harmonisation of reference ranges · 2016-09-29 · a/prof ken sikaris 24th june 2014 ....
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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
A/Prof Ken Sikaris 24th June 2014
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
A/Prof Ken Sikaris 24th June 2014
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)
A/Prof Ken Sikaris 24th June 2014
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
A/Prof Ken Sikaris 24th June 2014
Harmonisation in Europe Money Tax Contracts
Rubbish
Law
Drugs Herbs Education Construction
Technical
A/Prof Ken Sikaris 24th June 2014
Sonic Healthcare Harmonisation
A/Prof Ken Sikaris 24th June 2014
A/Prof Ken Sikaris 24th June 2014
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
A/Prof Ken Sikaris 24th June 2014
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.................
A/Prof Ken Sikaris 24th June 2014
Why reference limits? Why flags?
A/Prof Ken Sikaris 24th June 2014
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.
A/Prof Ken Sikaris 24th June 2014
What’s in a name?
A/Prof Ken Sikaris 24th June 2014
ISO15189 ‘Reference Interval’
A/Prof Ken Sikaris 24th June 2014
CLSI C28:A3
A/Prof Ken Sikaris 24th June 2014
Reference Interval
R e f e r e n c e R a n g e
2.5%
R
efer
ence
Li
mit
97.5
%
Ref
eren
ce
Lim
it
95% Reference Interval
A/Prof Ken Sikaris 24th June 2014
A/Prof Ken Sikaris 24th June 2014
SPECIFICITY 0.5
0 0.1 0.3 4.0 20 100
Unaffected Affected
Tumour Marker Level
SENSITIVITY
PRIORITIZE SENSITIVITY
1.0
1.5
A/Prof Ken Sikaris 24th June 2014
SENSITIVITY SPECIFICITY 0.5
0 0.1 0.3 4.0 20 100
Unaffected Affected
Tumour Marker Level
PRIORITIZE SPECIFICITY
1.0
1.5
A/Prof Ken Sikaris 24th June 2014
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
–
A/Prof Ken Sikaris 24th June 2014
0.5
0 0.1 0.3 4.0 20 100
Unaffected Affected
Tumour Marker Level
PRIORITIZE SPECIFICITY
1.0
1.5
SENSITIVITY
A/Prof Ken Sikaris 24th June 2014
A/Prof Ken Sikaris 24th June 2014
SPECIFICITY 0.5
0 0.1 0.3 4.0 20 100
Unaffected Affected
Tumour Marker Level
SENSITIVITY
PRIORITIZE SENSITIVITY
1.0
1.5
Good NPV
Bad PPV
A/Prof Ken Sikaris 24th June 2014
0.5
0 0.1
SENSITIVITY
0.3 4.0 20 100
Unaffected Affected
Tumour Marker Level
PRIORITIZE SPECIFICITY
1.0
1.5
SPECIFICITY
Fair NPV
Good PPV
A/Prof Ken Sikaris 24th June 2014
Reference Intervals • Default classification
– Minimise false positives in ‘healthy’
• Simple 95% distribution – ???
A/Prof Ken Sikaris 24th June 2014
Bivariate 95% (Sodium, Potassium, Calcium)
95% 95%
2.5% 2.5%
A/Prof Ken Sikaris 24th June 2014
Univariate 95% (TBil, ALT, AST, GGT)
95%
5.0%
A/Prof Ken Sikaris 24th June 2014
Univariate 99% (hsTnT?, CA125?)
99%
1.0%
A/Prof Ken Sikaris 24th June 2014
Bivariate 99% (?)
>99% 99%
0.5% 0.5%
A/Prof Ken Sikaris 24th June 2014
CBN 2011
WORKSHOP 2012 WORKSHOP 2013 WORKSHOP 2014
A/Prof Ken Sikaris 24th June 2014
Harmonisation Workshop Participants
A/Prof Ken Sikaris 24th June 2014
A/Prof Ken Sikaris 24th June 2014
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
A/Prof Ken Sikaris 24th June 2014
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
A/Prof Ken Sikaris 24th June 2014
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.
