August 2008

GP29-A2
Assessment of Laboratory Tests When
Proficiency Testing Is Not Available; Approved
Guideline—Second Edition

This document offers methods to assess test performance when

proficiency testing (PT) is not available; these methods include examples
with statistical analyses. This document is intended for use by laboratory
managers and testing personnel in traditional clinical laboratories as well
as in point-of-care and bedside testing environments.

A guideline for global application developed through the Clinical and Laboratory Standards Institute consensus process.

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 Clinical and Laboratory Standards Institute
Setting the standard for quality in medical laboratory testing around the world.

The Clinical and Laboratory Standards Institute (CLSI) is a not-for-profit membership organization that brings
together the varied perspectives and expertise of the worldwide laboratory community for the advancement of a
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applicability.

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 GP29-A2
Vol. 28 No. 21
ISBN 1-56238-673-5 Replaces GP29-A
ISSN 0273-3099 Vol. 22 No. 26
Assessment of Laboratory Tests When Proficiency Testing Is Not
Available; Approved Guideline—Second Edition
Volume 28 Number 21
Stephen J. Sarewitz, MD
Harvey George, PhD
W. Gregory Miller, PhD
Daniel W. Tholen, MS
Paul Valenstein, MD

Abstract
Clinical and Laboratory Standards Institute document GP29-A2—Assessment of Laboratory Tests When Proficiency Testing Is
Not Available; Approved Guideline—Second Edition offers methods to assess test performance when formal proficiency testing
(PT) programs (also known as external quality assessment [EQA] programs) are not available. The guideline includes examples
with statistical analyses. This document is intended for use by laboratory managers and testing personnel in traditional clinical
laboratories as well as in point-of-care and bedside testing environments.

Clinical and Laboratory Standards Institute (CLSI). Assessment of Laboratory Tests When Proficiency Testing Is Not Available;
Approved Guideline—Second Edition. CLSI document GP29-A2 (ISBN 1-56238-673-5). Clinical and Laboratory Standards
Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087 USA, 2008.

The Clinical and Laboratory Standards Institute consensus process, which is the mechanism for moving a document through
two or more levels of review by the health care community, is an ongoing process. Users should expect revised editions of any
given document. Because rapid changes in technology may affect the procedures, methods, and protocols in a standard or
guideline, users should replace outdated editions with the current editions of CLSI documents. Current editions are listed in
the CLSI catalog and posted on our website at www.clsi.org. If your organization is not a member and would like to become
one, and to request a copy of the catalog, contact us at: Telephone: 610.688.0100; Fax: 610.688.0700; E-Mail:
[email protected]; Website: www.clsi.org.

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 Number 21 GP29-A2

Copyright ©2008 Clinical and Laboratory Standards Institute. Except as stated below, any reproduction of
content from a CLSI copyrighted standard, guideline, companion product, or other material requires
express written consent from CLSI. All rights reserved. Interested parties may send permission requests to
[email protected].

CLSI hereby grants permission to each individual member or purchaser to make a single reproduction of
this publication for use in its laboratory procedure manual at a single site. To request permission to use
this publication in any other manner, e-mail [email protected].

Suggested Citation

CLSI. Assessment of Laboratory Tests When Proficiency Testing Is Not Available; Approved Guideline—
Second Edition. CLSI document GP29-A2. Wayne, PA: Clinical and Laboratory Standards Institute;
2008.

Proposed Guideline
July 2001

Approved Guideline
December 2002

Approved Guideline—Second Edition

August 2008

ISBN 1-56238-673-5
ISSN 0273-3099

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 Volume 28 GP29-A2

Committee Membership

Area Committee on Quality Systems and Laboratory Practices

Sheila M. Woodcock, MBA, Margaret M. Grimes, MD Steven I. Gutman, MD, MBA

FCSMLS(D) Medical College of Virginia FDA Ctr. for Devices/Rad. Health
Chairholder Campus Rockville, Maryland
QSE Consulting Richmond, Virginia
Rose Bay, Nova Scotia, Canada Stephen J. Sarewitz, MD
Devery Howerton, PhD Valley Medical Center
Carl D. Mottram, BA, RRT, Centers for Disease Control and Renton, Washington
RPFT, FAARC Prevention
Co-Vice Chairholder Atlanta, Georgia Jennifer Schiffgens, MBA,
Mayo Clinic MT(ASCP)
Rochester, Minnesota Peter L. Minetti, CQA, CQE, California Pacific Medical Center
CQMgr(ASQ) San Francisco, California
Albert Rabinovitch, MD, PhD Fujirebio Diagnostics, Inc.
Co-Vice Chairholder Malvern, Pennsylvania Daniel W. Tholen, MS
NovoMetrics, Inc. A2LA
Mountain View, California Bruce D. Tually, BAppSc, MAppSc Traverse City, Michigan
Hunter Area Pathology Service
Eric Arendash, MT(ASCP) New South Wales, Australia Staff
Centers for Medicare & Medicaid
Services Advisors Clinical and Laboratory Standards
Philadelphia, Pennsylvania Institute
Eileen Carreiro-Lewandowski, Wayne, Pennsylvania
Lucia M. Berte, MA, CLS(NCA)
MT(ASCP)SBB, DLM; CQA(ASQ) University of Massachusetts Lois M. Schmidt, DA
CQMgr N. Dartmouth, Massachusetts Vice President, Standards
Laboratories Made Better! Development and Marketing
Broomfield, Colorado Kay M. Creed
Bon Secours Health Partners Jennifer K. McGeary, MT(ASCP),
Theresa Billups, MBA, Laboratories MSHA
MT(ASCP)DLM Richmond, Virginia Staff Liaison
Remel, Inc.
Lake Charles, Louisiana Dennis J. Ernst, MT(ASCP) Melissa A. Lewis
Center for Phlebotomy Education Editor
Ramsey, Indiana

Acknowledgment

CLSI gratefully acknowledges the following individuals for their help in preparing the approved-level, second
edition of this guideline:

Stephen J. Sarewitz, MD Daniel W. Tholen, MS

Valley Medical Center A2LA
Renton, Washington Traverse City, Michigan

Harvey George, PhD Paul Valenstein, MD

MA Dept. of Public Health Laboratories Trinity Health
Jamaica Plain, Massachusetts Ann Arbor, Michigan

W. Gregory Miller, PhD

Virginia Commonwealth University
Richmond, Virginia

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 Number 21 GP29-A2

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 Volume 28 GP29-A2

Contents

Abstract ....................................................................................................................................................i

Committee Membership........................................................................................................................ iii

Foreword .............................................................................................................................................. vii

1 Scope .......................................................................................................................................... 1

2 Terminology............................................................................................................................... 1
2.1 Note on Terminology .................................................................................................... 1
2.2 Definitions .................................................................................................................... 1
2.3 Abbreviations/Acronyms .............................................................................................. 4
3 Rationale .................................................................................................................................... 4

4 Circumstances Under Which Proficiency Testing Is Not Available .......................................... 6

5 Alternative Assessment Procedures (AAPs) .............................................................................. 7

5.1 Split-Sample Procedures ............................................................................................... 8
5.2 Audit-Sample Procedure ............................................................................................... 8
5.3 Analysis of Manufacturer’s Product Calibrator or Trueness Control Material............. 8
5.4 Analysis of Interlaboratory Quality Control Data......................................................... 9
5.5 Analysis of Patient Data ............................................................................................... 9
5.6 Reevaluation of Interpreted Results ............................................................................ 10
5.7 Direct Observation of Technique-Dependent Tests .................................................... 10
5.8 Clinical Correlation Studies ........................................................................................ 10
5.9 Surrogate Organisms................................................................................................... 10
5.10 Government and University Interlaboratory Comparison Programs .......................... 10
6 Analysis of Data From Qualitative Alternative Assessment Procedures ................................. 11

References ............................................................................................................................................. 12

Additional References ........................................................................................................................... 15

Appendix A. Procedure to Determine Allowed Differences Between Laboratories X and Y in a

Split-Sample Program ........................................................................................................................... 17

Appendix B. Method for Determination of Agreement With a Reference Method .............................. 21

Appendix C. Statistical Evaluation of Qualitative Split-Sample Results.............................................. 22

Summary of Consensus Comments and Working Group Responses ................................................... 23

Summary of Delegate Comments and Working Group Responses ...................................................... 24

The Quality Management System Approach ........................................................................................ 26

Related CLSI Reference Materials ....................................................................................................... 27

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 Volume 28 GP29-A2

Foreword
Proficiency testing (PT), also known as external quality assessment (EQA), is an important part of quality
management in the clinical laboratory. PT complements internal quality control (QC) to help ensure
patient test results are valid.1 Many agencies and associations, governmental and nongovernmental, offer
PT for numerous analytes. In many cases, accrediting bodies and governmental agencies that oversee
clinical laboratories require participation in a formal PT program.

