Public health and NHS laboratories as key partners in COG-UK's sequencing network

Alongside academic centres, COG-UK drew on the sequencing support of public health and NHS laboratories. The public health laboratories are organised under different agencies in England, Wales, Scotland and Northern Ireland, reflecting the devolved nature of healthcare between the four nations. Forming the backbone of microbiology services, outside of the pandemic these laboratories play a major role in the management of infectious disease in the community and in hospitals. Furthermore, public health agencies were a major end-user of the genome data during the pandemic response. They hold patient-level data and epidemiological information on the population, which when combined with genome data led to impactful outcomes for the UK. As in the case of the academic partners, public health and NHS labs built up their sequencing capacity in coordination with COG-UK to varying degrees, depending on their capabilities at the start of the pandemic. Click here for more information on the history of public health laboratories in the UK.

Public Health England

Formerly known as the Health Protection Agency, Public Health England began operating in April 2013 and was renamed the UK Health and Security Agency (UKHSA) in April 2021. Falling under the executive agency of the Department of Health and Social Care in England, PHE grew out of the reorganisation of the NHS in 2012. Set up to protect and improve the nation's health, PHE had a laboratory in Colindale, North London, another in Porton Down and eight regional public health laboratories based in large NHS laboratories (Saunders).

When PHE was first formed in 2013, moves were underway to incorporate whole genome sequencing (WGS) into microbiology testing. The potential benefits of the technique for the management of infectious disease was flagged up in 2011 by Professor Dame Sally Davies, the Chief Medical Officer of England, in her Annual Report on Infections and the Rise of Antimicrobial Resistance. At the time of writing, the cost and complexity of WGS was still considered to be too high for it to be widely used in routine diagnostic microbiology laboratories, but it was noted that it could provide a powerful tool for investigating 'emerging pathogens, most of which are novel viruses'. In the Report's introduction, Davies also pointed out 'The emerging science of genomics will soon allow much faster routine identification of pathogens than is possible with conventional diagnostic microbiology but will also yield data for tracking pathogens and enhance the possibilities for routine surveillance at local and national level' (CMO 2011).

The inclusion of WGS into PHE laboratories was helped by the establishment of the 100,000 Genomes Project. Announced by the British Prime Minister David Cameron in December 2012, this project was designed to understand the role of genes in health and disease and integrate genomics into the NHS. While predominantly focused on sequencing and using information collected from human genomes to better understand the role of genes in cancer and rare diseases, the Project included the development of a Pathogen Genome Service at PHE Colindale to sequence bacterial and viral genomes behind infectious diseases (GOV UK). The funding was seen as crucial to enabling 'self sufficiency for PHE in case of national incidents or emergencies, but also to providing cost-effective access to genomics-informed services across PHE's infectious disease functions'. As part of this process, PHE formed a number of collaborations with academic partners to develop and deploy WGS methods for use in diagnostic laboratories for tuberculosis, HIV and Hepatitis C (PHG).

PHE Laboratory, Colindale

Equipped with high throughput, automated sequencers and dedicated high performance computers, the PHE Colindale laboratory was able to perform large-scale data analysis and provide data storage, and the laboratory built up its own team of bioinformaticians, systems administrators, software developers and computer scientists (PHG). From April 2014, the Colindale laboratory began rolling out its genomics services for pathogens including Salmonella, SSalmonella aureus, Campylobacter, S. pneumoniae, influenza and Mycobacterium tuberculosis. Within four years of its adoption of WGS technology, the laboratory had sequenced more than 100,000 bacterial and viral genomes (Grant 2018). Directed towards surveillance and outbreak management, this meant the laboratory was well equipped to do sequencing by the time the first COVID-19 cases arrived in the UK in early February 2019 which it helped to identify (Myers transcript).

Within days of COG-UK being set up, the PHE laboratory in Colindale was contributing to its sequencing effort. By 27 April 2020 the laboratory had sequenced 3,294 samples, just over 30% of the 10,843 total samples sequenced by the consortium (COG-UK Report #6). The laboratory continued to be a major sequencer of samples for COG-UK over the following months (Figure 1a, COG-UK Report #10). Figure 7.1 shows the number of sequences per 1,000 positive COVID-cases between April 2020 and July 2021.

