CRI - Validation and Implementation First Panel

CRI - Validation and Implementation First Panel

Graham Jones

Department of Chemical Pathology

SydPath

Adult CRI – Serum / Plasma

• Sodium

• Potassium

• Chloride

• Bicarbonate

• Creatinine (to age 60)

• ALP

• LDH (L to P)

• Calcium (corrected Calcium)

• Magnesium

• Phosphate

Process • Assessment of method differences

– Bias 1, Bias 2 – Manufacturer’s traceability claims – RCPAQAP – Liquid Serum Chemistry – Average of normals (local, Empower*)

• Selection of reference intervals – Common usage (RCPAQAP Survey) – Expert groups (eg UK, ARQAG, NORIP) – Published values – Data mining (local laboratories)

• Pre-analytical factors – Sample types, collection and handling

• Other Factors – Partitioning (age, sex), significant figures

Process

• Gathering Data (2010 – 2011)

• 1st Harmonisation meeting (2011)

• Documentation and review

• 2nd Harmonisation meeting (2012)

• Documentation and review

• Adoption assessment

• 3rd Harmonisation meeting (today!)

• Formal acceptance

• Promotion and implementation

Adult CRI – JCTLM Listed References

• Sodium (P,S,M,L) • Potassium (P,S,M,L) • Chloride (P,S,M,L) • Bicarbonate • Creatinine (to age 60) (P,S,M,L) • ALP (M,L*) • LDH (L to P) (M,L*) • Calcium (P,S,M,L) • Magnesium (P,S,M,L) • Phosphate (M) P - Pure ref material; S - Serum ref material; M - reference method; L - Reference Laboratory; * Method is reference

Combined Gender

Na (mmol/L) 136-145 (n = 1838)

K (mmol/L) 3.7-4.9 (n = 1826)

Cl (mmol/L) 101-110 (n = 1827)

Bicarbonate (mmol/L) 20-29 (n = 727)

T. Bilirubin (umol/L) 5-20 (n = 758)

B. Bilirubin (umol/L) 2-8 (n = 743)

Total Protein (g/L) 62-79 (n = 1846)

Albumin (g/L) 26-48 (n = 1852)

Ca (mmol/L) 2.19-2.56 (n = 1840)

Mg (mmol/L) 0.77-1.04 (n = 1845)

Lipase (U/L) 10-54 (n = 735)

1-antitrypsin (g/L) 0.9-1.8 (n = 1693)

Haptoglobin (g/L) 0.3-2.0 (n = 768)

Rheumatoid factor (IU/mL) <15.2 (n = 676)

ACCP (U/mL) <1.1 (n = 607)

C3 (g/L) 0.76-1.61 (n = 1818)

C4 (g/L) 0.13-0.40 (n = 1807)

IgG (g/L) 6.5-15.2 (n = 1798)

IgA (g/L) 0.76-3.89 (n = 1769)

CRP (mg/L) <5.6 (n = 1703)

Fe (umol/L) 8-28 (n = 753)

Transferrin (g/L) 1.8-3.3 (n = 757)

Transferrin saturation (%) 10.7-47 (n = 652)

TSH (mU/L) 0.34-3.40 (n = 1801)

FT4 (pmol/L) 10.7-17.0 (n = 1822)

FT3 (pmol/L) 3.4-5.4 (n = 763)

Folate (nmol/L) 14-43 (n = 755)

B12 (pmol/L) 137-581 (n = 738).

Aussie Normals

Combined Gender Male Female

LDH (U/L) 124-231 (n= 766) 130-230 (n = 366) 122-232 (n = 400)

PO4 (mmol/L) 0.85-1.40 (n = 1853) 0.83-1.36 (n = 892) 0.88-1.44 (n = 961)

UA (umol/L) 139-458 (n = 786) 199-484 (n = 374) 129-373 (n = 412)

Ferritin (ug/L) 9-302 (n=734) 20-318 (n = 335) 8-228 (n = 399)

Homocysteine (umol/L) 6.4-16.0 (n = 1625) 7.6-16.5 (n = 777) 6.0-15.5 (n = 848)

Aussie Normals

Age

Combined Gender 18-39 40-69 70+

Creatinine (umol/L)

45-96 (n = 1709)

Male 55-106 (n = 816)

66-103 (n = 96)

53-100 (n = 280)

47-102 (n = 307)

Female 42-87 (n = 893)

54-81 (n = 88)

44-86 (n = 321)

40-88 (n = 347)

ALP (U/L) 40-111 (n = 1821)

Male 43-111 (n = 882)

42-113 (n = 93)

44-100 (n = 408)

43-112 (n = 381)

Female 39-114 (n = 896)

34-89 (n = 89)

39-106 (n = 397)

44-118 (n = 410)

Documentation

• All data summaries available

• BIG thanks to Maxine!!!

