Impact case study database

Through highly original reverse translational research and innovative laboratory methodologies, LILH were integral to the development of mepolizumab – a new class of highly effective treatment therapies for severe asthma. First licensed in 2015, the drug is prescribed worldwide, providing substantial economic benefits and significant patient outcome improvements.

Using novel targeting of distinct pathophysiological traits identified through innovative laboratory approaches by the team, with a classical precision medicine approach, LILH have trail-blazed therapy development for asthma and related diseases, achieving global impact in three main areas.

Economic Impact

Prior to LILH intervention, GSK intended to cease mepolizumab development. Leicester research prevented this and opened new markets enabling global release of mepolizumab (Nucala™), now a key pillar of GSK’s continued success. Nucala™ was first licensed in 2015 [E1] and has grown exponentially, with sales revenue rising from GBP1,000,000 in 2015 to GBP768,000,000 in 2019. To date, Nucala™ has generated GSK revenue of ~GBP1,800,000,000 [E2].

Significantly, Nucala™ is the fastest growing respiratory product within the GSK portfolio and, despite its relatively recent market introduction, has compensated for the general decline of sales within the GSK pharmaceuticals area. The 2019 Annual Report states that “respiratory sales were up 18% AER, 15% CER to [GBP]3,081 million, on growth of Trelegy, Elipta and Nucala”. Of the drugs listed as continuing successes, Nucala™ is the highest selling drug class [E2].

Beyond GSK, mepolizumab’s benefits are widespread within the healthcare sector. Of the GBP1,100,000,000 annual NHS cost of asthma treatment, GBP137,000,000 results from patient hospitalisation [E11]. Studies into mepolizumab’s efficacy demonstrate that its use provides a 73% reduction in hospitalisation, thereby saving the NHS an estimated ~GBP19,000,000 annually [E8].

Changing Clinical Practice

In 2016, a joint committee of the British Thoracic Society and the Scottish Intercollegiate Guideline Network, on which Brightling provided expert advice, produced their ‘British Guideline on the Management of Asthma’. This guideline, for the first time, recommended the use of mepolizumab as a treatment option for severe asthma based on LILH research. The guideline also extensively utilised LILH research to inform and underpin best-practice recommendations for eosinophilic disease detection. These recommendations were adopted and included in guidelines issued the same year by the British Society for Haematology, European Academy of Allergy and Clinical Immunology, and American Academy of Allergy, Asthma and Immunology [E4].

National clinical standards in the UK are defined by NICE whose recommendations are implemented as standard procedure within all NHS hospitals and represent the gold standard globally. Following the BTS-SIGN guideline, NICE began consultation on the use of mepolizumab as a treatment for severe asthma, resulting in the 2017 guideline ‘Mepolizumab for treating severe refractory eosinophilic asthma’. This codified the drug as a treatment option in the NHS for the first time, noting that prior to its creation “there was a need for alternative treatments for people with severe refractory eosinophilic asthma” [E3].

Since 2016, as a result of ground-breaking LILH research, mepolizumab is recommended for use in treatment of severe eosinophilic asthma in clinical practice guidelines worldwide including Japan, the EU, Canada, Australia, New Zealand, and Saudi Arabia [E4].

The Global Initiative for Asthma (GINA) is the leading international medical guidelines organisation covering asthma prevalence, morbidity, and mortality. Each year, GINA publish evidence-based guidelines titled ‘Global Strategy for Asthma Management and Prevention’, used by clinicians worldwide. In each iteration since 2017, mepolizumab is a recommended treatment option. This demonstrates the paradigm shift driven and enabled by LILH [E5].

Improving Patient Health Outcomes

Following NICE approval, a statement was released by the Director of the NICE Centre for Health Technology Evaluation, Professor Carole Longson, in which the novelty and efficacy of Mepolizumab was foregrounded. Longson stated that the 100,000 adults in England and Wales with severe, uncontrolled asthma previously “had limited treatment options” with many using inhaled corticosteroids for prolonged periods causing further complications such as diabetes and high blood pressure; “as the first biologic treatment to target immune cells called eosinophils. These cells are responsible for symptoms in thousands of asthma patients”. Mepolizumab would enable significant treatment and quality of life improvements for sufferers [E6].

