Evaluating and implementing CytoSure™ microarrays

Monday 2 February 2015

How adopting the highest quality microarray technology is far easier than might be expected, following the results of the UK’s National Health Service tender.

Introduction

With the speed of technological advances in the field of genetics, researchers can gain a host of benefits by continuing to consider the best options available, utilising the latest developments to enhance their work. Switching array platforms, however, might seem both daunting and potentially risky, and yet this can yield many advantages, improving efficiency and generating more insightful data in the most costeffective manner possible.

Kath Smith In line with this, the UK’s National Health Service (NHS) recently put the microarray supply for a consortium of its clinical genetics research laboratories out to tender. The consortium, led by four prominent laboratories located across the country, devised a comprehensive and objective assessment of microarray platforms. In order to assess the quality of the platforms, each laboratory submitted a variety of challenging samples for processing, and as a result of this highly stringent process, Oxford Gene Technology’s (OGT) CytoSure™ ISCA 8x60k platform was selected over a number of alternative array suppliers. Designed in collaboration with the International Collaboration for Clinical Genomics (formerly known as the International Standards for Cytogenomic Arrays [ISCA] Consortium), the array delivers standardised, evidence-based designs, and Sheffield Children’s NHS Foundation Trust was the first of the laboratories to transfer to the OGT platform.

Discussing the smooth transition to OGT’s platform, and how this has enhanced the Sheffield laboratory’s work, Product Manager for CytoSure, Dr Ruth Burton spoke to Kath Smith, Consultant Clinical Scientist at Sheffield Children’s NHS Foundation Trust about her laboratory’s experience.

Genetics research at Sheffield

The Sheffield Children’s NHS Foundation Trust delivers firstclass genetic analysis services for a wide variety of inherited and acquired genetic disorders, utilising a variety of technologies. The field of genetics research has undergone significant transformation over the last few years, changing and enhancing the way the Trust works. As molecular technologies have emerged and evolved, these have not only become central to molecular genetics applications, but also turned out to be increasingly ingrained within cytogenetics. Reflecting this trend, three years ago the Molecular Genetics and Cytogenetics Services at Sheffield were merged into a single department made up of approximately 90 staff. The department is split into three sections: Laboratory Services, the Constitutional Genetics Service and the Oncology Genetics Service. Head of the Constitutional Genetics Service, Kath Smith, commented: “I grew up traditionally as a cytogeneticist, and now I’m head of the Constitutional Genetics Service that covers both cytogenetics and molecular genetics disciplines — we’ve been witnessing some quite exciting times.”

She went on to explain: “Microarrays were the start of this — we adopted this method in around 2004, and found it to sit across the two disciplines. With most genetics services being broader, what we’ve found is that more and more of what we do requires technologies from both cytogenetics and molecular genetics disciplines.” A particular focus of the Sheffield lab lies in the area of developmental delay disorders, for which the microarray is a particularly powerful analytical tool.

Well-established within genetics research laboratories, performance of both the microarray and data analysis software is rapidly evolving, especially as the latest genomic discoveries guide new content. Quality and cost can vary significantly between platforms, and the NHS decided to look for the highest quality platform on the market with the most accurate and user-friendly data interpretation capabilities.

Why switch?

The driver for change was ensuring cost-effectiveness within the NHS, without compromising on the quality of results and ease of use. “At Sheffield, we decided beforehand to go with the results of the tender, being a higher level of assessment than we were ever able to do inhouse,” stated Kath.

The CytoSure ISCA array was selected by the NHS
consortium after extensive evaluations

However, changing supplier is a big decision, and one that cannot be taken lightly, demanding a thorough and objective selection process. The process of switching raises many concerns in terms of maintaining the laboratory’s productivity, which could potentially be put at risk by many factors, from the practicality of transferring the historic data to the new system and getting to grips with new software, through to the quality of the new system itself. As such, the tender’s validation process was both comprehensive and highly stringent, involving a consortium of four UK NHS Genetics Labs (Bristol, Manchester, Salisbury and Sheffield), with an additional eight labs also able to take advantage of the agreed supply framework. The tender was based on a comparison of sample processing, with each of the four leading laboratories submitting a number of samples for testing on each of the selected array platforms.