SODIUM Alternative name (NA) Reported to (# DP) 0

Units mmol/L Sample type Serum/plasma

Methods Direct and Indirect ISE Paediatric intervals: Yes See below for details

LOINC Pregnancy intervals: No

Reference interval survey data: 132 - 145 mmol/L

Manufacturers intervals: Dimension 136 145 Vitros 137 145

Advia 136 146 Modular 133 145

AU 136 146 Integra 136 145

DxC/Dxi 136 144 cobas 6000 136 145

Architect 136 145 cobas 8000 136 145

Manufactures traceable to: Traceability Reference method Traceability

Reference

method

Dimension (RXL/EXL) NIST SRM 2201

Flame Atomic

Absorption

Photometry Vitros

NIST SRM

919a

Dimension (Vista) NIST STM 9096 Flame photometry Modular NIST 909 Flamephotometry

Advia

SRM 909b

CDC Flame

Photometry reference

Method Integra NIST 909 Flamephotometry

AU SRM 956a cobas 6000 NIST 909 Flamephotometry

DxC/Dxi SRM 919a cobas 8000 NIST 909 Flamephotometry

Architect NIST 909 Flamephotometry

Analytical platforms assessed in Bias survey: Advia 2400, Architect, AU2700, DxC, Integra, Modular, RxL, Vitros

Bias assessment outcome: No sign. method bias

Flame atomic

emission spectoscopy

Seek Laboratory Acceptance

• A set of “Common Intervals” are just another set of intervals unless they are put into place

• Invited laboratories to respond to 2013 recommendations

• Responses from 24 Australian Labs – Representing all states and ACT – Large and small private – State-wide (Qld,SA,WA) and smaller public

• Full acceptance: Na,Cl,Creat • >90%: Bicarbonate, LDH, TP, Calcium, Phosphate • Fewer agreed for: K, ALP, Mg

Adoption Principles

• “Should be adopted unless there is evidence that other intervals are superior” (after KDIGO 2013 CKD document)

• Local Validation – Laboratory Directors are responsible

• If not suitable – consider pre/analytical issues (population differences unlikely)

Adoption Principles

NATA 15189 FAD

• 5.5.5 The sources of biological reference intervals and/or medical decision points must be documented and should include references to the information used in deciding the intervals, any statistical processes used, literature studies considered and the personnel involved in deciding the intervals.

• Where possible and relevant, customers of the laboratory with appropriate expertise should also be involved in the determination of reference intervals.

• Consideration should be given to adopting intervals/decision points consistent with those in other laboratories, and those recommended by professional groups, where possible and appropriate.

Laboratory Documentation

• State use of CRI

– Summary of “intended use” to be provided

– Developed by… inputs of… consideration of … etc

• Provide evidence of suitability (one or more)

– Lab unbiased cw method group (QAP)

– “20+ normals” (CLSI approach)

– “20+++ normal” within estimation error

– Data mining of outpatients (bias of median)

Analyte Specific Issues

Sodium

• 100% accept 135 – 145 (134.5 – 145.5)

• Allowable Bias ~ +/- 1 mmol/L

• Laboratories must be vigilant for bias.

• Local “average of normals”

– Tight between-person biological control

• Validation data from “Empower” program

– Linda Thienpont, Dietmar Stockl and others

– University of Ghent

Common Reference Interval

True reference interval width ~ 8 mmol/L (Bhattacharya on outpatients) CRI width 11 mmol/L (145.5 minus 134.5) Allowable bias >1 mmol/L

Sodium – Outpatient Medians / flagging

Empower

Outpatient daily medians from multiple laboratories

Empower (Nov 2013)

“Median of Normals”

• Assesses: Population, pre-analytical and analytical variation

• More robust with analytes:

– Under tight biological control

– Measured frequently

• Less robust with analytes:

– Varying with age or sex (affected by population)

– Analytes with high within and between person CV

CRI: 135 – 145 (Midpoint: 140, Range +/- 1)

Sodium

• Flagging rate with single outpatient samples within acceptable limits (KD data)

• Approved?

Analyte Specific Issues - Potassium

• 3.5 – 5.2 recommended

• Heparin plasma is lower but CRI may be used

• Note: agreement is not complete for private laboratories with sample delivery issues where an upper reference limit of 5.5 is commonly used.

