the genomics england 100,000 genomes project...2005/10/17 · nevin-ridley1, olivia niblock1,...

Confidential: For Review Only

The Genomics England 100,000 Genomes Project

Journal: BMJ

Manuscript ID BMJ.2017.041782

Article Type: Analysis

BMJ Journal: BMJ

Date Submitted by the Author: 05-Oct-2017

Complete List of Authors: Turnbull, Clare; Queen Mary University of London, William Harvey Research Institute; Institute of Cancer Research, Boardman-Pretty, Freya; Genomics England Scott, Richard; Genomics England; Great Ormond Street Hospital NHS Trust Thomas, Ellen; Genomics England; Guys and St Thomas NHS Foundation Trust Halai, Dina; Genomics England Jones, Louise; Genomics England; Barts Cancer Institute, Queen Mary University of London

Murugaesu, Nirupa; Genomics England; St George's University Hospitals NHS Foundation Trust O’Neill, Amanda; Genomics England; University of Cambridge Henderson, Shirley; Genomics England; Oxford Universities NHS FoundationTrust Devereau, Andrew; Genomics England Hamblin, Angela; Genomics England; Oxford Universities NHS FoundationTrust Patch, Christine; Genomics England; Guys and St Thomas NHS Foundation Trust Baple, Emma; Genomics England; University of Exeter Mason, Joanne; Genomics England

Smith, Katherine; Genomics England Rueda-Martin, Antonio; Genomics England Ryten, Mina; Genomics England; University College London Lawson, Kay; Genomics England Smedley, Damian; Genomics England; Queen Mary University of London, William Harvey Research Institute Antoniou, Pavlos; Genomics England Athanasopoulou, Maria; Genomics England Boustred, Chris; Genomics England Brittain, Helen; Genomics England Campbell, Chris; Genomics England

Coll-Moragon, Jacobo; Genomics England Craig, Clare; Genomics England Cranage, Alison; Genomics England Daugherty, Louise; Genomics England

https://mc.manuscriptcentral.com/bmj

BMJ

Confidential: For Review OnlyDinh, Lisa; Genomics England Foulger, Rebecca; Genomics England Furio-Tari, Pedro; Genomics England Garikano, Kristina; Genomics England Goddard, Peter; Genomics England Gordon, Duncan; Genomics England Hackett, Joanne; Genomics England Hatwal, Atul; Genomics England Hubble, Samuel; Genomics England

Jackson, Rob; Genomics England Jang, Mikyung; Genomics England Kasperaviciute, Dalia; Genomics England Leigh, Sarah; Genomics England Logie, Cameron; Genomics England Lopez, Javier; Genomics England McDonagh, Ellen; Genomics England McGrath, Kenan; Genomics England Medina, Ignacio; Genomics England Mueller, Michael; Genomics England Nevin-Ridley, Katrina; Genomics England Niblock, Olivia; Genomics England

Ocampo, Ernesto; Genomics England Parker, Matthew; Genomics England Prapa, Matina; Genomics England Riley, Laura; Genomics England Rimmer , Andy; Genomics England Rogers, Tim; Genomics England Serra, Enric; Genomics England Shallcross, Laura; Genomics England; University College London, Department of Infection and Population Health Sosinsky, Alona; Genomics England Stals, Karen; Genomics England

Sultana, Razvan; Genomics England Thompson, Simon; Genomics England Tregidgo, Carolyn; Genomics England Tucci, Arianna; Genomics England Tuff-Lacey, Alice; Genomics England Witkowska, Katarzyna; Genomics England; Queen Mary University of London, William Harvey Research Institute Mahon-Pearson, Jeanna; Genomics England Bale, Mark; Genomics England Fowler, Tom; Genomics England Hubbard, Tim; Genomics England; Kings College London, Medical and Molecular Genetics

Rendon, Augusto; Genomics England; University of Cambridge Caulfield, Mark; Genomics England; Queen Mary University of London, William Harvey Research Institute

Keywords: Whole Genome Sequencing, Next Generation Sequencing, Rare Disease, Cancer Genomics, Secondary Findings

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Confidential: For Review OnlyThe Genomics England 100,000 Genomes Project

