11 BMTA, Teddington, 20 th 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: essential 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: deficiencytoxicity To determine deficiency or toxicity. screening method 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 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 SerumISO Accredited Al, Cr, Co, Cu, Se, Zn Whole bloodISO Accredited As, Cd, Cr, Co, Pb, Mg, Mn, Hg, Se, Tl, Zn UrineISO Accredited As, Cd, Cr, Co, Cu, Fe, Mn, Hg, Ni, Se. Tl, Zn Water and dialysis fluids EducationalAl Solid MatrixEducationalCu, 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 STATISTICS Assignment of target values Calculation of statistics including performance scores DISSEMINATION OF PERFORMANCE REPORTS Explanation of performance Correction of results EVALUATION OF PERFORMANCE OVER TIME Scrutiny 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 (Conformity assessment - General requirements for proficiency testing).  ISO (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 / SD PT where x = laboratory result X = target value SD PT = 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 SD PT 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 SD PT %fixed% Serum Copper  mol/L Selenium  mol/L Zinc  mol/L Blood Chromiumnmol/L Cobaltnmol/L Lead  mol/L Urine Copper  mol/L Iron  mol/L

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 Requirements 4.2 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 stability 4.5 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 Requirements 5.1 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 must be audited 5.15 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 failure rates Hip-resurfacing works well in young active men, but failure rates in women are higher. Failure rates total hip-replacement 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% 22% DePuy ASR THR: 22% 24% 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. …”how do I know any change in value is not due to the testing lab…” 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 COBALTCHROMIUM JulyAugustJulyAugust sampl eZ score a b a b a b a b a b a b a b 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.