Reference intervals for serum total vitamin B12 and holotranscobalamin concentrations and their change points with methylmalonic acid concentration to assess vitamin B12 status during early and mid-pregnancy

Abstract Background Maternal vitamin B12 (B-12) adequacy is important for maternal health and optimal fetal growth. However, pregnancy-specific cut-offs for B-12 biomarkers are lacking. Methods Reference intervals for serum total B-12, holotranscobalamin (holoTC) and methylmalonic acid (MMA) concentrations were calculated following CLSI EP28-A3c guidelines in 723 pregnant women of European (50%) and South Asian (50%) ethnicity, residing in British Columbia, Canada, at median (range) 11.4 (8.3–13.9) and 16.1 (14.9–20.9) weeks of gestation. Change point analyses described relationships between log serum MMA concentration with serum total B-12 and holoTC concentrations, assuming linear-linear relationships. Results The central 95% reference interval limits indicated that serum total B-12 <89.9 and <84.0 pmol/L, holoTC <29.5 and <26.0 pmol/L and MMA >371 and >374 nmol/L, in the first and second trimesters, respectively, may indicate B-12 deficiency in pregnant women. The lower limits of total B-12 and holoTC and the upper limits of MMA significantly differed by ethnicity in both trimesters. According to the change point analysis, total B-12 <186 and <180 pmol/L and holoTC <62.2 and <67.5 pmol/L in the first and second trimesters, respectively, suggested an increased probability of impaired intracellular B-12 status, with no difference between ethnicities. Conclusions We present novel reference limits and change points for B-12 biomarkers, which may be employed to identify possible B-12 deficiency in women during early and mid-pregnancy. Future research is needed to validate these cut-offs and determine the predictors and functional outcomes associated with impaired B-12 status in ethnically diverse populations.

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Evaluation of Thyroid Function in Pregnant Women Using Automated Immunoassays

Clinical Chemistry ◽

10.1093/clinchem/hvab009 ◽

2021 ◽

Author(s):

K Aaron Geno ◽

Matthew S Reed ◽

Mark A Cervinski ◽

Robert D Nerenz

Keyword(s):

Pregnant Women ◽

Equilibrium Dialysis ◽

Reference Interval ◽

First Trimester ◽

Reference Intervals ◽

Free Thyroxine ◽

Specific Reference ◽

Childbearing Age ◽

Thyroid Autoantibody ◽

The Impact

Abstract Introduction Automated free thyroxine (FT4) immunoassays are widely available, but professional guidelines discourage their use in pregnant women due to theoretical under-recoveries attributed to increased thyroid hormone binding capacity and instead advocate the use of total T4 (TT4) or free thyroxine index (FTI). The impact of this recommendation on the classification of thyroid status in apparently euthyroid pregnant patients was evaluated. Methods After excluding specimens with thyroid autoantibody concentrations above reference limits, thyroid-stimulating hormone (TSH), FT4, TT4, and T-uptake were measured on the Roche Cobas® platform in remnant clinical specimens from at least 147 nonpregnant women of childbearing age and pregnant women at each trimester. Split-sample comparisons of FT4 as measured by the Cobas and equilibrium dialysis were performed. Results FT4 decreased with advancing gestational age by both immunoassay and equilibrium dialysis. TSH declined during the first trimester, remained constant in the second, and increased throughout the third, peaking just before delivery. Interpretation of TT4 concentrations using 1.5-times the nonpregnant reference interval classified 13.6% of first trimester specimens below the lower reference limit despite TSH concentrations within trimester-specific reference intervals. Five FTI results from 480 pregnant individuals (about 1.0%) fell outside the manufacturer’s reference interval. Conclusions Indirect FT4 immunoassay results interpreted in the context of trimester-specific reference intervals provide a practical and viable alternative to TT4 or FTI. Declining FT4 and increasing TSH concentrations near term suggest that declining FT4 is not an analytical artifact but represents a true physiological change in preparation for labor and delivery.

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Reference interval for immature platelet fraction on Sysmex XN hematology analyzer: a comparison study with Sysmex XE-2100

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2014-0839 ◽

2015 ◽

Vol 53 (7) ◽

Cited By ~ 13

Author(s):

Young Jin Ko ◽

Mina Hur ◽

Hanah Kim ◽

Sang Gyeu Choi ◽

Hee-Won Moon ◽

...