However, formal PT programs are not available for a substantial number of laboratory tests; the reasons
vary. Some analytes are unstable, precluding the preparation of PT materials, or matrix effects may
prevent reliable analysis. Some tests are performed in only a few laboratories, so it is not practical to
develop a formal PT program. PT is not available for certain pathogenic microorganisms because of the
hazards of transporting the organisms. In some parts of the world, competent PT programs may not be
available or may not be affordable.

This document offers methods to assess test performance when PT is not available. These methods are
termed “alternative assessment procedures,” or AAPs.a The document addresses a variety of tests,
including quantitative analyses of blood, microbiological cultures, morphologic analyses, and in vivo
tests. The options for some of these tests are necessarily rather limited.

Overview of Changes
This document replaces the first edition approved guideline, GP29-A, which was published in 2002.
Principal among the changes in this edition are revised/harmonized terminology (see Section 2.1),
updated examples of tests for which PT is not available, and examples of government comparison
programs. References were updated throughout.

Key Words

Alternative assessment procedure, external quality assessment, proficiency testing

a
Neither PT nor the procedures described in this document are adequate by themselves to comprehensively validate a test
method.
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 Volume 28 GP29-A2

Assessment of Laboratory Tests When Proficiency Testing Is Not Available;

Approved Guideline—Second Edition

1 Scope
This document offers methods to assess test performance when proficiency testing (PT), or external
quality assessment (EQA), is not available. The guidelines in this document apply to clinical laboratory
tests performed in the traditional laboratory setting, as well as point-of-care testing, and testing in clinics’
laboratories. The subcommittee believes assessment procedures (either PT or alternative assessment
procedures [AAPs]) to validate ongoing performance are important for all laboratory tests. However, the
scope of the document does not include home testing (ie, patient self-testing). Quality assessment
programs for home testing have been described.2

This document makes no distinction between “regulated” and “nonregulated analytes” as defined in the
United States under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ‘88).3,4 The
subcommittee believes assessment procedures (either PT or AAPs) to validate ongoing performance are
important for all laboratory tests.

This document suggests general approaches and provides examples, but does not prescribe specific
assessment procedures for individual analytes. The responsibility for selecting specific assessment
procedures lies with the individual clinical laboratory.

The document may be useful for managers, supervisors, and laboratory personnel in traditional
laboratories, as well as personnel performing point-of-care and bedside testing.

2 Terminology

2.1 Note on Terminology

In many countries, the PT programs for clinical laboratories are called “external quality assurance” or
“external quality assessment” (EQA) programs. The preferred term now is the latter, and is defined in
Section 2.2. The recommendations in this document relate equally to PT and EQA. However, in this
document, only the term “proficiency testing” will be used, for two reasons. First, the committee
determined that the phrase “PT/EQA” was awkward. Second, CLSI has a policy to use international
harmonized terminology where appropriate; currently, the generally accepted international terminology is
“proficiency testing.”5-8 PT is the term currently in use in many countries, including the United States.

2.2 Definitions

accepted reference value – value that serves as an agreed-upon reference for comparison and which is
derived as a theoretical or established value based on scientific principles; an assigned value based on
experimental work of some national or international organization; or a consensus value based on
collaborative experimental work under the auspices of a scientific or engineering group (ISO 5725-1, ISO
Guide 30).9,10

accuracy (of measurement) – closeness of the agreement between a measured quantity value and a true
quantity value of a measurand (VIM07).11

analyte – component represented in the name of a measurable quantity (ISO 17511)8; NOTE: In the type
of quantity “mass of protein in 24-hour urine,” “protein” is the analyte. In “amount of substance of

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 Number 21 GP29-A2

glucose in plasma,” “glucose” is the analyte. In both cases, the long phrase represents the measurand (ISO
17511).8 The analyte is the particular component of interest to the patient.

assessment event – test assessment procedure(s) performed at one point in time.

audit-sample testing – testing of stored aliquots from a biologic sample repeatedly over time in a
specific assay system.

bias (measurement) – estimate of systematic measurement error (VIM07).11

calibration material//calibrator – material or device of known, or assigned quantitative characteristics

(eg, concentration, activity, intensity, reactivity, responsiveness) used to adjust the output of a
measurement procedure or to compare the response obtained with the response of a test specimen and/or
sample.

coefficient of variation (CV) – for a non-negative characteristic, the ratio of the standard deviation to the
average (ISO 3534-1)12; NOTE: It is often multiplied by 100 and expressed as a percentage.

common cause variation – variation resulting from sources inherent in the testing process; NOTE: Also
known as “random variation” or “process variation.”

commutability (of a material) – ability of a material to yield the same numerical relationships between
results of measurements by a given set of measurement procedures, purporting to measure the same
quantity, as those between the expectations of the relationships obtained when the same procedures are
applied to other relevant types of material (ISO 15194, ISO 15197, ISO 17593).13-15

external quality assessment (EQA) – 1) evaluation of the laboratory’s performance on examination of

samples of external origin for the purposes of determining adequacy of the laboratory’s preexamination,
examination, and postexamination activities (ISO Guide 43-1)5; 2) interlaboratory comparisons and other
performance evaluations that may extend throughout all phases of the testing cycle, including interpretation
of results; and the determination of individual and collective laboratory performance characteristics of
examination procedures by means of interlaboratory comparison; NOTE: The primary objectives of EQA
are educational and may be supported by additional elements.

manufacturer’s product calibrator – calibration material provided to the customer for use with a
routine clinical measurement procedure.

matrix effect – influence of a property of the sample, other than the measurand, on the measurement of
the measurand according to a specified measurement procedure and thereby on its measured value (ISO
17511)8; NOTE: Viscosity, surface tension, turbidity, ionic strength, and pH are common causes of
matrix effects.

measurand – quantity intended to be measured (VIM07)11; NOTE 1: Generally includes the analyte as
measured with respect to specific conditions; NOTE 2: For example, the enzymatic activity of alkaline
phosphatase at 37 °C; NOTE 3: In the example above, the measurand includes not only the entity being
measured (alkaline phosphatase), but the particular quantity being measured (enzymatic activity), and the
specific environmental condition under which it is being measured (37 °C); NOTE 4: The term
“measurand” and its definition encompass all quantities, while the commonly used term “analyte” refers to a
tangible entity subject to measurement; for example, “substance” concentration is a quantity that may be
related to a particular analyte.

power of error detection – the statistical probability that a quality control system will detect changes that
exceed defined limits.
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 Volume 28 GP29-A2

precision – the closeness of agreement between independent test results from the same sample obtained
under prescribed (stipulated) conditions (modified from ISO 3534-1)12; NOTE: Precision is not typically
represented as a numerical value but is expressed quantitatively in terms of imprecision—the standard
deviation (SD) or the coefficient of variation (CV) of the results in a set of replicate measurements.

proficiency testing (PT) – a program in which multiple samples are periodically sent to members of a
group of laboratories for analysis and/or identification, in which each laboratory’s results are compared
with those of other laboratories in the group and/or with an assigned value, and reported to the
participating laboratory and others.

quality control (QC) – the operational techniques and activities that are used to fulfill and verify
requirements for quality (modified from ISO 9000).16

quality management – coordinated activities to direct and control an organization with regard to quality
(ISO 9000)16; NOTE: Direction and control with regard to quality generally includes establishment of the
quality policy and quality objectives, quality planning, quality control, quality assurance, and quality
improvement.

quantity value – number and reference together expressing magnitude of a quantity (VIM07).11

reference method – a thoroughly investigated method, in which exact and clear descriptions of the
necessary conditions and procedures are given for the accurate determination of one or more property
values, and in which the documented trueness and precision of the method are commensurate with the
method’s use for assessing the trueness of other methods for measuring the same property values or for
assigning reference method values to reference materials.

regression analysis – the process of estimating the parameters of a model by optimizing the value of an
objective function and then testing the resulting predictions for statistical significance against an
appropriate null hypothesis model; the process of describing mathematically the relationship between two
or more variables; NOTE: This can include the parametric testing of the statistical significance of the
relationship, if random errors are assumed to be normal.

sensitivity (of a measuring system) – quotient of the change in an indication of a measuring system and
the corresponding change in a value of the quantity being measured (VIM07)11; NOTE 1: In the context
of QC, the power of error detection of a QC system; NOTE 2: In qualitative testing, the test method’s
ability to obtain positive results in concordance with positive results obtained by the reference method.

special cause variation – variation from sources outside the testing process; also known as “assignable
cause variation,” or “process error”; NOTE: Sources of special cause variation include interferences,
operator error, instrument malfunction, and deterioration of reagents.

specificity – ability of a test or procedure to correctly identify or quantify an entity in the presence of
interfering phenomena/influence quantities; the ability of a measurement procedure to measure solely the
measurand; NOTE: In the context of QC, the probability that a QC system will indicate absence of
special cause variation (ie, process error) when special cause variation is truly absent; 1 minus the
probability of “false alarms” wherein QC data points exceed tolerance limits yet no error can be identified
in the test system.

split-sample testing – a testing condition in which a single sample is divided into aliquots with one
aliquot tested on a particular instrument or laboratory and the other aliquot(s) tested on other
instrument(s), or laboratory, followed by the comparison of results.

