koch ◽

U J Mehta ◽

H C Nipper

Keyword(s):

Creatine Kinase ◽

Clinical Performance ◽

Reference Population ◽

Reference Ranges ◽

Diagnostic Specificity ◽

Electrophoretic Method ◽

Reference Limit ◽

Coronary Care ◽

Upper Reference Limit ◽

Creatine Kinase Isoenzyme Mb

Abstract We studied the analytical and clinical performance of six methods for creatine kinase (EC 2.7.3.2) isoenzyme MB (CK-MB): three immunoassays (Behring, Hybritech, and International Immunoassay Labs); one immunoinhibition assay (Roche); one immunoinhibition/column method (Du Pont); and one electrophoretic method (Beckman). Between-day precision for all kits was poor at the upper reference limit. All methods gave results linearly related to CK-MB concentration and all were free from CK-MM, CK-BB, and adenylate kinase interference. Only the Du Pont method was adversely affected by atypical isoenzymes. For diagnosis of acute myocardial infarction in a coronary care population (n = 40; prevalence = 45%), all methods were approximately 95% efficient, when appropriate reference criteria were used. Some manufacturers fail to provide data for an appropriate (acutely ill, non-infarct) reference population; decreased diagnostic specificity may result from use of reference ranges based on results for healthy subjects. Expression of CK-MB as a percent of total CK degrades efficiency unless total CK is markedly increased.

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Experience with the Urinary Tetrasaccharide Metabolite for Pompe Disease in the Diagnostic Laboratory

Metabolites ◽

10.3390/metabo11070446 ◽

2021 ◽

Vol 11 (7) ◽

pp. 446

Author(s):

Jennifer T. Saville ◽

Maria Fuller

Keyword(s):

Pompe Disease ◽

Late Onset ◽

Reference Interval ◽

Laboratory Diagnosis ◽

Reference Intervals ◽

Confirmatory Test ◽

Diagnostic Laboratory ◽

Age Related ◽

Initial Drop ◽

Monitoring Treatment

Following clinical indications, the laboratory diagnosis of the inherited metabolic myopathy, Pompe disease (PD), typically begins with demonstrating a reduction in acid alpha-glucosidase (GAA), the enzyme required for lysosomal glycogen degradation. Although simple in concept, a major challenge is defining reference intervals, as even carriers can have reduced GAA, and pseudodeficiencies complicate interpretation. Here, we developed a mass spectrometric assay for quantification of a urinary glycogen metabolite (tetrasaccharide) and reported on its utility as a confirmatory test for PD in a diagnostic laboratory. Using two age-related reference intervals, eight returned tetrasaccharide concentrations above the calculated reference interval but did not have PD, highlighting non-specificity. However, retrospective analysis revealed elevated tetrasaccharide in seven infantile-onset (IOPD) cases and sixteen late-onset (LOPD) cases, and normal concentrations in one heterozygote. Prospective tetrasaccharide analysis in nine individuals with reduced GAA confirmed IOPD in one, LOPD in six and identified two heterozygotes. Using this metabolite as a biomarker of therapeutic response was not overly informative; although most patients showed an initial drop following therapy initiation, tetrasaccharide concentrations fluctuated considerably and remained above reference intervals in all patients. While useful as a confirmation of PD, its utility as a biomarker for monitoring treatment warrants further investigation.

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Cerebrospinal Fluid Protein Concentration in Healthy Older Japanese Volunteers

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18168683 ◽

2021 ◽

Vol 18 (16) ◽

pp. 8683

Author(s):

Tatsuya Yoshihara ◽

Masayoshi Zaitsu ◽

Kazuya Ito ◽

Ryuzo Hanada ◽

Eunhee Chung ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Asian Population ◽

Reference Interval ◽

Reference Limit ◽

Neurological Emergencies ◽

Precise Diagnosis ◽

The Mean ◽

Upper Reference Limit ◽

Age Range ◽

Cerebrospinal Fluid Protein

The concentration of cerebrospinal fluid total protein (CSF-TP) is important for the diagnosis of neurological emergencies. Recently, some Western studies have shown that the current upper reference limit of CSF-TP is quite low for older patients. However, little is reported about the concentration of CSF-TP in the older Asian population. In this study, we retrospectively analyzed the CSF-TP concentrations in healthy older Japanese volunteers. CSF samples in 69 healthy Japanese volunteers (age range: 55–73 years) were collected by lumbar puncture, and the data of CSF were retrospectively analyzed. The mean (standard deviation) CSF-TP was 41.7 (12.3) mg/dL. The older group (≥65 years old) had higher CSF-TP concentration than the younger group (55–64 years old). The 2.5th percentile and 97.5th percentile of CSF-TP were estimated as 22.5 and 73.2 mg/dL, respectively, which were higher than the current reference range in Japan (10–40 mg/dL). Conclusions: The reference interval of CSF-TP in the older population should be reconsidered for the precise diagnosis of neurological emergencies.

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Establishment of variation source and age-related reference interval models for 22 common biochemical analytes in older people using real-world big data mining

Age and Ageing ◽

10.1093/ageing/afaa096 ◽

2020 ◽

Vol 49 (6) ◽

pp. 1062-1070

Author(s):

Chaochao Ma ◽

Liangyu Xia ◽

Xinqi Chen ◽

Jie Wu ◽

Yicong Yin ◽

...