PHE regional laboratories

Beyond Colindale, the adoption of WGS by other PHE laboratories was more varied. Some idea of what happened on the ground within the context of the pandemic is brought out by the interview with Dr Peter Muir, a consultant clinical scientist in virology who began managing the PHE laboratory based at Southmead Hospital in Bristol in 2002. Prior to COVID-19 he recalls not being able to make the business case to put sequencing in place locally. This contrasted with other PHE laboratories tracking drug resistance among HIV and tuberculosis cases that already had considerable experience with sequencing before the pandemic unfolded. For Muir, the collaboration with COG-UK helped to kick-start getting WGS in place within the laboratory which it did in partnership with the genetics department at Bristol University (Muir transcript).

For other PHE laboratories who had WGS in place, many were only sequencing very small numbers of samples each year. For these places, joining the COG-UK sequencing effort called for a much greater capacity than they were used to. This came at a time when many of the laboratories were already becoming overloaded by the pressure to perform diagnostic testing which they needed to set up and validate from scratch (Harrison transcript; Duerden).

Public Health Wales laboratories

Wales has a cohesive laboratory system, reflecting retention of much of its microbiology laboratory network following the dismantling of the Public Health Laboratory Service in 2003. The nation was also well placed to contribute to the COG-UK sequencing effort through the Pathogen Genomics Unit, or PenGU for short. Set up in Cardiff in 2017, with substantial funding from the Welsh government as part of its Genomics for Precision Medicine Strategy, PenGU developed sequencing for pathogens of public health importance starting with HIV and influenza, under the leadership of the bioinformatician Tom Connor, a professor at Cardiff University and one of the founders of the CLIMB database. Embedded within the Welsh NHS, PenGU designed a modular and expandable sequencing facility which gave it a head-start when it came to COVID-19 (Guildford; Gaskin transcript).

A core participant in the founding of COG-UK, Connor coordinated getting the COVID-19 sequencing off the ground in Wales. This began to happen before COG-UK became fully operational. Using the Nanopore sequencing protocol circulated by the ARTIC network, the team at PenGU performed the first test to validate the method for COVID on 5 March 2020, which proved it worked. The following day they sequenced the first Welsh SARS-CoV-2 genome sequence. With this in hand they were able to 'inform the Welsh Government and Public Health Wales' that they 'could be considered as a site for COVID sequencing for Wales' (Gaskin transcript; Connor).

Managed by a small team, the sequencing operation was split into two main tasks: sequencing and bioinformatics. Handled by a total of five people, the number of sequences generated in Wales grew very rapidly (Gaskin transcript). By 14 May 2020, the Welsh team had successfully sequenced a total of 7,710 genomes (COG-UK Report #6). Wales continued to sequence very high numbers of samples, recording 6,000 for the week ending 11 August 2020. At this point Wales was the second largest contributor to the total number of sequences recorded by COG-UK centres (COG-UK Report #6). Using three sequencing machines the team at Public Health Wales were able to 'process genomes in blocks of 400 base pairs, producing up to 120Gb of data a day' (Mathieson).

Wales continued to perform strongly (Figure 7.1). Between April 2020 and July the number of SARS-CoV-2 genomes sequenced was 179.17 per head in Wales compared to 145.15 in England (Marjanovic, Annexes, table 7-2). Amy Gaskin, a bioinformatician and genomic epidemiologist at PenGU, argues that one of the reasons for the success was because Wales has a relatively small population of three to four million and her team had 'a unique sense of autonomy' which facilitated rapid action. This allowed them to build a 'world-class sequencing service for a country that is very small' and then 'when COG-UK came along, it allowed us to have that key set of collaborations, but also to do things our own way in order to directly benefit the population of Wales.' She concludes, 'Without that funding, without that infrastructure, and without that vision, I think that Wales would not have been in such a unique position to handle the pandemic in its own way, which I think is commendable' (Gaskin transcript).

Gaskin's view is echoed by Dr Michael Chapman, Director of Health Informatics at Health Data Research in Cambridge. As part of the early management team at COG-UK, he saw upfront the onboarding process of different sites. From his perspective Wales was 'the poster child' in that 'they had a very, very cohesive structure'. He argues Wales was helped by the fact that they had 'the same people, like Tom Connor' who 'was sitting across academia and the Public Health Agency. And they had joint laboratories' (Chapman).

