Harmonisation of Reference Ranges · 2016-09-29 · A/Prof Ken Sikaris 24th June 2014 ....

A/Prof Ken Sikaris 24th June 2014

Harmonisation of Reference Ranges

Ken Sikaris BSc(Hons), MBBS, FRCPA, FAACB, FFSc

Vice President, AACB (Education) Chemical Pathologist, Melbourne Pathology

Director of Clinical Support Systems, Sonic Healthcare Associate Professor, Dept Pathology, Melbourne University

Harmonisation of Reference Intervals

Ken Sikaris BSc(Hons), MBBS, FRCPA, FAACB, FFSc

Vice President, AACB (Education) Chemical Pathologist, Melbourne Pathology

Director of Clinical Support Systems, Sonic Healthcare Associate Professor, Dept Pathology, Melbourne University

Why Harmonise? Give me any word, and I show you how the root is Greek! • Language

– ἁρμόζω (harmozo), • "to fit together, to join”

– ἁρμονία (harmonia) • "joint, agreement,

concord”

• Music

– 2 notes (Greeks) – 3 notes (Renaissance)

Standardisation vs. Harmonisation • Standardisation

– Agreed reference exists – Agreed process to test compliance

• Harmonisation – Standardisation does not exist

• Come together - Collaborate

• Define issues - Investigate

• Pragmatic agreement - Consensus

Harmonisation in Europe Money Tax Contracts

Rubbish

Drugs Herbs Education Construction

Technical

Sonic Healthcare Harmonisation

Adults: 18 – 99 years Pregnant: 4/40 – 42/40

Boys: 0 - 18 years Girls: 0 - 16 years

Sonic Australia Reference Intervals Level 3 Professional Consensus

The Sonic Pathology Handbook

• Mammoth collaborative process – 3 years in the making for 65 / 250 Pathologists – Over 800 topics

• Diseases • Tests

– >1,000 pages

– eBook.................

Why reference limits? Why flags?

ISO15189 • 5.8.5 Report Content

– The report shall include, but be limited to, the following • (j) Biological reference intervals or

diagrams/nomograms supporting clinical decision values, where applicable.

What’s in a name?

ISO15189 ‘Reference Interval’

CLSI C28:A3

Reference Interval

R e f e r e n c e R a n g e

95% Reference Interval

SPECIFICITY 0.5

0 0.1 0.3 4.0 20 100

Unaffected Affected

Tumour Marker Level

SENSITIVITY

PRIORITIZE SENSITIVITY

SENSITIVITY SPECIFICITY 0.5

0 0.1 0.3 4.0 20 100

Unaffected Affected

Tumour Marker Level

PRIORITIZE SPECIFICITY

ISO15189 • 5.8.5 Report Content

– The report shall include, but be limited to, the following • (j) Biological reference intervals or

diagrams/nomograms supporting clinical decision values, where applicable.

– Sodium: 135 – 145 mmol/L – Fasting Glucose: ≤6.0 mmol/L, ≤5.5 mmol/L, <7.0 mmol/L

0 0.1 0.3 4.0 20 100

Unaffected Affected

Tumour Marker Level

SENSITIVITY

SPECIFICITY 0.5

0 0.1 0.3 4.0 20 100

Unaffected Affected

Tumour Marker Level

SENSITIVITY

PRIORITIZE SENSITIVITY

Good NPV

Bad PPV

SENSITIVITY

0.3 4.0 20 100

Unaffected Affected

Tumour Marker Level

SPECIFICITY

Fair NPV

Good PPV

Reference Intervals • Default classification

– Minimise false positives in ‘healthy’

• Simple 95% distribution – ???

Bivariate 95% (Sodium, Potassium, Calcium)

95% 95%

2.5% 2.5%

Univariate 95% (TBil, ALT, AST, GGT)

Univariate 99% (hsTnT?, CA125?)

Bivariate 99% (?)

