ms_07212771190V3.

Vitamin B12 II
MODULAR ANALYTICS E170
cobas e 411
07212771 190 100
cobas e 601
cobas e 602

English a) Tris(2,2'-bipyridyl)ruthenium(II)-complex (Ru(bpy) )

System information Test principle

For cobas e 411 analyzer: test number 1410 Competition principle. Total duration of assay: 27 minutes.
For MODULAR ANALYTICS E170, cobas e 601 and cobas e 602 ▪ 1st incubation: By incubating the sample (15 µL) with the vitamin B12
analyzers: Application Code Number 224 pretreatment 1 and pretreatment 2, bound vitamin B12 is released.
Intended use ▪ 2nd incubation: By incubating the pretreated sample with the ruthenium
Binding assay for the in vitro quantitative determination of vitamin B12 in labeled intrinsic factor, a vitamin B12-binding protein complex is formed,
human serum and plasma. the amount of which is dependent upon the analyte concentration in the
The electrochemiluminescence immunoassay “ECLIA” is intended for use sample.
on Elecsys and cobas e immunoassay analyzers. ▪ 3rd incubation: After addition of streptavidin-coated microparticles and
vitamin B12 labeled with biotin, the still-vacant sites of the ruthenium
Summary labeled intrinsic factor become occupied, with formation of a ruthenium
Vitamin B12, also referred to as cobalamin, is a complex organometallic labeled intrinsic factor vitamin B12 biotin complex. The entire complex
compound in which a cobalt atom is situated within a corrin ring. It is a becomes bound to the solid phase via interaction of biotin and
water-soluble vitamin which is synthesized by microorganisms. It cannot be streptavidin.
synthesized in the human body and is seldom found in products of plant
origin. Main sources of vitamin B12 are meat, fish, eggs and dairy ▪ The reaction mixture is aspirated into the measuring cell where the
products.1 The uptake in the gastrointestinal tract depends on intrinsic microparticles are magnetically captured onto the surface of the
factor, which is synthesized by the gastric parietal cells, and on the “cubam electrode. Unbound substances are then removed with
receptor” in the distal ileum. The most frequent cause of severe vitamin B12 ProCell/ProCell M. Application of a voltage to the electrode then induces
deficiency is a lack of intrinsic factor due to autoimmune atrophic gastritis. chemiluminescent emission which is measured by a photomultiplier.
The disease is historically called “pernicious anemia”, even though many ▪ Results are determined via a calibration curve which is instrument-
patients present with mainly neurologic manifestations. Examples of other specifically generated by 2‑point calibration and a master curve provided
causes for vitamin B12 deficiency are malabsorption due to gastrectomy, via the reagent barcode or e‑barcode.
inflammatory bowel disease or dietary deficiency, e.g. in strict vegetarians
(vegans).2 Reagents - working solutions
The reagent rackpack (M, R1, R2) and the pretreatment reagents (PT1,
Vitamin B12 is the cofactor for two enzymes, methionine synthase and PT2) are labeled as B12 II.
methylmalonyl CoA mutase.2,3 Methionine synthase, located in the
cytoplasm, requires vitamin B12 in the form of methylcobalamin and PT1 Pretreatment reagent 1 (white cap), 1 bottle, 4 mL:
catalyzes the conversion of homocysteine to methionine, an essential
amino acid. During this step a methyl group is transferred from Dithiothreitol 1.028 g/L; stabilizer, pH 5.5.
methyltetrahydrofolate to the amino acid.3 This enzyme links the
methylation pathway through synthesis of the methyl donor S‑Adenosyl PT2 Pretreatment reagent 2 (gray cap), 1 bottle, 4 mL:
methionine and the pathway in which purine and pyrimidine are synthesized Sodium hydroxide 40 g/L; sodium cyanide 2.205 g/L.
via generation of tetrahydrofolate.3 In the form of
5’‑deoxyadenosylcobalamin, vitamin B12 is also required for the M Streptavidin-coated microparticles (transparent cap), 1 bottle, 6.5 mL:
mitochondrial enzyme methylmalonyl CoA mutase, which converts Streptavidin-coated microparticles 0.72 mg/mL; preservative.