Public Health Scotland (formerly called Health Protection Scotland)

According to Chapman, Scotland 'had a very cohesive system set up with the labs and some of the academic groups, and were able to work very well locally'. Chapman recalls that the challenge there was the fact that Public Health Scotland (PHS) was only just beginning to take shape when the pandemic unfolded (Chapman transcript). Starting operations in April 2020, PHS succeeded the Health Protection Scotland, a body established in 2004 to take over the function of Scottish Centre for Infection and Environmental Health. On the ground level, there are 14 NHS boards in Scotland. Each of these are responsible for their own microbiology testing which comes under the umbrella of the PHS (Holden transcript). The sequencing for COG-UK in Scotland was coordinated by the Public Health Microbiology team at PHS.

While consulted at the start of COG-UK, unlike PHE and Public Health Wales, PHS was not named in its original financial proposal. However, PHS quickly got involved in the consortium because it had academic partners who were generating data, specifically Professor Emma Thomson and her colleagues at the Centre for Viral Research and the team led by Professor Andrew Rambaut and Dr Kate Templeton both based at Edinburgh University. A lot of the sequencing for COVID-19 was provided by the Specialist Virology Centre at the Royal Infirmary of Edinburgh and West of Scotland Specialist Virology Centre at the Glasgow Royal Infirmary (PHS). Another key person involved in the effort was Professor Matthew Holden, an advisor to PHS. He worked very closely with these teams to make sure the sequencing data they generated flowed into PHS (Holden transcript). By July 2022 a total of around 350,000 genome sequences had been generated for SARS-CoV-2 in Scotland (PHS 2022).

Northern Ireland Public Health Agency

As in the case of Wales, Northern Ireland had the advantage of covering a relatively small population, but the sequencing facilities and service there were less well developed. Formed in 2009, the Northern Ireland Agency was reliant on other public health agencies for sequencing prior to the pandemic.

Dr Tim Wyatt, a consultant microbiologist whose job involves liaising between the Agency and NHS Trusts, had been lobbying the Department of Health to get 'a sequencing set up in Northern Ireland' for some years before the pandemic, because he could see 'that this was the way diagnostics was going in microbiology.' But he made limited headway in part because of the complex structure within Northern Ireland for public health. Sequence capabilities were present in the University of Belfast, the University of Ulster and the Department of Agriculture and Rural Affairs (DAERA]. Wyatt says 'There were bits of this [sequencing] dotted about all over the place, and at that time I was trying to think, how could we join all this up because it's expensive in terms of kit and in terms of people.?' The problem, as he saw it, was Northern Ireland had sequencing going on 'but it was all in silos' (Wyatt transcript).

The arrival of COVID-19 and setting up of COG-UK helped open up a new opportunity for Wyatt to improve the sequencing situation in Northern Ireland. It rapidly became clear to him that the best way forward was to leverage the sequencing capacity within Queen's University Belfast alongside help from DAERA and elsewhere. Based on this he and Dr Derek Fairley at Queen's persuaded the Department of Health that this was the way to go. Wyatt points out that being part of COG-UK was enormously helpful in making the case to the Department and getting the sequencing operation going (Wyatt transcript).

Some idea of how the sequencing became organised in Northern Ireland is outlined in the interview with Dr Derek Bradley who was a Principal Investigator for COG-UK within the Public Health Agency. All positive samples from the five Health and Social Care Trusts in Northern Ireland were centralised through the Regional Virus Laboratory in the Royal Victoria Hospital in Belfast which received the first positive sample in February 2020. By November the laboratory was testing 1,976 samples (Fillmore). Unable to perform sequencing at scale in the early days of the response, the laboratory transferred samples for sequencing to the Genomics Core technology Unit at Queen's University Belfast (Bradley transcript; Miskelly transcript).

By 18 June 2020, Northern Ireland had sequenced 486 genomes out of the total 28,971 sequences generated by COG-UK (Queen's University Belfast 2020). Over the course of 18 months the Unit 'delivered over 40,000 sequences, and reports weekly to the Public Health Agency'. These sequences were generated not only from samples provided through the hospital, but also from residual RNA taken from the community tests performed by Randox, a company that was part of the Lighthouse Labs system in the UK (Queen's University Belfast; Miskelly transcript).

Both Miskelly and Wyatt make the point that COG-UK was crucial to getting the sequencing effort off the ground in Northern Ireland. They both feel that without it Northern Ireland would have found it more difficult to get the genomics infrastructure in place for COVID-19. In addition, they argue that it left an important legacy for the roll-out of genomics for other pathogens in the future (Miskelly transcript; Wyatt transcript).