Keyword(s):

Large Scale ◽

Reference Interval ◽

Reference Intervals ◽

Modular System ◽

Future Research ◽

Healthy Individuals ◽

Platelet Counts ◽

Immature Platelet Fraction ◽

Hematology Analyzer ◽

Non Parametric

AbstractRecently introduced hematology analyzer, the Sysmex XN modular system (Sysmex, Kobe, Japan), has newly adopted a florescent channel to detect platelets and immature platelet fraction (IPF). This study aimed to establish new reference intervals for %-IPF and absolute number of IPF (A-IPF) on Sysmex XN. Platelet counts, %-IPF, and A-IPF were also compared between Sysmex XN and XE-2100 systems (Sysmex).Except outliers, blood samples from 2104 healthy individuals and 140 umbilical cord blood were analyzed using both Sysmex XN and XE-2100. The results of two systems were compared using Bland-Altman plot. The reference intervals for %-IPF and A-IPF were defined using non-parametric percentile methods according to the Clinical and Laboratory Standard Institute guideline (C28-A3).The platelet counts, %-IPF, and A-IPF showed non-parametric distributions. The mean difference between Sysmex XN and XE-2100 in healthy individuals revealed a positive bias in platelets (+8.0×10This large-scale study demonstrates a clear difference of platelet counts and IPF between Sysmex XN and XE-2100. The new reference intervals for IPF on Sysmex XN would provide fundamental data for clinical practice and future research.

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Reference intervals for plasma vitamin B12 and plasma/serum methylmalonic acid in Danish children, adults and elderly

Clinica Chimica Acta ◽

10.1016/j.cca.2021.12.015 ◽

2021 ◽

Author(s):

Abildgaard Anders ◽

Knudsen Cindy Soendersoe ◽

Hoejskov Carsten Schriver ◽

Greibe Eva ◽

Parkner Tina

Keyword(s):

Vitamin B12 ◽

Methylmalonic Acid ◽

Reference Intervals ◽

Plasma Vitamin

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CHANGE POINT ANALYSIS: A STATISTICAL APPROACH TO DETECT POTENTIAL ABRUPT CHANGE

Jurnal Teknologi ◽

10.11113/jt.v79.10388 ◽

2017 ◽

Vol 79 (5) ◽

Cited By ~ 2

Author(s):

Siti Nur Afiqah Mohd Arif ◽

Mohamad Farhan Mohamad Mohsin ◽

Azuraliza Abu Bakar ◽

Abdul Razak Hamdan ◽

Sharifah Mastura Syed Abdullah

Keyword(s):

Relative Humidity ◽

Change Point ◽

Abrupt Change ◽

Carbon Dioxide Concentration ◽

Change Points ◽

Change Point Analysis ◽

Total Rainfall ◽

Essential Information ◽

Point Analysis ◽

Annual Means

Change-point analysis has proven to be an efficient tool in understanding the essential information contained in meteorological data, such as rainfall, ozone level, and carbon dioxide concentration. In this study, change-point analysis was used to discover potential significant changes in the annual means of total rainfall, temperature and relative humidity from 25 years of Malaysian climate data. Two methods, the CUSUM and bootstrap, were used in the analysis, where the CUSUM was used to analyze the data trends and patterns and bootstrapping was used to calculate the occurrence of change points based on the confidence level. The results of the analysis showed that potential abrupt shifts seem to have taken place in 1999, 2001 and 2002 with respect to the annual means for relative humidity, temperature and total rainfall, respectively. These identified change points will be further analyzed as potential candidates of abrupt change by extending the proposed method in a future study.

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Reference Intervals of Thyroid Function Tests Assessed by Immunoassay and Mass Spectrometry in Healthy Pregnant Women Living in Catalonia

Journal of Clinical Medicine ◽

10.3390/jcm10112444 ◽

2021 ◽

Vol 10 (11) ◽

pp. 2444

Author(s):

José María Hernández ◽

Berta Soldevila ◽

Inés Velasco ◽

Fernando Moreno-Flores ◽

Laura Ferrer ◽

...

Keyword(s):

