07028121500V7.

Elecsys Vitamin B12 II

cobas e 402
07028121190 07028121500 300
cobas e 801

English Test principle

System information Competition principle. Total duration of assay: 27 minutes.
▪ 1st incubation: By incubating the sample (9 µL) with the vitamin B12
Short name ACN (application code number) pretreatment 1 and pretreatment 2, bound vitamin B12 is released.
B12 2 10088 ▪ 2nd incubation: By incubating the pretreated sample with the
Intended use ruthenium‑labeled intrinsic factor, a vitamin B12‑binding protein complex
is formed, the amount of which is dependent upon the analyte
Binding assay for the in vitro quantitative determination of vitamin B12 in concentration in the sample.
human serum and plasma.
▪ 3rd incubation: After addition of streptavidin-coated microparticles and
The electrochemiluminescence immunoassay “ECLIA” is intended for use vitamin B12 labeled with biotin, the still-vacant sites of the
on cobas e immunoassay analyzers. ruthenium‑labeled intrinsic factor become occupied, with formation of a
Summary ruthenium‑labeled intrinsic factor vitamin B12 biotin complex. The entire
Vitamin B12, also referred to as cobalamin, is a complex organometallic complex becomes bound to the solid phase via interaction of biotin and
compound in which a cobalt atom is situated within a corrin ring. It is a streptavidin.
water-soluble vitamin which is synthesized by microorganisms. It cannot be ▪ The reaction mixture is aspirated into the measuring cell where the
synthesized in the human body and is seldom found in products of plant microparticles are magnetically captured onto the surface of the
origin. Main sources of vitamin B12 are meat, fish, eggs and dairy electrode. Unbound substances are then removed with ProCell II M.
products.1 The uptake in the gastrointestinal tract depends on intrinsic Application of a voltage to the electrode then induces chemiluminescent
factor, which is synthesized by the gastric parietal cells, and on the “cubam emission which is measured by a photomultiplier.
receptor” in the distal ileum. The most frequent cause of severe vitamin B12
deficiency is a lack of intrinsic factor due to autoimmune atrophic gastritis. ▪ Results are determined via a calibration curve which is instrument-
The disease is historically called “pernicious anemia”, even though many specifically generated by 2‑point calibration and a master curve provided
patients present with mainly neurologic manifestations. Examples of other via the cobas link.
causes for vitamin B12 deficiency are malabsorption due to gastrectomy, Reagents - working solutions
inflammatory bowel disease or dietary deficiency, e.g. in strict vegetarians The cobas e pack (M, R1, R2) and the pretreatment reagents (PT1, PT2)
(vegans).2 are labeled as B12 2.
Vitamin B12 is the cofactor for two enzymes, methionine synthase and
methylmalonyl CoA mutase.2,3 Methionine synthase, located in the PT1 Pretreatment reagent 1, 1 bottle, 7.3 mL:
cytoplasm, requires vitamin B12 in the form of methylcobalamin and Dithiothreitol 1.028 g/L; stabilizer, pH 5.5.
catalyzes the conversion of homocysteine to methionine, an essential
amino acid. During this step a methyl group is transferred from PT2 Pretreatment reagent 2, 1 bottle, 6.3 mL:
methyltetrahydrofolate to the amino acid.3 This enzyme links the Sodium hydroxide 40 g/L; sodium cyanide 2.205 g/L.
methylation pathway through synthesis of the methyl donor S‑adenosyl M Streptavidin-coated microparticles, 1 bottle, 12.4 mL:
methionine and the pathway in which purine and pyrimidine are synthesized Streptavidin-coated microparticles 0.72 mg/mL; preservative.
via generation of tetrahydrofolate.3 In the form of
5’‑deoxyadenosylcobalamin, vitamin B12 is also required for the R1 Intrinsic factor~Ru(bpy) , 1 bottle, 18.8 mL:
mitochondrial enzyme methylmalonyl CoA mutase, which converts Ruthenium labeled recombinant porcine intrinsic factor 4 µg/L;
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, cobinamide dicyanide 15 µg/L; stabilizer; human serum albumin;
vitamin B12 is important for DNA synthesis, regenerating methionine for phosphate buffer, pH 5.5; preservative.
protein synthesis and methylation, as well as for the development and initial R2 Vitamin B12~biotin, 1 bottle, 15.8 mL:
myelination of the central nervous system (CNS) and for the maintenance
of normal CNS function.2,3 Biotinylated vitamin B12 25 µg/L; biotin 3 µg/L; phosphate buffer,
pH 7.0; preservative.
Vitamin B12 deficiencies are common in wealthier countries principally
among the elderly and are most prevalent in poorer populations. In general Precautions and warnings
the prevalence increases with age.4,5 For in vitro diagnostic use for health care professionals. Exercise the
Vitamin B12 deficiency impacts red blood cell synthesis, resulting in normal precautions required for handling all laboratory reagents.
megaloblastic anemia due to abnormal DNA synthesis.3 In addition it Infectious or microbial waste:
impairs neurological function, in particular demyelination of nerves in part Warning: handle waste as potentially biohazardous material. Dispose of
due to abnormal methylation, leading to peripheral neuropathy, dementia, waste according to accepted laboratory instructions and procedures.
poor cognitive performance, and depression.3 Other effects of vitamin B12
deficiency or depletion are increased risk of neural tube defects, Environmental hazards:
osteoporosis, cerebrovascular and cardiovascular diseases.3 Early Apply all relevant local disposal regulations to determine the safe disposal.
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.
a) Tris(2,2'-bipyridyl)ruthenium(II)-complex (Ru(bpy) )
H314 Causes severe skin burns and eye damage.