• Suggest: 3.5 – 5.2 recommended

– 3.5 – 5.5 may be selected as alternative

– Advice should be made available in lab manual

– All heparin laboratories / ABGs may select lower RI

CRI: 3.5 – 5.2 (Midpoint: 4.35, Range +/- 0.17)

Routine sample handling may affect results

Chloride

• 100% acceptance of 95 - 110

• Between-method differences significant

• Wide CRI interval accepted (95 – 110)

CRI: 95 - 110 (Midpoint: 102.5, Range +/- 1.5)

Local Medians: 102 – 105 (flagging rates mostly <2.5% Hi and Lo)

Bicarbonate

• 100% acceptance of 22 – 32 mmol/L (pending revision of Abbott assay)

• Note no reference method

Bicarbonate – Pre-analytical

• Effect of delay on analyser (Modular system, Hitachi cups)

Analyte Specific Issues - Creatinine

• (M) 60 – 110 umol/L; (F) 45-90 umol/L recc.

• 18 – 60 years agreed

• Creatinine WG not agreed on limits above 60 years (note eGFR used for decision making)

• Same as younger: simpler, clear description (based on younger age), not indicating different action with age

• Increase with age: (slightly) fewer asterisks, evidence base poorer, (what limits, what ages)

Calcium

• 22/24 accepting 2.10 – 2.60

• Tight Biological control (within and between person)

• Analytical quality satisfactory (Bias study)

• Flagging rates low (high and low)

Calcium

Analyte Specific Issues - Phosphate

• 0.75 – 1.50 mmol/L recommended (2 DP)

• 22/24 accepted

• 1 to review flagging rate

• 1 not acceptable due to Vitros bias

• Cross-over with paediatric ranges

• Adult ranges commencing at 20 years

Phosphate Minimal Bias Std

Desirable Bias Std

Magnesium

• 23 / 24 accepted 0.70 – 1.10 (2DP) (Exception was SydPath)

• Concern that low flagging rate was high

MAGNESIUM OP Median 0.80 – 0.87 Low flagging rate 4 – 20%


Empower median – 0.84 mmol/L (0.8 – 0.86)

MAGNESIUMAlternative name Reported to (# DP) 2

Manufacturers intervals: Dimension 0.74 0.99 Vitros 0.7 1

Advia 0.53 1.11 Modular 0.65 1.05

AU 0.73 1.06 Integra 0.7 1.05

DxC/Dxi 0.74 1.03 cobas 6000 0.7 1.05

Architect 0.66 1.07 cobas 8000 0.7 1.05

Evidence base

Sonic data 0.8 - 1.5 mmol/L Adult NORIP 0.71 - 0.94 mmol/L Unisex ≥18y

0.8 - 1.5 mmol/L Pregnancy All trimesters Aussie Norms

1.0 - 2.3 mmol/L Paed 1 - 4w UK Harmony 0.7 - 1.0 mmol/L Unisex

ARQAG 0.70 -1.00 mmol/L

SIQAG 0.6 - 1.2 mmol/L

The Alfred

WA ranges 0.7 - 1.1 mmol/L Unisex, 0.7 - 1.2 mmol/L Unisex, 0.65 mmol/L Unisex, 0.7 - 1.0 mmol/L Unisex

Proposed intervals from Workshop:

Adult Unisex 0.70 - 1.10 mmol/L Bottom of range in question based on data mining

Paediatric Birth - <1w 0.60 - 1.00 mmol/L

≥1w - Adult 0.70 - 1.10 mmol/L

RCPAQAP Reference Intervals Program (40 yo)

LRL: 0.7 mmol/L most common (56 labs), followed by 0.6 (33)

URL: 1.1 mmol/L most common (42 labs), followed by 0.95 (13), 1.05 (11) and 1.0 (10)

Analyte Specific Issues - ALP

Alkaline Phosphatase

• 30 – 110 U/L recommended

• 12/24 accepted

• Age and Sex-specific limits in use.

• Eg Sonic: CRI OK for male, and post menopausal female. ?F post menopausal

• Note also cross-over with paediatric ranges

• Adult ranges commencing at age 22

CRI: 30 - 110 (Midpoint: 70, Range +/- 8)

RCPAQAP – Liquid Serum Chemistry

• 2 x Fresh serum pools (frozen, distributed)

• Request for reference intervals (40 yo male)

• Interpretation

– Allows comparison of methods

– Allows comparison of reference intervals

– Allows comparison of effect of reference intervals

RCPAQAP – Liquid Serum Chemistry

y = 0.0075x + 74.366R² = 0.0008

0

20

40

60

80

100

0 50 100 150 200

Sam

ple

Res

ult

s (U

/L)

ALP - Upper Reference Limits (U/L)

CV results 5%

CV URL 12%

0

20

40

60

80

100

120

140

160

1 4 7 1013161922252831343740434649525558616467707376798285889194

ALP - Raw Data

Res 1 Res 2 URL

0

0.2

0.4

0.6

0.8

1

1.2

1 4 7 1013161922252831343740434649525558616467707376798285889194

ALP (normalised v Lab RI)

