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This guidance was written prior to the February 27, 1997 implementation of FDAs Good Guidance Practices, GGPs. It does not create or confer rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both. This guidance will be updated in the next revision to include the standard elements of GGPs.
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Review Criteria for Assessment of Glycohemoglobin (Glycated or Glycosylated) Hemoglobin In Vitro Diagnostic Devices |
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REVIEW CRITERIA FOR ASSESSMENT OF GLYCOHEMOGLOBIN (GLYCATED or
GLYCOSYLATED) HEMOGLOBIN IN VITRO DIAGNOSTIC DEVICES.
This is a flexible document representing the current major concerns and
suggestions regarding glycohemoglobin in vitro diagnostic devices. It is
based on 1) current basic science, 2) clinical experience and 3) previous
submissions by manufacturers to the FDA, and 4) the Safe Medical Devices
Act of 1990 (SMDA) and FDA regulations in the Code of Federal Regulations
(CFR). As advances are made in science and medicine and changes in
implementation of Congressional legislation, these review criteria will be
re-evaluated and revised as necessary.
PURPOSE OF THE GUIDANCE DRAFT
This document is an adjunct to the 21 CFR Parts 800-1299. While it is not
to supersede the CFR, this document provides additional guidance and
clarification on what information is necessary before the Food and Drug
Administration (FDA) can clear a device for marketing. The FDA can make
more informed decisions based on a uniform data base. We hope this will
lead to more reliable, reproducible and standardized commercial tests.
DEFINITION
This document discusses all generic type devices intended for use in
clinical laboratories as in vitro diagnostic tests for the quantitative
determination of the fraction (expressed as per cent) of glycohemoglobin
(glycated or glycosylated) hemoglobin (GHb%) in blood samples.1
PRODUCT CODE: LCP
REGULATION NUMBER: 21 CFR 864.7470
CLASSIFICATION. Class II
PANEL: Hematology (81)
REVIEW REQUIRED: Premarket Notification (510(k).
1.0 CLINICAL INDICATION/SIGNIFICANCE/INTENDED USE OF GLYCOHEMOGLOBIN
TESTS.
1. Clinical Indication/Significance/Intended Use
Glycohemoglobin (GHb) is being used with increasing frequency to monitor
long-term blood glucose control and compliance in patients with diabetes
mellitus. The GHb test provides an index of the mean concentration of
blood glucose during the preceding two to three months. It complements
more traditional measures of glucose control, such as glucose quantitation
in urine and blood.2
Diabetes mellitus is a metabolic disorder characterized by impairment of
carbohydrate metabolism. Two major types have been identified. In type I
insulin dependent diabetes) the pancreatic B cells fail to produce insulin,
the protein hormone necessary for glucose oxidation to take place within
cells of the body. Type II or Non-Insulin-Dependent-Diabetes Mellitus
(NIDDM) patients are of two subtypes: nonobese and obese. Nonobese Type II
diabetics have impaired insulin production. Type II obese NIDDM patients
manifest ineffective insulin stimulation of target cells which is believed
to be a post-receptor defect in target tissues. The different types of
diabetics present with different signs and symp-toms, but all have
characteristic fasting hyperglycemia or elevation of glucose at 1 to 2
hours. The goal of treatment of diabetes mellitus has been to control
blood glucose levels to as near normal as possible in the hope that this
will impede, if not prevent, progression of vascular disease, e.g., stroke,
blindness, renal failure, heart attack, circulatory insufficiency to lower
extremities, etc. This may be accomplished through diet, weight loss, oral
hypoglycemic drugs or by regular injections of insulin, depending on the
type of diabetes and individual patient differences.3,4
The term "glycohemoglobin" (GHb) refers to a series of minor hemoglobin
components that are stable adducts formed by hemoglobin with various
sugars. The reaction between glucose and hemoglobin is an example of a
nonenzymatic condensation of glucose with the free amino groups on the
globin (protein) component of hemoglobin1. This process is slow,
continuous and irreversible. The human erythrocyte is freely permeable to
glucose. Within each erythrocyte, GHb is formed from hemoglobin at a rate
dependent on the ambient concentration of glucose.5 The higher the
prevailing ambient levels of blood glucose, the higher will be the levels
of GHb. Per cent GHb is increased within the erythrocytes of patients with
diabetes mellitus.6
Tests for glycohemoglobin are unreliable for the diagnosis of diabetes
mellitus. Such use yields too many false negative and false positive
results.2 It may be useful, however, to screen for those at greatest risk
for diabetes complications. It is not yet clear if patients diagnosed as
having diabetes based on oral glucose tolerance test results with
persistent normal per cent glycohemoglobin GHb%) values develop typical
diabetic complications. A claim for GHb tests to diagnose diabetes
mellitus then would require premarket approval.