>99% 99%

0.5% 0.5%

CBN 2011

WORKSHOP 2012 WORKSHOP 2013 WORKSHOP 2014

Harmonisation Workshop Participants

Analyte Male Female

Calcium 2.10 – 2.60 mmol/L

Calcium (albumin adjusted) 2.10 – 2.60 mmol/L

Phosphate 0.75 – 1.50 mmol/L

Magnesium 0.7 – 1.1 mmol/L

LD [L to P] (IFCC) 120 – 250 U/L

Sodium 135 – 145 mmol/L

Potassium (serum) 3.5 – 5.2 mmol/L

Chloride 95 – 110 mmol/L

Bicarbonate 22 – 32 mmol/L

Creatinine 60 – 110 umol/L 45 – 90 umol/L

ALP 30 – 110 U/L

AST* <40 U/L <35 U/L

ALT* <40 U/L <30 U/L

Total Protein 60 – 80 g/L

*Albumin (BCP/Immunoassay) 33 – 48 g/L

*Globulins (BCP/Immunoassay Alb) 26 – 39 g/L

*Total Bilirubin <21 umol/L

*GGT (IFCC) <50 U/L <35 U/L

*Lipase <66 U/L

NATA: Field Application Document

• Reference intervals and their source must be documented • Customers should be involved • Other laboratories intervals should be considered • Age and gender must be considered • Record of changes must be made

ISO15189 ‘Reference Interval’

Harmonised Reference Intervals Shall be considered at yearly review. Are a reason to believe other intervals may be inappropriate,

therefore they shall be investigated. When methods change, should also consider harmonised reference

intervals, if appropriate.

Sonic Documentation

Australia AACB 2011

Data Courtesy Julie Ryan

Australia AACB 2011

Data Courtesy Julie Ryan

Germany

Sonntag O, J Lab Med 2003;28:302-10

RCPAQAP Survey 2013: Potassium Vitros Labs

Reference Interval Survey: Sodium Vitros Labs

A/Prof Ken Sikaris 24th June 2014 IMEP-17

Reference intervals vary much more than results!

Heirarchy for reference intervals. Level Principle Reference Limits Common Interval

1 Clinical Outcome Based on clinical outcome

Glucose, Lipids, HbA1c

2A Biological

variation

2.5%-97.5% distribution of

reference population

NORIP (Direct)

SONIC (Indirect)

2B Clinician Survey Based on survey of clinician

response to results.

Troponin NHF

3 Professional

Recommendations

Based on Laboratory

Experts.

ARQAG, SIQAG,

4 Proficiency survey Based on survey of common

reference intervals used.

UK Harmony

5 State of the Art Based on what is available. Kit Insert

Kit Inserts

Publications

CLSI / IFCC C28-A3 November 2008

In-house studies

Validation of Reference Intervals (1)

Validation (2)

N=20 18 or more must fall into reference interval

Validation (3)

N=60 Compare results: if not significantly different – transfer If significantly different – use new interval

INDIRECT STATEGY – Assume that significant subset of laboratory

results are from ‘unaffected’ patients.

– Use statistical means to derive the ‘healthy’ subpopulation.

Harmonised Reference Intervals • What is necessary:

• Methods are ‘the same’.

• Populations are ‘the same’.

From Gowans EM, Hyltoft Petersen P, Blaaberg O, Horder M, “Analytical goals for the acceptance of common reference intervals for laboratories throughout a geographical area.” Scand J Clin Lab Invest. 1988 Dec;48(8):757-64.

Sodium: Gus Koerbin Bias Study

+/- 1 mmol/L

Potassium: Gus Koerbin Bias Study

+/- 0.1 mmol/L

Creatinine: Gus Koerbin Bias Study

+/- 4 umol/L

Albumin: Gus Koerbin Bias study

+/- 2 g/L

GGT: Gus Koerbin Bias Study

+/- 5 IU/L

Harmonised Reference Intervals • What is necessary:

• Methods are ‘the same’.

• Populations are ‘the same’.