By 2019, there were an estimated 17,507 UK patients eligible for mepolizumab, with 3,258 receiving the treatment [E11]. Global adoption of mepolizumab immediately provided significant patient health improvements. The French mepolizumab early-access programme demonstrated 86% reduction in severe exacerbations with 65% of patients stopping continuous corticosteroid treatment [E7], while the Australian Mepolizumab Registry showed 60% reduction in severe exacerbations. Follow-up studies demonstrated a 73% reduction in hospitalisations in patients receiving the drug between 2015 and 2017 [E8].

The real-world benefits of mepolizumab were confirmed by the US Institute for Clinical and Economic Review which concluded that use of the drug was associated with a 53% reduction in asthma exacerbations with similar reductions demonstrated in the annual per-patient rates of emergency department visits (61% reduction) and hospitalisations generally (69% reduction) [E9]. To date, an estimated 150,000 people worldwide have been treated with mepolizumab since 2015 [E10].

Without the expert intervention of LILH, mepolizumab would have been abandoned, falsely regarded as ineffective based on an incorrect understanding of asthma pathophysiology. Instead, thousands of patients globally now benefit from new treatment options and drastically improved life quality. Drug discovery methods have been revolutionised and avenues for novel, effective treatments have been opened, ensuring continued progress in the global battle against asthma.

University of Leicester (UoL) research has underpinned developments benefiting victims of violent crime and their families, wrongfully convicted individuals, police, forensic practitioners and forensic service providers, legal teams, government and policy makers, and companies manufacturing and selling DNA testing kits. Increasing the power of Y-STR typing: The UoL team’s research contributed to the 2001 origin and subsequent growth of YHRD [R2, R5], the only global and open database of Y-DNA reference profiles. Originally the USA maintained its own database ( www.usystrdatabase.org), but in 2018 this was decommissioned, and its 35,295 profiles were transferred into YHRD, recognising its primacy and the need for a single global standard. YHRD now allows forensic scientists, police, prosecutors, and defence teams anywhere in the world to search >320,000 profiles and determine the significance of a crime-scene match: without it, Y-STR profiling simply could not be applied in forensic casework. For example, YHRD underpins the use of Y-STR profiling in the UK as set out in the Forensic Science Regulator’s Guidelines [E1]. Because it is classified into populations, the database also provides information about the likely biogeographic ancestry of a profile. YHRD users typically made around 4,000 visits/month up to 2018, and, following the transfer of US profiles into YHRD, 8,600 visits/month. Guidelines and evidence interpretation: UoL contributed to internationally agreed principles for the application of Y-STR profiling, vital given the differences among criminal justice systems worldwide. The International Society for Forensic Genetics (including Jobling) published its first recommendations for the use and interpretation of Y-STR profiling in 2001 [E2], and these form the basis of current recommendations that reflect new technologies. In the UK, Jobling and Wetton were invited to join the Y-STR Working Group of the Government’s Forensic Science Regulator, and the Association of Forensic Science Providers DNA Working Group, to develop the UK’s guidelines [E3]. In interpreting evidence, naming STRs and (since the implementation of MPS) STR sequences in a consistent way is essential. Work carried out in Leicester [R7] proposed allele nomenclatures for Y-STRs, leading to an invitation to a 2019 STRAND Working Group meeting, contributing to key decisions on nomenclature [E3] and feeding into forensic and manufacturer practice. New Y-STRs developed in UoL research [R4] drove a step-change in the discriminatory power of commercial profiling kits. As well as publications, Jobling gave invited keynote talks on these new developments at international conferences that included company representatives (e.g. International Society for Human Identification meeting, National Harbor, MD, USA, 2011; 27^th Congress of the International Society for Forensic Genetics, Seoul, 2017). The current generation of kits produced by the US-based global companies Promega and Thermo Fisher Scientific are respectively PPY23 ( [E4]; 23 STRs, including seven from [R4], developed 2012) and YFiler Plus ( [E5]; 27 STRs, including nine from [R4], 2014). Three Chinese companies, PeopleSpot, AGCU ScienTech, and Microread Genetics also developed kits using STRs from [R4], which are used mostly in China. The UK’s forensic service providers (LGC, Cellmark, Key Forensic Services, Scottish Police Authority and Forensic Science Ireland) chose PPY23 as their Y-profiling tool in 2014 [E1]. Supporting convictions & exonerations is the goal of Y-STR profiling and is enabled by UoL’s contribution to the development and application of this technology. In the UK ONS Crime Survey (2018) ~700,000 people reported sexual assault (10,127 prosecutions in 2018-19). Since 99% of cases involve male assailants, Y-STR testing is invaluable: without this technology, 10% of cases could not be prosecuted, and detecting multiple male assailants is three times more likely when using Y- compared to autosomal STR profiling [E6]. In the UK, Y profiling is increasing (80,550 PPY23 tests since 2014). Biogeographic ancestry prediction from Y-STR profiles is valuable: for example, in Operation Pettyridge (2015), a Leeds rapist thought to be Middle Eastern from witness testimony was identified via the demonstration that his Y-STR profile was SE European: this led to the identification and extradition of a Slovakian man now serving a 20-year sentence [E7]. Y-STR profiling is used in the exonerations of prisoners via testing of archived case materials. Although Y-STR profiles cannot individually identify, a single Y-STR mismatch is sufficient for an exoneration. In the US-based Innocence Project, Y-STR profiling was the key evidence in 16% of 194 exonerations [E8]. More discriminating profiling kits have helped: for example, a man convicted of rape in Taiwan based on a 17 Y-STR test was exonerated in 2014 when the PPY23 kit was applied [E9]. Sale of kits for forensic DNA analysis has been enabled by the research. Generating reference data for YHRD brought sales to Thermo Fisher and Promega of GBP10,800,000 and GBP9,800,000 respectively. In the UK alone, the 80,550 PPY23 (Promega) tests done by forensic service providers in sexual assault and other criminal casework to date represent GBP1,980,000 sales, with an upward trend [E10]. Solving cold cases: 2018 work by Wetton and May brought UoL’s involvement with forensic DNA analysis full circle by recreating and validating legacy techniques in DNA fingerprinting. This was key evidence in securing the conviction of a suspect linked to violent rape and burglary committed in 1988, for which a contemporaneous DNA fingerprint was the key evidence [E11]. Other cold cases can now be investigated in the same way.