methylmalonyl CoA to succinyl CoA. This is a step in the oxidation of odd-
chain fatty acids and catabolism of ketogenic amino acids.3 Thus, R1 Intrinsic factor~Ru(bpy) (gray cap), 1 bottle, 10 mL:
vitamin B12 is important for DNA synthesis, regenerating methionine for
protein synthesis and methylation, as well as for the development and initial Ruthenium labeled recombinant porcine intrinsic factor 4 µg/L;
myelination of the central nervous system (CNS) and for the maintenance cobinamide dicyanide 15 µg/L; stabilizer; human serum albumin;
of normal CNS function.2,3 phosphate buffer, pH 5.5; preservative.
Vitamin B12 deficiencies are common in wealthier countries principally R2 Vitamin B12~biotin (black cap), 1 bottle, 8.5 mL:
among the elderly and are most prevalent in poorer populations. In general
the prevalence increases with age.4,5 Biotinylated vitamin B12 25 µg/L; biotin 3 µg/L; phosphate buffer,
Vitamin B12 deficiency impacts red blood cell synthesis, resulting in pH 7.0; preservative.
megaloblastic anemia due to abnormal DNA synthesis.3 In addition it
impairs neurological function, in particular demyelination of nerves in part Precautions and warnings
due to abnormal methylation, leading to peripheral neuropathy, dementia, For in vitro diagnostic use.
poor cognitive performance, and depression.3 Other effects of vitamin B12 Exercise the normal precautions required for handling all laboratory
deficiency or depletion are increased risk of neural tube defects, reagents.
osteoporosis, cerebrovascular and cardiovascular diseases.3 Early Disposal of all waste material should be in accordance with local guidelines.
diagnosis is essential, because of the latent nature of this disorder and the Safety data sheet available for professional user on request.
risk of permanent neurological damage.3,5 This kit contains components classified as follows in accordance with the
Generally, the primary test performed to confirm the diagnosis of Regulation (EC) No. 1272/2008:
vitamin B12 deficiency is measurement of serum vitamin B12 level.2 Recent
publications suggest that in addition the following biomarkers should be
measured to improve the specificity of diagnosis: folate, methylmalonic acid
(MMA), homocysteine and holotranscobalamin.2,5,6,7
The Elecsys Vitamin B12 II assay employs a competitive test principle using
intrinsic factor specific for vitamin B12. Vitamin B12 in the sample competes Danger
with the added vitamin B12 labeled with biotin for the binding sites on the
ruthenium‑labeled intrinsic factor complexa). H290 May be corrosive to metals.

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Vitamin B12 II
H314 Causes severe skin burns and eye damage. Na‑heparin, Li‑heparin, K2‑EDTA and K3‑EDTA plasma. Li‑heparin plasma
tubes containing separating gel can be used.
H412 Harmful to aquatic life with long lasting effects. Criterion: Slope 0.9‑1.1 + intercept within < ± 2x Limit of Blank + coefficient
Prevention: of correlation ≥ 0.95.
Stable for 2 hours at 15‑25 °C, 48 hours at 2‑8 °C, 56 days at
P273 Avoid release to the environment. ‑20 °C (± 5 °C). Freeze once only.
Stability of serum obtained with separating tubes: 24 hours at 2‑8 °C (note
P280 Wear protective gloves/ protective clothing/ eye protection/ the data provided by the tube manufacturer).
face protection. The sample types listed were tested with a selection of sample collection
Response: tubes that were commercially available at the time of testing, i.e. not all
available tubes of all manufacturers were tested. Sample collection systems
P301 + P330 IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. from various manufacturers may contain differing materials which could
+ P331 affect the test results in some cases. When processing samples in primary
tubes (sample collection systems), follow the instructions of the tube
P303 + P361 IF ON SKIN (or hair): Take off immediately all contaminated manufacturer.
+ P353 clothing. Rinse skin with water/shower. Centrifuge samples containing precipitates before performing the assay.
Do not use heat‑inactivated samples.
P304 + P340 IF INHALED: Remove person to fresh air and keep Avoid hemolysis.
