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Lipid Metabolism and Cardiac Test
Markers:
Importance of Standardization
Barbara M. Goldsmith, Ph.D., FACB
Vice President, Marketing, Membership
and Education
Clinical and Laboratory Standards
Institute (CLSI)
Outline of Presentation
• CLSI Background Information
• Standards and Guidelines
• Lipid Standardization and Traceability
• Cardiac Markers and Risk Assessment
• Summary
2
CLSI Background
• Established in 1968
• Nonprofit organization based in the United States
• American National Standards Institute (ANSI)–
accredited standards-development organization
• Volunteer driven through our governance structure
and technical operations
• An organization of organizations
• More than 200 standards and guidelines
CLSI’s Vision
To be the leader in clinical and
laboratory standards to improve
the quality of medical care.
CLSI’s Mission
To develop best practices in clinical and laboratory
testing and promote their use throughout the world,
using a consensus-driven process that balances
the viewpoints of industry, government, and the
health care professions.
CLSI Today
• $7M annual budget
• 45 employees
• 2,000 member organizations
• nearly 2,000 active volunteers (>600
Non-North American memberships, >70
countries)
• consensus standards and guidelines
• >75,000 documents each year distributed
CLSI consensus process
• Meetings are open to everyone
• Meeting materials are fully available
• Balanced interests
• Conflicts of interest are fully disclosed
• Appeals process
• All comments addressed
• Developed in conjunction with Analyse-it®
Software
• Only software to faithfully implement the
eight most popular CLSI method evaluation
guidelines
• Evaluates and verifies performance
characteristics of laboratory methods
• Provides clear step-by-step advice on
performing a study
• Delivers tools for accreditation
preparedness
• Easy-to-use workflow
• Provides timely, accurate statistical results
• Professional reports, customizable graphs
and charts
New method evaluation software
Benefits
• Large hospital laboratories
• Small hospital laboratories
• Physician office laboratories
• Reference laboratories
• In vitro diagnostic customer
support departments
Use of CLSI Documents
• Regulatory Compliance- Compliance with recognized CLSI consensus documents to facilitate regulatory review of IVD devices.
• Professional Practice - Implementation of CLSI best practices for accreditation preparedness
• Education in Clinical Laboratory Sciences
• Translations include: - Japanese -Spanish
- Korean (In progress) -Turkish
- Portuguese -Chinese (In progress)
- Russian - German
CLSI Members & Volunteers
15
Diverse representation from three constituencies
Industry Government Professions
IVD Manufacturers Public Health Agencies Hospitals and Laboratories
LIS Vendors Regulatory Bodies Healthcare Delivery Systems
Startup Companies Accrediting Organizations Educational Institutions
Suppliers Others Professional Societies
Trade Organizations
CLSI Area Committees
• Automation and
Informatics
• Clinical Chemistry and
Toxicology
• Evaluation Protocols
• Hematology
• Immunology and Ligand Assay
• Microbiology
• Molecular Methods
• Point-of-Care Testing
• Quality Systems and Laboratory Practices
Global Health Partnerships
• Grant funding from U.S.
government
• 10 staff members
• More than 60 volunteers
qualified as trainers
17
Global Health Partnerships
CLSI Lab Strengthening Program Services:
• Assessment/Gap Analysis
• Training and Education
• Mentoring
• Laboratory Self-assessment
• Continuous Quality Improvement
Global Health Partnerships
Current programs planned
or underway in
- Côte d’Ivoire Mali
- Tanzania Azerbaijan
- Ethiopia Georgia
- Namibia Uzbekistan
- Vietnam Kazakhstan
- Nigeria Ghana
Preparing laboratories for
WHO-Afro accreditation
Cote
d'Ivoire
Nigeria
SenegalEthiopia
Rwanda
Botswana
CLSI’s Key Global Activities
International Organization for Standardization (ISO)
• CLSI is Secretariat for ISO Technical Committee 212
“Clinical Laboratory Testing and in vitro Diagnostic Test
Systems” and its working groups:
• CLSI is administrator of the ANSI-Accredited US
Technical Advisory Group (TAG) to ISO/TC 212.