Clare Turnbull1-4

, Freya Boardman Pretty1¸Richard Scott

1,5, Ellen Thomas

1,2, Dina Halai

1, Louise Jones

1,6, Nirupa

Murugaesu1,7

, Amanda O’Neill1,10

, Shirley Henderson1,11

, Andrew Devereaux1, Angela Hamblin

1,11, Christine

Patch1,2,12

, Emma Baple1,9

, Joanne Mason1, Katherine Smith

1, Antonio Rueda Martin

1, Mina Ryten

1,2,8, Kay

Lawson1, Damian Smedley

1,3, Pavlos Antoniou

1, Maria Athanasopoulou

1, Chris Boustred

1, Helen Brittain

1, Chris

Campbell1, Jacobo Coll Moragon

1, Clare Craig

1, Alison Cranage

1, Louise Daugherty

1, Lisa Dinh

1, Rebecca

Foulger1, Pedro Furio Tari

1, Kristina Garikano

1, Peter Goddard

1, Duncan Gordon

1, Joanna Hackett

1, Atul

Hatwal1, Samuel Hubble

1, Rob Jackson

1, Mikyung Jang

1, Dalia Kasperaviciute

1, Sarah Leigh

1, Cameron

Logie1, Javier Lopez

1, Ellen M. McDonagh

1, Kenan McGrath

1, Ignacio Medina

1, Michael Mueller

1, Katrina

Nevin-Ridley1, Olivia Niblock

1, Ernesto Ocampo

1, Matthew Parker

1, Matina Prapa

1, Laura Riley

1, Andy

Rimmer1, Tim Roger

1, Enric Serra

1, Laura Shallcross

1, Alona Sosinsky

1, Karen Stals

1, Razvan Sultana

1, Simon

Thompson1, Carolyn Tregidgo

1, Arianna Tucci

1, Alice Tuff-Lacey

1, Katarzyna Witkowska

1, Jeanna Mahon-

Pearson1, Mark Bale

1, Tom Fowler

1, Tim Hubbard

1,14, Augusto Rendon

1,10, Mark Caulfield

1,3

1 Genomics England, Charterhouse Square, London, EC1M 6BQ

2 Guys and St Thomas NHS Foundation Trust, London, SE1 9RT.

3 William Harvey Research Institute, Queen Mary University of London, EC1M 6BQ

4 Institute of Cancer Research, London, SM2 5NG.

5 Great Ormond Street Hospital NHS Trust, London, WC1N 3JH

6 Barts Cancer Institute, Queen Mary University of London, EC1M 6BQ

7 St George's University Hospitals NHS Foundation Trust, London SW17 0QT.

8 University College London, Gower Street, London, WC1E 6BT

9 University of Exeter, Exeter, EX4 4SB.

10 University of Cambridge, Cambridge, CB2 1TN.

11 Oxford Universities NHS Foundation Trust, Oxford, OX3 9DU.

12 Florence Nightingale Faculty of Nursing & Midwifery, King’s College, London SE1 8WA.

13 University of Oxford, Oxford, OX1 2JD.

14 Medical and Molecular Genetics, Kings College London, WC2R 2LS.

On behalf of the 100,000 Genomes Project

Word count: 2471

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Confidential: For Review OnlyAbstract

The 100,000 Genomes Project is a government-led initiative to sequence 100,000 whole genomes from

patients recruited from the National Health Service (NHS) in England. The project was established to develop

the infrastructure and expertise necessary to transform delivery of genomic medicine into the NHS, to deliver

benefit to patients, to enable high quality research and to boost the UK genomics industry.

Background

The UK has long been at the forefront of human genomics, from descriptions in the 1950s by Franklin, Watson

and Crick of the 3D structure of DNA through to early development by Cambridge scientists of the technology

for solid phase colony sequencing that underpins current next-generation sequencing (box a)1. Sequencing of

the first human genome, delivered collaboratively by 20 research sequencing centres through The Human

Genome Project, took 13 years and cost an estimated $3 billion2 3

. Recent advances in next-generation

sequencing (NGS) have enabled ‘massively parallel’ simultaneous sequencing of millions of fragments of DNA

such that a whole genome can be now be sequenced in less than a day at a cost of less than $1,000 (and

falling, fig a)4.

This technological renaissance offers dramatic opportunities for more widespread applications of genomics in

healthcare. Our increasing understanding of how molecular (genomic) changes correlate with clinical

diagnosis, prognosis, risk and/or therapeutic response is making more possible the delivery of so-called

‘precision’, ‘personalised’, or ‘stratified’ medicine (box b)5 6

.