+ P310 comfortable for breathing.
Do not use samples and controls stabilized with azide.
Immediately call a POISON CENTER/doctor.
Vitamin B12 determinations should be performed on serum or plasma
P305 + P351 IF IN EYES: Rinse cautiously with water for several samples from fasting patients.
+ P338 minutes. Remove contact lenses, if present and easy to do. Note: Samples with extremely high total protein concentrations (e.g.
patients suffering from Waldenström's macroglobulinemia) are not suitable
+ P310 Continue rinsing. Immediately call a POISON CENTER/ for use in this assay, since they may lead to the formation of protein gel in
doctor. the assay cup. Processing protein gel may cause a run abort. The critical
Product safety labeling follows EU GHS guidance. protein concentration is dependent upon the individual sample composition.
The formation of protein gel was seen in samples (spiked with human IgG
Contact phone: all countries: +49-621-7590 or human serum albumin) having a total protein concentration > 160 g/L.
All human material should be considered potentially infectious. All products Ensure the samples, calibrators and controls are at 20‑25 °C prior to
derived from human blood are prepared exclusively from the blood of measurement.
donors tested individually and shown to be free from HBsAg and antibodies
to HCV and HIV. The testing methods used assays approved by the FDA or Due to possible evaporation effects, samples, calibrators and controls on
cleared in compliance with the European Directive 98/79/EC, Annex II, the analyzers should be analyzed/measured within 2 hours.
List A. Materials provided
However, as no testing method can rule out the potential risk of infection See “Reagents – working solutions” section for reagents.
with absolute certainty, the material should be handled with the same level
of care as a patient specimen. In the event of exposure, the directives of the Materials required (but not provided)
responsible health authorities should be followed.8,9 ▪  07212780190, Vitamin B12 II CalSet, for 4 x 1.0 mL
Avoid foam formation in all reagents and sample types (specimens, ▪  05618860190, PreciControl Varia, for 4 x 3.0 mL
calibrators and controls).
▪  11732277122, Diluent Universal, 2 x 16 mL sample diluent or
Reagent handling  03183971122, Diluent Universal, 2 x 36 mL sample diluent
The reagents in the kit have been assembled into a ready‑for‑use unit that ▪ General laboratory equipment
cannot be separated.
All information required for correct operation is read in from the respective ▪ MODULAR ANALYTICS E170 or cobas e analyzer
reagent barcodes. Accessories for cobas e 411 analyzer:
Storage and stability ▪  11662988122, ProCell, 6 x 380 mL system buffer
Store at 2‑8 °C. ▪  11662970122, CleanCell, 6 x 380 mL measuring cell cleaning
Do not freeze. solution
Store the Elecsys reagent kit upright in order to ensure complete ▪  11930346122, Elecsys SysWash, 1 x 500 mL washwater additive
availability of the microparticles during automatic mixing prior to use. ▪  11933159001, Adapter for SysClean
Stability: ▪  11706802001, AssayCup, 60 x 60 reaction cups
unopened at 2‑8 °C up to the stated expiration date ▪  11706799001, AssayTip, 30 x 120 pipette tips
after opening at 2‑8 °C 84 days (12 weeks) ▪  11800507001, Clean‑Liner
Accessories for MODULAR ANALYTICS E170, cobas e 601 and
on the analyzers 35 days (5 weeks) onboard cobas e 602 analyzers:
or
▪  04880340190, ProCell M, 2 x 2 L system buffer
60 days when stored alternatively in
the refrigerator and on the analyzer, ▪  04880293190, CleanCell M, 2 x 2 L measuring cell cleaning
solution
with the total time onboard on the
analyzer not exceeding ▪  03023141001, PC/CC‑Cups, 12 cups to prewarm ProCell M and
CleanCell M before use
10 x 8 hours
▪  03005712190, ProbeWash M, 12 x 70 mL cleaning solution for run
Specimen collection and preparation finalization and rinsing during reagent change
Only the specimens listed below were tested and found acceptable. ▪  03004899190, PreClean M, 5 x 600 mL detection cleaning solution
Serum collected using standard sampling tubes or tubes containing ▪  12102137001, AssayTip/AssayCup, 48 magazines x 84 reaction
separating gel. cups or pipette tips, waste bags

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Vitamin B12 II
▪  03023150001, WasteLiner, waste bags Criterion: Recovery within ± 10 % of initial value with samples > 200 pg/mL
▪  03027651001, SysClean Adapter M and ≤ ± 20 pg/mL with samples ≤ 200 pg/mL.