WG 1: Quality and competence in the medical laboratory.
WG 2: Reference SystemsWG 3: In vitro diagnostic productsWG 4: Antimicrobial susceptibility testing
Relationship of CLSI and ISO Standards
Complimentary, not conflicting, roles
broad, standard
requirements
detailed help and
practical guidance
Standards & the Lab
• Most medical lab errors
are caused by systems
and process issues, not
people.
• They are the areas
where standards can
help the most.
Why do Standards Matter?
• Raise levels of quality, safety, reliability, efficiency, and interchangeability
• Lower trade barriers
• Act as a base for legislation (or avoid the need for legislation)
• Aid in technology transfer
• Provide easy access to best-in-class practices
• Deliver improved outcomes at an economical cost
25
Standards Development Consensus Process
A consensus standard or guideline is a
document developed to promote uniform
products, materials, methods, or practices.
Levels of the consensus process:
• Proposed Level
• Approved Level
26
Standard or Guideline?
• A standard must be followed exactly as written.
- Written using verbs such as will, must, and shall
• A guideline may be modified by the user.
- Written using verbs such as should, could, may,
or might
27
Reasons for testing
• To identify individuals at increased risk of disease and/or monitor disease management
• To develop epidemiologic data from which to establish public health strategies for disease management
G. Myers, CDC, with permission
Requirements to meet testing goals
• Precise and accurate assays
• Results must be comparable, independent of
where and when test performed and assay used
• Specific measurement standards of higher order
– Reference measurement procedure(s) (RMP)
– Reference laboratories that provide RMPs
– Reference material(s)
• Process or program to establish and maintain
traceability to established standards
G. Myers, CDC, with Permission
Standardization of Laboratory Results In the context of laboratory medicine we really
mean Metrological Traceability
G. Myers, CDC, with permission
Traceability: ISO Definition
• Traceability - property of the result of a
measurement or the value of a standard whereby it
can be related to stated references, usually national
or international standards, through an unbroken
chain of comparisons all having stated uncertainties.
G. Myers, CDC, with permission
Traceability in Laboratory Medicine
Tools Needed for Traceability
• Reference measurement procedure(s)
• Gold Standard
• Reference MP Laboratories
• Reference materials (commutable)
G. Myers, CDC, with permission
Traceability in Laboratory Medicine
Patient Sample Result
Routine MP Patient Sample Result
Reference Materials
(commutable)
process that ensures patient sample results by a routine
measurement procedure areequivalent to RMP results
RMP
Met
rolo
gica
l Tra
ceab
ility
G. Myers, CDC, with permission
Standardization vs. Proficiency Testing
• Standardization is NOT the same as proficiency testing (PT)– Most PT programs in the US are NOT accuracy-
based programs
– PT programs use peer-group grading where laboratories are evaluated using the group mean for a particular instrument/method
– Standardization programs must be accuracy-based and provide an analytical anchor for traceability purposes
G. Myers, CDC, with permission
To establish traceability and be standardized, a laboratory must be: Precise and Accurate
Precise, not accurate
Neither accurate nor precise
Precise and accurate
Accurate, not precise
RMP
G. Myers, CDC, with permission
When and Why Is Traceability Most
Important?
• To insure the reliability and comparability of
research findings across studies
• When patients are seen in a variety of health care
settings, each using different clinical labs
• When patient’s clinical test results are being
compared to guidelines from the medical literature
and/or large national or international research
studies (e.g., estimated GFR for CKD, HbA1c for
diabetes, cholesterol for CVD, etc.).
G. Myers, CDC, with permission
Three Separate Measurement Components that
Require Traceability to Reference Standards
• Research Laboratories that support
investigational studies
• Manufacturers that develop and provide routine
clinical assays
• Clinical laboratories that provide test results for
assessing risk and monitoring therapy
G. Myers, CDC, with permission
Calibration
Patient SampleCorrelation
Manufacturer
Clinical Lab.