A/Prof Ken Sikaris 24th June 2014 Ichihara K et al, Clin Chem 2008;54:356-365

Potassium variations 82.4% between individual 14.8% between city

• Variance Components

• Between Individual

– All but Creat & Urate • Between Gender

– CK, Creat, – Trig, HDL, ALT, Urate

• Between Age* (20-62) – ALP, Chol

• Between City

– LD, C3, C4, TP, Glob, IgG, CRP

– Na, K, Cl, Urea (not Cr)

Ichihara K et al, Clin Chem 2008;54:356-365

• Variance Components

• BMI

– Trig, HDL, ALT, Urate – C3, C4

• Alcohol

– GGT, HDL • Fish

– Urate, Urea

• Fruit

– AST, Na

Ichihara K et al, Clin Chem 2008;54:356-365

Flag Rates 12

mmol/LSodium

r of P

2.05% 2.86%

Analyte Male Female

Sodium 135 – 145 mmol/L Potassium (serum) 3.5 – 5.2 mmol/L

Calcium’ 2.10 – 2.60 mmol/L

LD [L to P] (IFCC) 120 – 250 U/L

ALP 30 – 110 U/L

Proposed Reference Intervals

Low High

Sodium

Low High

PotassiumAnalyte Male Female

LD [L to P] (IFCC) 120 – 250 U/L

ALP 30 – 110 U/L

Private Labs 5.4/5.5

Low High

Creatinine (M)Analyte Male Female

LD [L to P] (IFCC) 120 – 250 U/L

ALP 30 – 110 U/L

NZ Labs 100/105

Sonic >60y/o

Low High

Calcium

Analyte Male Female

LD [L to P] (IFCC) 120 – 250 U/L

ALP 30 – 110 U/L

Low High

ALPAnalyte Male Female

LD [L to P] (IFCC) 120 – 250 U/L

ALP 30 – 110 U/L

NZ 20-110, 30-140, Age, Gender

Consensus

Next steps: • Formal Acceptance

– AACB SRAC endorsement – RCPA AC endorsement – Publication – Promotion – Monitoring via RCPAQAP Survey

• More Harmonisation – Paediatrics, Obstetrics, Critical Limits – Haematology

NATA • Possible Review of FAD?

– Consideration should be given to adopting intervals/decision points consistent with those in other laboratories, where possible and appropriate.

– Consideration must be given to adopting intervals/decision points endorsed by relevant colleges and societies. • NPAAC ‘Standard’ for ‘Harmonisation’ unlikely.

Conclusions • “Reference Interval”

– Clinical Decision Limit / Therapeutic Range (“Reference”)

– Quality of Analysis = Quality of Reference Limits

• Validation – Is the method the same?

• Usually by method validation – Is the population the same?

• Assessed by comparing flag rates (“Outpatients”)

• ISO15189 & FAD – Existing Expectations: Source, Validation, Other labs. – Future FAD??

Acknowledgements

• AACB Harmonisation Group

– Jill Tate – Andrew Griffin – David Kanowski – George Koumantakis – Graham Jones – Gus Koerbin – Janice Gill – Julie Ryan – Leslie Burnett – Maxine Reed – Peter Vervaart – Que Lam – Rita Horvath – Robert Flatman – Tony Badrick – Tony Prior

• Sonic Biochemistry Group

– Alan McNeil – Andy Liu – Bryan Jones – Chris Ison – Clive Beng – David Kanowski – Gary Morris – Grahame Caldwell – Grant McBride – Greg Ward – John Andriolo – John Bothman – Lee Price – Leigh Murfett – Michael Freemantle – Michael Metz – Nick Taylor

– Paul Glendenning – Ranjeni Rajah – Richard Hanlon – Robert Flatman – Sydney Sacks – Tina Yen – Tony Badrick – Zhong Lu

• IFCC Committee -RIDL

– Kiyoshi Ischihara – George Klee – Julian Barth – Yesim Ozarda – 10 corresponding

members – 6 corporate members

Harmonisation of Reference Ranges · 2016-09-29 · A/Prof Ken Sikaris 24th June 2014 ....

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