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split-specimen testing – a test involving two biologic samples obtained at the same time from the same
source on two or more different assay systems (or by two or more analysts), often in two or more different
laboratories; NOTE: For example, testing two tubes of blood collected from a particular patient during
the same venipuncture.

standard deviation (SD) – the quantity characterizing the dispersion of the results for a series of
measurements of the same measurand (modified from VIM93).17

systematic error – component of measurement error that in replicate measurements remains constant or
varies in a predictable manner (VIM07).11

trueness – closeness of agreement between the average value obtained from a large series of test results
and an accepted reference value (ISO 3534-1).12

trueness control material – reference material that is used to assess the bias of measurement of a
measuring system.

validation – confirmation, through the provision of objective evidence, that requirements for a specific
intended use or application have been fulfilled (ISO 9000).16

variance – a measure of dispersion of observations in a sample/population, which is the sum of the

squared deviations of observations from their average divided by the degrees of freedom; NOTE:
Usually, the degrees of freedom equals one less than the number of observations (ISO 3534-1).12

2.3 Abbreviations/Acronyms

AAP alternative assessment procedure

CDC Centers for Disease Control and Prevention (USA)
CLIA Clinical Laboratory Improvement Amendments (USA)
CSF cerebrospinal fluid
CV coefficient of variation
DNA deoxyribonucleic acid
EEE Eastern equine encephalitis
EQA external quality assessment
ISO International Organization for Standardization
PFGE pulsed field gel electrophoresis
PT proficiency testing
QC quality control
SD standard deviation
STD sexually transmitted disease
VIM International vocabulary of metrology—Basic and general concepts and associated terms
(ISO/IEC Guide 99)
VZV varicella-zoster virus

3 Rationale
Clinical laboratories use internal quality control (QC) procedures as a primary tool to ensure the validity
of patient test data. For quantitative assays, these procedures generally employ manufactured materials
that are used as surrogates for patient samples and are tested along with patient samples. Routine QC
allows laboratorians to separate variation that is inherent in the testing process (ie, common cause
variation) from special cause variation resulting from an abnormal condition affecting the testing process,
such as operator error, reagent problems, incorrect calibration, or instrument malfunction. However, QC
has limitations. Among them are the following:
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 Volume 28 GP29-A2

• QC is not perfectly sensitive or specific; it does not detect all instances of special cause variation, and
it sometimes inappropriately flags variation inherent in the testing process (ie, false rejection).

• QC does not necessarily assess test trueness.

• QC does not assess comparability of results with other laboratories.

PT can serve as an additional quality monitor to address these limitations:

• PT may detect problems/errors that were not detected by the internal QC system (see CLSI document
GP27).18

• When level of analyte in PT materials can be traced to a reference method, a laboratory can determine
the accuracy of its analysis under some circumstances (eg, in the absence of significant matrix effects
when the PT material was validated as commutable with native clinical samples).19

• Participation in a PT program enables a laboratory to compare its performance against other

laboratories using similar methods/reagents/instruments.

The functions of PT have been well-described in the literature.1,18,20-24 However, PT is not available for
many tests, so laboratories should, when appropriate and practical, implement AAPs.b

Some regulatory and accrediting bodies require participation in PT and also require laboratories to
implement AAPs in the absence of PT. However, regardless of the requirements of certifying/accrediting
bodies, PT and AAPs are important quality elements in their own right and implementing them represents
good laboratory practice.

Laboratories, including those performing unique or low-volume analyses (eg, research laboratories),
should try to develop AAPs that provide information similar to that provided by participation in PT. For
example, patient samples may be sent to another laboratory(ies) to generate data on interlaboratory
comparability (eg, split-sample procedures; see below). If an AAP can be traced to a reference method,
accuracy can be assessed. Even if neither interlaboratory comparison nor evaluation of accuracy is
practical for a particular test, it is still worthwhile to use an AAP to complement QC, because QC is not
perfectly sensitive or specific.

AAPs may often use patient samples, which have certain advantages over the manufactured materials
frequently used in PT.

• Matrix effects are reduced or eliminated when patient samples are used.

• The steps in the preexamination phase of clinical patient testing—sample acquisition, transportation,
and processing—are not evaluated by PT programs using manufactured testing materials, because the
preexamination phase of PT differs from patient testing.c In contrast, variables related to
preexamination processing may be evaluated by an AAP that uses patient samples. Patient samples
used for AAPs require attention to stability during storage and transportation between laboratories, to
minimize introduction of additional variability not related to clinical testing performance.

In-house AAPs provide more timely data than does a PT program.

b
Neither PT nor the AAPs discussed in this document are adequate, in themselves, to validate a test method.
c
Most laboratory errors occur in the preexamination and postexamination (results reporting) phases.3,25,26 The critical domain of
quality management of specimen identification, accessioning, and results reporting lies outside the scope of this document.

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4 Circumstances Under Which Proficiency Testing Is Not Availabled

Tests for which PT may not be available include, but are not limited to:

• Pulsed field gel electrophoresis (PFGE), many molecular method assays other than for sexually
transmitted diseases (STDs) (eg, polymerase chain reaction), 17-hydroxyprogesterone, biotinidase,
various metabolites, toxoplasmosis.

• Emerging technologies.

• Uncommonly performed/esoteric tests, for example:

– antibodies to certain organisms (eg, Bordetella pertussis, Histoplasma, Blastomyces, Influenza A

and B, Parvovirus, Legionella);
– skeletal muscle antibodies;
– pancreatic polypeptide;
– cerebrospinal fluid (CSF) myelin basic protein;
– vitamin A; and
– β-carotene.

• Certain drugs:

– felbamate;
– gabapentin; and
− anabolic steroids.

Other reasons for unavailability of PT include:

• Limitations of PT materials:

– instability of material or lability of analyte (eg, erythrocyte osmotic fragility, erythrocyte sucrose
hemolysis, cold agglutinins, serum acetoacetate, cryoglobulins, stool leukocyte counts, nasal
smear eosinophil count, breath tests);
– cellular function assays (eg, studies of neutrophil or lymphocyte function);
– contamination in highly sensitive analyses (eg, molecular amplification techniques); and
– inability of vendor to provide sufficient material for market demand (eg, whole-blood
cytogenetics).

• Tests requiring extensive manipulation of sample, such as detection of markers of environmental

exposure or injury:

– chemical and biologic toxins;

– toxin metabolites (ie, breakdown products of toxins);
– protein and deoxyribonucleic acid (DNA) adducts; and
– heavy metals.

• Analytes in unusual matrixes/milieus:

– interstitial fluid (glucose);

– stool (cholesterol, yeast culture, leukocyte counts);
– saliva (therapeutic drug monitoring, detection of drugs of abuse, ethanol, serology, hormones);
– hair analysis (detection of drugs of abuse); and

d
To the knowledge of the subcommittee, PT was not available for the analytes/tests listed in this section at the time of writing.
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 Volume 28 GP29-A2

– dried blood spots (detection of drugs of abuse; therapeutic drug monitoring).

• Microbiology issues:

– fastidious, difficult-to-grow microorganisms (eg, Helicobacter pylori);

– minimal inhibitory antibiotic concentrations for anaerobes;
– serotyping when number of serotypes is large (eg, Salmonella spp.);
– DNA fingerprinting—number of strains of organisms is large;
– hazardous organismse (eg, dimorphic fungi [Coccidioides, Histoplasma spp.], Salmonella typhi,
Yersinia pestis); and
– fungal susceptibility.

• In vivo testing:

– bleeding time;
– reflectance bilirubinometry;
– pulse oximetry;
– monitoring of anesthetic gas concentrations;
– Schilling test; and
– fetal scalp pH.

• Geography: laboratory located in area where relevant PT is not offered.

5 Alternative Assessment Procedures (AAPs)

The laboratory should identify those tests for which PT is not available and develop an AAP for such tests
whenever possible. AAPs should be documented in the laboratory procedure manual. Each laboratory
should define the frequency of performance and procedures for evaluation of results. In many cases,
performing an AAP twice yearly is adequate.

The laboratory should define the limits of acceptability for each quantitative assessment procedure in
advance, before performing the procedure. Laboratories may develop limits of acceptability from internal
QC data (eg, ± 2 or 3 standard deviations [SD] from the mean), provided that sufficient QC data exist; or
from data in the literature (ie, clinical practice-based limits derived from biologic variation or clinical
decision points).27-29 A procedure for developing analytic bias and imprecision (uncertainty) tolerance
limits from patient data has been described,30,31 although a large patient database is required (20 000 test
values). A summary of statistical methods for evaluation of PT data is available.5 This information may
be helpful to laboratories in analyzing results of AAPs.

Over time (ie, multiple assessment events over years), and when it is practical to obtain suitable samples,
AAPs should employ samples across the clinically relevant range of the analysis.