2
Proficiency Testing
1 3
Commutable Samples
Calibration
Reference procedure
(GC-IDMS or LC-IDMS)
Reference Laboratories
Primary Calibrator
Calibration Traceability Scheme
SRM
G. Meyers
Metro
logical Trace
ability
NIST IDMS
CDC AK
CRMLN AK
Manufacturer
Clinical Laboratory
Patient
SRM 1951b 1º reference material
CDC 2º reference materials
Fresh sample comparison
Mfr working calibrator
QC and GLP
SRM 911 (pure cholesterol standard)
Cal
ibra
tio
n H
iera
rch
yTraceability Chain for Cholesterol Measurement
G. Myers, CDC, with permission
Reference Measurement Procedure, HDL & LDL
Beta-quantification
1. Ultracentrifuge
serum
3. Abell-Kendall Chol.(LDL + HDL) – HDL = LDL
Chylo
VLDL
LDL
HDL
Rem.
IDL
Lp(a)
Apo E
2. Hep/Mn++ precipitate
HDL
LDL
G. Myers, CDC, with permission
UC density cut
Hep-Mn ppt
Hep-Mn soluble
Lipoproteins include a range of particles
Used with permission
Beta-quantification limitations
• A range of lipoprotein particles are included in
HDL, LDL and VLDL fractions
• Consequently, the measurand is poorly defined
• Lipoproteins may be distributed differently in
diseased vs. normal serum
• A particular lipoprotein may be present in unusually
high proportion
• A lipoprotein that is normally a minor component may
be present in relatively high concentration
G. Myers, CDC, with permission
NCEP performance criteria
Total Error Bias* CV*
TC 9% 3% 3%
HDL-C 13% 5% 4%a
LDL-C 12% 4% 4%
TG 15% 5% 5%
*Suggested limits to meet TE requirement
a CV 4% at 42 mg/dL; SD 1.7 at 42 mg/dL
Clinical Chemistry 1988;34:193-201 (TC), and 1995;41:1414-1433 (HDL,LDL, TG)
NCEP = National Cholesterol Education Project
Trueness (accuracy) TraceabilityR
ou
tin
e M
eth
od
Reference Method
Patient Specimens
Ro
uti
ne M
eth
od
Reference Method
Patient Specimens
Manufacturer comparison with a CDC Network Reference Lab
Cannot mix calibrators and reagents from different manufacturers
Traceability to the reference system is through the
manufacturer’s method specific calibrators
Calibrator value
SIG
NA
L
Routine Method
Calibration
Reportable
patients’
results are
traceable
to
G. Myers, CDC, with permission
Lipids: method evaluation
• Precision
– CLSI EP5
• Bias vs. RMP using patient specimens
– CLSI EP9
• Interferences
G. Myers, CDC, with permission
Lipids: method evaluation
• Interferences:
– Metabolites, drugs (e.g. Hb, bilirubin, ascorbate) that
cause a measurement interference
• CLSI EP7
– Distinguish between a measurement interference and a
physiologic effect
• E.g. bilirubin can cause spectrophotometric effect,
react with H2O2, and correlates with liver disease that
may produce an abnormal lipoprotein (e.g. LpX)
G. Myers, CDC, with permission
Lipids: method evaluation
• Interferences:
– Method non-specificity is important
– Influence on physicochemical separation of lipoprotein molecular forms
• To normal lipoproteins in abnormal concentrations
• To abnormal lipoproteins
• To other proteins
• CLSI EP21 total error
G. Myers, CDC, with permission
HDL COLOR
Chol esterase
Chol oxidase
Dye
Peroxidase
Step 2: convert HDL-C to a measurable substance
Homogeneous HDL-C: approach 1
Chylo VLDL LDL
+ -+ -+ -
+ -
+ -
+ -+ - + -Y
Y
Y
Y
Step 1: prevent reaction of non-HDL-C
YY
G. Myers, CDC, with permission
Chol esterase
Chol oxidase
Catalase
Chylo VLDL LDLHDL NO COLOR
1. Protect HDL-C from reaction and convert non-HDL-
C to non-measurable substances
Homogeneous HDL-C: approach 2
++
-
-
HDL
Dye
PeroxidaseCOLOR
2. Un-protect HDL-C and convert to a measurable substance
HDL ++
-
-
G. Myers, CDC, with permission
+ -
Chylo VLDL HDL
+ -+ -+ -
+ -
+ -+ - + -
1. Protect non-LDL
LDL COLOR
Chol esterase
Chol oxidase
Dye
Peroxidase
2. Convert LDL-C