Accessories for all analyzers: Samples should not be taken from patients receiving therapy with high
biotin doses (i.e. > 5 mg/day) until at least 8 hours following the last biotin
▪  11298500316, ISE Cleaning Solution/Elecsys SysClean, administration.
5 x 100 mL system cleaning solution No interference was observed from rheumatoid factors up to a
Assay concentration of 1500 IU/mL.
For optimum performance of the assay follow the directions given in this In vitro tests were performed on 16 commonly used pharmaceuticals. No
document for the analyzer concerned. Refer to the appropriate operator’s interference with the assay was found.
manual for analyzer‑specific assay instructions. In rare cases, interference due to extremely high titers of antibodies to
Resuspension of the microparticles takes place automatically prior to use. analyte‑specific antibodies, streptavidin or ruthenium can occur. These
Read in the test‑specific parameters via the reagent barcode. If in effects are minimized by suitable test design.
exceptional cases the barcode cannot be read, enter the 15‑digit sequence Because intrinsic factor is typically used as the binding protein in serum
of numbers (except for the cobas e 602 analyzer). vitamin B12 assays, anti-intrinsic factor antibodies (which are common in
MODULAR ANALYTICS E170, cobas e 601 and cobas e 602 analyzers: pernicious anemia) can lead to elevated vitamin B12 measurement
PreClean M solution is necessary. values.2,11,12 The Elecsys Vitamin B12 II assay is designed to avoid
Bring the cooled reagents to approximately 20 °C and place on the reagent interference due to anti-intrinsic factor antibodies.13
disk (20 °C) of the analyzer. Avoid foam formation. The system For diagnostic purposes, the results should always be assessed in
automatically regulates the temperature of the reagents and the conjunction with the patient’s medical history, clinical examination and other
opening/closing of the bottles. findings.
Calibration Note: The presence of immunoglobulin-vitamin B12 complexes may cause
Traceability: This method has been standardized against the Vitamin B12 unexpectedly high values of vitamin B12.14,15
assay (  04745736190). Limits and ranges
Accuracy to WHO Standard 03/178: A study was performed to evaluate the Measuring range
accuracy of the Elecsys Vitamin B12 II assay using the Vitamin B12 World 50.0‑2000 pg/mL or 36.9‑1476 pmol/L (defined by the Limit of Blank and the
Health Organization International Standard 03/178.10 Two reagent lots were maximum of the master curve). Values below the Limit of Blank are
used on 16 instruments. The mean recovery of the target value of reported as < 50.0 pg/mL or < 36.9 pmol/L. Values above the measuring
WHO IS 03/178 (480 pg/mL) was 102 %. range are reported as > 2000 pg/mL or > 1476 pmol/L.
Every Elecsys reagent set has a barcoded label containing specific Lower limits of measurement
information for calibration of the particular reagent lot. The predefined
master curve is adapted to the analyzer using the relevant CalSet. Limit of Blank, Limit of Detection and Limit of Quantitation
Calibration frequency: Calibration must be performed once per reagent lot Limit of Blank = 50 pg/mL (36.9 pmol/L)
using fresh reagent (i.e. not more than 24 hours since the reagent kit was Limit of Detection = 100 pg/mL (73.8 pmol/L)
registered on the analyzer). Limit of Quantitation = 150 pg/mL (111 pmol/L)
Calibration interval may be extended based on acceptable verification of The Limit of Blank, Limit of Detection and Limit of Quantitation were
calibration by the laboratory. determined in accordance with the CLSI (Clinical and Laboratory Standards
Renewed calibration is recommended as follows: Institute) EP17‑A requirements.