Triangulation of multidisciplinary applications, underpinned by University of Leicester research, has contributed to the expansion of interest in genealogical heritage. The research has enabled the identification of ancient remains via the historical lineage of their descendants, most famously, those of King Richard III (RIII) and opened access to ancestral data for members of the public to explore their own ancestry.

Heritage, tourism and economic impact

Discovery of RIII’s skeleton beneath a Leicester carpark and the identification of his remains significantly contributed to Leicestershire’s transformation into a national and global tourism destination. The Tourism Growth Plan (2019) stated : “The economic potential of Leicester and Leicestershire was significantly enhanced by the discovery of the remains of King Richard III… and his reinterment in Leicester Cathedral in 2015. The value of this remarkable story to the area… provided a spotlight that enabled both the City and the County to showcase the area’s rich heritage and tourism potential” [E1Eii].

A 2015 Leicester City Council (LCiC) report showed that the discovery and identification of RIII drove significant economic impacts. In the period between the discovery and March 2015, 622,562 additional visitors to RIII-related events in Leicester spent GBP54,625,048; an additional 1,012 FTE jobs were created; an estimated GBP79,082,740 gross value added to Leicester’s economy; and volunteering valued at GBP118,566 [E1A]. Although impacts and data relating to the discovery began in the REF2014 census period, the Leicester research has delivered significantly greater impacts since August 2013. 2020 LCiC [E1Eii] and 2019 Leicestershire County Council (LCoC) [E1Eiii] reports showed that the RIII discovery and identification, along with other regional attractions, contributed to the region’s overall tourism growth. Since 2013, there has been “an increase of 26.9% in value from the tourism sector, an 18.6% increase in visitors and a 12.6% increase in employment”. [E1Eii]. In 2018 alone, 34.9 million people visited Leicestershire [E1Eii] and 11.5 million people visited the city of Leicester, valued at GBP651 million—significantly driven by the discovery of RIII [E1Eiii].LCiC invested GBP4 million in the new King Richard III Visitor Centre (RIIIVC) at the Greyfriars site which showcases the team’s research, including King’s genetic genealogy work [E1A]. The RIIIVC’s permanent exhibition is explicitly designed around the team’s research on RIII’s burial [R1]; his Bosworth battle wounds [R2]; a 3D model of CT scans of his bones to reconstruct his scoliosis [R3]; and the team’s identification procedures, including King’s DNA testing [R4] [E1B]. Between its opening on 26 July 2014 and 31 December 2020, the RIIIVC had 347,155 visitors from the UK and beyond. Overseas visitors came from as far away as the USA, Australia, and China [E1C]. In 2018, the RIIIVC won the Group Leisure and Travel Awards’ ‘Best Museum or Gallery’ by reader vote, beating the British Museum and Tate Britain [E1C]. Lonely Planet added the RIIIVC to their ‘Ultimate United Kingdom Travelist’ in 2019, stating it “reveals… one of the world’s greatest archaeological detective stories” [E1Eiii]. The discoveries published in [R1] prompted Historic England to designate the Greyfriars site as a Scheduled Ancient Monument in 2017 [E1D]. In 2014 alone, Leicester Cathedral drew 398,500 more visitors than in 2012 (an increase from 29,500 to 428,000 total, a 14-fold increase), and between 2013 and 2018 it attracted 1,223,560 total