Homogeneous LDL-C: analogous to HDL-C
LDL
Chol esterase
Chol oxidase
Catalase
Chylo VLDL NO COLOR
1. Protect LDL and convert non-LDL-C
HDL
Dye
PeroxidaseCOLOR
2. Unprotect and convert LDL-C
LDLLDL
G. Meyers, CDC, with permission
Homogeneous measurement challenges
• Measure the same lipoprotein fractions that are
measured by beta-quant
• Not measure anything else
• Do it for a wide range of clinical conditions with
abnormal lipoproteins and other proteins
• Do it with acceptable total error for individual
samples (not just trueness and imprecision) and cost
G. Myers, CDC, with permission
Comparison of HDL and LDL Cholesterol Methods
to Reference Measurement Procedures
Background:
• Current guidelines on use of LDL-C and HDL-C
for cardiovascular risk assessment based on early
epidemiologic studies that established link
between lipoproteins and cardiovascular disease
• Based on older methods that depended on
physical separation of different lipoprotein classes
and not direct methods
• Direct measurements prompted by NCEP panel
that stated LDL-C should be measured directly
54Miller WG et al Clin Chem 56:6 977-986 (2010)
Comparison of HDL and LDL Cholesterol Methods
to Reference Measurement Procedures
• Methods from 7 manufacturers and 1 distributer for direct
measurement of HDL-C and LDL-C were evaluated for
imprecision, trueness, total error, and specificity in
nonfrozen serum samples
• 6 of 8 HDL-C and 5 of 8 LDL-C direct methods met NCEP
total error goals for non-diseased individuals
• Patients included individuals with and without disease and
patients with various types of lipoprotein disorders (unlike
previous studies)
• All methods failed to meet NCEP goals for diseased
individuals due to lack of specificity toward abnormal
lipoproteins
55Miller WG et al Clin Chem 56:6 977-986 (2010)
Comparison of HDL and LDL Cholesterol Methods
to Reference Measurement Procedures
Authors’ Conclusions:
• NCEP accuracy goals based on laboratory testing when
guidelines were developed (e.g. precipitation-based
methods for HDL-C, Friedewald equations for LDL-C) and
clinical need to classify CHD risk and monitor lipid
treatment (drugs)
• Composition of lipoproteins in various dyslipidemias affect
direct methods in specifically measuring cholesterol
content of one lipoprotein class in presence of other
lipoproteins; challenging for manufacturers of direct
methods
56Miller WG et al Clin Chem 56:6 977-986 (2010
Comparison of HDL and LDL Cholesterol Methods
to Reference Measurement Procedures
Authors’ Conclusions (Con’t)
• Cannot rule out interferences (drugs, co-
morbidities, triglycerides, nutrition, nonfasting
specimens)
• Differences between direct methods and RMPs
could affect diagnosis and clinical management of
patients
• 30-45% test results outside of NCEP total error
goals for some methods; could reduce overall
effectiveness of screening for CV risk assessment
57Miller WG et al Clin Chem 56:6 977-986 (2010
Published NACB LMPGs
• Therapeutic Drug Monitoring 1999
• Cardiac Markers 1999
• Hepatic Injury 2000
• Diabetes Mellitus 2002
• Thyroid Disease (2nd edition) 2002
• Tumor Markers in the Clinic 2003
• Emergency Toxicology 2005
• Maternal-fetal Risk Assessment 2006
• Biomarkers of ACS 2007 *
• Point of Care Testing 2007
• Tumor Marker Quality Requirements 2009
• Expanded Newborn Screening 2009
• Emerging Biomarkers for CV Risk Factors 2009 *
• Major Tumor Markers 2009
• Pharmacogenetics 2010
• Liver Tumor Markers 2010
Steps to consider in evaluating
Biomarkers
• Is concentration different in persons affected by
disease in comparison to those not affected
• Is there a body of evidence from case-control and
prospective studies that have evaluated the test
