11

BMTA, Teddington, 20th October 2015

Dr Chris Harrington

Deputy Director

SAS Trace Element Laboratory,

Surrey Pathology Services (SPS)

External Quality Assurance (EQA) in

Clinical Trace Element Laboratories

Overview of Presentation

• What are trace elements and why do

we measure them clinically?

• EQA in clinical laboratories – the

Barnes report 2003

• UKNEQAS for Trace Elements

Scheme run from Guildford

• ISO 17043:2010 accreditation vs CPA

• Real World EQA - hip replacements

3

Why Trace Elements ?

Elemental Classification

4

5

Trace Elements

� Significance:

� 14 elements are essential for bacteria, plants and

animals (including humans);

• transition elements V, Cr, Mn, Fe, Co, Ni, Cu, Mo, Zn;

• metalloids B, Si and Se;

• halogens F and I.

� Why?:

� There are three main reasons for their measurement in

a clinical-nutritional setting:

� To determine deficiency or toxicity.

� As a screening method for failing hip replacements

6

EQA in Clinical Laboratories

Clinical EQA

• Clinical science was one of the first disciplines to use

EQA and implement schemes in the hospital laboratory.

• The first proficiency survey of UK clinical pathology

laboratories was reported in 1953 and revealed a wide

spectrum of results for the common tests.

• In 1969, the National Quality Control Scheme was

initiated by the Wolfson Research Laboratories,

Birmingham

– Involved the distribution of specimens every 14 days.

• Now known as the UK National External Quality

Assessment Scheme (UKNEQAS) and is responsible

for about 30 different schemes.

• Other centres operate under the UKNEQAS structure.

Rationale

• EQA is the cornerstone of quality assurance and

laboratory accreditation in clinical testing laboratories.

• Ensures that the results of patient investigations are

reliable and comparable wherever they are produced.

• It is used to highlight poor performing laboratories.

• Where poor performance is highlighted schemes work

with the laboratory to improve testing.

• Schemes have a role to educate participants.

• Where this is unsuccessful participants will suspend

their service until good performance is restored.

Ian Barnes Report 2003

• The Review assessed current NHS quality assurance

frameworks and governance mechanisms for

pathology services.

• It gathered a diverse range of evidence; examining

expectations of pathology services; identifying areas

for improvement

• It recommended strengthening and standardising the

current quality assurance structures

– RCPath Joint Working Group for Quality Assessment

(JWGQA)

– co-ordinates and oversees the standards and performance of

EQA schemes for all schemes

10

UKNEQAS for Trace Elements

History and Development

• Established (1979) with a monthly distribution to UK

hospitals measuring Cu and Zn in serum.

• Growth in participants and inclusion of additional

analytes and specimen types (1979 – 1984).

• EU funded serum Al programme (1986) for

laboratories monitoring patients with Chronic Renal

Failure.

• UK DoH links scheme to UK NEQAS for referral of

poor performers to Clinical Chemistry Advisory Panel.

• Link formally established by the Advisory Committee

on Analytical Laboratory Standards in 1988.

• Introduction of ISO15189:2012 places emphasis on

EQA participation with ISO accredited schemes.

Rationale

• The aims of the scheme are consistent with the

intentions of UK NEQAS, to:

• Provide professionally-led and scientifically-based

scheme with a primarily educational objective.

• Provide regular distributions of specimens, 2 per

month of each matrix blood, serum and urine.

• Provide rapid feedback of performance.

• Support participants where problems occur.

• Stimulate the overall improvement in performance

among all participating laboratories.

• 153 participants from 27 countries.

• 49 participants in the UK.

Elements and Matrices Offered

Scheme Analytes

Serum ISO

Accredited

Al, Cr, Co, Cu, Se, Zn

Whole blood ISO

Accredited

As, Cd, Cr, Co, Pb, Mg,

Mn, Hg, Se, Tl, Zn

Urine ISO

Accredited

As, Cd, Cr, Co, Cu, Fe,

Mn, Hg, Ni, Se. Tl, Zn

Water and

dialysis fluids

Educational Al

Solid Matrix Educational Cu, Fe

14

Scheme Operation

Scheme Operation 1 of 2

15

DESIGN OF SCHEME Analytes

Matrices

Clinical relevant

concentrations

Time-scale

PARTICIPANT REGISTRATION Enrolment

Invoicing

PREPARATION OF SPECIMENS

Testing homogeneity

Testing the target value

Spiking samples under

controlled conditions

Testing stability under the

scheme conditions (storage,

temperature, time)