visitors [E1B]. In March 2015, approximately 43,000 people attended reinterment events at the Cathedral, and the burial service was viewed by more than 600 million worldwide. In the year following the identification, Bosworth Battlefield Heritage Centre (BBHC) ticket sales increased by 62% (2013: GBP95,375; 2014: GBP154,425) and retail sales increased by 74% (2013: GBP74,215; 2014: GBP129,440), with smaller rises in visitor numbers in subsequent years [E1F]. .The “remarkable King Richard III discovery and [his] connection with Leicester and Leicestershire” [E1F] continues to drive regional economic and tourism investment and planning. The Leicester and Leicestershire Tourism Growth Plan 2019 has designed “a critical mass” of RIII experiences through 2024 [E1Eii]. The Leicester Tourism Action Plan 2020-2025 is “anchored by the King Richard III story”. This includes relocating the city’s tourist information centre to the RIIIVC “for the 130,000-plus visitors now coming each year, many drawn to see the tomb of RIII” [E1Eiii]. LCoC created a Conservation Plan for BBHC to foster “a local economy that supports . . . protection of the archaeological resources” stating that the Battle of Bosworth “has accrued even greater significance following the discovery of the remains of Richard III” (August 2013) [E1Ev]. Leicester Cathedral’s 2020-2023 Strategic Plan confirmed that RIII is a core driver for its GBP11.3 million project, funded by the National Lottery Heritage Fund (2016), to restore the Cathedral and build a Heritage Learning Centre, stating: “The Cathedral changed enormously leading up to, during and in the aftermath of March 2015 when King Richard III was reinterred …. This new situation has become increasingly embedded and we are now into the next major redevelopment phase entitled ‘Leicester Cathedral Revealed’” [E1Ei, iv].

Outreach and education impactA- and AS-level Wars of the Roses History curricula incorporated the team’s research (September 2015). The RIIIVC also incorporated the research into educational and outreach programmes, which, since opening in July 2014, have reached approximately 12,000 learners. In the 2018/2019 academic year alone, they reached 3,324 (62% KS 1&2; 23% KS 3&4; 15% FE/HE, July 2019) [E2A]. The underpinning research was a key feature of the seven-day RIII exhibit at the Royal Society’s ‘Festival of Science’ (June 2015), with 13,000 visitors, where of those responding to the visitor survey 85% strongly agreed or agreed that the exhibition had increased their interest in ‘science’. The replica skeleton and research displays travelled to Birmingham’s ‘Big Bang Fair’ (2014, c.70,000); Galway Science and Technology Festival (2017, c. 20,000); and Bulgaria’s Sofia Science Festival (2017, c.17,000) [ E2B]. The University of Leicester RIII website and educational materials have had 1,782,871 unique page views from the UK (39.5%), the USA (33.1%), Australia (7.1%), and worldwide (August 2013 – December 2020) [E2C]. By December 2020, more than 83,000 people had enrolled in the research team’s six-week MOOC, England in the Time of King Richard III. Participants’ satisfaction scores averaged a high 4.7 out of 5, with 278 reviews stating, for example: “[T]his course has reignited my passion for history and archaeology and led me to apply to do a Masters Degree in an archaeology discipline” [E2D]. In 2015, the Scout and Guiding associations produced a RIII challenge badge drawing on the RIII research and story, with approximately 2,000 challenges completed in Leicestershire alone by May 2020 [E3]. Cultural impact