R1(%) R2(%) URL

0

0.2

0.4

0.6

0.8

1

1.2

1 4 7 1013161922252831343740434649525558616467707376798285889194

ALP (normalised v CRI)

R1 (%CRI) R2(%CRI) URL

CV~12%

CV~5%

ALP

• High “High” flagging rate

• Possibly post-menopausal women

• Two information sets yesterday

– Zhong Lu: URL of 110 U/L OK with N PTH and Vit D

– Penny Coates: URL of 110 not high with validated healthy women

• Proposal: accept limits

LDH

• 23 / 24 accept limits of 30 – 250 U/L

• 1 to check with haematologists

LDH

LDHAlternative name Reported to (# DP)

Units U/L Sample type Serum/plasma

Methods [L → P] IFCC method Paediatric intervals: N

LOINC Pregnancy intervals: Y See below for details

Reference interval survey data: Lower level Upper level Overall

Manufacturers intervals: Dimension 85 227 Vitros 313 618


AU <248 Integra 135 225

DxC/Dxi <248 cobas 6000 135 225

Architect 125 220 cobas 8000 135 225

Sonic data 120 - 250 U/L Unisex NORIP 105 - 205 U/L Unisex 18 - 69y

100 - 200 U/L Pregnancy 1st & 2nd Trimesters 115 - 255 U/L Unisex 70+y

100 - 220 U/L Pregnancy 3rd Tirmester Aussie Norms 125 - 244 U/L Unisex [Interim data]

ARQAG 120 - 250 U/L Unisex

SIQAG 110 - 220 U/L Unisex

LDH

• High Flagging rate at high values seen (KS)

• Cause uncertain – possibly sample handling

• 250 most common URL for Ref Int Study (n=21, followed by 190)

• Aussie Normals (Abbott)

BMI (kg/m2)

Limited cohort

Full cohort 18.5-24.9 25+

LD

All 124-231 121-222 127-240

Male 130-230 125-215 134-233

Female 122-232 120-224 125-240

Total Protein

• 22/24 for range of 60 – 80 g/L

• 1 – Vitros too high

• 1: 60 - 82

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

12.0%

0

10

20

30

40

50

60

70

80

90

DX

c

Ro

che

-2

Ab

bo

tt-2

Ro

che

-4 x-2

Inte

gra-

1

Ro

che

-1 x

Ab

bo

tt-1

Ad

via-

1

Ad

via-

2

Ab

bo

tt-3

Ad

via-

3

OC

D-1

OC

D-2

H-Mid

Average

Median

LRL

URL

%low

%High

"2.5%"

TOTAL PROTEINManufacturers intervals: Dimension 64 82 Vitros 63 82


AU 66 83 Integra 66 87

DxC/Dxi 61 79 cobas 6000 66 87

Architect 64 83 cobas 8000 66 87

Evidence base

Sonic data 66 - 83 g/L Males 18- 39y NORIP 62 -78 g/L Unisex ≥18y SERUM

63 - 80 g/L Males 40 - 79y 64 - 79 g/L Unisex ≥18y PLASMA

61 - 78 g/L Males 80 - 90+y Aussie Norms

64 - 81 g/L Females 18 - 49y UK Harmony 60 - 80 g/L Unisex Adult

63 - 80 g/L Females 50 - 79y

61 - 78 g/L Females 80 - 90+y

ARQAG 45 - 75 g/L Paed 0 - 30d

45 - 65 g/L Paed 30 - 60d

50 - 75 g/L Paed 60 - 180d

55 - 80 g/L Paed 6 - 12m

66 - 84 g/L 1 - 70y

64 - 82 g/L >70y

SIQAG 45 - 70 g/L Paed 0 - 2m

50 - 80 g/L Paed >2m - 1y

55 - 80 g/L Paed 1y - 11y

64 - 83 g/L >11y

The Alfred

WA ranges 60 - 80g/L Unisex, 65 - 85 g/L Unisex, 60 - 83 g/L Unisex, 63 - 80g/L Unisex, 60 - 82 g/L Unisex

Proposed intervals from Workshop:

Adult Unisex 60 - 80 g/LRCPAQAP Reference Intervals Program (40 yo)

LRL: 60 g/L most common (49 labs), followed by 65 (35)

URL: 85 g/L most common (47 labs), followed by 80 (40) and 83 (16)

Conclusions

• Decimal places as shown

• Magnesium? (seek further information)

• Write (short) formal recommendations

• Seek RCPA, AACB endorsement

• IMPLEMENT!

CRI - Validation and Implementation First Panel

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