NHS laboratories

NHS laboratories process samples from GPs as well as provide infection prevention and control advice in hospitals and provide a clinical service to inform the treatment of patients with infections. When COG-UK began, both Dr Catherine Ludden and Beth Blane put considerable effort into getting as many NHS labs on board as possible so that their positive samples flowed to a regional sequencing site. Ludden explains that this was essential to making sure COG-UK maximised population coverage (Ludden and Blane transcript).

To aid this effort, Ludden created a map to track how many hospitals were enrolled over time. Ludden treasures the moment the number of hospitals sending in samples surpassed a hundred (Ludden and Blane transcript). By early February 2021, they had recruited more than 100 diagnostic laboratories (UK wide) to submit samples to COG-UK sequencing sites. Many of these laboratories were processing samples from over 250 hospitals (Blane email).

Ludden realised it was important to find a way to automatically update the map every week to capture sites as they came on board. This she did with input from Elias Allara, a data engineering scientist seconded from Health Data Research UK to help COG-UK. Together, they were able to generate regular reports showing what coverage had been achieved since the start of the consortium, what was sequenced and this progressed week by week. The system also tracked turnaround times it took to get samples sequenced, which was calculated from the time the sample was collected and couriered to when the genome data was finally uploaded. It was designed to capture the turnaround times for both hospital (pillar 1) and community (pillar 2) samples. Throughout the pandemic efforts were made to improve the quality of the samples collected and sequenced as well as increase capacity (Ludden and Blane transcript).

Barts Health NHS Trust

A joint interview with Drs Beatrix Kele and Maria Teresa Cutino-Moguel gives some sense of the experience of one diagnostic hospital that joined the COG-UK effort. Respectively a clinical scientist and virology clinical lead, they work for a diagnostic laboratory at St Bartholomew's Hospital under the auspices of Barts Health NHS Trust, which prior to the pandemic was primarily set up to 'genotype blood borne viruses and the resistance testing for these viruses'. Initially when the COG-UK management team contacted them, in April 2020, they envisaged the hospital sending positive COVID-19 samples to one of the consortium's sequencing centres. But, as Kele recalls 'we were not in a position to send away samples because it would take up so many resources, staff and logistics, that we just didn't have in place because we were just flooded with samples'. Cutino-Moguel adds, 'When we were approached by COG-UK we felt that sending away our samples was not going to be that simple because it takes a long time to prepare samples for sending away'. In addition, they were still perfecting the assays for PCR to increase their testing capacity for COVID-19, which at the time was limited to 60 samples per day (Kele and Cutino transcript).

Although over-stretched, Cutino-Moguel says they were eager to contribute to COG-UK, seeing it as an opportunity to 'learn and implement and do our own sequencing.' At the time the prospect 'was pretty scary' because just before the pandemic started, they had lost a key member of their sequencing team and were shifting to new generation sequencing technology (Illumina), for virus sequencing. But Cutino-Moguel emphasises, they 'were just willing to do whatever it took' and used discretionary funds available to the lab for training to get the sequencing going and also applied to Barts Charity, which proved very supportive of their efforts (Kele and Cutino transcript).

Sequencing samples proved relatively straightforward since they simply added COVID-19 samples to spare flow cells on their Illumina sequencer which were not needed for their routine work and using the ARTIC protocol. Their biggest stumbling block was being able to analyse the data and share it with the consortium. Part of the problem was rooted in the fact that they did not have a bioinformatician internally and did not have any internet connection on a Linux server. They managed to resolve the issue with the goodwill of Kele's husband, a software developer, who spent an afternoon talking to Anthony Underwood, a bioinformatician and member of COG-UK (Kele and Cutino transcript).

Kele argues that, while 'number-wise' Barts proved 'a tiny little drop in the ocean of samples' that were sequenced within COG-UK, the samples they did manage to sequence were important because they were taken from hospitalised patients. Covering a number of hospitals based in East London, an area known to have high deprivation, Cutino-Moguel points out that Barts also had access to samples from a diverse ethnic population not necessarily represented elsewhere (Kele and Cutino transcript).

The decision to sequence internally and not send samples away was a huge learning curve for the Barts team, but Cutino-Moguel believes it was 'totally worth it' because it allowed them to develop 'the expertise and resources locally'. As she points out, 'we've grown, we now can do it, and that wouldn't have happened if we had just relied on someone else doing it for us. We've been able to give results to our teams, to our patients, to our colleagues that are in the rest of Northeast London. And that wouldn't have happened if we had decided not to do it locally' (Kele and Cutino transcript).