▪ after 1 month (28 days) when using the same reagent lot The Limit of Blank is the 95th percentile value from n ≥ 60 measurements of
analyte‑free samples over several independent series. The Limit of Blank
▪ after 7 days (when using the same reagent kit on the analyzer) corresponds to the concentration below which analyte‑free samples are
▪ as required: e.g. quality control findings outside the defined limits found with a probability of 95 %.
Quality control The Limit of Detection is determined based on the Limit of Blank and the
For quality control, use PreciControl Varia. standard deviation of low concentration samples. The Limit of Detection
corresponds to the lowest analyte concentration which can be detected
In addition, other suitable control material can be used. (value above the Limit of Blank with a probability of 95 %).
Controls for the various concentration ranges should be run individually at The Limit of Quantitation is defined as the lowest amount of analyte in a
least once every 24 hours when the test is in use, once per reagent kit, and sample that can be accurately quantitated with a allowable imprecision of
following each calibration. ≤ 20 %.
The control intervals and limits should be adapted to each laboratory’s It has been determined using low concentration vitamin B12 samples.
individual requirements. Values obtained should fall within the defined
limits. Each laboratory should establish corrective measures to be taken if Dilution
values fall outside the defined limits. Samples with vitamin B12 concentrations above the measuring range can
If necessary, repeat the measurement of the samples concerned. be manually diluted 1:2 with Diluent Universal. The concentration of the
diluted sample must be > 738 pmol/L or > 1000 pg/mL. After manual
Follow the applicable government regulations and local guidelines for dilution, multiply the results by the dilution factor 2.
quality control.
Note: Sample-dependent non‑linearity upon dilution is seen with samples
Calculation having analyte levels beyond the measuring range. As Diluent Universal
The analyzer automatically calculates the analyte concentration of each may contain low levels of endogenous vitamin B12, it is recommended that
sample (either in pmol/L or pg/mL). linearity studies be performed using a known low analyte-containing serum
pool. Samples outside the measuring range can be diluted 1:2 with Diluent
Conversion factors: pmol/L x 1.36 = pg/mL Universal; the effect of endogenous vitamin B12 concentration is
pg/mL x 0.738 = pmol/L insignificant at these levels.
Expected values
Limitations - interference
Because differences may exist with respect to population and dietary
The assay is unaffected by icterus (bilirubin ≤ 1112 µmol/L or ≤ 65 mg/dL), status, it is recommended that normal ranges be determined by each
hemolysis (Hb ≤ 0.025 mmol/L or ≤ 0.04 g/dL), lipemia (Intralipid laboratory over a suitable period of time and in a statistically significant
≤ 17.1 mmol/L or ≤ 1500 mg/dL), biotin (≤ 205 nmol/L or ≤ 50 ng/mL), IgG number of assays before clinical significance is attached to the results of
≤ 28 g/L, IgA ≤ 16 g/L and IgM ≤ 10 g/L. these tests.

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The values shown below were performed on samples from an apparently MODULAR ANALYTICS E170, cobas e 601 and cobas e 602 analyzers
healthy population, using the Elecsys Vitamin B12 II assay. The calculation
is based on 135 sera (68 men, 67 women). The age range was between 20 Repeatability Intermediate
and 78 years. Pregnant women were excluded. The reference population precision
was selected according to normal homocysteine values. Sample Mean SD CV SD CV
N Median Range (2.5th-97.5th percentile) pg/mL pg/mL % pg/mL %
pg/mL pmol/L pg/mL pmol/L Human serum 4 1230 19.8 1.6 28.8 2.3
135 425 314 197-771 145-569 Human serum 5 1890 29.8 1.6 41.5 2.2
These values should only be used as guidelines. PreciControl Varia1 448 7.16 1.6 15.3 3.4
Each laboratory should investigate the transferability of the expected values PreciControl Varia2 917 12.0 1.3 27.8 3.0
to its own patient population and if necessary determine its own reference
ranges. MODULAR ANALYTICS E170, cobas e 601 and cobas e 602 analyzers
Specific performance data Repeatability Intermediate
Representative performance data on the analyzers are given below. precision
Results obtained in individual laboratories may differ.