• Does measurement improve ability to assess risk
above and beyond current approaches
• Are there reliable analytical methods available for
measurement
62NACB LMPG, ACS, 2007
Risk Stratification of Acute Coronary
Syndromes (ACS)
• Tools:
– History and physical
– Standard ECG and non-standard ECG leads
– Cardiac biomarkers (Troponin I or T, CK-MB, Myoglobin, others)
– Predictive indices/schemes (better as research tools than for real-time decision-making)
– Non-invasive imaging studies (echo, stress test)
NACB LMPG, ACS, 2007
NACB Guideline Recommendations (selected
recommendations for ACS)
• Biomarkers of myocardial necrosis should be measured in all patients who present with symptoms consistent with ACS
• Cardiac troponin is the preferred marker for the diagnosis of MI. CK-MB by mass assay is an acceptable alternative when cardiac troponin is not available
• Blood should be obtained for testing at hospital presentation followed by serial sampling with timing of sampling based on clinical circumstances. For most patients, blood should be obtained at presentation, 6-9 hrs, and 12-24 hrs if earlier sample negative
Note – Recommendation Classes omitted
NACB Recommendations (Con’t)
• For patients who present within 6 hrs of onset of
symptoms, an early marker may be considered in
addition to troponin. Myoglobin is the most
extensively studied marker for this purpose
• Total CK, AST, beta-hydroxybutyric
dehydrogenase, and/or LD should NOT be used
as biomarkers for the diagnosis of MI
NACB LMPG, ACS, 2007
NACB Recommendations (Con’t)
• A cardiac troponin is the preferred marker for
risk stratification and, if available, should be
measured in all patients with suspected ACS. In
patients with a clinical syndrome consistent with
ACS, a maximal concentration exceeding the 99th
percentile of values for a reference control group
(with acceptable precision) should be considered
indicative of increased risk of death and recurrent
ischemic events
NACB LMPG, ACS, 2007
Troponin as a Marker of Increased Risk in
ACS
30%
12% 11%
34%
22%
19% 19%
23%
12%
6%6%
0%1%2%4% 4%
0%
10%
20%
30%
40%
Hamm
(1992)
FRISC
(1996)
TRIM
(1999)
Pettijohn
(1997)
Hamm
(1997)
Hamm
(1997)
Polanczyk
(1998)
Galvanni
(1997)
De
ath
or
MI
Troponin +
Troponin -
Strengths of Troponin as biomarker:
• Almost 100% sensitivity for acute MI with serial draws
• Cardio-specific• Remains elevated in circulation up to 7
days• Excellent for retrospective diagnosis of
acute MI• Best prognostic indicator for ACS
NACB LMPG, ACS, 2007
Limitations of Troponin
• Not an early marker
• No standardization of methods across
troponin I assays from different
manufacturers
• Sporadic elevations from minor myocardial
damage may confuse interpretation
NACB LMPG ACS, 2007
Not all Troponins are Alike
• Analytical recommendations (NACB Guidelines): 99th percentile with a CV <10%
• Troponin I-multiple manufacturers; issue with standardization
• Troponin T-only one manufacturer (Roche); no issue with standardization
• Cutoffs NOT interchangeable
NACB LMPG, ACS, 2007
Myoglobin
• Early rising necrosis marker
• Rises within 1-3 hours of onset of ACS
• Doubles in concentration over a two hour
period
• Specificity of >95-98% for acute MI
• 2 negative results 2 hours apart rules out
acute MI in 97-99% patients
NACB LMPG, ACS, 2007
Limitations of Myoglobin
• Can be cleared in 6 hrs
• Present in cardiac and skeletal muscle
(non-specific)
• Elevated in muscle trauma and renal
dysfunction
NACB LMPG, ACS, 2007
Optimal TAT for Cardiac Biomarkers
for ACS
• NACB Recommendations:
– Laboratory should perform cardiac marker testing with
TAT of 1 hour, optimally 30 minutes or less.