University College London Hospitals NHS Foundation Trust

Another NHS diagnostic laboratory that sequenced their own samples and then contributed this towards the COG-UK effort was University College London Hospital (UCLH). The team, based in the Advanced Pathogen Diagnostics Unit, already had good infrastructure for doing this work. Led by Professor Eleni Nastouli, a consultant clinical virologist with affiliations to Great Ormond Street Hospital and the Crick Institute, this unit had a strong history of using sequencing technologies to determine how viruses become transmitted in hospitals and how this knowledge could improve patient care. Nastouli had been a pivotal player in InfeCtion respONse through vIrus genomiCs (ICONIC), a project designed to test real-time detection of influenza outbreaks in hospitals using next generation sequencing technologies. The project involved combining genomic data with routine hospital data to track a patient's journey through different hospital wards (Hayward). In addition to influenza, the unit had experience in sequencing a variety of viruses including HIV, hepatitis B and other blood-borne viruses (Nastouli transcript).

As soon as the genome sequence was released for the SARS-CoV-2 virus in Wuhan, Nastouli and her colleagues set about to design a diagnostic PCR for it. Doing this before any cases arrived in the UK, they initially had no means to validate the test and also struggled to get extraction kits and reagents. Developed in-house with the aid of scientists at the Crick Institute, the team published their test in bioRxiv in April 2020 highlighting its possible use in national testing for a pandemic (Grant 2020).

Nastouli joined the COG-UK initiative as a representative of the UCLH-Crick partnership and UCLH site after learning about it from a virologist colleague at University College London. Based on previous work, she and colleagues decided against sequencing through COG-UK sites because having a large population of immunocompromised patients at ULCH they also wanted direct access to any sequences that revealed mutations that emerged in this population. As she explains, 'Obviously for us, it made no sense to send samples away and then not really have the results back in a timeframe that would be useful to us.' But they wanted to be part of COG-UK and contribute to its national effort so were willing to share data from the samples they sequenced which they self-funded. The process of sequencing and data analysis was helped by the fact that the unit had two bioinformaticians and a wet lab scientist (Nastouli transcript).

References

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Interview transcripts

Note: The position listed by the people below is the one that they held when interviewed and may have subsequently changed.

Interview with Dr Declan Bradley, clinical lecturer, Queen's University Belfast and consultant in the Public Health Agency, Northern Ireland.Back

Interview with Dr Michael Chapman Director of Health Informatics, Health Data Research UK Cambridge.Back

Chapman, Michael

Interview with Amy Gaskin, Bioinformatician and Genomic Epidemiologist at Pathogen Genomics Unit, Public Health Wales.Back

Interview with Dr Ian Harrison, SARS CoV2 genomics analysis cell, Public Health England (UKHSA).Back

Interview with Professor Matthew Holden, Director of Impact, St Andrew’s University,Whole Genome Sequencing Advisor Public Health Scotland.Back

Interview with Dr Beatrix Kele (Clinical Scientist), Dr Maria Teresa Cutino-Moguel (Virology Clinical Lead), Barts Health NHS Trust.Back

Interview with Dr Catherine Ludden, Director of Operations, COG-UK and Beth Blane, Logistics Manager for COG-UK, Research Assistant in the Department of Medicine, University of Cambridge.Back

Interview with Dr Julia Miskelly, Manager of the Genomics Core Technology Unit, Queen's University Belfast.Back

Interview with Dr Peter Muir, Clinical scientist at Public Health England (now UKHSA), Public Health England, Public Health Laboratory Bristol. Back

Interview with Dr Richard Myers, Head of the Bioinformatics Unit at Public Health England (now UKHSA), Principal Investigator COG-UK.Back

Nastouli, Eleni, Professor of Virology, University College London Hospitals NHS Foundation Trust and Great Ormond Street Hospital (interviewed 27 Jan 2022, unpublished transcript).Back

Interview with Joanne Watkins, Senior Biomedical Scientist, Deputy Head, Pathogen Genomics Unit, Public Health Wales.Back

Interview with Dr Tim Wyatt, Consultant Microbiologist at the Health and Social Care (HSC) Public Health Agency of Northern Ireland.Back