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H317 May cause an allergic skin reaction. from various manufacturers may contain differing materials which could
affect the test results in some cases. When processing samples in primary
H412 Harmful to aquatic life with long lasting effects. tubes (sample collection systems), follow the instructions of the tube
manufacturer.
Prevention:
Centrifuge samples containing precipitates before performing the assay.
P261 Avoid breathing dust/fume/gas/mist/vapours/spray. Do not use heat‑inactivated samples.
Do not use samples and controls stabilized with azide.
P273 Avoid release to the environment.
Vitamin B12 determinations should be performed on serum or plasma
P280 Wear protective gloves/ protective clothing/ eye protection/ samples from fasting patients.
face protection/ hearing protection. Ensure the samples and calibrators are at 20‑25 °C prior to measurement.
Due to possible evaporation effects, samples and calibrators on the
Response: analyzers should be analyzed/measured within 2 hours.
P303 + P361 IF ON SKIN (or hair): Take off immediately all contaminated Materials provided
+ P353 clothing. Rinse skin with water. See “Reagents – working solutions” section for reagents.
P304 + P340 IF INHALED: Remove person to fresh air and keep Materials required (but not provided)
+ P310 comfortable for breathing. ▪ 07212780190, Vitamin B12 II CalSet, for 4 x 1.0 mL
Immediately call a POISON CENTER/ doctor. ▪ 05618860190, PreciControl Varia, for 4 x 3.0 mL
▪ 07299001190, Diluent Universal, 45.2 mL sample diluent
P305 + P351 IF IN EYES: Rinse cautiously with water for several
+ P338 minutes. Remove contact lenses, if present and easy to do. ▪ General laboratory equipment
+ P310 Continue rinsing. Immediately call a POISON CENTER/ ▪ cobas e analyzer
doctor. Additional materials for cobas e 402 and cobas e 801 analyzers:
Product safety labeling follows EU GHS guidance. ▪ 06908799190, ProCell II M, 2 x 2 L system solution
Contact phone: all countries: +49-621-7590 ▪ 04880293190, CleanCell M, 2 x 2 L measuring cell cleaning
All human material should be considered potentially infectious. All products solution
derived from human blood are prepared exclusively from the blood of ▪ 07485409001, Reservoir Cup, 8 cups to supply ProCell II M and
donors tested individually and shown to be free from HBsAg and antibodies CleanCell M
to HCV and HIV. The testing methods use assays that have been approved
by the FDA or that are in compliance with the legal rules applicable to ▪ 06908853190, PreClean II M, 2 x 2 L wash solution
placing in vitro diagnostic medical devices for human use on the market in ▪ 05694302001, Assay Tip/Assay Cup tray, 6 magazines
the European Union. x 6 magazine stacks x 105 assay tips and 105 assay cups, 3 wasteliners
However, as no testing method can rule out the potential risk of infection ▪ 07485425001, Liquid Flow Cleaning Cup, 2 adaptor cups to supply
with absolute certainty, the material should be handled with the same level ISE Cleaning Solution/Elecsys SysClean for Liquid Flow Cleaning
of care as a patient specimen. In the event of exposure, the directives of the Detection Unit
responsible health authorities should be followed.8,9
▪ 07485433001, PreWash Liquid Flow Cleaning Cup, 1 adaptor cup
Avoid foam formation in all reagents and sample types (specimens, to supply ISE Cleaning Solution/Elecsys SysClean for Liquid Flow
calibrators and controls). Cleaning PreWash Unit
Reagent handling ▪ 11298500316, ISE Cleaning Solution/Elecsys SysClean,
The reagents in the kit have been assembled into a ready‑for‑use unit that 5 x 100 mL system cleaning solution
cannot be separated. Assay
All information required for correct operation is available via the cobas link. For optimum performance of the assay follow the directions given in this
Storage and stability document for the analyzer concerned. Refer to the appropriate operator’s
Store at 2‑8 °C. manual for analyzer‑specific assay instructions.
Do not freeze. Resuspension of the microparticles takes place automatically prior to use.
Store the cobas e pack upright in order to ensure complete availability of Place the cooled (stored at 2‑8 °C) cobas e pack on the reagent manager.
the microparticles during automatic mixing prior to use. Avoid foam formation. The system automatically regulates the temperature
of the reagents and the opening/closing of the cobas e pack.
Stability: Calibration
unopened at 2‑8 °C up to the stated expiration date Traceability: This method has been standardized against the Elecsys
Vitamin B12 assay ( 04745736190).
on the analyzers 16 weeks
Accuracy to WHO Standard 03/178: A study was performed to evaluate the
Specimen collection and preparation accuracy of the Elecsys Vitamin B12 II assay using the Vitamin B12 World
Only the specimens listed below were tested and found acceptable. Health Organization International Standard 03/178.10 Two reagent lots were
used on 16 instruments. The mean recovery of the target value of
Serum collected using standard sampling tubes or tubes containing WHO IS 03/178 (480 pg/mL) was 102 %.
separating gel.
The predefined master curve is adapted to the analyzer using the relevant
Na‑heparin, Li‑heparin, K2‑EDTA and K3‑EDTA plasma. CalSet.
Li‑heparin plasma tubes containing separating gel can be used. Calibration frequency: Calibration must be performed once per reagent lot
Criterion: Slope 0.9‑1.1 + intercept within ≤ ± 2x Limit of Blank + coefficient using fresh reagent (i.e. not more than 24 hours since the cobas e pack
of correlation ≥ 0.95. was registered on the analyzer).
Stable for 2 hours at 15‑25 °C, 48 hours at 2‑8 °C, 56 days at Calibration interval may be extended based on acceptable verification of
‑20 °C (± 5 °C). Freeze only once. calibration by the laboratory.
The sample types listed were tested with a selection of sample collection Renewed calibration is recommended as follows:
tubes that were commercially available at the time of testing, i.e. not all ▪ after 12 weeks when using the same reagent lot
available tubes of all manufacturers were tested. Sample collection systems