Keyword(s):

Big Data ◽

Older People ◽

Real World ◽

Reference Interval ◽

Reference Intervals ◽

Ageing Population ◽

Factors Affecting ◽

Age Related ◽

The Status ◽

Source Models

Abstract Background the ageing population has increased in many countries, including China. However, reference intervals (RIs) for older people are rarely established because of difficulties in selecting reference individuals. Here, we aimed to analyse the factors affecting biochemical analytes and establish RI and age-related RI models for biochemical analytes through mining real-world big data. Methods data for 97,220 individuals downloaded from electronic health records were included. Three derived databases were established. The first database included 97,220 individuals and was used to build age-related RI models after identifying outliers by the Tukey method. The second database consisted of older people and was used to establish variation source models and RIs for biochemical analytes. Differences between older and younger people were compared using the third database. Results sex was the main source of variation of biochemical analytes for older people in the variation source models. The distributions of creatinine and uric acid were significantly different in the RIs of biochemical analytes for older people established according to sex. Age-related RI models for biochemical analytes that were most affected by age were built and visualized, revealing various patterns of changes from the younger to older people. Conclusion the study analysed the factors affecting biochemical analytes in older people. Moreover, RI and age-related RI models of biochemical analytes for older people were established to provide important insight into biological processes and to assist clinical use of various biochemical analytes to monitor the status of various diseases for older people.

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Intra- and interindividual variability of carbohydrate-deficient transferrin, γ-glutamyltransferase, and mean corpuscular volume in teetotalers

Clinical Chemistry ◽

10.1093/clinchem/44.10.2120 ◽

1998 ◽

Vol 44 (10) ◽

pp. 2120-2125 ◽

Cited By ~ 30

Author(s):

Anders Helander ◽

Erling Vabö ◽

Klas Levin ◽

Stefan Borg

Keyword(s):

Mean Corpuscular Volume ◽

Iron Concentration ◽

Reference Interval ◽

Reference Intervals ◽

Mean Value ◽

Corpuscular Volume ◽

Mean Values ◽

Reference Limit ◽

Carbohydrate Deficient Transferrin ◽

The Mean

Abstract Blood samples for determination of the biochemical alcohol markers carbohydrate-deficient transferrin (CDT) in serum, γ-glutamyltransferase (GGT) in serum, and erythrocyte mean corpuscular volume (MCV) were collected once every 1–2 weeks over ∼5 months from 10 female and 4 male teetotalers. Mean values for serum CDT (using the CDTectTM assay) ranged from 9.9 to 29.4 units/L (median, 14.2 units/L), and the highest results were obtained in the women. The mean values for serum GGT ranged from 0.15 to 0.49 μkat/L (median, 0.30 μkat/L, or 18 U/L) except for one woman with a very high mean of 3.07 μkat/L. For MCV, the mean values ranged from 79.5 to 91.5 fL. Two women showed several CDT results above the upper reference limit (mean values, 27.6 and 29.4 units/L, respectively); however, their GGT and MCV values fell within the reference intervals. One of these women exhibited an increased total transferrin concentration (mean value, 5.38 g/L), which was possibly related to the use of oral contraceptives and/or a low serum iron concentration. When the CDTect value was expressed relative to total transferrin, a ratio within the reference interval was observed for this woman but not for the other woman with increased CDTect values. The present study demonstrates a considerable variation between individuals in CDT, GGT, and MCV without drinking any alcohol. The results also show that these baseline values are fairly constant over time within the same individual.

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Disappearance Rate of Catecholamines, Total Metanephrines, and Neuropeptide Y from the Plasma of Patients after Resection of Pheochromocytoma

Clinical Chemistry ◽

10.1093/clinchem/47.6.1075 ◽

2001 ◽

Vol 47 (6) ◽

pp. 1075-1082 ◽

Cited By ~ 43

Author(s):

Eric Grouzmann ◽

Marc Fathi ◽

Michel Gillet ◽

Antoine de Torrenté ◽

Claudia Cavadas ◽

...

Keyword(s):

Neuropeptide Y ◽

Plasma Concentrations ◽

Amperometric Detection ◽

Reference Interval ◽

Diagnostic Value ◽

Relative Increase ◽

Time Curve ◽

Reference Limit ◽

Upper Reference Limit ◽

Total Sulfate

Abstract Background: Plasma free metanephrines are a more reliable analyte to measure than catecholamines for the biochemical diagnosis of pheochromocytomas. We hypothesized that the long persistence of total (sulfate-conjugated plus free) metanephrines in the blood might have a significant diagnostic value. Methods: We measured plasma concentrations of catecholamines and total metanephrines (sulfate-conjugated plus free forms) by HPLC with amperometric detection, and neuropeptide Y (NPY) by an amplified ELISA in seven patients before and after removal of their pheochromocytomas. The results for catecholamine, total metanephrines, and NPY in each patient were analyzed for up to 120 min, starting from the time of tumor vessel clamping. The persistence of analytes was quantified as the area under the concentration–time curve over 120 min. Results: On the basis of the upper reference limit for each variable, plasma free norepinephrine (NE) and epinephrine (E) concentrations were increased preoperatively in at least one sample in seven and six patients, respectively. Total normetanephrine (NMN) and metanephrine (MN) were increased in all samples in seven and six patients, respectively. NPY was increased 2- to 465-fold. After removal of the tumor, MN and NMN showed a higher average relative increase above the upper limit of the reference interval than NE and E (P = 0.05), whereas NPY was intermediate. The persistence of increased values was significantly shorter for catecholamines than for metanephrines. The half-life estimated by nonlinear regression was 12.3 ± 7.8 min for NPY. Significant correlations were observed among NE, E, NMN, MN, and NPY concentrations, but parent markers (E and MN or NE and NMN) did not appear significantly intercorrelated. Conclusions: A larger increase and a longer persistence of total metanephrines (reflecting predominantly sulfo-conjugated metanephrines) than catecholamines and NPY in plasma may contribute to their greater diagnostic accuracy in pheochromocytoma.

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