Rosalind J. Hastings

Genome‐wide arrays: Quality criteria and platforms to be used in routine diagnostics

Whole‐genome analysis using genome‐wide arrays, also called “genomic arrays,” “microarrays,” or “arrays,” has become the first‐tier diagnostic test for patients with developmental abnormalities and/or intellectual disabilities. In addition to constitutional anomalies, genomic arrays are also used to diagnose acquired disorders. Despite the rapid implementation of these technologies in diagnostic laboratories, external quality control schemes (such as CEQA, EMQN, UK NEQAS, and the USA QA scheme CAP) and interlaboratory comparisons show that there are huge differences in quality, interpretation, and reporting among laboratories. We offer guidance to laboratories to help assure the quality of array experiments and to standardize minimum detection resolution, and we also provide guidelines to standardize interpretation and reporting. Hum Mutat 33:906–915, 2012.

An Internet-based external quality assessment in cytogenetics that audits a laboratory's analytical and interpretative performance

A novel approach to external quality assessment (EQA) using the Internet mimics the diagnostic situation so that multiple tests can be requested and EQA cases can be ‘tailor made’ to address a specific chromosome syndrome, disease, or clinical dilemma. The web-based EQA system was trialled on a large UK EQA scheme, UK NEQAS for Clinical Cytogenetics. It has also been used to implement a new Cytogenetics European Quality Assessment scheme, CEQA, set up with the intention of providing laboratories in countries without access to a local EQA scheme the opportunity of participation in EQA. Overall, Internet-based EQA allows for a varied EQA programme. Poor performance was detected in both CEQA and UK NEQAS constitutional EQA schemes and also in the UK NEQAS oncology EQA scheme. The Internet-based EQA overcomes submission delays due to international surface mail. There is also a reduction in administration and assessors’ time compared to a retrospective EQA involving the submission of unique cases for EQA assessment, as participants analyse the same three Internet-based EQA cases simultaneously. Many EU27 (EU member states) laboratories still do not participate in their national EQA schemes, so until EQA participation becomes mandatory as a component of compulsory laboratory accreditation, the quality of laboratory diagnostic service is unpredictable.

Guidelines for cytogenetic investigations in tumours

Cytogenetic and molecular genetic data are of paramount importance in the diagnosis, prognosis, and risk stratification of patients with malignant diseases. Sometimes they even directly guide the choice of therapy.1 Disease-specific abnormalities, particularly translocations, can provide essential information to assist the Pathologist and/or Oncologist in assigning a diagnosis. In several diseases, tumour genetics correlate strongly with clinical risk; thus, cytogenetic information may help the Oncologist counsel the patient, choose a specific treatment, and/or modulate treatment intensity. Clinical trials may involve cytogenetic classification of patients to the appropriate treatment regimens. Currently, the provision of specific assays for acquired neoplasiaspecific genomic changes varies among and within countries as a range of laboratories offer diagnostic solid tumour genetics; these may include Cytogenetic, Pathology, Haematology, and Molecular Genetics laboratories. Technical standards and general guidelines for the analysis and the report of results on most solid tumours are lacking. To address these deficits, a tumour best practice meeting with invited tumour experts without conflict of interest was held on 23rd April 2013 in Oxford, United Kingdom. The aim was to produce professional guidelines for tumour genetic laboratories and to incorporate the standards imposed by generic European guidelines,2 regulatory bodies (ISO15189, 2012 Medical laboratories – requirements for quality and competence),3 reporting guidelines,4 ISCN,5 and acquired best practice guidelines, while taking into account the current practice in Europe. The guidelines are aimed principally at giving guidance on the minimum, standard cytogenetic analyses, which are applicable to different types of laboratories operating under different regulatory arrangements and are relevant if more specific recommendations are not available. It was universally acknowledged that information on ancillary techniques in use in most cytogenetic laboratories (eg, RTPCR) or advanced techniques not always extensively performed in all laboratories (eg, next-generation sequencing (NGS)) were considered. The process for developing these evidence-based consensus guidelines included agreement on the need of general uniform rules on solid tumour analysis and reporting, discussion on the architecture of the guidelines, working group formation with different tasks (collection, analysis and comparison of any existing guidelines on this subject, type of tumours to be included according to published data and database consultation, method of analysis to be included, report formulation), circulation of the working group activities, formulation and circulation of the initial recommendations, draft and discussion, final consensus, and approval. It is noted that some elements of the tumour diagnostic service not subject to statute may be varied according to local constraints and agreements. Therefore, these guidelines are minimum requirements and additional professional judgment may be of paramount importance under many circumstances. In addition, as new techniques, particularly NGS, as well as clinical evidence, are becoming available all the time, these should be kept under constant review. Notes: The use of ‘must’ in this document indicates a requirement and the use of ‘should’ indicates a recommendation. Where there appears to be contradiction between available guidelines, the most recently published ones should be taken to apply to all. All diagnostic laboratories should be accredited to national or internationally accepted standards (ISO15189).3,6 Laboratories should participate in an External Quality Assessment Scheme7 in all aspects of their service for which a scheme is available.

Cytogenetic Nomenclature and Reporting.

A standardized nomenclature is critical for the accurate and consistent description of genomic changes as identified by karyotyping, fluorescence in situ hybridization and microarray. The International System for Human Cytogenomic Nomenclature (ISCN) is the central reference for the description of karyotyping, FISH, and microarray results, and provides rules for describing cytogenetic and molecular cytogenetic findings in laboratory reports. These laboratory reports are documents to the referring clinician, and should be clear, accurate and contain all information relevant for good interpretation of the cytogenetic findings. Here, we describe guidelines for cytogenetic nomenclature and laboratory reports for cytogenetic testing applied to tumor samples.

Reply to Sajantila and Budowle

We thank Drs Sajantila and Budowle1 for raising this interesting and important topic. They correctly point out that our Recommendations for reporting results of diagnostic genetic testing2 do not cover the special circumstances surrounding the reporting of post-mortem genetic testing. We did not consider this issue while preparing our recommendations, focusing instead on reporting of routine genetic testing (biochemical, cytogenetic and molecular genetic). Although some of our recommendations will apply to all reports of genetic testing, there may be important exceptions when post-mortem results are being reported.

Reply: Postmortem medicolegal genetic diagnostics also require reporting guidance : Reply to Sajantila and Budowle

We thank Drs Sajantila and Budowle1 for raising this interesting and important topic. They correctly point out that our Recommendations for reporting results of diagnostic genetic testing2 do not cover the special circumstances surrounding the reporting of post-mortem genetic testing. We did not consider this issue while preparing our recommendations, focusing instead on reporting of routine genetic testing (biochemical, cytogenetic and molecular genetic). Although some of our recommendations will apply to all reports of genetic testing, there may be important exceptions when post-mortem results are being reported.

Postmortem medicolegal genetic diagnostics also require reporting guidance Reply

We thank Drs Sajantila and Budowle1 for raising this interesting and important topic. They correctly point out that our Recommendations for reporting results of diagnostic genetic testing2 do not cover the special circumstances surrounding the reporting of post-mortem genetic testing. We did not consider this issue while preparing our recommendations, focusing instead on reporting of routine genetic testing (biochemical, cytogenetic and molecular genetic). Although some of our recommendations will apply to all reports of genetic testing, there may be important exceptions when post-mortem results are being reported.