Results of AAPs should be documented and retained by the laboratory so trends can be identified.
Corrective action in response to unacceptable results should be documented.

Some AAPs use patient samples/data. As noted above, advantages of using patient results include
independence from the routine QC system; avoidance of matrix effects; and the capability of evaluating
preexamination factors, such as the effect of collection systems (eg, gel-containing blood collection
tubes32), quality of phlebotomy procedure, delays in processing, etc. In addition, the external split-sample
procedure (described below) provides interlaboratory comparison. When adopting split-sample
procedures, laboratories should consider their institutions’ requirements for informed patient consent and
maintenance of patient confidentiality.

e
Centers for Disease Control and Prevention (CDC) Biosafety Levels 3 and 4.
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 Number 21 GP29-A2

5.1 Split-Sample Procedures33,34

5.1.1 Split-Sample With Another Laboratory

One common procedure for externally verifying test results is to send aliquots of samplesf to another
laboratory (or other laboratories) for testing. Split-sample procedures evaluate interlaboratory agreement
and testing errors, but do not evaluate trueness (ie, bias compared to a reference measurement procedure)
per se. Comparison to another routine method may provide assurance of comparability of results.
However, there may be sample-specific interferences that are different between different routine methods,
and can influence the comparability of results between them.26,g It is the responsibility of the individual
laboratory to determine the appropriate number of samples to send for split-sample testing. For many
analytes, two samples per assessment event are adequate.

For example, in one investigation, the power of split-sample testing to detect problems in the analysis of
serum total cholesterol and potassium was studied. In this study, the absence of a discrepancy between
samples in the split-sample procedure strongly predicted that the original result was correct (negative
predictive value of 93% to 100%); however, the presence of discrepancy in the split-sample procedure
was less predictive of error in the original result (positive predictive value of 43% to 67%).33

Please refer to Appendixes A and B for an example of a procedure to determine limits of acceptability for
results of quantitative split-sample procedures.

5.1.2 Internal Split-Sample Procedures

Examples of internal split-sample procedures include:

(1) Retest patient sample by a different method; and

(2) For operator-dependent testing, retest sample using a different operator (for example, in morphologic
analysis, or interpretation of electrophoretic patterns).

5.2 Audit-Sample Procedure

For stable measurands, aliquots of a patient sample are stored by the laboratory and analyzed periodically
across time.h Periodic analysis of aliquots of the audit sample assesses reproducibility and stability of
calibration of the assay. The audit-sample procedure does not evaluate trueness,33 nor does it provide
interlaboratory comparison.

5.3 Analysis of Manufacturer’s Product Calibrator or Trueness Control Material

The correct performance of a method can be confirmed by use of the calibration material provided by the
method manufacturer, or another reference material documented as commutable with the patients’
samples for the test procedure and traceable to a reference material or procedure.23 When the method
manufacturer’s calibration material or trueness control material is used for an AAP, it is best to use a
different lot of material from that used for method calibration to ensure independence of the verification.

f
In split-sample testing, a single biologic sample (eg, tube of blood) is divided into aliquots. If testing is performed on different
biologic samples obtained at the same time (eg, two tubes of blood obtained at the same venipuncture), then the term split-
specimen testing is used. These procedures are treated identically for the purposes of this document.
g
Evaluation of trueness may be problematic even in organized PT programs.19
h
After an aliquot is removed from storage and tested, it should be discarded and not returned to storage. Returning an aliquot to
storage for later testing may compromise specimen integrity because of denaturation, evaporation, contamination, etc.
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 Volume 28 GP29-A2

Caution should be used, however, because for some methods, a lot of calibration material may be specific
for a lot of reagent. (NOTE: It is suggested to use manufacturers’ product calibrator or trueness control
material only when there is no other alternative material or process to provide independent verification of
method performance.)

5.4 Analysis of Interlaboratory Quality Control Data

This assessment procedure includes participation in peer comparison programs that evaluate QC data
submitted from multiple laboratories. Many manufacturers have such programs. Usually, however, when
PT is not available for a particular analyte, neither are peer comparison programs.

5.5 Analysis of Patient Data

5.5.1 Averages of Patient Data

There is extensive literature describing the use of patient data for the QC of clinical laboratory
measurements. In the 1950s and 1960s, tracking the daily average of hematology measurements such as
hemoglobin, hematocrit, and red cell counts was proposed as a QC measure.35,36 This monitoring of the
averages of patient data came into widespread application in the 1970s in a form commonly known as
“Bull’s algorithm.”37-40 This technique compared the average of 20 consecutive patient values vs an
established patient mean value. Methods to monitor a daily mean or an “average of normals” need not be
limited to hematology and have been applied as QC measures for a wide variety of clinical laboratory
tests (see CLSI/NCCLS document H38).28,32,33,35-50

The assumption made for this approach is the average result, or other statistic, of a group of patients’
samples will be relatively constant when the test procedure is stable. For this condition to be true, the
results included in the mean must not include values that are outliers relative to the reference population
distribution. This technique is best applied for test procedures that have a fairly high volume of results
during a reasonably short time period. However, the approach can be considered for lower-volume tests
when a population of test samples can be identified that are expected to have a predictable distribution of
results. In an acute care hospital setting, if the laboratory can identify specific days when it receives an
increased proportion of abnormal samples (eg, weekends, or days when samples are received from an
oncology clinic or dialysis facility), the best practice might be to exclude the patient data obtained on
those days from the calculations. The literature cited above provides guidance on selecting suitable
numbers of observations and acceptance criteria.

The median of patient data, rather than the mean, may be used. Medians are more resistant to outlier
effects, but require a large number of patient results.51

5.5.2 Reference Intervals

Usually, reference intervals are used within a laboratory to provide information for evaluation of
individual patient data. Here, periodic reevaluation of reference intervals is proposed to validate test
procedure stability within a laboratory and to verify agreement between laboratories.52-56 For effectiveness
of this approach, the original reference interval determination must be robust and clinically appropriate
for the population served by the laboratory, and the new sample must represent the same reference
population with the same preexamination parameters. The general approach is to obtain test procedure
results for a minimum of 20 subjects (see CLSI/NCCLS document C28).57 A nonparametric analysis that
18 of the 20 results are within the original reference range validates the continuing applicability of that
interval with an approximate 7% probability of false rejection of the existing reference interval. If the
criteria are not met, a second set of 20 samples should be obtained and the evaluation repeated. Failure to
validate the reference interval would initiate a more detailed investigation to determine if the cause was

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 Number 21 GP29-A2

due to problems with the analytic test procedure, with preexamination conditions for sample collection
and handling, or with sampling the appropriate healthy population.

When larger numbers of results are available (for example, from a computer query over a time period of
weeks or months), histograms of the result distributions can be prepared and compared to previous time
periods and/or to other laboratories’ results. Considerations of outlier identification and exclusion can be
applied to obtain more homogeneous populations for purposes of comparing stable population groups.
Several statistical approaches have been described to extract adequate reference interval data from
hospitalized and clinic patient populations that can be used for AAPs.28,48,52-56,58

5.6 Reevaluation of Interpreted Results

Reevaluation of interpreted results by a second person provides a process to confirm correct test
performance. This approach is applicable to: morphologic analyses, electrophoretic patterns,
chromatographic patterns, etc. This approach can identify discrepancies in interpretation and in technical
quality of the morphologic or other pattern being evaluated.

For evaluation of morphologic analyses, glass slides or electronic images can be reviewed as unknowns
by testing personnel, with subsequent educational feedback, if necessary, to achieve uniformity of
interpretation.

5.7 Direct Observation of Technique-Dependent Tests

Personnel performing technique-dependent tests (eg, sweat test, bleeding time) may be observed by
experienced senior analysts or supervisors. A checklist delineating the factors to be observed should be
used in the evaluation. For more information on competence assessment, refer to CLSI/NCCLS document
GP21.59

5.8 Clinical Correlation Studies

Clinical correlation studies have limited application to routine test assessment, because of the imperfect
correlation of clinical events to laboratory results, as well as biases that may be operating (eg, test referral
bias, disease classification bias). However, correlation studies may be useful in certain circumstances,
when a specific disorder can be diagnosed or strongly suggested if the laboratory test result exceeds a
threshold value, and the presence of the disorder can be independently determined at a reasonable point in
time after testing.

5.9 Surrogate Organisms

Culture of attenuated strains or morphologically similar organisms can be used as an AAP for culture of
dangerous organisms.

5.10 Government and University Interlaboratory Comparison Programs

For some population-based testing that has high sample throughput and an important public health
function, but only a small number of laboratories conducting testing, government or university reference
laboratories provide interlaboratory comparison programs. Examples include testing for very long chain
fatty acids, dried blood spot assays for inborn errors of metabolism in neonates, genetic testing PFGE,
rabies, and arbovirus (eg, Eastern equine encephalitis [EEE], varicella-zoster virus [VZV], West Nile
virus).