False results could suggest incorrect long term blood glucose control. When
used with the more immediate testing of glucose in blood and urine,
however, false GHb% test results can be evaluated before disastrous
measures are taken, because there could be short term low or high glucose
levels in blood and/or urine with high or low GHb% levels (long term
effect).
Specimen types:
List all specimen types/matrix(ices) claimed by the manufacturer for use in
the test. Matrix is defined as the milieu containing the analyte in the
patient sample submitted for analysis (hereinafter "specimen type" includes
considerations for matrix or milieu)15. It can be whole blood, packed
erythrocytes and/or lysed washed packed red cells, etc.
2. DEVICE DESCRIPTION:
Discuss the principles of the device methodology and whether it is
well-established or new and unproven.
3. NONCLINICAL LABORATORY STUDIES: SPECIFIC PERFORMANCE CHARACTERISTICS
FDA requests different types and amounts of data and statistical analyses
in applications to market in-vitro diagnostic devices. The amount and type
of data requested depends on: 1) the test analyte, 2) the intended use
(which determines whether the application is a 510(k), an original
Premarket Approval application (PMA), 3) whether the test is quantitative
or qualitative, 4) whether the data design is independent or paired, and 5)
certain claims made by the manufacturer.
The performance of the device can be established by comparison of the
device to a predicate device (any legally marketed device). The National
Committee for Clinical Laboratory Standards (NCCLS) is an example of a
source for reference methods. Prove all claims for substantial equivalence
and specific parameters for using the device. Include data to support use
of the test with all claimed specimen types/matrices.
A. Analytical/Laboratory/In Vitro Studies.
1. Statistical
Describe statistical methods, assumptions used, statistical analyses and
corresponding computer outputs and references well enough so a
knowledgeable reader with access to the original data can verify the
reported results.
Provide data and statistical analyses determined with the device to support
performance parameters specific to and important for operating the device,
e.g., reproducibility.
Discuss the statistical methods for the type of data submitted, e.g.,
quantitative continuous data, qualitative discrete data, etc. The
distribution of data (normal vs. Non-normal type of data (paired vs.
independent).
Use references for study design and statistical methods that are from
standard texts and/or refereed biomedical journals.
Test data:
2. Performance Characteristics
Establish the linearity of the test in relation to the hemoglobin
concentration of the sample. Using varying concentrations of hemoglobin,
document the range of hemoglobin in which accurate GHb% results are
obtained.
In the package insert state the hemoglobin levels which may cause the test
to become over- or under-loaded and give aberrant results. Give
instructions in the package insert for the action to be taken when samples
are above or below linearity ranges.
3. Specificity/Cross-Reactivity/Interference Studies
If the manufacturer makes a claim for restricted assay specificity, e.g.,
it is claimed that an immunologically-based test, electrophoresis or
cation exchange methodology detects HbA1c rather than HbA1 only, the
specificity of that test for the claimed restricted species should be
demonstrated.
For Tests Employing Cation Exchange, HPLC and Electrophoresis
Methodologies, present chromatograms from gas-liquid and liquid
chromatography or electrophoregrams from electrophoretic techniques so
that users can see the efficiency of the separation of the claimed
glycohemoglobin peak from other peaks and observe the resolution from
interfering substances in the matrix. Express migration by Rf (or
retention times for columns). State temperature conditions. Describe in
detail the solvents or carriers and their order of use.17 Include similar
types of information for electrophoresis as for chromatography as
applicable.17
Present chromatograms or electrophoregrams of samples containing
Hemoglobin F to determine whether of not there is interference.
Present chromatograms or electerophoregrams of samples from patients with
various hemoglobinopathies (such as HbS, HbG, HbH, Hb Wayne, HbC,
thalassemia, etc., to determine whether or not there is interference.