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▪ after 28 days when using the same cobas e pack on the analyzer Note: The presence of immunoglobulin-vitamin B12 complexes may cause
▪ as required: e.g. quality control findings outside the defined limits unexpectedly high values of vitamin B12.22,23
Quality control Limits and ranges
For quality control, use PreciControl Varia. Measuring range
In addition, other suitable control material can be used. 100‑2000 pg/mL or 73.8‑1476 pmol/L (defined by the Limit of Detection and
the maximum of the master curve). Values below the Limit of Detection are
Controls for the various concentration ranges should be run individually at reported as < 100 pg/mL or < 73.8 pmol/L. Values above the measuring
least once every 24 hours when the test is in use, once per cobas e pack, range are reported as > 2000 pg/mL or > 1476 pmol/L (or up to 4000 pg/mL
and following each calibration. or 2952 pmol/L for 2‑fold diluted samples).
The control intervals and limits should be adapted to each laboratory’s Lower limits of measurement
individual requirements. Values obtained should fall within the defined
limits. Each laboratory should establish corrective measures to be taken if Limit of Blank, Limit of Detection and Limit of Quantitation
values fall outside the defined limits. Limit of Blank = 50 pg/mL (36.9 pmol/L)
If necessary, repeat the measurement of the samples concerned. Limit of Detection = 100 pg/mL (73.8 pmol/L)
Follow the applicable government regulations and local guidelines for Limit of Quantitation = 150 pg/mL (111 pmol/L)
quality control. The Limit of Blank, Limit of Detection and Limit of Quantitation were
Calculation determined in accordance with the CLSI (Clinical and Laboratory Standards
The analyzer automatically calculates the analyte concentration of each Institute) EP17‑A2 requirements.
sample (either in pmol/L or pg/mL). 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
Conversion factors: pmol/L x 1.36 = pg/mL corresponds to the concentration below which analyte‑free samples are
found with a probability of 95 %.
pg/mL x 0.738 = pmol/L
The Limit of Detection is determined based on the Limit of Blank and the
Limitations - interference standard deviation of low concentration samples. The Limit of Detection
The effect of the following endogenous substances and pharmaceutical corresponds to the lowest analyte concentration which can be detected
compounds on assay performance was tested. Interferences were tested (value above the Limit of Blank with a probability of 95 %).
up to the listed concentrations and no impact on results was observed. The Limit of Quantitation is the lowest analyte concentration that can be
reproducibly measured with an intermediate precision CV of ≤ 20 %.
Endogenous substances
It has been determined using low concentration vitamin B12 samples.
Compound Concentration tested
Dilution
Bilirubin ≤ 1112 µmol/L or ≤ 65 mg/dL Samples with vitamin B12 concentrations above the measuring range can
Hemoglobin ≤ 0.621 mmol/L or ≤ 1000 mg/dL be diluted with Diluent Universal. The recommended dilution is 1:2 (either
automatically by the analyzer or manually). The concentration of the diluted
Intralipid ≤ 1500 mg/dL sample must be ≥ 1000 pg/mL or ≥ 738 pmol/L.
Biotin ≤ 205 nmol/L or ≤ 50 ng/mL After manual dilution, multiply the result by the dilution factor.