A/Prof Ken Sikaris 24th June 2014
Sonic Documentation
A/Prof Ken Sikaris 24th June 2014
USA
A/Prof Ken Sikaris 24th June 2014
Australia AACB 2011
Data Courtesy Julie Ryan
A/Prof Ken Sikaris 24th June 2014
Australia AACB 2011
Data Courtesy Julie Ryan
A/Prof Ken Sikaris 24th June 2014
Germany
Sonntag O, J Lab Med 2003;28:302-10
3.3
3.9
4.5
5.6
A/Prof Ken Sikaris 24th June 2014
RCPAQAP Survey 2013: Potassium Vitros Labs
Low
High
A/Prof Ken Sikaris 24th June 2014
Reference Interval Survey: Sodium Vitros Labs
Low
High
A/Prof Ken Sikaris 24th June 2014
A/Prof Ken Sikaris 24th June 2014
A/Prof Ken Sikaris 24th June 2014 IMEP-17
Reference intervals vary much more than results!
A/Prof Ken Sikaris 24th June 2014
USA
A/Prof Ken Sikaris 24th June 2014
A/Prof Ken Sikaris 24th June 2014
A/Prof Ken Sikaris 24th June 2014
A/Prof Ken Sikaris 24th June 2014
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,
AACB
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
A/Prof Ken Sikaris 24th June 2014
Kit Inserts
A/Prof Ken Sikaris 24th June 2014
Publications
A/Prof Ken Sikaris 24th June 2014
A/Prof Ken Sikaris 24th June 2014
A/Prof Ken Sikaris 24th June 2014
A/Prof Ken Sikaris 24th June 2014
CLSI / IFCC C28-A3 November 2008
In-house studies
A/Prof Ken Sikaris 24th June 2014
A/Prof Ken Sikaris 24th June 2014
A/Prof Ken Sikaris 24th June 2014
Validation of Reference Intervals (1)
A/Prof Ken Sikaris 24th June 2014
Validation (2)
N=20 18 or more must fall into reference interval
A/Prof Ken Sikaris 24th June 2014
Validation (3)
N=60 Compare results: if not significantly different – transfer If significantly different – use new interval
A/Prof Ken Sikaris 24th June 2014
INDIRECT STATEGY – Assume that significant subset of laboratory
results are from ‘unaffected’ patients.
– Use statistical means to derive the ‘healthy’ subpopulation.
A/Prof Ken Sikaris 24th June 2014
A/Prof Ken Sikaris 24th June 2014
Harmonised Reference Intervals • What is necessary:
• Methods are ‘the same’.
• Populations are ‘the same’.
A/Prof Ken Sikaris 24th June 2014
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.