Press and media coverage in March 2015 relating to the reinterment alone totalled 2,071 stories and reached 358 million people. By 2017, press and media coverage of the discovery and reinterment reached an estimated one billion people around the globe [E4]. In November 2013, the University of Leicester Archaeology Service (ULAS) won the Queen’s Anniversary Prize: “The University of Leicester is recognised for its long record of exceptional research, commercial archaeology and public engagement in history and heritage, highlighted by the work of the team that discovered the remains of King Richard III beneath a car park” [E5A]. BBC’s History Extra website visitors voted RIII as their number one historical figure of interest in the ‘Top 100’ poll 2015 – 2017, and in July 2020, they voted ‘Did RIII order the murder of the Princes in the Tower?’ as “history’s greatest mystery” with 35% of the votes, “almost three times as many as the building of Stonehenge” [E5B].

The RIII story and the research underpinning it [R1 – R5] stimulated significant cultural responses. It generated new publications and music, largely aimed at general audiences. Books include Mike Pitts’ Digging for Richard III: How Archaeology Found the King and David Horspool’s Richard III: A Ruler and his Reputation, as well as literature aimed specifically at children, such as former Children’s Laureate Michael Morpurgo’s The Fox and the Ghost King (fiction) and Rosalind Adams’s Children’s Book of Richard III [E7]. It inspired three creative responses for RIII’s 2015 reburial service at Leicester Cathedral: Ghostly Grace, a choral piece by Judith Bingham; an anthem by Judith Weir; and Richard, a eulogy by Poet Laureate Carol Ann Duffy, read by Benedict Cumberbatch, with more than 265,000 views (December 2020). Nico Muhly composed the song, ‘Old Bones’, using the words of ULAS lead Richard Buckley and RIII Society’s Philippa Langley, for countertenor Lestyn Davies [E8].

The project also inspired major dramatic productions and television documentaries [E4 – E8]. The Hollow Crown (BBC2, 2016), starring Benedict Cumberbatch, used the team’s analysis of RIII’s skeleton [R2], and opened with a shot of his spinal curvature. The production reached 0.84 million viewers in one week, and 0.94 million in 28 days [E6A]. The Leicester research also inspired Ralph Fiennes’ 2016 portrayal of Shakespeare’s Richard III at the Almeida Theatre. Fiennes stated: “They found the spine and it is very curved, so we tried to base his physicality as close as possible to the evidence that came out of the excavation in Leicester” [E6B]. The performance, which featured a reconstruction of the excavation site on stage, sold 21,850 tickets and its live broadcast reached 50,000 additional viewers worldwide [E6B].

Channel 4’s Richard III: The New Evidence (August 2014), featured University of Leicester research [R1, R3–R5], reaching 1,760,000 viewers in seven days [E6C], while PBS (USA) ran the director’s cut, Secrets of the Dead: Resurrecting Richard III (September 2014). Both starred actor Dominic Smee as RIII. Smee, who shares the king’s condition, stated that the analysis of the king’s condition profoundly impacted his confidence and his acceptance of his own body. Removing his shirt during filming “was a defining point in my life. This was the first time that I had been truly honest and open about a part of me that I had kept hidden for so many years” [E6C] . Smee stated the experience made him feel like he was reliving RIII’s last moments, and he is now “confident enough to give lectures about his experiences and the research” [E4]. Patented Ancestry.com DNA test reaches millions worldwideKing established that combining molecular genetics and surname analysis can help identify population structure and history [R7], which can be applied to 'genetic genealogy' procedures. Because of the growing popularity of individual DNA testing, this research has indirectly reached 14 million people by 2019. The US-based Ancestry.com, the world’s largest for-profit genealogical company, used King’s [R7] findings as the sole underpinning research for their exclusive DNA-testing patent (2017). The patent applies to the company’s AncestryDNA tests, which are sold to the public for GBP79 each. AncestryDNA sold 14 million DNA test kits worldwide in 2019, doubling their 2018 sales of 7 million [E9].