The UK has a mature network of Regional Genetics Laboratories and Clinical Genetics departments,

established over the last 30 years. However, as highlighted in genomics strategy reports from the House of

Commons Science and Technology Committee, the Human Genome Strategy Group and the Chief Medical

Officer (CMO), considerable transformation of NHS genomics services is required to truly capitalise upon the

opportunities afforded by the revolution in genomic technologies for more accurate and cost-effective

healthcare7-9

. Needs repeatedly highlighted are (i) establishing high-throughput, cost-effective large-scale

sequencing capacity; (ii) developing consistent, quality-assured pipelines for data processing, analysis,

interpretation and storage of data (iii) capturing of clinical data of consistent quality and format; (iv) improving

equity of patient access to genomic services and; (v) centralised storage of linked clinical and molecular data10-

12. Furthermore, review of policies around consent, data federation and data security are urgently required.

This is key to ensuring that the nationally streamlined genomic data resource can be used across the ‘virtual

laboratory of the NHS’ to optimise real time clinical genomic interpretation for patients, whilst also enabling

access by researchers from academia and industry to advance genomic understanding in the longer term8. As

well as increasing genetic literacy across the entire clinical workforce, it was highlighted that urgent workforce

expansion was required in specific areas such as clinical bioinformatics. Furthermore, the role of clinical

scientists is expanding as their remit expands to include advanced computing skills, in addition to the

established laboratory proficiencies8.

Initiation of the 100,000 Genomes Project

In December 2012, then Prime Minister the Right Honourable David Cameron announced that as part of the

Olympic Legacy funding would be committed to sequence 100,000 genomes from patients in the English NHS.

As well as catalysing transformation of NHS genomics, key objectives were to deliver benefit for patients,

stimulate research and industry and to evolve public trust through transparency (box c). Genomics England

was created to deliver the project, funded by the National Institute for Health Research (NIHR) with the

Department of Health as the sole shareholder of the company. Substantial contributions to the programme

also came from NHS England, Public Health England and Health Education England, with additional support

from the Wellcome Trust, Medical Research Council and Cancer Research UK (box d). Rare disease and cancer

were agreed as the initial priority areas 13

.

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Setting up the 100,000 Genomes Project through partnership

Genomics Medicine Centres as hubs of expertise in the NHS

In 2014, NHS trusts were invited to tender to become NHS Genomic Medicine Centres (GMCs): regional hubs

of excellence in genomic medicine through which existing expertise in molecular genetics, molecular

pathology, clinical genetics services and molecular oncology would be grown. Following two rounds of

evaluation, 13 NHS Genomic Medicine Centres have now been established, each comprising a lead NHS trust

and up to 12 local delivery partner hospitals. In total the NHS GMC network comprises over 85 hospital trusts

and provides full geographic coverage of England (Fig b). In addition, Northern Ireland and Wales are

developing capabilities as Genomic Medicine Centres and Scotland has a parallel sequencing project in

collaboration with Genomics England.

Harnessing the expertise of the research community through the Genomics England Clinical Interpretation

Partnership (GeCIP)

To leverage the wealth of genomic expertise across the UK clinical academic community, the Genomics

England Clinical Interpretation Partnership (GeCIP) was established. Following a call for expressions of interest,

>2600 researchers, comprising >2300 UK-based academics and NHS clinicians and >280 international

collaborators, spanning 343 institutions worldwide, responded and self-organised into 41 domains. These

domains span rare disease, tumour types and cross-cutting themes such as ethics, health economics and

advanced analytical approaches (fig c)14 15

. GeCIP researchers have been providing expert support in clinical

interpretation of the genomes and in return are receiving priority access to deidentified genome data via

research data embassies: a quid pro quo partnership (fig d).

Partnering with and stimulating the Genomics Industry in the UK

Following a competitive tender between multiple sequencing providers, in 2014 Illumina was selected to

partner with the programme to provide sequencing services. 29 suppliers of genomic analysis, annotation and

interpretation services were also evaluated, a subset of which have become 'clinical interpretation partners',

supplying decision support software and variant prioritisation algorithms for use by the NHS GMCs. In parallel,

Genomics England, in partnership with Innovate UK, awarded £10 million of forward investment via the Small

Business Research Initiative (SBRI) to 9 companies with the most promising proposals to further develop

genome annotation tools and services.