Describe the exact source of columns and packing materials, and their
handling. Give the solvent sources and solvent compositions, and describe
the history of experience with each column.
Data should be provided to demonstrate that the specimen does not exhibit
test interference if it is hemolyzed, lipemic (affinity chromatography
only) or bilirubinemic at specified levels24. Any of these conditions
found to interfere with the test should be declared as interfering
conditions in the package insert.
It is already documented that electrophoresis tests are unaffected by
hypertriglyceridemia25 and that tests employing cation exchange methodology
are affected by severe lipemia26 and bilirubinemia27. HPLC is also
affected
by bilirubinemia27. If these limitations are declared and referenced in
the respective package insert, the respective data does not have to be
provided.
Labile GHb is an acutely generated, non-enzymatic, reversibly linked
glucose intermediary product present in blood after a heavy meal which can
cause a falsely elevated GHb% test.
Submit data to support a claim that the presence of labile GHb does not
cause a statistically significant elevation of the true GHb% value.
Several test protocols are acceptable for this purpose.
Show that normal and diabetic specimens incubated for 3 to 4 hours at 37oC
with at least 55 Mm/L or 1400mg/Dl of glucose28,29 give the same GHb%
values
as the original untreated specimen.
If the test cannot meet this stringent, non-physiological test, it will be
acceptable to show that for 21 samples in the high GHb range there is not
a clinical statistically significant difference between GHb% values
obtained with the new test vs. GHb% values obtained using an accepted
(published) labile removal method analyzed by paired student's t test, and
that the "labile-removed" value is lower than that with no labile removal,
i.e., labile GHb was present in the sample. For example, take 21 samples
with HbA1c values between 10 and 15%. Divide each sample into 3 aliquots:
a) aliquot #1 - no treatment, b) aliquot #2 remove labile by the method
being tested, c) aliquot #3 - remove labile by incubation of washed
erythrocytes in saline at 37oC for 5 hours or by another accepted
(published) method. Run aliquots #1, #2 and #3 in the same assay.
Aliquot #2 and #3 should give the same results and be lower than #1 (or
equal to #1 if the assay itself is not affected by labile GHb).
If an interference is not examined, then add a statement to the
Limitations Section of the package insert that the device has not been
tested for cross-reactivity or interference of one or more substances.
Analysis of Variance of Reproducibility17,19,20,22,23
The National Committee for Clinical Laboratory Standards (NCCLS)
recommends23 an analysis of variance experiment testing two clinically
significant levels near medical decision limits (subnormal, normal, or
elevated) of an analyte, in this case normal and elevated. Use controls
simulating patient samples or actual patient specimens 2 times in the same
run and in two different runs each day for 20 days. This permits separate
estimation of between-day, between-run and within-day standard deviations
(SD), as well as within-run and total SDs. Acceptable alternatives that
include only one run per day are also discussed in the cited document.23
The three important assumptions (homogeneity of error variances,
additivity, and normality) of analysis of variance should be used to
demonstrate the validity of the above results.
Calculate total, between- and within-day, and between- and within-run
means and coefficients of variation of imprecision for each set of values.
5. Comparison Studies.
Compare the device to a FDA-cleared device. In addition the device may be
compared to a reference method. GHb A1c by HPLC or an affinity
chromatography method is recommended for use as a reference method14. HPLC
products are commercially available. HPLC shows excellent assay precision
and permits rapid separation of HbA1c from the other minor components.3
The A1c peak suffers less variability from sample storage does the HbA1
peak.4 Affinity chromatography has far fewer interferences including sample
degradation problems than do any of the ion-exchange or electrophoresis
methods. The reference method chosen should be used for all comparisons
throughout the study.