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 Volume 28 GP29-A2

6 Analysis of Data From Qualitative Alternative Assessment Procedures

Results of tests that have categorical (ie, nominal) results (for example, binary results of “positive” or
“negative”; or cell identifications) can be validated if there are ways to determine definitive diagnosis.
When there is no definitive diagnosis, or comparisons are needed between methods or laboratories, split-
sample testing can be valuable, but it poses a particular problem because of the likelihood of chance
agreement. Refer to Appendix C for a statistical technique to evaluate data from split-sample studies of
qualitative tests. This situation is also discussed in CLSI document EP12.60

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 Number 21 GP29-A2

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Tan I, Gajra B, Lim MSF. External proficiency testing programmes in laboratory diagnoses of inherited metabolic disorders. Ann Acad Med,
Singapore. 2006;35:688.

Thomson S, Lohmann RC, Crawford L, Dubash R, Richardson H. External quality assessment in the examination of blood films for malarial
parasites within Ontario, Canada. Arch Pathol Lab Med. 2000;124:57-60.

Westgard JO, Westgard S. The quality of laboratory testing today: an assessment of σ metrics for analytic quality using performance data from
proficiency testing surveys and the CLIA criteria for acceptable performance. Am J Clin Path. 2006;125:343-357.

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 Volume 28 GP29-A2

Appendix A. Procedure to Determine Allowed Differences Between Laboratories X

and Y in a Split-Sample Program
The following discussion assumes the laboratory has sufficient experience with the method to know the
capabilities of the method, including internal precision (ie, repeatability, variance) and biases, if any,
across the entire clinical range of test results. If these are not known, then there is no suitable way to
validate method performance by split-sample procedures.

In external split-sample procedures, usually the outside laboratory (or laboratories) uses the same method,
but this is not necessary as long as the relationship between the methods is known. The laboratories
should understand any differences, including differences in specificity (interferences) between the
methods (see CLSI document EP07 and CLSI/NCCLS documents EP09 and EP21).1-3

It is important that the laboratories involved have agreed-on criteria for test assessment before initiating
the split testing. This agreement should include the following:

• test methods and numbers of samples to use;

• criteria for determining agreement;

• whether assessment will be at specific levels or across a range of levels; and

• procedures to resolve disagreements, which may include:

– retests by one or both laboratories;

– whether one of the laboratories is considered the reference for the other(s); and
– whether to consult a third laboratory.

The laboratories should retain the results so eventually, comparisons will cover a wide range of
concentrations. The laboratories can assess agreement across this range by plotting results on a two-
dimensional graph with the result from the laboratory of highest authority (if either*) on the horizontal (X)
axis and the other laboratory on the vertical (Y) axis, and a line of perfect agreement (Y=X) drawn in the
body of the graph. The laboratories may discover that their results tend to disagree in a predictable way
(that perhaps is correctable), or that disagreements are random, but are scattered on both sides of the line
of perfect agreement. Visual assessment should be adequate to identify predictable trends, or least squares
regression analysis may be used to assist in the determination.†

It is important that the capabilities of the assessment method are consistent with the desired uncertainty.
For example, if at a certain level, the internal QC data show typical repeatability (CV) of ± 2%, then the
laboratory can be sure only that real changes of 4% or more (approximately, depending on the QC rules
used internally) will be reflected in test results on single samples. If for clinical reasons, it is important to
detect a change of 3%, then the method is not adequate (it is said to have insufficient power to detect
changes of 3%). In such a case, the laboratory can perform the test in duplicate or triplicate and use the
mean as the test result. Because the internal QC CV of a single assay in this example is 2%, the mean of
two test results has a CV of 1.4% (CV single assay/ N ), and thus the use of duplicate testing provides
the laboratory with reasonable power to detect real changes of 3% or more.

*
Traditionally, the horizontal axis is used for the independent variable and the vertical axis for the dependent variable. If one of
the laboratories is considered of “higher authority,” then in this context, it is considered the comparison laboratory, and its values
should be placed on the horizontal axis.
†
Technically, orthogonal regression should be used, since both sets of results have variance in them, but this may not be
necessary for the purpose at hand, and orthogonal regression procedures are not widely available. Least squares regression can be
used for basic descriptive purposes if the test samples cover a broad range of concentrations. Differences between least squares
regression and orthogonal regression are minimal if the tests cover a broad range of concentrations.
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 Number 21 GP29-A2

Appendix A. (Continued)
The following example demonstrates the use of a formula to calculate the allowance for the difference
(confidence interval) between results from two procedures or two laboratories, based on data that have
been accumulated over several years of split-sample testing. For this analysis to be valid, the testing
systems in each laboratory must have been stable over the period of data accumulation.

Two laboratories perform a test for serum antibody IgZ1. Occasionally, they send samples to each other
for validation of the performance of the test, and each laboratory performs each test in duplicate. Table
A1 shows the results for 18 samples tested by the two laboratories. For convenience, they are ordered by
concentration.

Table A1. IgZ1 Results From Laboratories X and Y. Results on duplicate samples for 18 patients,
arranged in ascending antibody levels. Actual differences between laboratory averages and the allowed
difference are noted.

Laboratory X Laboratory Y Averages from X and Y

Sample Rep1 Rep2 Rep1 Rep2 Average Average Diff. X-Y Allowed‡
X Y
1 790 800 630 577 795.0 603.5 191.5 290.3
2 861 905 543 664 883.0 603.5 279.5 322.4
3 1051 1174 725 784 1112.5 754.5 358.0 406.2
4 1846 1846 1419 1632 1846.0 1525.5 320.5 674.0
5 1894 1820 1974 2363 1857.0 2168.5 −311.5 678.0
6 2014 2270 1550 1451 2142.0 1500.5 641.5 782.1
7 2484 2460 1640 1416 2472.0 1528.0 944.0 902.5
8 2405 2684 2096 2535 2544.5 2315.5 229.0 929.0
9 2560 3065 2181 2340 2812.5 2260.5 552.0 1026.9
10 2612 3065 1961 1887 2838.5 1924.0 914.5 1036.4
11 5755 5585 8415 8166 5670.0 8290.5 −2620.5 2070.2
12 5812 5812 6424 7171 5812.0 6797.5 −985.5 2122.0
13 8705 8473 6619 5989 8589.0 6304.0 2285 3135.9
14 9116 8671 10591 9875 8893.5 10233.0 −1339.5 3247.1
15 10029 9880 10697 10486 9954.5 10591.5 −63.0 3634.5
16 11736 12585 9393 10591 12160.5 9992.0 2168.5 4439.9
17 12554 12807 13874 13509 12680.5 13691.5 −1011.0 4629.7
18 14473 14705 15106 15174 14589.0 15140.0 −551.0 5326.6

Assume that the laboratories have assessed their tests in-house by performing routine replicates on patient
samples. Laboratory X is more experienced with the test, and serves as the comparison laboratory for this
test. The SDs from the in-house repeat tests show that in Laboratory X, the repeatability (precision) CV is
approximately 10% across the range of concentrations tested. In Laboratory Y, the repeatability is
approximately CV 12%. Further, a published study suggests that interlaboratory variability is
approximately CV 15%, which will be used as the clinically acceptable agreement.

Therefore, assume the following:

A = antibody level measured by Laboratory X

σX 2
= repeatability variance for Laboratory X ≈ (0.10 x A)2

‡
Calculated as shown by formula (1) below.
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Appendix A. (Continued)

σY2 = repeatability variance for Laboratory Y ≈ (0.12 x A)2

σl2 = interlaboratory variance ≈ (0.15 x A)2
nX = nY = number of replicates from each laboratory (can be 1)
α = confidence level
z1-α/2 = percentile of the normal distribution corresponding to the level 1-α/2

Note that repeatability variances can come from QC data or published method capability sources as in this
example.§ If QC data are used, σX2 and σY2 equal the square of the SD of the applicable internal QC data.
Repeatability variances can also be estimated from the split-sample data, if multiple replicates are used.
The laboratory repeatability is calculated as the pooled proportional difference between replicates [(Rep1-
Rep2)/((Rep1+Rep2)/2))]. This ratio is squared, the squared terms are then summed over all samples, and
the sum is divided by the number of samples minus 1 to give the σX2 or σY2, respectively. Similarly, the
interlaboratory variance could be estimated by first calculating the sum of squared differences, divided by
the number of samples minus 1. This is the variance of the differences; the interlaboratory variance would
then be estimated by subtracting the combined repeatability variance (S2r = (sx2 + sy2)/2). If the
repeatability variance exceeds the variance of differences, the interlaboratory variance is set at zero. If
interlaboratory variance is unknown at the initiation of a split-sample comparison program, or if it can be
assumed that the laboratories should produce equivalent results, interlaboratory variance can be set at
zero.

If the estimates of variability had not been available elsewhere, they could have been estimated from the
data in Table A1.

Allowed differences between results are determined with Formula 1, as follows:

[Formula (1)]

⎛ σX σ
2 2
⎞
Allowed difference D = z1−α /2 ⎜ σ 1 + + Y ⎟
2
⎜ nX nY ⎟
⎝ ⎠

If the difference between any pair of individual results lies within ± D, the difference is not statistically
significant, and the results can be considered equivalent for the individual sample.