• TAT defined as time from blood collection to the reporting of
results
– Institutions that cannot consistently deliver cardiac
marker TAT of 1 hour should implement POC platform
– Acceptable harmonization to central lab results should
be < 20%
NACB LMPG, ACS, 2007
NACB Recommendations-BNP
• Plasma BNP or NT-proBNP testing should be
performed to confirm the diagnosis of HF in
patients with suspected diagnosis, but with
presenting signs and symptoms that are
ambiguous with confounding disease (COPD)
• In diagnosis of patients with HF, routine plasma
BNP or NT-proBNP with obvious clinical diagnosis
is not necessary
NACB LMPG, ACS, 2007
BNP and NT-proBNP - NACB
Recommendations
• No primary reference materials are validated for
calibration of BNP or NT-proBNP. Harmonization
around the current presumed optimal diagnostic
medical decision cutoff of 100 pg/mL for BNP
should be validated. There is only one source of
antibodies and calibrators for NT-proBNP so
harmonization of NT-proBNP assays should not
be a problem
NACB LMPG, ACS, 2007
BNP and NT-proBNP – NACB
Recommendations
• Normal reference limits (95th or 97.5th percentile)
should be independently established for both BNP
and NT-proBNP based on age (by decade) and
by gender. Each commercial assay should be
validated separately. The effect of ethnicity needs
to be evaluated as a possible independent
variable
NACB LMPG, ACS, 2007
National Academy of Clinical
Biochemistry (NACB) Laboratory
Medicine Practice Guidelines
(LMPG):
Emerging Biomarkers for Primary
Prevention of Cardiovascular
Disease and Stroke
(Published 2009)
78
Emerging Risk Factors for
Cardiovascular Disease
• C-Reactive Protein
• Serum amyloid A
• Soluble CD-40 ligand
• Fibrinogen
• D-dimer
• Factovs V,VII,VIII
• Lipoprotein(a)
• LDL and HDL subtypes
• Homocysteine
• Microalbuminuria
• Cystatin C
• Apo E genotype
• Remnant lipoproteins
• Interleukins (eg, IL-6)
• Vascular and cellular adhesion
molecules
• Leukocyte count
• Plasminogen activator inhib 1
• Tissue-plasminogen activator
• Small dense LDL
• Apoliproproteins A1 and B
• Oxidized LDL
• Lipoprot-assoc phopholipaseA2
• Creatinine (GFR)
• Infectious agenst
• Fibrinopeptide A
• Von Willebrand factor antigen
79NACB LMPG Emerging Biomarkers for CVD 2009
Biomarkers and Cardiovascular Disease
Risk – NACB Guidelines
• Inflammation Biomarkers *
• Lipoprotein Subclasses and Particle
Concentration
• Lipoprotein (a)
• Apolipoproteins A-I and B *
• Markers of Renal Function
• Homocysteine *
• Natriuretic Peptides (BNP and NT-proBNP)
Inflammation Biomarkers and
Cardiovascular Disease Risk - hsCRP
High-sensivity C-Reactive Protein (hsCRP)
• Recommendation 1: After standard global risk
assessment, if the 10-year predicted risk is <5%,
hsCRP should not be measured
• Recommendation 2: If risk is intermediate (10-
20%) and uncertainty remains as to the use of
preventive therapies (statins or aspirin) then
hsCRP measurement might be useful for further
stratification into a higher or lower risk category
NACB LMPG , CVD, 2009
Inflammation Biomarkers and
Cardiovascular Disease Risk (Cont)
• Recommendation 3 – There are insufficient data
that therapeutic monitoring using hsCRP over
time is useful to evaluate effects of treatments in
primary prevention
• Recommendation 4 – The utility of hsCRP
concentrations to motivate patients to improve
lifestyle behaviors has not been demonstrated
• Recommendation 5 – Evidence is inadequate to
support concurrent measurement of other
inflammatory markers in addition to hsCRP for
coronary risk assessment
82NACB LMPG, CVD, 2009
Apolipoproteins A-I and B and
Cardiovascular Disease Risk