Compare results obtained using packed red cells (if claimed) and/or whole
blood samples free from interfering substances from 40 to 100 persons
covering the whole assay range (from normal to clinically relevant high
levels of GHb%) to results obtained with another test already on the market
or to a reference method.17,18
Analyze the data using linear regression methods18. (The X axis is the
independent variable or comparison test. The Y axis is the dependent
variable or new test.)19,20 Linear-regression analysis is often most
useful for estimating the differences or errors between two analytical
methods, because the errors can be calculated at any medically important
concentration within the range studied; furthermore, the slope and
intercept may give some indication of the type of systematic error, which
may aid in reducing the analytical errors. Because the reliability of the
estimates of slope and intercept can be affected by nonlinearity in the
data set, outliers, a narrow range of data, and variability of the
comparison method, samples preferably should cover the complete range of
concentrations that might be encountered.21 The slope, intercept, and
their estimated standard errors, correlation coefficient, the standard
error of the estimate, the assay range, and nature and size of samples
tested should be reported in the Performance Characteristics section of the
package insert.
B. Clinical Data/Reference Ranges.
The device results may correlate well using linear regression (slope close
to 1.0 and intercept close to zero)17,18 with a method that has a published
reference range for healthy individuals. If the device results correlate
well, 40-60 subjects are sufficient to confirm agreement.30,31
If the device results do not correlate well, establish a reference range
with samples from 120 to 200 normal persons characterized by age, sex,
geographic location, any symptoms of disease and any other factors that
would influence the values obtained, e.g., pregnancy.31
It is suggested that the statistics used to characterize the population and
the confidence limits used be stated in the package insert. The
populations studied should be characterized according to age and disease
status. The number of persons tested should be stated. Investigate all
sample type(s) claimed in the intended use unless other data proves that
there is no difference between them. A range of analyte values for samples
from specified patient groups, e.g., diabetics, may also be provided.
4. LABELING CONSIDERATIONS
Do not make unproven claims for clinical significance in the package
insert.
The following are additional details for labeling.
A. The Intended Use Statement [ 809.10(b)(2)]
Whether it is for use in clinical laboratories, doctors' offices, or over-
the-counter (OTC). (The Limitations section should include any specific
training required for test performance or use.)
Whether it is for screening, monitoring, confirmation or exclusion and/or
to aid in the diagnosis as an adjunct to other procedures.
Clinical significance, if it can be stated in a few words. (If the
clinical significance statement is lengthy or complicated, create a
separate heading entitled "Clinical Significance".)
A typical intended use statements:
"ABC's *** test is a laboratory test intended for the quantitative
determination of percent glycated hemoglobin in whole blood by
[methodology] using the ABC automated system (if applicable) to monitor
long term blood glucose control in individuals with diabetes mellitus."
Conditions for Use
Describe any special applications of the device or specific
contraindications or indications for use not addressed in the Intended Use
Statement, e.g., "Despite serious consideration the measurement of
glycohemoglobin has not been shown to be reliable in the diagnosis of
diabetes mellitus."2,5 For example, one study shows that even though a
cutoff of three standard deviations above the mean of a "normal" population
has a specificity of 99% for diabetes, the sensitivity is only 48%49.
B. Summary and Explanation of the Test [ 809.10(b)(3)]
It is suggested that this section should discuss the following merits and
limitations of this test:
1. For Affinity Chromatographic Methods Only;
This method detects all glycohemoglobins, not just HbA132,
This method is not affected by the presence of abnormal hemoglobins.
This method is unaffected by carbamlyated hemoglobins in uremic patients.
In uremic patients there is condensation of urea-derived cyanate with the
N-terminal amino groups on the beta chains of HbA. This urea bound
hemoglobin elutes with HbA1 on cation-exchange columns producing falsely
elevated results33,34.
2. Labile Glycohemoglobin (All methods, if data so demonstrates.)
This method is unaffected by the presence of "labile" glycosylated
hemoglobin.
C. Specimen collection and preparation for analysis [ 809.10(b)(7)]
Data or literature references should be provided in the 510(k) to back all
statements made.
Include a description of:
The type of specimen to be collected, e.g., whole blood, packed cells,
washed packed cells, and acceptable anticoagulants.
Acceptable anticoagulants or other additives, preservatives, etc., to
maintain specimen.
Collection Precautions:
Special conditions for patient preparation, e.g., fasting, timing of
collection, intervals of collection, etc.
For routine clinical use, testing every 3 to 4 months is generally
sufficient. In certain clinical situations such as diabetic pregnancy, or
after a major change in therapy, it may be useful to obtain GHb% values in
2 to 4 week intervals5.
Electrophoresis Methodology
A statement that hypertriglyceridemia does not interfere electrophoresis
methodology25.