At, for example, A = 2470:

σX2 = (0.10 x 2470)2 = 61 009

σY2 = (0.12 x 2470)2 = 87 853
σl2 = (0.15 x 2470)2 = 137 270
nX = nY = 2
α = confidence level = 0.95
z1-α/2 = 1.96
D = 1.96 [137270 + 61009 / 2 + 87853 / 2]
D = 1.96 (460) = 902

§
Refer to the first part of Section 5 for further suggestions of ways to define limits of acceptability for variance in AAPs.
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 Number 21 GP29-A2

Appendix A. (Continued)
At this level of antibody, a difference of up to 900 would be expected. Note that Sample 7 was at this
level of antibody, and the observed difference exceeds the allowed difference. Sample 11 shows an even
greater difference.

The following chart shows the averages plotted, with the line of equality and the allowed differences.
Sample 7 barely exceeds the limits, while Sample 11 is quite far from the allowed difference. Both
samples should be investigated for anomalies.

Antibody IgZ1 in Laboratories X & Y

16000

14000

12000

10000
Laboratory Y

Sample 11
8000

6000

4000

2000
Sample 7
0
0 2000 4000 6000 8000 10000 12000 14000 16000
Laboratory X

The middle line represents perfect agreement; the upper and lower lines represent the allowed difference
for results.

Calculations are not shown here, but for these samples, get estimates of variance as follows:

sx = 0.08 (compared with 0.10 from internal QC data)

sy = 0.11 (compared with 0.12 from internal QC data)
sl = 0.21 (compared with 0.15 assumed from literature report)

References for Appendix A

1
CLSI/NCCLS. Method Comparison and Bias Estimation Using Patient Samples; Approved Guideline—Second Edition.
CLSI/NCCLS document EP09-A2. Wayne, PA: NCCLS; 2002.
2
CLSI. Interference Testing in Clinical Chemistry; Approved Guideline—Second Edition. CLSI document EP07-A2. Wayne,
PA: Clinical and Laboratory Standards Institute; 2005.
3
CLSI/NCCLS. Estimation of Total Analytical Error for Clinical Laboratory Methods; Approved Guideline. CLSI/NCCLS
document EP21-A. Wayne, PA: NCCLS; 2003.

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 Volume 28 GP29-A2

Appendix B. Method for Determination of Agreement With a Reference Method

If the method of the outside laboratory is considered to be the reference method for split-sample testing,
use the following calculation of confidence intervals to determine agreement:

The formula for a confidence interval (CI) at any level L can be expressed as:

[Formula (2)]

σ2
CI = L + B ± Z1− α/2
n

where:

z1-α/2 = percentile of the standard normal distribution for stated confidence level 1-α (eg, 95% or 99%)
L = concentration level of interest (usually the level measured by the external reference method)
B = known bias or difference between test method and reference method (often B=0)
σ2 = variance of the test method at level L
n = number of replicates used in verification procedure

If the external test result lies within the confidence interval, then the method is considered to have passed
the verification at that level.

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 Number 21 GP29-A2

Appendix C. Statistical Evaluation of Qualitative Split-Sample Results*

Tests that have binary results (eg, positive or negative) pose a particular problem in split-sample testing,
because of the likelihood of chance agreement between two laboratories. To evaluate the contribution of
chance to agreement between two sets of data, the kappa statistic may be used. The kappa statistic
compares observed agreement with agreement that might be expected by chance. Kappa values range
from +1 (complete agreement) through 0 (no agreement beyond that expected by chance) to –1 (complete
disagreement, which in the laboratory setting suggests systematic reversal of results, perhaps by clerical
or programming error). Kappa values above 0.8 can be considered excellent analytic agreement, and those
between 0.6 and 0.8 can be considered reasonable agreement. With samples of 20 or more, kappa larger
than 0.5 is statistically significant, indicating that agreement is not entirely due to chance.

The kappa statistic is calculated as follows for two laboratories, A and B:

Kappa = (observed agreement – chance agreement)/(1-chance agreement)

Chance agreement = (proportion of negative results, Laboratory A) x (proportion of negative results,

Laboratory B) + (proportion of positive results, Laboratory A) x (proportion of positive results,
Laboratory B)

For example, laboratories A and B have performed split-sample testing on 29 samples† over the past
several years, with the following result:

Laboratory A Total
Negative Positive
Laboratory B
Negative 9 5 14 (48.3%)
(31.0%) (17.2%)
Positive 1 14 15 (51.7%)
(3.5%) (48.3%)
Total 10 19 29 (100%)
(34.5%) (65.5%)

Using the data from the table (and multiplying the percentage figures by 0.01):

observed agreement = (9+14)/29 = 0.793.

chance agreement = (0.483 x 0.345) + (0.517 x 0.655) = 0.505.

Thus, kappa = (0.793 − 0.505)/(1 − 0.505) = 0.58.

With this size sample, kappa = 0.58 indicates that the agreement between laboratories is not extremely
strong, but is greater than could have occurred by chance alone.

Kappa is useful for comparing agreement on different tests, agreement between different laboratories, or
tracking changes over time. This can assist in finding causes for the disagreement.

*
From: Dunn G, Everitt BS. Clinical Biostatistics: An Introduction to Evidence Based Medicine. London, UK: Edward Arnold;
1995. Reproduced in adapted form by permission of Edward Arnold (Publishers) Ltd.
†
NOTE: Use of a smaller sample size (eg, 10 samples) is valid if the samples include a fairly equal distribution of positive and
negative results.
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 Volume 28 GP29-A2

Clinical and Laboratory Standards Institute consensus procedures include an appeals process that
is described in detail in Section 8 of the Administrative Procedures. For further information,
contact CLSI or visit our website at www.clsi.org.

Summary of Consensus Comments and Working Group Responses

GP29-A: Assessment of Laboratory Tests When Proficiency Testing Is Not Available; Approved
Guideline

Section 7.1.1, Split Sample with Another Laboratory (now Section 5.1.1)

1. The GP29-A guideline describes in Section 7.1.1 on “split-sample with another laboratory” as an “alternative
assessment procedure” when proficiency testing is not available. What is the difference between this split-
sample procedure and the “split-sample testing scheme” described in Clause 4.4 of ISO/IEC Guide 43-1,
Proficiency testing by interlaboratory comparisons – Part 1: Development and operation of proficiency testing
schemes?

• They are very similar. This may be confusing because in ISO/IEC Guide 43-1, it is mentioned as a type of
proficiency testing (PT), while in GP29, it is mentioned as an alternative to PT.

The actual design, operation, and analysis of the schemes are pretty much the same, except in the GP29-A
protocol, there is no assumption of evaluation of the suitability of the performance of any particular
laboratory, which is assumed in ISO/IEC Guide 43-1. For that reason, ISO/IEC Guide 43-1 also assumes
that one laboratory will be a coordinator, and will follow guidelines for sample preparation, handling,
and competence of staff, etc. This is not necessary for a GP29-type split-sample protocol.

Appendix A, Procedure to Determine Allowed Differences Between Laboratories X and Y in a Split-Sample

Program

2. I’m currently looking for statistical methods used in analyzing results from split-sample experiments between
two laboratories. One of the guides I’ll use as a reference is the CLSI GP29-A guideline. I have one question
regarding the statistical formula used on page 18 for the calculation of the “allowed difference D” (Appendix
A). What is the origin of that formula (ie, how was it derived)? Is it a common formula that can be found in
statistics textbooks or was it developed just for the purpose of the guideline (laboratory assessment)?

• The formula was developed for this document, and did not come from a textbook or published article, as
there were no published references for guidance with split-sample testing. However, Formula 1 is a very
conventional procedure for combining independent variances, and is consistent with traditional statistical
practices. There may be more statistically rigorous procedures, but the subcommittee favored simplicity.
Also, it may be preferable to determine acceptable differences based on clinical need rather than
statistics, but that is up to the user.

In reviewing the appendix, two errors were discovered and have been corrected in the second edition of
the guideline (ie, the formula for S2r has incorrect placement of the right parenthesis; and above Formula
1, the text “Formula XYZ” should say “Formula 1”).

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 Number 21 GP29-A2

Summary of Delegate Comments and Working Group Responses

GP29-A2: Assessment of Laboratory Tests When Proficiency Testing Is Not Available; Approved
Guideline—Second Edition

Section 5.5.1, Averages of Patient Data

1. This section could be expanded to include the medians of patient data. The medians are more resistant to outlier
effects, but require large N. See Lott JA, Smith DA, Mitchell LC, Moeschberger. Use of medians and “average
normals” of patients’ data for assessment of long-term analytical stability. Clin Chem. 1996;42(6 Pt 1):888-892.

• In response to the commenter’s recommendation, the following text has been added to Section 5.5.1:

“The median of patient data, rather than the mean, may be used. Medians are more resistant to outlier
effects, but require a large number of patient results.”