• Recommendation 1 – The first step to monitor
efficacy of lipid lowering therapies is to measure
LDL-C (and non-HDL-C) in patients with elevated
triglycerides
• Recommendation 2 – Although apoB measures
atherogenic lipoproteins and is a good predictor of
CVD risk (equal at least to LDL-C and non-HDL-
C), it is only a marginally better predictor than the
current lipid profile and should not be routinely
measured at this time for use in global risk
assessment
83NACB LMPG, CVD, 2009
Apolipoproteins A-I and B and
Cardiovascular Disease Risk
• Recommendation 3 – Measurement of apo-B can
be used to monitor efficacy of lipid-lowering
therapies as an alternative to non-HDL-C
• Recommendation 4 – The apo B/apo A-I ratio can
be used as an alternative to the usual total
cholesterol/HDL-C ratio to determine lipoprotein-
related risk for CVD
• Recommendation 5 – Manufacturers of apo-B and
apo-A I assays should establish traceability to
accepted standards to assure reliable and
comparable results
84NACB LMPG, CVD, 2009
Homocysteine (Hcy) and Cardiovascular
Disease Risk
• Recommendation 1 – Hcy concentrations (umol/L)
derived from standardized assays categorize
patients as follows:
– Desirable < 10
– Intermediate (low to high) >10 to <15
– High > 15 - <30
– Very high > 30
85NACB LMPG, CVD, 2009
Homocysteine and Cardiovascular
Disease Risk
• Recommendation 2 – The analytical performance
goal for clinical usefulness for measurement of
Hcy should be <10% for bias, <5% for precision,
and <18% for total error. Manufacturers of
diagnostic assays for Hcy should follow approved
value transfer protocols to assure that
standardized assays are used for vascular risk
assessment
86NACB LMPG, CVD, 2009
Point of Care Cardiac Markers
• Benefits of cardiac marker POCT:
– Reduced bottleneck in the ED
– Identification of cardiac patients more quickly
– Reduce inappropriate treatment pathways
– Allow for more rapid rule-out of a cardiac event
– Reduction in LOS for chest pain, CHF, and MI
NACB Guideline Recommendations-”Evidence-
Based Practice for Point of Care Testing”: POC
Cardiac testing
• The laboratory should perform cardiac marker
testing (for the ED) with a TAT of 1 hour, optimally
30 minutes or less. TAT is defined as the time
from blood collection to the reporting of results
• Comments: timeframe required to determine need
for thrombolytic therapy. Rule out of MI requiring
serial samples diminishes the need for a very
rapid TAT on any single sample
NACB LMPG, POC, 2007
NACB POC Cardiac Marker
Recommendations (Con’t)
• Institutions that cannot consistently deliver cardiac
marker TAT of approximately 1 hour should
implement POC testing devices • Performance characteristics should not be
different between central laboratory and POC platforms
• While it is recognized that qualitative systems do provide useful information, it is recommended that POC systems provide quantitative results
NACB LMPG, POC, 2007
Summary
• CLSI is an internationally recognized, consensus-based
standards organization producing a large number of
documents and related materials
• Standards and Guidelines are essential in establishing
uniform good laboratory practices
• Standardization and traceability of methods allow
commutability of results and improve quality and clinical
care
• Although work has been done in areas of lipid and cardiac
marker standardization/harmonization, further work is
needed
91
Contact Information – Speaker
• Barbara M. Goldsmith, Ph.D., FACB
• Email: Bgoldsmith@clsi.org
• Phone: 610-688-0100 Ext 112
• Address: 940 West Valley Road
Suite 1400
Wayne, Pennsylvania 19087 USA
92
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