Mass Spectrometry ◽

Pregnant Women ◽

Thyroid Function ◽

Prospective Observational Study ◽

Reference Interval ◽

First Trimester ◽

Reference Intervals ◽

Thyroid Function Tests ◽

Liquid Chromatography Mass Spectrometry ◽

Local Reference

Background: Recent guidelines recommend establishing a local reference interval (RI) for thyroid function. We aimed to establish trimester-specific RIs for thyrotropin (TSH) and free thyroxine (FT4) in a cohort of healthy pregnant women in Catalonia (Spain). Methods: A prospective observational study was conducted with 332 healthy pregnant women, from the first trimester (1T) to delivery. TSH was measured using an Architect® immunoassay (Abbott) and FT4 by two immunoassays, Architect® (Abbott) and Cobas® (Roche), in the three trimesters. FT4 was also measured by liquid chromatography mass spectrometry (LC/MS/MS) in the 1T. Results: TSH (µUI/mL) increased throughout pregnancy (1T: 0.03–3.78; 2T: 0.51–3.53; 3T: 0.50–4.32; p < 0.0001) and FT4 (pmol/L) progressively decreased (Architect® 1T: 10.42–15.96; 2T: 8.37–12.74; 3T: 8.24–12.49; p < 0.0001; and Cobas®: 1T: 11.46–19.05; 2T: 9.65–14.67; 3T: 8.88–14.54; p < 0.0067). The FT4 RI during 1T determined LC/MS/MS was 8.75–18.27. Despite the 1T FT4 results measured by LC/MS/MS and with the two immunoassays being significantly correlated, the results obtained by the three methods were found to be non-interchangeable. Conclusions: We established trimester-specific RIs for TSH and for FT4 with immunoassays in our population. We also validated the 1T FT4 using LC/MS/MS to confirm the results of FT4 lower than the 2.5th percentile or higher than the 97.5th percentile.

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Age dependency of plasma vitamin B12 status markers in Dutch children and adolescents

Pediatric Research ◽

10.1038/s41390-021-01372-2 ◽

2021 ◽

Author(s):

M. Rebecca Heiner-Fokkema ◽

Ineke J. Riphagen ◽

Nicole S. Wiersema ◽

Jelmer J. van Zanden ◽

Jenny E. Kootstra-Ros ◽

...

Keyword(s):

Young Children ◽

Vitamin B12 ◽

Reference Values ◽

Methylmalonic Acid ◽

Early Recognition ◽

Vitamin B12 Deficiency ◽

Reference Intervals ◽

Cobalamin Deficiency ◽

Plasma Vitamin ◽

B12 Deficiency

Abstract Background Vitamin B12 deficiency in children may be associated with (severe) neurological manifestations, therefore recognition is important. Diagnosing vitamin B12 deficiency in children is challenging. This study aimed to investigate plasma methylmalonic acid, holotranscobalamin, and total cobalamin in children 0–18 years of age and to estimate age-dependent reference intervals. Methods Plasma vitamin B12 markers were measured in collected plasma samples of 170 children 0–18 years visiting a local primary care laboratory. All had within-reference hemoglobin and MCV values. Pediatric plasma vitamin B12 biomarkers were measured and reference values were derived thereof. Results Plasma methylmalonic acid was higher in young children, in particular between 1 and 6 months of age; total cobalamin and holotranscobalamin were highest from 0.5 to 4 years and decreased till 10 years of age. Plasma holotranscobalamin was highly correlated with plasma total cobalamin; their ratio was independent of age. Plasma methylmalonic acid was slightly more related to total cobalamin than to holotranscobalamin. A large proportion of mainly young children would be misclassified when adult references are applied. Conclusions Pediatric reference values for cobalamin markers are necessary to allow for early recognition and monitoring of children suspect of (clinical) cobalamin deficiency. Impact We analyzed three plasma vitamin B12 status markers, i.e., total cobalamin, holotranscobalamin, and methylmalonic acid, in the plasma of 170 children 0–18 years of age and were able to derive reference intervals thereof. Recognition of vitamin B12 deficiency in children is important but challenging as pediatric reference intervals for plasma vitamin B12 status markers, particularly plasma holotranscobalamin, are not well described. We think that our results may help early recognition and monitoring of children suspect of (clinical) vitamin B12 deficiency.

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Two radioassays for serum vitamin B12 and folate determination compared in a reference interval study.

Clinical Chemistry ◽

10.1093/clinchem/31.8.1358 ◽

1985 ◽

Vol 31 (8) ◽

pp. 1358-1360 ◽

Cited By ~ 16

Author(s):

R H Christenson ◽

G A Dent ◽

A Tuszynski

Keyword(s):

Vitamin B12 ◽

Serum Vitamin ◽

Hemoglobin Concentration ◽

Reference Interval ◽

Reference Intervals ◽

The Other ◽

Mean Values ◽

Folate Status ◽

Standard Curve ◽

Low Concentrations

Abstract For 154 subjects, we verified that vitamin B12 and folate status was normal, using as criteria the average polymorphonuclear lobe count, mean corpuscular volume, and hemoglobin concentration. We then used blood from these subjects to compare values obtained with two radioassay kits, each designed for simultaneous vitamin B12 and folate determination. Although regression analysis showed reasonable correlation between the folate (r = 0.87) and vitamin B12 (r = 0.94) kits, we observed significant differences in the overall mean values for vitamin B12 (p less than 0.01) and folate (p less than 0.001) as measured with the kits in this population. Radioassay standard-curve data for the folate assays were similar, but these data indicated greater sensitivity at low concentrations for one vitamin B12 kit than the other. Using reference intervals recommended in the kit inserts, we found that the vitamin B12 status for 9% of these subjects would have been misclassified by one kit, 2% by the other.

