Harmonisation of Reference Ranges

Transcription

1 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

2 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

3 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)

4 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

5 Harmonisation in Europe Money Tax Contracts Law Technical Education Herbs Drugs Rubbish Construction

6 Sonic Healthcare Harmonisation

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8 Level 3 Professional Consensus Sonic Australia Reference Intervals Adults: years Pregnant: 4/40 42/40 Boys: 0-18 years Girls: 0-16 years

9 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...

10 Why reference limits? Why flags?

11 ISO 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.

12 What s in a name?

13 ISO15189 Reference Interval

14 CLSI C28:A3

15 Reference Interval 2.5% Reference Limit 97.5% Reference Limit 95% Reference Interval R e f e r e n c e R a n g e

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17 Unaffected Affected 0.5 SPECIFICITY SENSITIVITY Tumour Marker Level PRIORITIZE SENSITIVITY

18 Unaffected Affected 0.5 SPECIFICITY SENSITIVITY Tumour Marker Level PRIORITIZE SPECIFICITY

19 ISO 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: mmol/l Fasting Glucose: 6.0 mmol/l, 5.5 mmol/l, <7.0 mmol/l

20 SENSITIVITY Unaffected Affected Tumour Marker Level PRIORITIZE SPECIFICITY

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22 Unaffected Affected 0.5 SPECIFICITY SENSITIVITY Tumour Marker Level PRIORITIZE SENSITIVITY Good NPV Bad PPV

23 Unaffected Affected SPECIFICITY SENSITIVITY Tumour Marker Level PRIORITIZE SPECIFICITY Fair NPV Good PPV

24 Reference Intervals Default classification Minimise false positives in healthy Simple 95% distribution???

25 Bivariate 95% (Sodium, Potassium, Calcium) 95% 95% 2.5% 2.5%

26 Univariate 95% (TBil, ALT, AST, GGT) 95% 5.0%

27 Univariate 99% (hstnt?, CA125?) 99% 1.0%

28 Bivariate 99% (?) >99% 99% 0.5% 0.5%

29 CBN 2011 WORKSHOP 2012 WORKSHOP 2013 WORKSHOP 2014

30 Harmonisation Workshop Participants

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32 Analyte Male Female Calcium mmol/l Calcium (albumin adjusted) mmol/l Phosphate mmol/l Magnesium mmol/l LD [L to P] (IFCC) U/L Sodium mmol/l Potassium (serum) mmol/l Chloride mmol/l Bicarbonate mmol/l Creatinine umol/l umol/l ALP U/L AST* <40 U/L <35 U/L ALT* <40 U/L <30 U/L Total Protein g/l *Albumin (BCP/Immunoassay) g/l *Globulins (BCP/Immunoassay Alb) g/l *Total Bilirubin <21 umol/l *GGT (IFCC) <50 U/L <35 U/L *Lipase <66 U/L

33 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

34 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.

35 Sonic Documentation

36 USA

37 Australia AACB 2011 Data Courtesy Julie Ryan

38 Australia AACB 2011 Data Courtesy Julie Ryan

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

40 RCPAQAP Survey 2013: Potassium Vitros Labs Low High

41 Reference Interval Survey: Sodium Vitros Labs Low High

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44 Reference intervals vary much more than results! IMEP-17

45 USA

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49 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. 3 Professional Recommendations Based on Laboratory Experts. 4 Proficiency survey Based on survey of common reference intervals used. Troponin NHF ARQAG, SIQAG, AACB UK Harmony 5 State of the Art Based on what is available. Kit Insert

50 Kit Inserts

51 Publications

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55 In-house studies CLSI / IFCC C28-A3 November 2008

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58 Validation of Reference Intervals (1)

59 Validation (2) N=20 18 or more must fall into reference interval

60 Validation (3) N=60 Compare results: if not significantly different If significantly different transfer use new interval

61 INDIRECT STATEGY Assume that significant subset of laboratory results are from unaffected patients. Use statistical means to derive the healthy subpopulation.

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63 Harmonised Reference Intervals What is necessary: Methods are the same. Populations are the same.