A/Prof Ken Sikaris 24th June 2014
A/Prof Ken Sikaris 24th June 2014
A/Prof Ken Sikaris 24th June 2014
A/Prof Ken Sikaris 24th June 2014
A/Prof Ken Sikaris 24th June 2014
Sodium: Gus Koerbin Bias Study
+/- 1 mmol/L
A/Prof Ken Sikaris 24th June 2014
Potassium: Gus Koerbin Bias Study
+/- 0.1 mmol/L
A/Prof Ken Sikaris 24th June 2014
Creatinine: Gus Koerbin Bias Study
+/- 4 umol/L
A/Prof Ken Sikaris 24th June 2014
Albumin: Gus Koerbin Bias study
+/- 2 g/L
A/Prof Ken Sikaris 24th June 2014
GGT: Gus Koerbin Bias Study
+/- 5 IU/L
A/Prof Ken Sikaris 24th June 2014
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
A/Prof Ken Sikaris 24th June 2014
• 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)
Bet
wee
n G
ende
r
Bet
wee
n In
divi
dual
Bet
wee
n A
ge
Bet
wee
n C
ity
Ichihara K et al, Clin Chem 2008;54:356-365
A/Prof Ken Sikaris 24th June 2014
• 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
A/Prof Ken Sikaris 24th June 2014
Flag Rates 12
512
612
712
812
913
013
113
213
313
413
513
613
713
813
914
014
114
214
314
414
514
614
714
814
915
0
mmol/LSodium
0
1
2
3
4
Thou
sand
sN
umbe
r of P
atie
nts
2.05% 2.86%
A/Prof Ken Sikaris 24th June 2014
Analyte Male Female
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
Calcium 2.10 – 2.60 mmol/L
Calcium’ 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
ALP 30 – 110 U/L
Total Protein 60 – 80 g/L
Proposed Reference Intervals
SN
PD
HM
Clin
Pat
hM
PD
OR
LAV
INTE
GR
AS
NP
DH
MC
linP
ath
MP
DO
RLA
VIN
TEG
RA
0.0%
2.5%
5.0%
7.5%
10.0%
% F
lag
Low High
Sodium
A/Prof Ken Sikaris 24th June 2014
SN
PD
HM
Clin
Pat
hM
PD
OR
LAV
INTE
GR
AS
NP
DH
MC
linP
ath
MP
DO
RLA
VIN
TEG
RA
0.0%
2.5%
5.0%
7.5%
10.0%
% F
lag
Low High
PotassiumAnalyte Male Female
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
Calcium 2.10 – 2.60 mmol/L
Calcium’ 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
ALP 30 – 110 U/L
Total Protein 60 – 80 g/L
Proposed Reference Intervals
Private Labs 5.4/5.5
A/Prof Ken Sikaris 24th June 2014
SN
PD
HM
Clin
Pat
hM
PD
OR
LAV
INTE
GR
AS
NP
DH
MC
linP
ath
MP
DO
RLA
VIN
TEG
RA
0.0%
2.5%
5.0%
7.5%
10.0%
% F
lag
Low High
Creatinine (M)Analyte Male Female
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
Calcium 2.10 – 2.60 mmol/L
Calcium’ 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
ALP 30 – 110 U/L
Total Protein 60 – 80 g/L
Proposed Reference Intervals
NZ Labs 100/105
Sonic >60y/o
A/Prof Ken Sikaris 24th June 2014
SN
PD
HM
Clin
Pat
hM
PD
OR
LAV
INTE
GR
AS
NP
DH
MC
linP
ath
MP
DO
RLA
VIN
TEG
RA
0.0%
2.5%
5.0%
7.5%
10.0%
% F
lag
Low High
Calcium
Proposed Reference Intervals
Analyte Male Female
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
Calcium 2.10 – 2.60 mmol/L
Calcium’ 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
ALP 30 – 110 U/L
Total Protein 60 – 80 g/L
A/Prof Ken Sikaris 24th June 2014
SN
PD
HM
Clin
Pat
hM
PD
OR
LAV
INTE
GR
AS
NP
DH
MC
linP
ath
MP
DO
RLA
VIN
TEG
RA
0.0%
2.5%
5.0%
7.5%
10.0%
12.5%
15.0%
% F
lag
Low High
ALPAnalyte Male Female
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
Calcium 2.10 – 2.60 mmol/L
Calcium’ 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
ALP 30 – 110 U/L
Total Protein 60 – 80 g/L
Proposed Reference Intervals
NZ 20-110, 30-140, Age, Gender
A/Prof Ken Sikaris 24th June 2014
Consensus
A/Prof Ken Sikaris 24th June 2014
Next steps: • Formal Acceptance
– AACB SRAC endorsement – RCPA AC endorsement – Publication – Promotion – Monitoring via RCPAQAP Survey
• More Harmonisation – Paediatrics, Obstetrics, Critical Limits – Haematology
A/Prof Ken Sikaris 24th June 2014
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.
A/Prof Ken Sikaris 24th June 2014
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??
A/Prof Ken Sikaris 24th June 2014
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