Rheumatoid factors ≤ 1500 IU/mL After dilution by the analyzer, the software automatically takes the dilution
into account when calculating the sample concentration.
IgG ≤ 2.8 g/dL Note: Sample-dependent non-linearity upon dilution is seen with samples
IgA ≤ 1.6 g/dL having analyte levels beyond the measuring range. As Diluent Universal
may contain low levels of endogenous vitamin B12, it is recommended that
IgM ≤ 1 g/dL linearity studies be performed using a known low analyte-containing serum
Criterion: For concentrations of 100‑200 pg/mL the deviation is ≤ 20 pg/mL. pool. Samples outside the measuring range can be diluted 1:2 with Diluent
For concentrations > 200 pg/mL the deviation is ≤ 10 %. Universal; the effect of endogenous vitamin B12 concentration is
insignificant at these levels.
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 Expected values
administration. Because differences may exist with respect to population and dietary
Because intrinsic factor is typically used as the binding protein in serum status, it is recommended that normal ranges be determined by each
vitamin B12 assays, anti-intrinsic factor antibodies (which are common in laboratory over a suitable period of time and in a statistically significant
pernicious anemia) can lead to elevated vitamin B12 measurement number of samples before clinical significance is attached to the results.
values.2,11,12 The Elecsys Vitamin B12 II assay is designed to avoid The values shown below were performed on samples from an apparently
interference due to anti-intrinsic factor antibodies.13 healthy population, using the Elecsys Vitamin B12 II assay. The calculation
Pharmaceutical substances is based on 135 sera (68 men, 67 women). The age range was between 20
In vitro tests were performed on 16 commonly used pharmaceuticals. No and 78 years. Pregnant women were excluded. The reference population
interference with the assay was found. was selected according to normal homocysteine values.
Samples with extremely high total protein concentrations N Median Range (2.5th-97.5th percentile)
(hyperproteinemia) are not suitable for use in this assay. Hyperproteinemia
may be caused by, but not limited to, the following conditions: pg/mL pmol/L pg/mL pmol/L
Lymphoma14,15, bone marrow disorders such as multiple myeloma, 135 425 314 197-771 145-569
monoclonal gammopathy of undetermined significance (MGUS),
Waldenström macroglobulinemia, plasmocytoma14,15,16,17,18,19,20, These values should only be used as guidance.
Amyloidosis20,21. Respective samples may lead to the formation of protein Each laboratory should investigate the transferability of the expected values
gel in the assay cup, which may cause a run abort. The critical total protein to its own patient population and if necessary determine its own reference
concentration is dependent upon the individual sample composition. ranges.
In rare cases, interference due to extremely high titers of antibodies to
analyte‑specific antibodies, streptavidin or ruthenium can occur. These Specific performance data
effects are minimized by suitable test design. Representative performance data on the analyzers are given below.
For diagnostic purposes, the results should always be assessed in Results obtained in individual laboratories may differ.
conjunction with the patient’s medical history, clinical examination and other
findings.

