Laboratory Perspective: The challenge of standardisation in the face of the revolution in biotechnology and data processing

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1 Laboratory Perspective: The challenge of standardisation in the face of the revolution in biotechnology and data processing Steven Edwards Consultant Editor, OIE Manual of Diagnostic Tests and Vaccines for Terrestrial Animals

2 Definition of a Standard Oxford English Dictionary has 12 distinct definitions. The most relevant today are: A document specifying nationally or internationally agreed properties for manufactured goods etc. Written standard or procedure An object or quality or measure serving as a basis or example or principle to which others conform or by which the accuracy or quality of others is judged Standard Reference Material

3 OIE Written Standards

4 The principal written standards Terrestrial Animal Health Code Standards for international movements, disease status and surveillance Manual of Diagnostic Tests and Vaccines for Terrestrial Animals Standards for laboratories, laboratory tests and reagents, and vaccine manufacture Aquatic Animal Health Code Manual of Diagnostic Tests for Aquatic Animals OIE Quality Standard and Guidelines for Veterinary Laboratories

5 The OIE Terrestrial Manual First edition ( ) Loose leaf Based on expert opinion (chapter authors) Consensus approval by OIE Member Countries Subsequent bound editions (every 4 years) Seventh edition 2012 Progressive development to broaden scope and increase rigour Incorporation of new technologies But only when the methods have been validated Recognition Widely used as a laboratory reference work WTO sanitary & phytosanitary agreement From the SPS Agreement For animal health and zoonoses: the standards, guidelines and recommendations developed under the auspices of the OIE

6 The Validation Framework Updated text in Manual adopted 2013 Research provides proof of principle Supported by publication Cannot be considered a standard method at this stage Validation pathway Fitness for purpose Established as a standard Continual monitoring of assay in use

7 Standard reference materials for diagnostic tests 1. Reference strains of pathogens Should be representative of organisms circulating in the field Maintained by Reference Laboratories in controlled repositories Defined characteristics, including passage levels Used to standardise diagnostic tests, or as standards for vaccines (eg specified in OIE Manual) Complex for pathogens with multiple circulating types Continual monitoring for changes in circulating field organisms

8 Standard reference materials for diagnostic tests 2. Serology the hierarchical approach Primary Standards Small quantities, use sparingly Extensively evaluated in multiple laboratories Defined activity level in a standard test protocol Designated at international level (eg OIE) Supplied to National Laboratories Secondary Standards Prepared by National Laboratory Calibrated against primary standards Supplied to diagnostic laboratories in that country Working standards (tertiary) Used by diagnostic laboratories as working controls

9 Currently available OIE-approved International Standard Sera (primary standards) FMD SVD Rinderpest PPR CBPP Bluetongue African horse sickness Classical swine fever Aujeszky s disease Rabies Brucellosis EBL IBR/IPV EIA Equine influenza EVA Obtained from OIE Reference Laboratories (see OIE website for details)

10 Important message For many important diseases we still have no OIE-designated primary reference materials, even for serology There are no OIE-designated primary reference materials for molecular tests

11 Standard reference materials for diagnostic tests 3. Molecular diagnostic methods Written standards (OIE Manuals) can specify eg primer sequences for PCR and related assays Do we need physical standard reference materials?

12 Parallels with human medicine Results need to be comparable across time and methods, either by producing the same value across methods and test versions or by using reliable and stable conversions. Universally available standards and reference materials specific to quantitative molecular technologies are critical to this process but are few in number. One of the most important considerations in the development of effective standards and reference materials is that the material be commutable, ie, behave as closely as possible to the test samples in the full range of measurement procedures expected to make use of the material. [Madej et al., 2010, Journal of Molecular Diagnostics 12: ]

13 Considerations for nucleic acid standards Target sequence, length of target sequence Multiple or single genotypes Method of preparation of standard Extraction, recombinant, synthetic Activity level Matrix Should give comparable results to real samples Should give comparable results to real samples Should work with all the available technologies Stability Consistency Evaluation and recognition Availability (cost, shipment issues) Based on a WHO consultation meeting

14 An example from avian influenza:

15 Standard reference materials for diagnostic tests 4. Mobile and hand-held methods In effect a subset of traditional technologies Immunoassay (detection of antigen or antibody) Nucleic acid detection Ease of use in the field is critical Kit formulations use of controls Standardisation needs to be incorporated at the development stage by manufacturer Ongoing QC vital to ensure consistency and accuracy

16 High throughput sequencing, bioinformatics and computational genomics (HTS-BCG) A big challenge for standardisation OIE ad hoc group identified opportunities and challenges from this technology The approach of agreed written standards still applies Technical standards for the OIE Manuals Standard approaches for data processing Consideration required on how to apply validation principles to this technology Criteria for the interpretation of HTS-BCG results

17 High throughput sequencing, bioinformatics and computational genomics (HTS-BCG) Standard Reference Materials? Traditional concepts don t work here Needs fresh thinking to ensure that when such methods are used, the results and interpretation are consistent, wherever or by whom the analyses are done

18 High throughput sequencing, bioinformatics and computational genomics (HTS-BCG) Ad hoc group report challenges related to standardisation Systems & infrastructure for data capture, handling, archiving and access need to be optimised and standardised Standards for HTS platforms need to be developed and incorporated into the OIE Manuals HTS-BCG needs to be fully validated and quality assured for use as a diagnostic tool

19 High throughput sequencing, bioinformatics and computational genomics (HTS-BCG) Ad hoc group report recommendations related to standardisation OIE should develop and adopt standards in the Manuals for HTS-BCG OIE should convene an ad hoc group which (inter alia) should recommend standard approaches for harmonisation and interpretation of HTS data OIE should assess feasibility of extending WAHIS to incorporate HTS data, with standards for data management.

20 Summary Standardisation is essential for end-users to have confidence in diagnostic test results Great progress has been achieved with the development of international written standards in the OIE Manuals Work must continue, including incorporation of new technologies Internationally recognised Standard Reference Materials are few: We need more, but funding is difficult May not apply to HTC-BCG technologies