The outcome

OGT’s CytoSure ISCA array was chosen based on both cost and quality, being the only platform to correctly identify all the genetic abnormalities tested, and the final decision was attributed to a combination of the array and associated CytoSure Interpret Software performance.

“To be honest, it was the quality of the results. Every lab submitted known abnormal samples to be processed by OGT and the results came back clean and clear, without any issues. The cases we submitted were ones we felt may present with challenges. For example, one of our cases was a low level mosaic, and the aneuploidy calling plot within OGT’s CytoSure Interpret Software was brilliant.” (Figure 1).

The aneuploidy summary plot allows rapid identification of whole chromosome gains and lossesFigure 1: The aneuploidy summary plot allows rapid identification of whole chromosome gains and losses.

“In terms of the deciding factor — this was a combination of everything. We looked at quality, the software’s ease of use, company support, as well as cost. Saying that, for me personally, it was the quality of the results.” Once the decision was made, it was then time to switch over to OGT’s CytoSure arrays.

A seamless transfer

Swapping to a new platform presents many potential challenges in terms of continuing normal productivity within the laboratory, and OGT worked hard to ensure a seamless transfer process. For Sheffield, the priorities of the transfer included several different factors: getting the new system itself up and running, operational training, transferring local legacy data and becoming familiar with the new software, as well as additional support from OGT in general.

System installation

"OGT made it very easy. The only real delay was a stalling point from our end, where at the same time we were also in a tender process for buying a new scanner and in the process of purchasing a new plate labeller. We wanted the system ready to make a complete change in one go. OGT kept us in the loop as to where the consumables were, and also offered us the loan of the plate labeller to help get us going.”

On-site database transfer

Retaining the library of local legacy data with the new system was a major priority at Sheffield. Since microarray interpretation benefits greatly from a higher level of information, such data is incredibly important, with every lab building up their own local database determined by local factors — both technically and genetically. “Without transferring this data across to the new platform, it would have felt like starting again from scratch,” said Kath. “OGT visited us on-site and the transfer of legacy data was all sorted very smoothly, despite the anxieties within our IT department — which were quickly resolved when they met with OGT’s experts and discussed the transfer strategy.” The Cytosure Interpret Software that accompanies each OGT array is the only software with a robust database, allowing sophisticated data querying and filtering to pull out the most relevant data when required, and Kath’s team found many benefits in the new software.

A positive approach to new software

Getting to grips with new software can present an area of concern when switching to a new system, with operators sometimes getting extremely attached to the software they use. To facilitate the transition, OGT visited the Sheffield lab to deliver full training on OGT’s CytoSure Interpret Software, allowing them to get up to speed. With the principle and interpretation of arrays remaining the same, this was simply a case of familiarity, and CytoSure Interpret Software confers several advantages for fast, accurate and user-friendly interpretation of aCGH data (Figure 2).

A combination of features allow a choice of standardised or customised, user-defined data analysis, in addition to fully integrated, automatic analysis of array image files.

CytoSure Interpret Software allows accurate and reliable aberration detection with extensive annotation tracks, providing context to resultsFigure 2: CytoSure Interpret Software allows accurate and reliable aberration detection with extensive annotation tracks, providing context to results.

CytoSure Interpret Software was embraced very positively — especially after the lead Genetic Technologist was able to share her previous experience of CytoSure arrays gained at the NHS Bristol Trust, offering additional encouragement within the team. Kath herself also remained positive about the software trials throughout the tender. She added, “Our team got familiarised pretty quickly, and I would actually say that they now feel the previous software is slightly odd, despite many years of familiarity.”

“Since we have been up and running, software questions really have been answered very readily, and all of my team — some of whom are less experienced or new to arrays — would not be concerned about contacting OGT for support.”

Expecting the unexpected — additional support from OGT

Outside of the on-site training sessions provided by OGT, very little additional support was required, although Kath did recall one incident where OGT came to the rescue. “We had one issue where we managed to crack the corner off one of our slides so it wouldn’t sit in the scanner properly,” she explained. “OGT managed to retrieve those images for us, which saved us a lot of time and effort. So once again I would say that the service and support has been great.”

