RCPA-AACB Chemical Pathology Course 2018

Graham WhiteChemical Pathology

SA Pathology at Flinders Medical Centre

Quantities and Measurement Units

Quantities

Quantity: property of a phenomenon, body, or substance,where the property has a magnitude that can be expressed as

a number and a reference e.g. 4.1 mmol/L

means 0.0041 x definition of 1 mole

The mole is the SI unit for amount of substance in chemistry

defined as:The mass of substance containing the same number of

fundamental units as there are atoms in exactly 12.000 g of 12C.

Fundamental units may be atoms, molecules, or formula units,depending on the substance concerned.

Use of mole allows quantities to be added, subtracted, multiplied

e.g. Calculation of anion gap, osmolality,solubility product for Ca/Phos etc.

Adelaide at 20°C and at 40°C has not doubled in temperature

Centigrade scale has no true zero

Technical Difficulty with using Mole for Many Analytes

Analytes must be of known purity and a single structure

e.g. Na, Ca, Mg, HbA1c etc.

Not TSH, hCG, TropT etc.

Which structure is of clinical importance?

Require International Units (IU)often arbitrary units of measurement

no relation to number of analyte entities

Measurements

Reference represents the appropriate measurement unit

Always a comparison of response by unknown sample withthat by reference

Quality of results depends on how well a reference representsthe measurement unit

Clinical biochemists need to know pedigree of calibrators used

• How are calibrator values assigned?• Are calibrators commutable?• Are calibrators reliable for comparing patient results with: Reference intervals? With results from other MPs for same measurand?

History of Measurement Units

TRADE

(~3000 BC)

Measurement Units Based on Body Parts

Foot; stride; arm length – (elbow to extended fingers) cubit

Used for local trade – unreliable between settlements

Standardisation – Pharaoh introduced a solid rod ‘Royal Cubit’

Smaller units: Finger breadth; 4 digits = 1 palm; 28 digits = 1 cubit

Babylonians ~1700 BC used cubit (530 mm); Egyptian cubit (524 mm)

Not reliable as trade spread further

1792: Traveller’s diary. In France the infinite perplexity ofthe measures exceeds all comprehension. They differ notonly in every province, but in every district and almost everytown.

1795: France adopts metric system

1820: Metric system only legal system in Low Countries

1860s:Made legal in Britain; USA, but not compulsory1875: Treaty of the Metre Conference (Paris) signed by17 nations to improve trade and international scientificcommunication

~ 800 names for ~250,000 differently sized measurement units

Measurement units should be founded on ‘constants of nature’International System of Units (SI)

1670: Metre invented as 1/10,000,000 of the distance fromequator to North Pole on meridian line

1911: USA 8 different state-based volumes termed ‘gallon’

Accurate and reliable measurements needed for:manufacturing industry, science, medical diagnostics

and therapy, global climate predictions

World-wide agreement needed on units of measurementand practical provision of accurate measurement standards

for all such purposes

Assured under the Convention of the Mètre

Also need to demonstrate equivalence betweennational measurement standards

Objectives are:• Stable

Long‐term trends can be used for decision-making

• ComparableResults from different laboratories can be broughttogether

• CoherentResults from different methods can be broughttogether

Metrology: Science and Practice of Measurement

The objectives of metrology achieved through the frameworkfor metrologically traceable measurements.

Note: Traceability is the property of the result of a measurement,not of an instrument or calibration report or laboratory

From the International Vocabulary of Basic and GeneralTerms in Metrology; VIM, 3rd edition, JCGM 200:2008

“Traceability” ‐ the property of a measurement resultwhereby the result can be related to a reference through a

documented unbroken chain of calibrations, eachcontributing to measurement uncertainty

SI units bring global coherence to scientific, technological,industrial and commercial measurements

1990s: Need for standard approach to:describingestimating

the variability of measurements (MU)

Theoretical definition

Governed by General Conference of Poids et Mesures

Realization

BIPM responsible for SI UNITS

Planned re-definitions of the SI base units:kilogram, ampere, kelvin and mole

will be in terms of constants of nature;based on fixed numerical values of

the Planck constant (h), the elementary charge (e),the Boltzmann constant (kB),

and the Avogadro constant (NA), respectively.

Unit of Length:MetreWas two marks on a platinum-iridium rodNow a constant of nature

Definition:Length of the path travelled by light in a vacuum during a time intervalof 1/299,792,458 of a second (BIPM 1998, p. 94).

Realizations of theoretical definitions responsibility of National MetrologyInstitutes (also provide calibration services)

SI unit of time is the second (s): Defined as the duration of 9 192 631 770periods of the radiation corresponding to the transition between the two

hyperfine levels of the ground state of the caesium 133 atom.

The international prototype of the kilogram – arbitrary artefact madeof platinum-iridium kept at the BIPM

7 SI Base Measurement Units

Comparisons

Mole: SI Unit for Amount of Substance in Chemistry

secondary RMP matrix-insensitive

Essential Features of aHigh Order Reference Material

Simple analytes of unique structure e.g. Mg+; HbA1C

Known purity by primary methods independent of MPe.g. Gravimetry; MS; NMR

Also needs a High Order Reference MeasurementProcedure (RMP)

Must comply with specific ISO standards that addressfeatures of RMPs

Must be commutable

e.g. Hbe.g. Enzyme activity

WHO FSH mIU/ampule

Immunoassays:e.g. tumour markers

B-E NOT SI-TRACEABLE – Termed Conventional References

ASSIGNMENT OF END-USER CALIBRATOR VALUES

ISO 17511: 2003 specifies how to assure themetrological traceability of values assigned tocalibrators and control materials intended toestablish or verify trueness of measurement.

EU made compliance with this Standarda Directive on IVD manufacturers .

10 years on –No improvement in metrological traceability

of patients’ results

EU has now made compliance a Regulation – much tougher

B-E NOT SI-TRACEABLE:

Describes majority of reference materials used by pathology labs

Majority of measurement units are arbitrary e.g. FSH etc. uses IU/L

Acceptable for comparing patient results: using same MP over time

with RI determined by same MP

Not acceptable for comparing with results by different labs/methods or MPs

Important to check full traceabilitychain (calibration hierarchy) of IVD

kit calibrators

• Update on current concepts and meanings in laboratory medicine- Standardization, traceability and harmonizationN GreenbergClinica Chimica Acta, 15 May 2014; 432: 49-54

• Mini-Review - Traceability in Clinical EnzymologyI Infusino, R Bonora, M PanteghiniClinical Biochemist Reviews, November 2007; 28(4): 155-161

• Metrological traceability in clinical biochemistryGH WhiteAnnals of Clinical Biochemistry 2011; 48: 393-409

• International vocabulary of metrology – Basic and general conceptsand associated terms (VIM) – JCGM 200:2012: (VIM) www.bipm.orgLocated under ‘Guides in Metrology’

• The International System of Units (SI): BIPM - www.bipm.org

• ISO 17511:2003 - Extensive revisions coming

Bibliography