DISTRIBUTION OF SPECIMENS

Scheme Operation 2 of 2

16

RECEIPT OF RESULTS

CALCULATION OF STATISTICSAssignment of target values

Calculation of statistics

including performance scores

DISSEMINATION OF

PERFORMANCE REPORTS Explanation of performance

Correction of results

EVALUATION OF

PERFORMANCE OVER TIMEScrutiny from National bodies

COMMUNICATION Education

Poor performance

Questionnaire feedback

Advice

Registration

Participant meetings

Evaluation of Performance

Measurements of performance are based on deviations of

results from target values. These deviations are used to

calculate a Z-score.

As EQA has developed, various organisations have

produced best practice documents.

Those from authoritative international bodies include:

• ISO 17043 (Conformity assessment - General

requirements for proficiency testing).

• ISO 13528 (Statistical methods for use in proficiency

testing by interlaboratory comparisons).

• IUPAC (The international harmonized protocol for the

proficiency testing of analytical chemistry laboratories,

Pure Appl. Chem. 2006; 78: 145–196, 2006). .

Evaluation of Performance

ISO and IUPAC recommend assessment of performance based on a

Z-score (or a derivative which takes uncertainty into consideration):

Z-score = x - X / SDPTwhere x = laboratory result

X = target value

SDPT = standard deviation for proficiency testing

• The ‘std dev for proficiency testing’ is set by the

scheme organiser.

• Value that will allow the score to demonstrate whether

or not performance is fit for the purpose.

• Set so that a Z-score of up to ±2 indicates acceptable

performance.

• Score of more than ±3 indicates unsatisfactory

performance.

Evaluation of Performance

The scheme uses quality specifications (QS) based on

biological variation for the SDPT

• The QS are presented as either a percentage of the

target value or a fixed value depending on the

concentration of the target value.

• This allows for the increase in imprecision at low

concentrations and conforms to a ‘funnel’ shape.

Quality Specifications

Matrix

Analyte

Scheme

Units

Quality

specification

SDPT

% fixed % fixed

Serum

Copper µmol/L 12 0.84 6 0.42

Selenium µmol/L 12 0.072 6 0.036

Zinc µmol/L 15 1.20 7.5 0.60

Blood

Chromium nmol/L 20 40.0 10 20.0

Cobalt nmol/L 20 25.0 10 12.5

Lead µmol/L 10 0.145 5 0.0725

Urine

Copper µmol/L 20 0.25 10 0.125

Iron µmol/L 15 4.00 7.5 2.0

Participant Report: Zinc in Serum

• Report shows the participants Target value (ALTM),

Bias and Z-score.

• This is split into the mean, SD and CV (%) for each

method.

• Frequency plot shows the distribution for all

methods and the participants method (shade).

Long Term and Poor Performance

• 3 or more z-scores >2 from the last 6 samples (3 months) or,

• 2 or more z-scores >3 from the last 4 samples (2 months)

• Organiser contacts participant to offer help.

• If performance fails to improve the Chairman of the

National Quality Assurance Advisory Panel for Clinical

Chemistry is notified.

• If issues still unresolved the laboratory will be referred to

the Care Quality Commission for further action.

23

Accreditation: ISO vs CPA

ISO Clause Additional ISO Requirements

4 Technical Requirements4.2 Personnel Competence records

4.3 Equipment, accommodation

and environment

Environment conditions

4.4 Design of the scheme Planning of the scheme

Metrological traceability

Measurement uncertainty

Homogeneity and stability4.5 Choice of method or

procedure

4.6 Operation of scheme Environmental conditions for

transport of items

4.7 Data analysis, evaluation of

results

Statistical design

4.8 Reports Information to be included in reports

4.9 Communication with

participants

Regulatory authorities

4.10 Confidentiality

Technical and Management Requirements

ISO Clause Additional ISO Requirements

5 Management Requirements5.1 Organisation Conflicts of interest

Impartiality

5.2 Management system Commitment to comply with ISO

17043:2010

Importance of customer requirements

5.3 Document control Control of computerized documents

5.4 Review of requests tenders and

contracts

5.5 Subcontracting services Subcontractors competence

5.6 Purchasing services and

supplies

Evaluating suppliers

5.7 Service to the customer

5.8 Complaints and appeals

5.9 Control of nonconforming work Responsibilities and authorities for the

management of nonconforming work

5.10 Improvement

5.11 Corrective actions Root cause analysis

5.12 Preventive actions

5.13 Control of records Alterations to records

5.14 Internal audits Each section of ISO 17043

must be audited5.15 Management reviews

26

Real World Clinical EQA:

Hip Replacements

27

Metal Hip Implant Systems

Components of hip implant:

femoral stem; femoral head; and acetabular cup

Failure Rates and Revisions

Hip-resurfacing works well in young active men, but

failure rates in women are higher.

Failure rates for total hip-replacement are higher in both

sexes.

Seven-year revision rate for any THR: 4.7%

Resurfacing: 11.8%

Large diameter femoral head, MoM THR: 13.6%

Five-year revision rate:

Birmingham THR: 3.4%

DePuy ASR THR: 22%

DePuy ASR hip resurfacing: 24%

29

The Regulator

• April 2010 MHRA issued an advisory notice

regarding MoM hip replacements:

• Follow up annually for 5 years post operatively.

• “put in place systems for the follow up of patients

receiving MoM hip replacements where appropriate

blood metal ion measurements and sectional

imaging”.

• If either Co or Cr levels are elevated above 7 ppb

then further testing should be performed.

• MHRA alerts stated that labs should be part of

UKNEQAS for Trace Elements scheme.

• Orthopedic consultants were unsure of test results

from one year to the next.

• Q”how do I know any change in value is not due to

the testing labQ”

• The scheme decided to look back over participant

performance between April 2011 and March 2012

for Co and Cr in whole blood EQA specimens.

• Results obtained by the participants (n = 23) were

assessed.

• The concentrations ranged from 10 to 60 µg L-1 for

Co and 10 to 35 µg L-1 for Cr.

• Letter published in British Medical Journal – BMJ 2012; 344:e4017

The Clinicians

• The mean recovery for the analysis of all 20 specimens:

• Co was 96.4% (SD 2.2, CV% 2.3)

• Cr was 96.1% (SD 3.2, CV% 3.3).

• The excellent agreement between the amounts in the

specimens (endogenous plus spike) and the mean

values indicates that results reported are accurate.

• The agreement between the pools distributed on

different occasions shows that results are also

reproducible.

• These results should reassure surgeons and patients

that the laboratories carrying out the measurement of Co

and Cr are producing results that are fit for purpose.

Long Term Performance

Recent Performance

32

COBALT CHROMIUM

July August July August

sampl

e Z score Z score Z score Z score

a 0.13 -0.3 -0.1 -0.46

b -0.03 -0.29 -0.3

a -0.35 0.42 0.3 0.34

b -0.11 0.19 -0.08 0.75

a -0.1 -0.45 0.24 0.51

b -0.1 -0.36 0.03 0.99

a -0.05 0.26 0 -0.04

b 0.06 0.14 -0.2 0.26

a -0.09 0.24 0.9 -0.22

b -0.07 0.18 0.92 0.17

a -0.19 0.66 -0.9 -0.51

b -0.19 0.27 -0.18 -0.35

a -0.51 -0.62 -1 -0.31

b -0.35 -0.29 -0.28 0

During the last 6 months, performance by all except 1 of the

31 participants have achieved satisfactory performance.

Summary

• EQA is paramount to clinical laboratories.

• The aim is to improve performance by regular testing

and education, referral through professional bodies as

a fall back.

• Accreditation of laboratories to ISO ISO15189:2012

places emphasis on EQA participation with ISO

accredited schemes.

• Performance evaluation requires an understanding of

biological and analytical variation.

• Many clinical examples showing EQA helps clinicians

make decisions about the treatment of patients.

34

Acknowledgements

• Andrew Taylor, Director UKNEQAS for Trace

Elements, Guildford, UK.

• Sarah-Jane Bainbridge, EQA Quality Manager,

Surrey Pathology Services, UK.

• Thermo X2-Series ICP-MS and iCAP ICP-OES

funded by UK National Health Service and

Department of Health.

The organisers for inviting me.