Life after the switch

Following the smooth switch to the new platform three months ago, Kath’s group have found additional improvements to their work, from the practicality of high-throughput plate-based labelling, through to enhancing their overall operation with more accurate aneuploidy calling.

Interestingly, a three month data audit carried out at Sheffield revealed more accurate data calling, resulting in a lower proportion of uncertain cases. Improving the accuracy of aneuploidy calling leads to fewer uncertain cases, saving time and resources involved in follow-up investigations. This has likely originated from the fouroligo calling setting recommended within CytoSure Interpret Software (although this can be set to three). Kath reasoned: “We used three-oligo calling before, so now we are seeing fewer uncertain results, which is easier to manage from a reporting perspective. We are still witnessing CNVs of different sizes, showing we are still picking up smaller abnormalities, we just feel it’s more accurately picking up true abnormality. We feel that it’s robust, technically cleaner and analytically quicker.”

Switching supplier: is it worth the effort?

We’ve received an amount of interest into how well our transfer to OGT has gone, and I can only be extremely positive about the whole process — so if anyone asks me if it was worth the time and effort of transferring, the answer is a clear yes. Kath Smith, Head of Constitutional genetics at Sheffield Diagnostic Genetics Service

Into the future — an integrated approach

Genetic research is changing all the time, especially with the increasingly widespread application of NGS. “Sheffield is a pretty big lab, and with NGS methods coming on, this has allowed us to expand as we get more work from NGS panels.” But how is the rise of NGS affecting Sheffield’s service as a whole?

“I’m sure NGS will affect us, moving into the future. However, at the moment there are issues in getting information on CNVs. A number of research groups claim to have robust CNV calling with NGS, and while this may one day impact on arrays, at the moment I’m not sure it’s good enough to replace arrays.”

Interestingly, there is a current shift within clinical research, where it is becoming increasingly popular for laboratories to employ an integrated molecular approach, employing microarrays for robust and insightful CNV analysis alongside NGS, in order to investigate a more comprehensive mutation spectrum. The Sheffield team is now looking towards a bespoke array design for this very purpose: “Another interesting option from OGT that we have been considering is designing a focussed exon array utilising some of the content in the CytoSure™ Medical Research Exome array. Testing for a specific disorder is a very different prospect to the broader, genome-wide analysis provided by developmental delay arrays. We have a clear idea what we are looking for and we only want information on certain genes”.

The CytoSure Medical Research Exome Array

Developed in collaboration with leading molecular genetics experts at Emory University, OGT’s CytoSure Medical Research Exome array content is the ideal base to create customised molecular array panels to complement NGS. Alternatively, the complete CytoSure Medical Research Exome array can be used across all studies, with irrelevant content masked out for each specific application, presenting a highly versatile approach to CNV detection.

Summary

A modern day genetics lab experiences frequent change, in terms of technology as well as suppliers, which can lead to numerous benefits if staff are open to adopting the latest high-performance technologies as they emerge. As we have seen, by putting its microarray supplier out to tender, the NHS Genetics Service has already reaped the rewards of switching to the best available microarray platform tested.

“When we entered the tender we really weren’t sure what would come back, but we made the decision that we would go with the results, whatever that meant for us as a lab.” Admits Kath, “moving through the process, it became more reassuring for us to look at the different factors, not just cost.”

Although ensuring cost-effectiveness within the NHS was the initial driver for change, the process actually established a best performing product, selecting OGT’s CytoSure ISCA platform based on a range of factors, from data quality and accuracy through to the intuitive nature of the CytoSure Interpret Software.

Why Sheffield Diagnostic Genetics Service chose OGT arrays

Rounding off the discussion, Kath affirmed: “I would definitely recommend OGT to any colleague. The platform has been easy to transfer to, improving our processes, and we’re very happy using it within our area of developmental delay. If anyone ever asks me if it was worth the effort of transferring to OGT, the answer is a clear yes.”

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CytoSure: For research use only; not for use in diagnostic procedures

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