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Precision Passing/Bablok24 Linear regression
Precision was determined using Elecsys reagents, pooled human sera and y = 0.989x + 10.7 y = 0.987x + 12.5
controls in a protocol (EP05‑A3) of the CLSI (Clinical and Laboratory
Standards Institute): 2 runs per day in duplicate each for 21 days (n = 84). τ = 0.968 r = 0.999
The following results were obtained: The sample concentrations were between 116 and 1861 pg/mL (85.6 and
cobas e 402 and cobas e 801 analyzers 1373 pmol/L).

Repeatability Intermediate Analytical specificity

precision The following cross-reactivities were found, tested with vitamin B12
concentrations of 193 pg/mL and 1196 pg/mL.
Sample Mean SD CV SD CV
pg/mL pg/mL % pg/mL % Cross-reactant Maximum Cross-reactivity
concentration tested %
Human serum 1 131 9.45 7.2 10.6 8.1
ng/mL
Human serum 2 168 8.50 5.1 9.74 5.8
Cobinamide dicyanide 210 0.0
Human serum 3 206 7.92 3.9 9.28 4.5
References
Human serum 4 999 11.8 1.2 18.3 1.8
1 Thomas L. Clinical Laboratory Diagnostics: Use and Assessment of
Human serum 5 1984 22.4 1.1 47.4 2.4 Clinical Laboratory Results; 1st Edition, Frankfurt/Main: TH-Books-
Verl.-Ges.,1998:424-431.
PreciControl Varia1 462 10.6 2.3 11.9 2.6
2 Stabler SP. Vitamin B12 deficiency. N Engl J Med 2013;368:149-160.
PreciControl Varia2 901 14.2 1.6 20.4 2.3
3 Allen LH. Vitamin B-12. Adv Nutr 2012;3(1):54-55. doi:
cobas e 402 and cobas e 801 analyzers 10.3945/an.111.001370. Epub 2012 Jan 5.
4 Allen LH. How common is vitamin B-12 deficiency? Am J Clin Nutr
Repeatability Intermediate 2009;89(2):693S-696S. Epub 2008 Dec 30.
precision
5 Chatthanawaree W. Biomarkers of cobalamin (vitamin B12) deficiency
Sample Mean SD CV SD CV and its application. J Nutr Health Aging 2011 Mar;15(3):227-313.
pmol/L pmol/L % pmol/L % 6 Yetley EA, Pfeiffer CM, Phinney KW, et al., Biomarkers of vitamin B-12
Human serum 1 96.7 6.97 7.2 7.82 8.1 status in NHANES: a roundtable summary. Am J Clin Nutr 2011
Jul;94(1):313S-321S.
Human serum 2 124 6.27 5.1 7.19 5.8
7 Hvas AM, Nexo E. Diagnosis and treatment of vitamin B12 deficiency -
Human serum 3 152 5.84 3.9 6.85 4.5 an update. Haematologica 2006;91(11):1506-1512.
Human serum 4 737 8.71 1.2 13.5 1.8 8 Occupational Safety and Health Standards: Bloodborne pathogens.
Human serum 5 1464 16.5 1.1 35.0 2.4 (29 CFR Part 1910.1030). Fed. Register.
9 Directive 2000/54/EC of the European Parliament and Council of
PreciControl Varia1 341 7.82 2.3 8.78 2.6 18 September 2000 on the protection of workers from risks related to
PreciControl Varia2 665 10.5 1.6 15.1 2.3 exposure to biological agents at work.
10 Thorpe SJ, Heath A, Blackmore S, et al. International Standard for
Method comparison serum vitamin B12 and serum folate: international collaborative study to
a) A comparison of the Elecsys Vitamin B12 II assay, 07212771190 (y) evaluate a batch of lyophilised serum for B12 and folate content. Clin
with the Elecsys Vitamin B12 assay (x) using clinical samples gave the Chem Lab Med 2007;45(3):380-386.
following correlations (pg/mL):
11 Yang DT, Cook RJ. Spurious elevations of vitamin B12 with pernicious
Number of samples measured: 100 anemia. N Engl J Med 2012;366:1742-1743.