64 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 Dec;48(8):

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69 Sodium: Gus Koerbin Bias Study +/- 1 mmol/l

70 Potassium: Gus Koerbin Bias Study +/- 0.1 mmol/l

71 Creatinine: Gus Koerbin Bias Study +/- 4 umol/l

72 Albumin: Gus Koerbin Bias study +/- 2 g/l

73 GGT: Gus Koerbin Bias Study +/- 5 IU/L

74 Harmonised Reference Intervals What is necessary: Methods are the same. Populations are the same.

75 Potassium variations 82.4% between individual 14.8% between city Ichihara K et al, Clin Chem 2008;54:

76 Variance Components Between City Between Gender Between Age Between Individual 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:

77 Variance Components BMI Trig, HDL, ALT, Urate C3, C4 Alcohol Fish Fruit GGT, HDL Urate, Urea AST, Na Ichihara K et al, Clin Chem 2008;54:

78 Flag Rates 4 Number of Patients Thousands % 2.86% Sodium mmol/l

79 Proposed Reference Intervals Analyte Male Female Sodium mmol/l Potassium (serum) mmol/l Chloride mmol/l Bicarbonate mmol/l Creatinine umol/l umol/l Calcium mmol/l Calcium mmol/l Phosphate mmol/l Magnesium mmol/l LD [L to P] (IFCC) U/L ALP U/L Total Protein g/l % Flag 10.0% 7.5% 5.0% 2.5% 0.0% Sodium Low High SNP DHM ClinPath MP DOR LAV INTEGRA SNP DHM ClinPath MP DOR LAV INTEGRA

80 Proposed Reference Intervals Analyte Male Female Sodium mmol/l Potassium (serum) mmol/l Chloride mmol/l Bicarbonate mmol/l Creatinine umol/l umol/l Calcium mmol/l Calcium mmol/l Phosphate mmol/l Magnesium mmol/l LD [L to P] (IFCC) U/L ALP U/L Total Protein g/l % Flag 10.0% 7.5% 5.0% 2.5% 0.0% Potassium Low High Private Labs 5.4/5.5 SNP DHM ClinPath MP DOR LAV INTEGRA SNP DHM ClinPath MP DOR LAV INTEGRA

81 Proposed Reference Intervals Analyte Male Female Sodium mmol/l Potassium (serum) mmol/l Chloride mmol/l Bicarbonate mmol/l Creatinine umol/l umol/l Calcium mmol/l Calcium mmol/l Phosphate mmol/l Magnesium mmol/l LD [L to P] (IFCC) U/L ALP U/L Total Protein g/l % Flag 10.0% 7.5% 5.0% 2.5% 0.0% Creatinine (M) Low High Sonic >60y/o SNP DHM ClinPath MP DOR LAV INTEGRA SNP DHM ClinPath MP DOR LAV INTEGRA NZ Labs 100/105

82 Proposed Reference Intervals Analyte Male Female Sodium mmol/l Potassium (serum) mmol/l Chloride mmol/l Bicarbonate mmol/l Creatinine umol/l umol/l Calcium mmol/l Calcium mmol/l Phosphate mmol/l Magnesium mmol/l LD [L to P] (IFCC) U/L ALP U/L Total Protein g/l % Flag 10.0% 7.5% 5.0% 2.5% 0.0% Calcium Low High SNP DHM ClinPath MP DOR LAV INTEGRA SNP DHM ClinPath MP DOR LAV INTEGRA

83 Proposed Reference Intervals Analyte Male Female Sodium mmol/l Potassium (serum) mmol/l Chloride mmol/l Bicarbonate mmol/l Creatinine umol/l umol/l Calcium mmol/l Calcium mmol/l Phosphate mmol/l Magnesium mmol/l LD [L to P] (IFCC) U/L ALP U/L Total Protein g/l % Flag 15.0% 12.5% 10.0% 7.5% 5.0% 2.5% 0.0% ALP Low High SNP DHM ClinPath MP DOR LAV INTEGRA SNP DHM ClinPath MP DOR LAV INTEGRA NZ , , Age, Gender

84 Consensus

85 Next steps: Formal Acceptance AACB SRAC endorsement RCPA AC endorsement Publication Promotion Monitoring via RCPAQAP Survey More Harmonisation Paediatrics, Obstetrics, Critical Limits Haematology

86 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.

87 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??

88 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