The following reference has also been added as suggested:

Lott JA, Smith DA Mitchell LC, Moeschberger ML. Use of medians and “average normals” of patients’
data for assessment of long-term analytical stability. Clin Chem. 1996;42(6 Pt 1):888-892.

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 Volume 28 GP29-A2

NOTES

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 Number 21 GP29-A2

The Quality Management System Approach

Clinical and Laboratory Standards Institute (CLSI) subscribes to a quality management system approach in the
development of standards and guidelines, which facilitates project management; defines a document structure via a
template; and provides a process to identify needed documents. The approach is based on the model presented in the
most current edition of CLSI/NCCLS document HS01—A Quality Management System Model for Health Care. The
quality management system approach applies a core set of “quality system essentials” (QSEs), basic to any
organization, to all operations in any health care service’s path of workflow (ie, operational aspects that define how
a particular product or service is provided). The QSEs provide the framework for delivery of any type of product or
service, serving as a manager’s guide. The QSEs are:

Documents & Records Equipment Information Management Process Improvement

Organization Purchasing & Inventory Occurrence Management Customer Service
Personnel Process Control Assessments—External & Facilities & Safety
Internal

GP29-A2 addresses the QSEs indicated by an “X.” For a description of the other documents listed in the grid, please
refer to the Related CLSI Reference Materials section on the following page.
Purchasing &

Improvement
Organization

Management

Management

Assessments

Facilities &
and Internal
Information

Occurrence
Documents

Equipment

—External
& Records

Personnel

Inventory

Customer
Control
Process

Process

Service

Safety
GP21 H38 X X EP07
C28 GP27 GP27
EP07
EP09
EP12
GP27
H38
Adapted from CLSI/NCCLS document HS01—A Quality Management System Model for Health Care.

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 Volume 28 GP29-A2

Related CLSI Reference Materials∗

C28-A2 How to Define and Determine Reference Intervals in the Clinical Laboratory; Approved Guideline—
Second Edition (2000). This document contains guidelines for determining reference values and reference
intervals for quantitative clinical laboratory tests.

EP07-A2 Interference Testing in Clinical Chemistry; Approved Guideline—Second Edition (2005). This document
provides background information, guidance, and experimental procedures for investigating, identifying, and
characterizing the effects of interfering substances on clinical chemistry test results.

EP09-A2 Method Comparison and Bias Estimation Using Patient Samples; Approved Guideline—Second Edition
(2002). This document addresses procedures for determining the bias between two clinical methods, and for
the design of a method comparison experiment using split patient samples and data analysis.

EP12-A2 User Protocol for Evaluation of Qualitative Test Performance; Approved Guideline—Second Edition
(2008). This document provides a consistent approach for protocol design and data analysis when evaluating
qualitative diagnostic tests. Guidance is provided for both precision and method-comparison studies.

GP21-A2 Training and Competence Assessment; Approved Guideline—Second Edition (2004). This document
provides background information and recommended processes for the development of training and
competence assessment programs that meet quality/regulatory objectives.

GP27-A2 Using Proficiency Testing to Improve the Clinical Laboratory; Approved Guideline—Second Edition
(2007). This guideline provides assistance to laboratories in using proficiency testing as a quality
improvement tool.

H38-P Calibration and Quality Control of Automated Hematology Analyzers; Proposed Standard (1999). This
document addresses calibration and quality control strategies for multichannel hematology analyzers;
assignment of values to calibrator materials; calibration using stabilized blood controls; internal quality
control; pair difference analysis; and use of the weighted moving average method. A joint project with ICSH.

∗
Proposed-level documents are being advanced through the Clinical and Laboratory Standards Institute consensus process;
therefore, readers should refer to the most current editions.