Sample Mean SD CV SD CV
Precision
Precision was determined using Elecsys reagents, pooled human sera and pmol/L pmol/L % pmol/L %
controls in a protocol (EP5‑A2) of the CLSI (Clinical and Laboratory Human serum 1 130 4.31 3.3 6.75 5.2
Standards Institute): 2 runs per day in duplicate each for 21 days (n = 84).
The following results were obtained: Human serum 2 300 6.08 2.0 9.37 3.1
Human serum 3 745 9.74 1.3 15.6 2.1
cobas e 411 analyzer
Human serum 4 908 14.6 1.6 21.3 2.3
Repeatability Intermediate
precision Human serum 5 1395 22.0 1.6 30.6 2.2
Sample Mean SD CV SD CV PreciControl Varia1 331 5.28 1.6 11.3 3.4
pg/mL pg/mL % pg/mL % PreciControl Varia2 677 8.86 1.3 20.5 3.0
Human serum 1 176 8.86 5.0 12.7 7.2 Method comparison
Human serum 2 405 13.0 3.2 17.5 4.3 a) A comparison of the Elecsys Vitamin B12 assay (calibrated with
Vitamin B12 CalSet II; x) and the Elecsys Vitamin B12 II assay (calibrated
Human serum 3 960 19.7 2.1 31.0 3.2 with Vitamin B12 II CalSet; y) using clinical samples gave the following
Human serum 4 1230 27.4 2.2 46.4 3.8 correlations (pg/mL):
Number of samples measured: 100
Human serum 5 1940 40.9 2.1 72.6 3.7
PreciControl Varia1 447 12.2 2.7 18.6 4.2 Passing/Bablok16 Linear regression
PreciControl Varia2 934 20.2 2.2 38.4 4.1 y = 0.952x + 15.1 y = 0.957x + 11.6
τ = 0.977 r = 0.999
cobas e 411 analyzer
The sample concentrations were between 69 and 1890 pg/mL (51 and
Repeatability Intermediate 1395 pmol/L).
precision b) A comparison of the Elecsys Vitamin B12 II assay (y) and a commercially
Sample Mean SD CV SD CV available method (x) using clinical samples gave the following correlations
(pg/mL):
pmol/L pmol/L % pmol/L % Number of samples measured: 106
Human serum 1 130 6.54 5.0 9.37 7.2
Passing/Bablok16 Linear regression
Human serum 2 299 9.59 3.2 12.9 4.3
y = 0.923x + 4.90 y = 0.881x + 27.6
Human serum 3 708 14.5 2.1 22.9 3.2
τ = 0.952 r = 0.993
Human serum 4 908 20.2 2.2 34.2 3.8
The sample concentrations were between 182 and 1797 pg/mL (134 and
Human serum 5 1432 30.2 2.1 53.6 3.7 1326 pmol/L).
PreciControl Varia1 330 9.00 2.7 13.7 4.2 c) A comparison of the Elecsys Vitamin B12 II assay on the cobas e 601
analyzer (y) and the Elecsys Vitamin B12 II assay on the cobas e 411
PreciControl Varia2 689 14.9 2.2 28.3 4.1 analyzer (x) using clinical samples gave the following correlations (pg/mL):
MODULAR ANALYTICS E170, cobas e 601 and cobas e 602 analyzers Number of samples measured: 117
Repeatability Intermediate Passing/Bablok16 Linear regression
precision y = 1.01x - 2.77 y = 1.01x + 3.22
Sample Mean SD CV SD CV τ = 0.933 r = 0.995
pg/mL pg/mL % pg/mL % The sample concentrations were between 56 and 1887 pg/mL (41 and
Human serum 1 176 5.84 3.3 9.14 5.2 1393 pmol/L).
Human serum 2 407 8.24 2.0 12.7 3.1 Analytical specificity
The following cross-reactivities were found, tested with vitamin B12
Human serum 3 1010 13.2 1.3 21.1 2.1 concentrations of 129 pg/mL and 550 pg/mL.

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Cross-reactant Maximum Cross-reactivity Volume after reconstitution or mixing
concentration tested %
GTIN Global Trade Item Number
ng/mL
Cobinamide dicyanide 210 0.003 COBAS, COBAS E, ELECSYS and PRECICONTROL are trademarks of Roche. INTRALIPID is a trademark of
Fresenius Kabi AB.
