Harmonization of Laboratory Testing, 08 04-2017

Harmonizationof Laboratory

Testing

Ola H. ElgaddarMD, PhD, MBA, CPHQ

Lecturer of Chemical Pathology Medical Research Institute

Alexandria [email protected]

Harmonization

Harmonization, in music, is theimplementation of harmony, usually byusing chords, including harmonized scales

Harmonization

Adjustment of differences and inconsistenciesamong different measurements, methods, procedure, specifications, or systems to make them uniform or mutually compatible

Clinical laboratory tests performedby different laboratories havecomparable results

Unfortunately, some guidelines base decisionson test results from a specific laboratorymeasurement procedure without consideringthe possibility or likelihood of differencesbetween various procedures. When thishappens, aggregation of data from differentclinical research investigations will be flawed,and erroneous decisions will be maderegarding a specific patient's care

The electronic record enables clinicians toeasily compare and evaluate test results overtime. However, the patient’s laboratory resultsmay be from multiple testing facilities that usedifferent measurement procedures.Comparing laboratory results from differentnon-harmonized measurement proceduresmay be confusing, which may contribute tomedical errors and unnecessary ordering ofrepeat tests

Harmonization of Measurements

Any process that enables the establishmentof equivalence of reported values producedby different measurement procedures for thesame measurand, (i.e. the quantityintended to be measured)

Harmonization is achieved via:

1) Method #1 = Standardization:

The conventional approach which dependson the application of a well-understoodreference measurement procedure (RMP)and commutable reference materials toestablish the calibration for each availableroutine measurement procedure.

The core component of standardization isthe “establishment of metrologicaltraceability” which requires the availability ofan ISO conform reference measurementsystem (RMS)

Components of ISO conform RMS:

ØDefined measurand,ØUnits for expression of measurement

results (ideally the Système Internationald’Unités or SI),

ØDifferent hierarchical levels of materialsand measurement procedures.

Metrological Traceability

Accordingly, the provided lab results in thelower part of the hierarchy (routine IVDmethods), will provide measurementstraceable to the top of the hierarchy, withinstated uncertainty constraints.

Joint Committee for Traceability in Laboratory Medicine (JCTLM)

Harmonization is achieved via:

2) Method #2:Considered only when RMPs are notavailable and is based on application ofsound statistical methodology to producearbitrary equivalence of otherwise disparateresults generated by the various non-standardized routine measurementprocedures (i.e: surrogate RMPs)

Key Stakeholders

ØClinical laboratory community,ØDiagnostic industry,ØClinicians,ØProfessional societies,ØInformation technology providers,ØRegulatory and governmental bodies

What is the status of harmonization activities globally?

The Working Group on the Harmonization ofthe Total Testing Process (WG-H) wasformed aiming at coordinating anddisseminating promising harmonizationinitiatives among the EFLM membersocieties, and specifically to harmonizenomenclature, units and reference intervalswhere possible at a European level.

A Global Effort to Improve Patient Care

• In October 2010 the AACC convened aninternational leadership conference toaddress how to improve harmonization oflaboratory test results for which there are nohigher-order reference measurementprocedures

• The conference proposed a roadmap and aninfrastructure to coordinate harmonizationactivities worldwide

The Roadmap to be addressed by ICHCLR

1) Prioritizing measurands by medical importance,2) Coordinating the work of different organizations,3) Developing technical processes to achieve

harmonization when there is no referencemeasurement procedure or no referencematerial

4) Promoting surveillance of the successes ofharmonization.

Harmonization Oversight Group (HOG)

1) Communicate with strategic partners (Lab andclinical practice groups, IVD manufacturers,metrology institutes, EQA providers, regulatoryorganizations,….)

2) Evaluate measurand proposals submittedby interested stakeholders and determinetheir priority and technical feasibility forharmonization.

Factors affecting Harmonization

A) Factors related to properties of the measurement procedures

B) Factors related to harmonization tools.


1. Reproducibility within one measurement procedure:

Variability of results within one measurementprocedure can derive from within laboratoryimprecision, batch to batch variability of reagents orcalibrators, lack of robustness resulting in betweenlaboratory, between instrument, between operatorand between environmental conditions differences.


2. Linearity of methods

In ideal measurement procedures, there is alinear relation between the measured quantityand the concentration of the measurand. Anon-linear relationship will have an impact onequivalence of results of differentmeasurement procedures.


3. Heterogeneity

For many analytes, the measurand isheterogeneous (e.g. different epitopes inimmunoassays) and in many measurementprocedures the reagent is heterogeneous(e.g. reacts with different epitopes inimmunoassays). This heterogeneity in bothmeasurand and reagent should be taken intoaccount.


4. Calibration

Variability in results of a laboratorymeasurement procedure can derive fromdifferences in calibration among differentprocedures. Such differences are typicallyreflected by simple relations likeY = aX or Y = aX + b.

Now, assess the possibility of harmonization!!

The assessment should clarify the contribution ofeach of these parameters to the variability. If themajor source of variability is calibration,harmonization can be achieved right away (using asimple factor). If the major source is a non-linearrelationship, harmonization - although less simple -can be achieved with appropriate statisticalmethods to manage non-linear relationship factors.

Now, assess the possibility of harmonization!!

If either reproducibility or heterogeneity is themajor source of variability for one or moremeasurement procedures, harmonization islikely not possible until the affectedmeasurement procedures are changed.

B) Factors related to Harmonization Tools

1. Commutability

The ability of a reference material to haveinter-assay properties comparable to theproperties demonstrated by authentic clinicalsamples when measured by more than onemeasurement procedure


2. Stability

It must be possible to store the calibrator for a long time.


3. Sustainability

Once a batch of calibrator is finished, the next batch should have the same properties to maintain the continuity of harmonization.


4. Value Assignment

There must be a sustainable and generally accepted way to assign a target value to the calibrator.


5. Cost and Availability

Where are we now?

Few measurands were successfully harmonized:HbA1cCholesterolGlucose

Harmonization of Laboratory Testing, 08 04-2017

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