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 Number 21 GP29-A2

NOTES

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NOTES

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Prevention, China Chen & Chen, LLC (IQUUM) TheraDoc Canadian Science Center for Human and
Centers for Disease Control and The Clinical Microbiology Institute Third Wave Technologies, Inc. Animal Health (Canada)
Prevention – Ethiopia Comprehensive Cytometric Consulting ThromboVision, Inc. Cape Breton Healthcare Complex (Canada)
Centers for Disease Control and Copan Diagnostics Inc. Transasia Bio-Medicals Limited Cape Cod Hospital (MA)
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Centers for Disease Control and Dade Behring Marburg GmbH – A Vital Diagnostics S.r.l. Services (Canada)
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Centers for Medicare & Medicaid Dahl-Chase Pathology Associates PA Watson Pharmaceuticals Campus (NJ)
Services David G. Rhoads Associates, Inc. Wellstat Diagnostics, LLC Capital Health/QE II Health Sciences
Centers for Medicare & Medicaid DiagnoCure US, GP Wyeth Research Centre (Nova Scotia, Canada)
Services/CLIA Program Diagnostica Stago XDX, Inc. Carilion Labs Charlotte (NC)
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Centralized Laboratory Services Site (NC) (Australia) Medical Center of McKinney (TX)
(NY) Dundy County Hospital (NE) Imelda Hospital (Belgium) Medical Centre Ljubljana (Slovenia)
Centre Hospitalier Anna-Laberge Durham VA Medical Center (NC) Indian River Memorial Hospital (FL) Medical College of Virginia
(Canada) DVA Laboratory Services (FL) Inova Fairfax Hospital (VA) Hospital (VA)
Centre Hospitalier Brome- Dwight D. Eisenhower Medical Institut fur Stand. und Dok. im Med. Medical Specialists (IN)
Missisquoi-Perkins (Canada) Center (KS) Lab. (Germany) Medical Univ. of South Carolina (SC)
Chaleur Regional Hospital (Canada) E. A. Conway Medical Center (LA) Institut National de Santé Publique du Quebec MediCorp - Mary Washington Hospital
Changhua Christian Hospital East Central Health (Canada) Centre de Doc. – INSPQ (Canada) (VA)
(Taiwan) East Georgia Regional Medical Institute Health Laboratories (PR) Memorial Hermann Healthcare System (TX)
Charleston Area Medical Center Center (GA) Institute of Clinical Pathology and Memorial Hospital at Gulfport (MS)
(WV) Eastern Health Pathology (Australia) Medical Research (Australia) Memorial Hospital Laboratory (CO)
The Charlotte Hungerford Hospital Easton Hospital (PA) Institute of Laboratory Medicine Memorial Medical Center (IL)
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Chatham - Kent Health Alliance Effingham Hospital (GA) Institute of Medical & Veterinary Memorial Regional Hospital (FL)
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Children’s Healthcare of Atlanta Evangelical Community Hospital International Health Management Methodist Hospital (TX)
(GA) (PA) Associates, Inc. (IL) Methodist Hospital Pathology (NE)
The Children’s Hospital (CO) Evans Army Community Hospital IWK Health Centre (Canada) MetroHealth Medical Center (OH)
Children’s Hospital and Medical (CO) Jackson County Memorial Hospital (OK) Metropolitan Hospital Center (NY)
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Children’s Hospital & Research Federal Medical Center (MN) Jackson Purchase Medical Center The Michener Inst. for Applied
Center at Oakland (CA) Fletcher Allen Health Care (VT) (KY) Health Sciences (Canada)
Children’s Hospital Medical Center Fleury S.A. (Brazil) Jacobi Medical Center (NY) Mid Michigan Medical Center – Midland
(OH) Florida Hospital (FL) John C. Lincoln Hospital (AZ) (MI)
Children’s Hospital of Philadelphia Florida Hospital Waterman (FL) John T. Mather Memorial Hospital (NY) Middelheim General Hospital (Belgium)
(PA) Fort St. John General Hospital Johns Hopkins Medical Institutions Middletown Regional Hospital (OH)
Children’s Hospitals and Clinics (Canada) (MD) Mike O'Callaghan Federal Hospital (NV)
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Children’s Medical Center (TX) Fox Chase Cancer Center (PA) JPS Health Network (TX) Monongalia General Hospital (WV)
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(VA) Fresenius Medical Care/Spectra East Kaiser Permanente Medical Care (CA) Mt. Sinai Hospital - New York (NY)
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Childrens Hospital of Wisconsin Sanitari de Terrassa (Spain) Program (Canada) National Cancer Center (S. Korea)
(WI) Gamma-Dynacare Laboratories King Abdulaziz University Hospital (Saudi National Healthcare Group (Singapore)
Chilton Memorial Hospital (NJ) (Canada) Arabia) National Institutes of Health, Clinical
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Christus St. John Hospital (TX) Geisinger Medical Center (Danville, NGHA (Saudi Arabia) National University Hospital Department of
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Clarian Health – Clarian Pathology Ghent University Hospital (Belgium) Lab Medico Santa Luzia LTDA (Brazil) NB Department of Health (Canada)
Laboratory (IN) Good Samaritan Hospital (OH) Labette Health (KS) The Nebraska Medical Center (NE)
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Authority (Canada) (WI) Lafayette General Medical Center (LA) New York University Medical Center (NY)
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of Alberta (Canada) Haga Teaching Hospital Lakeland Regional Medical Center (FL) Newton Memorial Hospital (NJ)
Columbia Regional Hospital (MO) (Netherlands) Lancaster General Hospital (PA) North Bay Hospital (FL)
Commonwealth of Virginia (DCLS) Hagerstown Medical Laboratory Landstuhl Regional Medical Center (APO, AE) North Carolina Baptist Hospital (NC)
(VA) (MD) Langley Air Force Base (VA) North Coast Clinical Laboratory, Inc. (OH)
Community Hospital of the Halton Healthcare Services (Canada) LeBonheur Children’s Medical Center North District Hospital (Hong Kong, China)
Monterey Peninsula (CA) Hamad Medical Corporation (Qatar) (TN) North Mississippi Medical Center (MS)
Community Medical Center (NJ) Hamilton Regional Laboratory Medicine Legacy Laboratory Services (OR) North Shore Hospital Laboratory (New
Community Memorial Hospital (WI) Program (Canada) Lethbridge Regional Hospital (Canada) Zealand)
Consultants Laboratory of WI LLC Hanover General Hospital (PA) Lewis-Gale Medical Center (VA) North Shore-Long Island Jewish Health
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Center (CA) Health Network Lab (PA) LifeLabs (Canada) Northridge Hospital Medical Center (CA)
Cook Children’s Medical Center Health Partners Laboratories Bon LifeLabs Medical Laboratory Services (Canada) Northside Hospital (GA)
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Cork University Hospital (Ireland) Health Sciences Research Institute Long Beach Memorial Medical Northwestern Memorial Hospital (IL)
Cornwall Community Hospital (Japan) Center (CA) Norton Healthcare (KY)
(Canada) Health Waikato (New Zealand) Los Angeles County Public Health Ochsner Clinic Foundation (LA)
Corpus Christi Medical Center (TX) Heidelberg Army Hospital (APO, Lab. (CA) Ohio State University Hospitals (OH)
Covance CLS (IN) AE) Louisiana Office of Public Health Onze Lieve Vrouw Ziekenhuis (Belgium)
The Credit Valley Hospital (Canada) Helen Hayes Hospital (NY) Laboratory (LA) Ordre Professionel des Technologistes
Creighton University Medical Center Hema-Quebec (Canada) Louisiana State University Medical Ctr. Medicaux du Quebec (Quebec, Canada)
(NE) Hennepin Faculty Association (MN) (LA) Orebro University Hospital (Sweden)
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Darwin Library NT Territory Health Henry M. Jackson Foundation (MD) Maccabi Medical Care and Health Fund (Isreal) Ospedale Casa Sollievo Della Sofferenza –
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David Grant Medical Center (CA) Hi-Desert Medical Center (CA) Madison Parish Hospital (LA) The Ottawa Hospital (Canada)
Daviess Community Hospital (IN) Hoag Memorial Hospital Mafraq Hospital (UAE) Our Lady of Lourdes Medical Center (NJ)
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Dean Medical Center (WI) Holy Family Medical Center (WI) Makerere University Walter Reed Project Our Lady’s Hospital for Sick Children
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Health (NC) (Canada) Marquette General Hospital (MI) Pathology and Cytology Laboratories,
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(HI) Hôpital Maisonneuve - Rosemont Martha Jefferson Hospital (VA) Pathology Associates Medical Laboratories
Diagnostic Services of Manitoba (Montreal, Canada) Martin Luther King, Jr. Harbor Hospital (WA)
(Canada) Hôpital Sacré-Coeur de Montreal (CA) Pathology Associates of Boone (NC)
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(Brazil) Hopital Santa Cabrini Ospedale Mary Hitchcock Memorial Hospital (NH) Pennsylvania Hospital (PA)
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Prince County Hospital (Canada) Center (NJ) Texas Department of State Health VA (Asheville) Medical Center (NC)
Princess Margaret Hospital (Hong St. Jude Children’s Research Services (TX) VA (Chillicothe) Medical Center
Kong, China) Hospital (TN) Thomason Hospital (TX) (OH)
Providence Alaska Medical Center St. Louis University Hospital (MO) Timmins and District Hospital VA (Cincinnati) Medical Center
(AK) St. Luke’s Hospital (FL) (Canada) (OH)
Providence Health Care (Canada) St. Luke’s Hospital (IA) The Toledo Hospital (OH) VA (Dallas) Medical Center (TX)
Providence Medford Medical Center St. Luke’s Hospital (PA) Touro Infirmary (LA) VA (Dayton) Medical Center (OH)
(OR) St. Martha’s Regional Hospital Tri-Cities Laboratory (WA) VA (Decatur) Medical Center (GA)
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Quest Diagnostics JV (IN, OH, PA) Samsung Medical Center (Korea) UC Davis Health System (CA) VA (San Diego) Medical Center
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(RHA4) (Canada) Scott & White Memorial Hospital UMC of Southern Nevada (NV) Vanderbilt University Medical
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Roxborough Memorial Hospital SJRMC Plymouth Laboratory (IN) Sherbrooke (CHUS) (Canada) (Ireland)
(PA) Sky Lakes Medical Center (OR) University Medical Center at Wayne Memorial Hospital (NC)
Royal Victoria Hospital (Canada) South Bend Medical Foundation (IN) Princeton (NJ) Weirton Medical Center (WV)
Rush North Shore Medical Center South Miami Hospital (FL) University of Alabama Hospital Lab Wellstar Douglas Hospital
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Arabia) Southern Maine Medical Center Sci. (AR) Wellstar Windy Hill Hospital
Sacred Heart Hospital (FL) (ME) University of Chicago Hospitals (IL) Laboratory (GA)
Sacred Heart Hospital (WI) Speare Memorial Hospital (NH) University of Colorado Health West China Second University
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St. Anthony Hospital (OK) Labs (WA) System (MD) Clinical Laboratories (WI)
St. Anthony’s Hospital (FL) Stillwater Medical Center (OK) University of Miami (FL) Wheeling Hospital (WV)
St. Barnabas Medical Center (NJ) Stony Brook University Hospital University of MN Medical Center - William Beaumont Army Medical
St. Christopher’s Hospital for (NY) Fairview (MN) Center (TX)
Children (PA) Sudbury Regional Hospital (Canada) University of MS Medical Center William Beaumont Hospital (MI)
St. Elizabeth Community Hospital Suncoast Medical Clinic (FL) (MS) William Osler Health Centre
(CA) Sunnybrook Health Science Center University of So. Alabama (Canada)
St. Eustache Hospital (Canada) (ON, Canada) Children’s and Women’s Hospital Winchester Hospital (MA)
St. Francis Hospital (SC) Sunrise Hospital and Medical Center (AL) Winn Army Community Hospital
St. John’s Hospital (IL) (NV) University of Texas Health Center (GA)
St. John’s Hospital & Health Ctr. Sydney South West Pathology (TX) Wisconsin State Laboratory of
(CA) Service Liverpool Hospital The University of Texas Medical Hygiene (WI)
St. John’s Mercy Medical Center (Australia) Branch (TX) Wishard Health Sciences (IN)
(MO) T.J. Samson Community Hospital University of the Ryukyus (Japan) Womack Army Medical Center (NC)
St. John’s Regional Health Center (KY) University of Virginia Medical Woodlawn Hospital (IN)
(MO) Taipei Veterans General Hospital Center (VA) York Hospital (PA)
St. Joseph Health Center (MO) (Taiwan) University of Washington (WA)
St. Joseph Mercy – Oakland (MI) Taiwan Society of Laboratory UPMC Bedford Memorial (PA)
St. Joseph Mercy Hospital (MI) Medicine (Taiwan) U.S.A. Meddac (Pathology Division)
St. Joseph’s Hospital (FL) Tallaght Hospital (Ireland) (MO)

OFFICERS BOARD OF DIRECTORS

Gerald A. Hoeltge, MD, Maria Carballo

President Health Canada Timothy J. O’Leary, MD, PhD
Cleveland Clinic Department of Veterans Affairs
Russel K. Enns, PhD
Janet K.A. Nicholson, PhD, Cepheid Robert Rej, PhD
President-Elect New York State Department of Health
Centers for Disease Control and Prevention Prof. Naotaka Hamasaki, MD, PhD
Nagasaki International University Donald St.Pierre
Mary Lou Gantzer, PhD, FDA Center for Devices and Radiological Health
Secretary Valerie Ng, PhD, MD
Siemens Medical Solutions Diagnostics Alameda County Medical Center/ Michael Thein, PhD
Highland General Hospital Roche Diagnostics GmbH
W. Gregory Miller, PhD,
Treasurer Luann Ochs, MS James A. Thomas
Virginia Commonwealth University BD Diagnostics – TriPath ASTM International

Robert L. Habig, PhD,

Immediate Past President
Habig Regulatory Consulting

Glen Fine, MS, MBA,

Executive Vice President

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