VariantValidator is the cumulative result of decades of research, expertise, and development of human genome sequence variation data, by Dalgleish and his team, providing solutions to major obstacles in treatment-programme development using genetic information. The beneficiaries range from individual parties (patients and healthcare professionals) to multinational organisations and research programmes. VariantValidator has defined the future direction for interpretation of genetic sequencing by simultaneously ensuring future NHS Clinical Scientists are trained to far higher standards, and by significantly reducing potentially catastrophic errors in scientific research outputs being made, disseminated or repeated. VariantValidator is the global gold-standard HGVS variant nomenclature validation software.

Freely available, the open access VariantValidator software supports data handling and validation in field-leading organisations worldwide. Between launch in 2016 and 2020, VariantValidator had been used ~55,000 times by 40,451 unique users from 118 countries, with total user numbers increasing rapidly each year [E1].

Example organisations who have embraced VariantValidator include:

• GEL: Responsible for delivering 100,000 Genomes Project [E2a]

• ClinVar: US National Institutes for Health database used globally for sequence variation interpretation [E3]

• Catalogue Of Somatic Mutations In Cancer (COSMIC): The world’s largest and most comprehensive resource for exploring the impact of somatic mutations in cancer [E2b]

• Laboratoire de Génétique Moléculaire, CHU de Montpellier, France: have developed a variant annotation and interpretation software platform (MobiDetails) for which the variant validation engine of VariantValidator is a central embedded component [E4]

• European Bioinformatics Institute: International Non-Governmental Organisation providing bioinformatics services, training, and resources to the science community globally [E5]

In each case, and countless others, VariantValidator has consistently demonstrated its superiority over competitors, “ similar systems known to us do not provide the modularity, code libraries or lack some key functionality” GEL [E2a], and is now built into workflows facilitating high-impact biomedical research [E6] through substantially improved accuracy, efficiency, and usability. VariantValidator reduces genome coordinate mapping time from ~60 minutes per case to ~3 minutes [E2c]. In many leading organisations VariantValidator has replaced existing tools or is the preferred sequence variation curation tool including:

• Global Alliance for Genomics and Health (GA4GH)

• Centre for Medical Genetics, Brussels, Belgium [E2d]

• Leiden Open Variation Database (LOVD) [E2e]

• London South Genomics Laboratory Hub, North West Genomic Laboratory Hub, and other NHS laboratories

• The Manchester Academy for Healthcare Scientist Education (MAHSE) training programmes in medical genomics and genomics bioinformatics

• Global PGCert, and MSc courses delivered by the University of Manchester [E8]

• Center for Genomics Interpretation, Utah, USA [E2f]

The widespread response to the software has been immensely positive with many echoing Professor Robinson of the Jackson Laboratory, “We have also used what is probably VariantValidator’s main competitor, Mutalyzer, but have chosen to use VariantValidator for our work because of the substantially greater amount of information presented to the user, the ease of use and the flexibility of the API and paramaterized URLs and the much better graphical user interface, all of which improves the efficiency of our work”’ [E2c]. At the Centre for Medical Genetics, Brussels, “ VariantValidator has been indispensable” and they “ are now validating thousands of variants every week with VariantValidator” [E2d].

New HGVS Variant Nomenclature recommendations have recently been developed by PF and RD to accommodate the use of Ensembl transcript reference sequences for variant reporting [E9]. This enables NHS laboratories, for the first time, to utilise genome sequencing variant data, generated by GEL. This novel development is being incorporated into a new reference sequence transcript archive that is, in direct collaboration with GEL and LOVD, being integrated into VariantValidator. The purpose of this development is to produce a tool enabling GEL processing to provide NHS laboratories with correctly formatted variant descriptions in the context of Ensembl reference sequences and enabling LOVD to accommodate Ensembl transcript data alongside existing RefSeq data. “At present, we are unable to do this for the RefSeq datasets which is an unmet requirement for reporting in the clinical setting. This is a common requirement among clinicians to facilitate interpretation of genomic variation.” GEL [E2a]. Immediate beneficiaries of this development include the GEL 100,000 Genomes Project [E2a], COSMIC [E3] and a wider set of NHS Genomics Laboratory Hubs who will soon be able to validate and safely share their variant data outputs.