For Tests Employing Cation Exchange Methodology, severely lipemic samples
may show elevated results26. If a sample appears lipemic, it is recommended
that washed packed red cells be used as the sample.
For Tests Employing Cation-Exchange or HPLC Test Methodology, it has been
reported that samples with elevated levels of bilirubin may exhibit
falsely elevated levels of glycohemoglobin27.
State in the package insert in range of oC (low to high), collection,
transport, handling and storage conditions to maintain stability of the
specimen. Do not use terms such as "room temperature" without
qualification. Provide data or appropriate literature references in the
510(k) to back any claims made.
Due to instability of the samples for Cation-Exchange and Electrophoresis
methodologies consistent storage conditions and time intervals between
samples should be recommended. For example, all samples should be
prepared into hemolysates on the same day of collection and tested on the
morning of the fourth day after collection.
A statement that each laboratory must develop and evaluate sample handling
procedures based on their specific situation should be made. The
laboratory should be responsible for educating clinicians concerning the
large analytical errors that can be introduced by inappropriate sample
handling.
[Storage conditions may contribute significantly to both cation-exchange
and electrophoresis assay imprecision6
The temperature variation for some cation exchange minicolumns may be 1%
HbA1 per 1oC46. This temperature problem must be addressed in any one of
several ways, for example:
However, reports indicate that a temperature vs. GHb concentration
conversion chart47 may not provide accurate results6. Such charts do not
compensate for temperature fluctuations during assay11.
Use three level calibrators to compensate for temperature variations and
recommendations for methods of strict temperature control.
Various substances other than sugars can form adducts with hemoglobin,
thereby altering its charge characteristics. Falsely elevated results can
occur if these adducts comigrate with GHb. Examples include individuals
with opiate addiction44, lead poisoning, uremia, and alcoholism,5 as well
as those receiving large doses of aspirin (acetylated hemoglobin).45
Clinically the most important of these interfering adducts occurs in
uremia.5 This increase correlates with the BUN (blood urea nitrogen) and
appears to result at least in part from the carbamylation of hemoglobin by
urea-derived cyanate (carbamylated hemoglobin).33
D. Quality Control [ 809.10(b)(8)(vi)]
Describe specimens or commercially available products that should be used
for positive and negative control including recommended levels of analyte,
if materials are not provided in the kit.
Recommendations for frequency and placement of quality control samples
within run and from run to run. Directions for interpretation of the
results of quality control samples (satisfactory limits of performance).
Conclude with a statement similar to the following: "If controls do not
behave as stated (above), test results are invalid."
E. Limitations of the Procedure [ 809.10(b)(10)]
The following are examples of the types of limitation statements for GHb%
that are suggested for inclusion:
1. Limitation applying to all GHb% test methods
This test is unreliable for the diagnosis of diabetes mellitus2,5. There
are too many false positive and/or false negative results, depending upon
where the test cutoff is set. For example, one study shows that even
though a cutoff of three standard deviations above the mean of a "normal"
population has a specificity of 99% for diabetes, the sensitivity is only
48%49.
This test is not useful in judging day-to-day glucose control, and should
not be used to replace daily home testing of urine and blood glucose5.
As with any other laboratory procedure, a large discrepancy between
clinical impression and test results usually warrants investigation. Some
of the following test limitations should be considered.
Any cause of shortened red cell survival will reduce exposure of red cells
to glucose with a consequent decrease in %Ghb values, e.g., hemolytic
anemia or other hemolytic diseases, pregnancy, recent significant blood
loss, etc. Per cent Ghb results are not reliable in any patients with
chronic blood loss and consequent variable erythrocyte
lifespan6,11,36,37,38.
2. All tests except those with data demonstrating lack of interference by
labile Ghb. [If the manufacturer claims that the methodology of the test
removes or is unaffected by labile glycohemoglobin, data should be
presented in the 510(k) to back the claims.] Falsely elevated %Ghb test
results can be caused by "labile Ghb", an acutely generated, reversible,
non-enzymatically linked glucose intermediary product present after a heavy
meal. The higher the prevailing ambient levels of blood glucose, the
higher will be the potential for falsely elevated results caused by labile
Ghb. The package insert should advise users that labile Ghb may be removed
by any one of the following methods, depending on the test methodology
employed:
1) Incubation of a twenty-fold sample dilution overnight in isotonic
saline at room temperature39.