Passing/Bablok24 Linear regression 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
y = 0.952x + 15.1 y = 0.957x + 11.6 2012;367:976.]
τ = 0.977 r = 0.999 13 Schilling KA, Wiesgigl M. The Elecsys® Vitamin B12 assay is not
The sample concentrations were between 69 and 1890 pg/mL (51 and affected by anti-intrinsic factor antibodies. Clin Chem Lab Med 2013
1395 pmol/L). Jun 29;51(11):e251-e252.
b) A comparison of the Elecsys Vitamin B12 II assay, 07028121190 14 Wu AHB. Tietz clinical guide to laboratory tests, 4th ed. St. Louis,
(cobas e 801 analyzer; y), with the Elecsys Vitamin B12 II assay, Saunders/Elsevier 2006:608-609, 916-917.
07212771190 (cobas e 601 analyzer; x), gave the following 15 Paricaud K, Moulis G, Combis MS, et al. Causes of protidemia above
correlations (pg/mL): 100 g/L. Eur J Intern Med 2014;25:e123.
Number of serum samples measured: 127 16 Filippatos TD, Liamis G, Christopoulou F, et al. Ten common pitfalls in
the evaluation of patients with hyponatremia. Eur J Intern Med
Passing/Bablok24 Linear regression 2016;29:22-25.
y = 1.01x + 0.004 y = 1.05x - 20.4 17 Mailankody S, Landgren O. Monoclonal gammopathy of undetermined
τ = 0.977 r = 0.998 significance and Waldenström's macroglobulinemia. Best Pract Res
Clin Haematol 2016;29:187-193.
The sample concentrations were between 113 and 1833 pg/mL (83.4 and
1353 pmol/L). 18 Morel P, Duhamel A, Gobbi P, et al. International prognostic scoring
system for Waldenström macroglobulinemia. Blood
c) A comparison of the Elecsys Vitamin B12 II assay, 07028121190 2009;113:4163-4170.
(cobas e 402 analyzer; y), with the Elecsys Vitamin B12 II assay,
07028121190 (cobas e 801 analyzer; x), gave the following 19 Rajkumar SV. Multiple Myeloma. Curr Probl Cancer 2009;33:7-64.
correlations (pg/mL): 20 Gertz MA. Immunoglobulin light chain amyloidosis: 2016 update on
Number of serum samples measured: 143 diagnosis, prognosis, and treatment. Am J Hematol 2016;91:947-956.

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21 Wu AHB. Tietz clinical guide to laboratory tests, 4th ed. St. Louis,
Saunders/Elsevier 2006: 916-917, 925.
22 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.
23 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.
24 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.
Any serious incident that has occurred in relation to the device shall be
reported to the manufacturer and the competent authority of the Member
State in which the user and/or the patient is established.
Symbols
Roche Diagnostics uses the following symbols and signs in addition to
those listed in the ISO 15223‑1 standard (for USA: see dialog.roche.com for
definition of symbols used):
Contents of kit
Analyzers/Instruments on which reagents can be used
Reagent
Calibrator
Volume after reconstitution or mixing
GTIN Global Trade Item Number

COBAS, COBAS E, ELECSYS and PRECICONTROL are trademarks of Roche. INTRALIPID is a trademark of
Fresenius Kabi AB.
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.
© 2021, Roche Diagnostics

Roche Diagnostics GmbH, Sandhofer Strasse 116, D-68305 Mannheim

www.roche.com
+800 5505 6606

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