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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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Measurement of Total Vitamin B12 and Holotranscobalamin, Singly and in Combination, in Screening for Metabolic Vitamin B12 Deficiency

Clinical Chemistry ◽

10.1373/clinchem.2005.061382 ◽

2006 ◽

Vol 52 (2) ◽

pp. 278-285 ◽

Cited By ~ 93

Author(s):

Joshua W Miller ◽

Marjorie G Garrod ◽

Alan L Rockwood ◽

Mark M Kushnir ◽

Lindsay H Allen ◽

...

Keyword(s):

Diagnostic Accuracy ◽

Vitamin B12 ◽

Methylmalonic Acid ◽

Vitamin B12 Deficiency ◽

Reference Intervals ◽

Plasma Vitamin ◽

Roc Curve Analysis ◽

Total Vitamin ◽

B12 Deficiency ◽

Elderly Cohort

Abstract Background: The standard screening test for vitamin B12 deficiency, measurement of total plasma vitamin B12, has limitations of sensitivity and specificity. Plasma vitamin B12 bound to transcobalamin (holoTC) is the fraction of total vitamin B12 available for tissue uptake and therefore has been proposed as a potentially useful alternative indicator of vitamin B12 status. Methods: We compared the diagnostic accuracy of total vitamin B12, holoTC, and a combination of both measures to screen for metabolic vitamin B12 deficiency in an elderly cohort (age ≥60 years). Plasma methylmalonic acid and homocysteine were used as indicators of vitamin B12 deficiency. Results: Low total vitamin B12 (<148 pmol/L) and low holoTC (<35 pmol/L) were observed in 6.5% and 8.0%, and increased methylmalonic acid (>350 nmol/L) and homocysteine (>13 μmol/L) were observed in 12.1% and 17.0% of the study participants. In multiple regression models, holoTC explained 5%–6% more of the observed variance in methylmalonic acid and homocysteine than did total vitamin B12 (P ≤0.004). ROC curve analysis indicated that total vitamin B12 and holoTC were essentially equivalent in their ability to discriminate persons with and without vitamin B12 deficiency. Individuals with low concentrations of both total vitamin B12 and holoTC had significantly higher concentrations of methylmalonic acid and homocysteine than did individuals with total vitamin B12 and/or holoTC within the reference intervals (P <0.001). Conclusions: HoloTC and total vitamin B12 have equal diagnostic accuracy in screening for metabolic vitamin B12 deficiency. Measurement of both holoTC and total vitamin B12 provides a better screen for vitamin B12 deficiency than either assay alone.

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Change Point Detection in Terrorism-Related Online Content Using Deep Learning Derived Indicators

Information ◽

10.3390/info12070274 ◽

2021 ◽

Vol 12 (7) ◽

pp. 274

Author(s):

Ourania Theodosiadou ◽

Kyriaki Pantelidou ◽

Nikolaos Bastas ◽

Despoina Chatzakou ◽

Theodora Tsikrika ◽

...

Keyword(s):

Time Series ◽

Change Point ◽

Hate Speech ◽

Change Point Detection ◽

Change Points ◽

Change Point Analysis ◽

Point Analysis ◽

Depth Analysis ◽

Textual Data ◽

Point Detection

Given the increasing occurrence of deviant activities in online platforms, it is of paramount importance to develop methods and tools that allow in-depth analysis and understanding to then develop effective countermeasures. This work proposes a framework towards detecting statistically significant change points in terrorism-related time series, which may indicate the occurrence of events to be paid attention to. These change points may reflect changes in the attitude towards and/or engagement with terrorism-related activities and events, possibly signifying, for instance, an escalation in the radicalization process. In particular, the proposed framework involves: (i) classification of online textual data as terrorism- and hate speech-related, which can be considered as indicators of a potential criminal or terrorist activity; and (ii) change point analysis in the time series generated by these data. The use of change point detection (CPD) algorithms in the produced time series of the aforementioned indicators—either in a univariate or two-dimensional case—can lead to the estimation of statistically significant changes in their structural behavior at certain time locations. To evaluate the proposed framework, we apply it on a publicly available dataset related to jihadist forums. Finally, topic detection on the estimated change points is implemented to further assess its effectiveness.

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