2) Dialysis overnight at 4oC vs. two changes of volumes of buffer
containing 4.59 g NaH2PO4.H2O, 1.18 g Na2HPO4 and 0.65 g KCN per liter
(pH
7.0)40.
3) Incubation at 37oC for 5 hours in 0.9% saline41.
4) Incubation for 30 minutes at 38oC in 30 mM semicarbazide and 12 mM
aniline, pH 5. Note: These chemicals are toxic28.
5) Lysis of erythrocytes for 15 minutes in 50 volumes of 0.05M potassium
biphthalate lysing buffer, Ph 5 at 37oC. Care must be taken to avoid
denaturation of hemoglobin29,42.
3. For all cation exchange (including HPLC), and electrophoresis
methodologies
Note that elevated levels of Hemoglobin F (HbF) usually found in infants
and some pregnant women result in falsely elevated results because HbF
comigrates with HbA1c43.
Patients with various hemoglobinopathies (such as HbS, HbG, HbH, Hb Wayne,
HbC, thalassemia, etc.) may have incorrect results depending on charge
characteristics of these variants6.
4. For assays quantifying HbA1 only, note that in most of the following
situations, including uremia, the HbA1a and b fraction is more affected
than the HbA1c fraction. Thus assays that quantify HbA1c specifically show
only slight alterations (rarely greater than 1 GHb%) from these
interferences.5
F.Interpretation of Results/Expected Results [ 809.10(b)(11)]
Actions to be taken if a samples' test result is above or below linearity
ranges according to hemoglobin concentration, e.g., dilution procedures.
Ranges for healthy persons
Ranges for defined disease groups.
Reference ranges from the scientific literature
Alternatively, reference range studies may also be reported from
literature references, especially if the new test was used by the authors,
or if the performance characteristics demonstrate results equivalent to
those obtained with a test used by the author, e.g., regression equation
slope = 1.0, r = approximately 0.95. Otherwise all expected values should
be determined with the submitted product.
In normal healthy individuals, GHb comprises approximately 4 to 8% of the
total hemoglobin. This level may be doubled in the diabetic patient.
Because glucose binding to hemoglobin occurs slowly and depends on the
circulating level of blood glucose, the GHb% level represents a time-
averaged blood glucose level. There is a time lag of approximately two to
four weeks before GHb% reflects changes in the blood glucose level.
Known insulin-dependent diabetic patients usually have elevated GHb%
levels48. Percent GHb quantitations on these patients may be in the 9-17%
range depending on the degree of hyperglycemia. Diabetic patients in good
control may have GHb% values in the normal range. To date, there is no
specific GHb% value that is accepted as indicating "good" or "poor"
control. When using GHb% to monitor the diabetic patient, results must be
interpreted individually; that is, the patient should be monitored against
him- or herself and values compared to the normal range for that
particular method.
For Electrophoresis and High Performance Liquid Chromatography Test
Methodology. Provide Graphics
Provide examples of electrophoregrams from common hemoglobinopathies,
e.g., HbS and C. Provide a detailed discussion with examples of how to
calculate GHb% in the presence of genetically abnormal hemoglobins.
G. Performance Characteristics [ 809.10(b)(12)]
Provide the statistical results of the comparison study. Scattergrams are
recommended but optional.
Report the mean, standard deviation and/or per cent coefficient of
variation for the various levels of %GHb in the within-run, within-day,
between-day and total assay precision studies. Mean values should be
arranged from lowest to highest (or vice-versa) to illustrate recognizable
trends.
Summarize studies performed to establish assay linearity depending on
hemoglobin concentration, and state conclusions.
5. BIBLIOGRAPHY
1. Fuentes-Arderiu X. "Glycohemoglobin," not "glycated hemoglobin" or
"glycosylated hemoglobin" Clin Chem 1990;36:1254.
2. Lester E. The clinical value of glycated hemoglobin and glycated
plasma proteins. Ann Clin Biochem 1989;26:213-9.