Collaboration between the University of Leicester and GEL has also resulted in the development of VariantFormatter software libraries enabling GEL to correctly present data using HGVS nomenclature. This system rapidly validates HGVS descriptions in the context of genomic reference sequences projecting them rapidly onto all relevant transcripts. In addition, the VariantValidator tool enables improved accuracy in variant descriptions for use in clinical reports and databases, lift-overs between Ensembl and pre-existing reference sequences, and interconversions between transcript and genomic-coordinate-based descriptions [E2a]. In addition, a novel version of the VariantFormatter tool has been created to produce accurately formatted data for the LOVD databases, and alongside VariantValidator, is being embedded directly into the LOVD analysis pipelines. This will have a huge impact on genomic medicine in Europe where LOVD is rapidly becoming a staple platform, replacing commercial solutions in diagnostic settings [E10].

The proven superiority of VariantValidator has changed industry direction. Since 2017, Alamut Visual, the flagship software product from SOPHiA Genetics, has incorporated links to VariantValidator to allow users of their software to ensure accurate validation of sequence variant descriptions and have recently installed the VariantValidator code on their servers for internal use [E8]. VariantValidator has also been adopted as the variant description validation program and interconversion tool of choice for the Global Alliance for Genomics and Health (GA4GH) ‘PhenoPackets’ and ‘Solving the Unsolved Rare Diseases’ (SOLVE-RD) projects [E6], is a key component of the Jackson Laboratory’s new HPO-based phenotype annotation software; HPOCaseAnnotator [E11], and is used as standard practice by the Center for Genomic Interpretation in Utah to improve their clinical reporting [E2f].

VariantValidator is having a profound impact on education in genomic bioinformatics, primarily in the UK, but also to a global audience. VariantValidator’s demonstrable success convinced the Manchester Academy for Healthcare Scientist Training (MAHSE) to incorporate the software into NHS Scientist Training Programmes (STP) that contain genomics-focused modules, in 2019. VariantValidator is now taught to NHS STP MSc Students in Clinical Genetics, Clinical Bioinformatics, Health Informatics, Cancer Genomics, Medical Physics, and Genomic Counselling. Over 150 students are trained annually using the software leading to a wider deployment in NHS Clinical Genomics Centres and Genetics Diagnostics Laboratories. As well as learning to use VariantValidator, the course also enables students to produce additional resources for the system thereby enabling continuous resource growth and improvement alongside the internationally praised training scheme [E8]. This training not only provides VariantValidator with a direct pathway into clinical practice, and establishes a community of practice who not only use the software, but also steer future iterations of the software to meet the evolving needs of the genomic medicine community.

VariantValidator is embedded into healthcare professional CPD courses ‘Fundamentals in Human Genetics and Genomics’ funded by Health Education England and taught at the University of Manchester [E12]. VariantValidator is also embedded into the ‘first of its kind’ distance-learning Postgraduate Certificate in Clinical Bioinformatics [E13]. The current run of the course includes 37 students from around the world from a broad range of professions, including clinicians in non-UK diagnostics laboratories and the Qatari genome project. The success of the 2019 PGCert was disseminated to audiences in international educational symposia as evidenced in a University of Manchester blog article [E8]. VariantValidator is also embedded into the MSc in Genomic Medicine at the University of Manchester.

In 2020, following a successful pilot published by Human Mutation (Wiley) and Genetics in Medicine (Nature), several leading biomedical journals formally adopted VariantValidator as one of two approved validation tools to ensure correctness of variant descriptions in published manuscripts and to minimise errors long-term [E14]. This critical change in professional practice has already yielded benefits to patients, including successfully identifying and correcting multiple invalid and incorrect sequence descriptions previously used to define treatment for cystic fibrosis patients: “ These efforts will undoubtedly lead to tangible improvements in patient care” [E2g].