References All other product names and trademarks are the property of their respective owners.
Additions, deletions or changes are indicated by a change bar in the margin.
1 Thomas L. Clinical Laboratory Diagnostics: Use and Assessment of
Clinical Laboratory Results; 1st Edition, Frankfurt/Main: TH-Books- © 2017, Roche Diagnostics
Verl.-Ges.,1998:424-431.
2 Stabler SP. Vitamin B12 deficiency. N Engl J Med 2013;368:149-160.
3 Allen LH. Vitamin B-12. Adv Nutr 2012;3(1):54-55. doi: Roche Diagnostics GmbH, Sandhofer Strasse 116, D-68305 Mannheim
10.3945/an.111.001370. Epub 2012 Jan 5. www.roche.com
4 Allen LH. How common is vitamin B-12 deficiency? Am J Clin Nutr
2009;89(2):693S-696S. Epub 2008 Dec 30.
5 Chatthanawaree W. Biomarkers of cobalamin (vitamin B12) deficiency
and its application. J Nutr Health Aging 2011 Mar;15(3):227-313.
6 Yetley EA, Pfeiffer CM, Phinney KW, et al., Biomarkers of vitamin B-12
status in NHANES: a roundtable summary. Am J Clin Nutr 2011
Jul;94(1):313S-321S.
7 Hvas AM, Nexo E. Diagnosis and treatment of vitamin B12 deficiency -
an update. Haematologica 2006;91(11):1506-1512.
8 Occupational Safety and Health Standards: Bloodborne pathogens.
(29 CFR Part 1910.1030). Fed. Register.
9 Directive 2000/54/EC of the European Parliament and Council of
18 September 2000 on the protection of workers from risks related to
exposure to biological agents at work.
10 Thorpe SJ, Heath A, Blackmore S, et al. International Standard for
serum vitamin B12 and serum folate: international collaborative study to
evaluate a batch of lyophilised serum for B12 and folate content. Clin
Chem Lab Med 2007;45(3):380-386.
11 Yang DT, Cook RJ. Spurious elevations of vitamin B12 with pernicious
anemia. N Engl J Med 2012;366:1742-1743.
12 Carmel R, Agrawal YP. Failures of cobalamin assays in pernicious
anemia. N Engl J Med 2012;367:385-386. [Erratum, N Engl J Med
2012;367:976.]
13 Schilling KA, Wiesgigl M. The Elecsys® Vitamin B12 assay is not
affected by anti-intrinsic factor antibodies. Clin Chem Lab Med 2013
Jun 29;51(11):e251-e252.
14 Jeffery J, Millar H, MacKenzie P, et al. An IgG complexed form of
vitamin B12 is a common cause of elevated serum concentrations. Clin
Biochem 2010 Jan;43(1-2):82-88. doi:
10.1016/j.clinbiochem.2009.08.022. Epub 2009 Sep 8.
15 Bowen RA, Drake SK, Vanjani R, et al. Markedly increased vitamin B12
concentrations attributable to IgG-IgM-vitamin B12 immune complexes.
Clin Chem 2006;52(11):2107-2114.
16 Bablok W, Passing H, Bender R, et al. A general regression procedure
for method transformation. Application of linear regression procedures
for method comparison studies in clinical chemistry, Part III.
J Clin Chem Clin Biochem 1988 Nov;26(11):783-790.
For further information, please refer to the appropriate operator’s manual for
the analyzer concerned, the respective application sheets, the product
information and the Method Sheets of all necessary components (if
available in your country).
A point (period/stop) is always used in this Method Sheet as the decimal
separator to mark the border between the integral and the fractional parts of
a decimal numeral. Separators for thousands are not used.
Symbols
Roche Diagnostics uses the following symbols and signs in addition to
those listed in the ISO 15223‑1 standard (for USA: see
https://usdiagnostics.roche.com for definition of symbols used):
Contents of kit
Analyzers/Instruments on which reagents can be used
Reagent
Calibrator

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