3. Karam JH. Diabetes mellitus, hypoglycemia, & lipoprotein disorders.
In Schroeder SA, Krupp MA, Tierney LM Jr, McPhee SJ, editors. Current
medical diagnosis and treatment 1991. Norwalk and San Mateo: Appleton &
Lange, 1991:852-893.
4. The National Diabetes Data Group. Diabetes 1979;28:1039
5. Goldstein DE, Little RR, Wiedmeyer HM, England JD, and McKenzie EM.
Glycated hemoglobin: methodologies and clinical applications. Clin Chem
1986;32:B64-B70.
6. Goldstein DE, Wiedmeyer HM, England JD, Little RR, Parker KM. Recent
advances in glycosylated hemoglobin measurements. CRC Crit Rev Clin Lab
Sci 1984;21:187-228.
7. Larsen ML, Hrder M, Mogensen EF. Effect of long-term monitoring of
glycosylated hemoglobin levels in insulin-dependent diabetes mellitus.
New Engl J Med 1990;323:1021-1025.
8. The DCCT Research Group. Diabetes control and complications trial
(DCCT); Update. Diabetes Care 1990;13:427-33.
9. Kunkel HG and Wallenuis G. New hemoglobins in normal adult blood.
Science 1955;122:288.
10. Bookchin RM, Gallop PM. Struycture of hemoglobin A1c: nature of the N-
terminal beta chain blocking group. Biochem Biophys Res Commun
1968;32:86-93
11. Peacock I. Glycosylated haemoglobin: measurement and clinical use. J
Clin Pathol 1984;37:841-51.
12. Mallia AK, Hermanson GT, Krohn RI, Fujimoto EK, Smith PK. Anal Lett
1981;14:649-61.
13. The DCCT Research Group. Feasibility of centralized measurements of
glycated hemoglobin in the diabetes control and complications trial: a
multicenter study. Clin Chem 1987;33:2267-71.
14. Little RR, England JD, Wiedmeyer HM, McKenzie EM, Mitra R, Erhart PM,
Durham JB, and Goldstein DE. Interlaboratory standardization of glycated
hemoglobin determinations. Clin Chem 1986;32:358-60.
15. Nomenclature and definitions for use in the national reference system
for the clinical laboratory. 5(21):561. Order code NRSCL8-P, ISBN 0273-
3099
16. International Committee of Medical Journal Editors. Special report.
Uniform requirements for manuscripts submitted to biomedical journals.
NEJM 1991;324:424-428.
17. Information for authors. Clin Chem 1991;37:1-3.
18. National Committee for Clinical Laboratory standards. User Comparison
of quantitative clinical laboratory methods using patient samples,
proposed guideline. 1985;6(1). Order code EP9-P.
19. Peters T, Westgard JO. Evaluation of methods, Chapter 7 in: Tietz NW,
editor. Fundamentals of clinical chemistry, Third Edition, Philadelphia:
Saunders. 1987: 225-37.
20. Westgard JO, de Vos DJ, Hunt MR, Quam EF, Carey RN, Garber CC. Method
evaluation. American Society of Medical Technology, Bellaire, TX, 1978.
21. Information for authors. Clin Chem 1990;36:1-4.
22. Vadlamudi SK, Stewart WD, Fugate KJ, and Tsakeris TM. Performance
characteristics for an immunoassay. Scand J Clin Lab Invest 1991;51:134-
138.
23. National Committee for Clinical Laboratory Standards. Evaluation of
precision performance of clinical chemistry devices - second edition;
tentative guidelines. 1991:1-56. Order Code EP5-T2.
24. National Committee for Clinical Laboratory Standards. Interference
Testing in clinical chemistry; proposed guideline. 1986 Order code EP7-P
25. Aleyassine H, Gardiner RJ, Blankstein LA, Dempsey ME. Agar gel
electrophoretic determination of glycosylated hemoglobin: effect of
variant hemoglobins, hyperlipidemia, and temperature. Clin Chem
1981;27:472.
26. Dix D, Cohen P, Kingsley S, Lea MJ, Senkbeil J, Sexton K. Interference
by lactesence in glycohemoglobin analysis. Clin Chem 1979;25: 494-5.
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HFK-440 NChace/chron 2/24/91 Version 9/27/91
This document was still considered current as of July 1997.
It will be reviewed again in July 1998.
Updated September 5, 1997
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