Sequencing infrastructure and data architecture to deliver a national genomics service

Supported by the Wellcome Trust, housed in the Bridget Ogilvie building, the 100,000 Genomes Project

Sequencing Centre was built at the Wellcome Genome Campus in Hinxton, Cambridgeshire, with capacity to

deliver >12,000 whole genome sequences (WGS) per week. Rigorous data security being paramount, the

100,000 Genomes Project data are stored in the highly secure government data centre in Corsham, utilising

strict systems for data permissions and access. Robustly-tested, versioned pipelines for data processing and

analysis have been established to ensure reliable and reproducible genomic analyses for return to the

clinicians and patients, with ISO 15189 (medical laboratory accreditation) of the sample and data pipelines

underway. While identifiable clinical and molecular data are returned to clinicians from NHS GMCs, de-

identified instances of the data are available in a secure Research Environment for approved researchers from

academia and industry (fig d).

Education and Training

In partnership with Health Education England (HEE), £20 million has been directed towards development of

educational resources and training opportunities delivered in parallel with the 100,000 Genomes Project.

Masters courses in Genomic Medicine have been established at 10 universities, with 446 having enrolled in the

full Masters to date with hundreds more enrolling in the PGCert, PGDip or individual modules. Funding has

been committed through to 202316

. A new Genomic Counsellor Masters and training programme was

established in 2016, through which 25 additional genetic/genomic counsellors are already being trained. HEE

research fellowships in genomics were awarded in 2017, with >£1.3 million awarded to 9 applicants. Online

training resources such as MOOCs (Massive Open Online Courses) have been developed for the broader

clinical workforce in areas such as consent, bioinformatics and molecular pathology 17 18

.

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Patient and Public Involvement (PPI)

Open town-hall style events held at inception of the project have enabled stakeholder groups, patients and the

public to aid in sculpting the programme19-21

. A national participant panel convening bimonthly also provides

representation to the Data Access Committee, Ethics Advisory Committee and GeCIP Board22

. As part of the

Genomics England Engagement Strategy, in 2016 a programme of activities – the Genomics Conversation –

was rolled out through a broad range of activities, including debates, discussions, presentations, and outreach

through social and traditional media23

.

Clinical pathways for patients, samples and data

The Rare Disease Programme

There are >200 phenotypic categories by which patients are eligible for recruitment to the Rare Disease

programme, which span over half of the >7000 OMIM disorders described (fig e)24

. These categories were

nominated by the clinical community on account of being underserved by current clinical diagnostic testing,

and/or because the genetic basis of the disorder required further elucidation through research25-29

. Eligibility

for each category is defined by a set of clinical and/or family characteristics, pre-testing of well-established

genes and an optimal family structure for recruitment (typically (i) trio including unaffected parents, (ii) multi-

generational affected individuals or (iii) isolated proband in later onset disorders). The analysed genomic

variants, ‘tiered’ for disease-causing potential based on allele frequency, familial inheritance, variant impact

and gene-phenotype association using ‘virtual panels’ of genes, are returned via decision-support tools. First

review is undertaken by clinical scientists at NHS GMC laboratories, followed by clinical interpretation at

local/regional genomic Multidisciplinary meetings (MDMs)30

.

The Cancer Programme

For the Cancer Programme, patients with a range of solid tumours and haematological malignancies are

eligible for recruitment at primary diagnosis. Whole genome sequencing is undertaken on paired constitutional

DNA derived from blood/saliva and tumour DNA derived from biopsy or surgical resection24

. Additional insights

around molecular determinant of response, progression and metastasis will be afforded from alignment of

recruitment to clinical studies and trials and collection of longitudinal and multi-region tumour samples.

Lifelong linkage will enable longitudinal clinical data capture on treatment, response and outcomes, including

ENCORE, COSD, SACT and RTDS datasets from the Cancer Registration service, as well as HES and ONS data31-35

(fig h). Serial blood samples are also being captured for the analysis of circulating tumour DNA (ctDNA)36

.

Analysed genomes are returned via interactive web-based formats for review at NHS GMC ‘tumour sequencing

boards’. Variants are annotated for potential diagnostic, predictive or prognostic ‘actionability’. The results

returned are annotated for (i) well-characterised mutations marking eligibility for NICE-approved targeted

drugs such as BRAF-inhibitors in melanoma and EGFR inhibitors in lung cancer (ii) other gene mutations,

fusions and copy number changes for clinical trials of experimental molecules are available (iii) analyses of

signatures and mutational burden which are emerging as clinical biomarkers of drug response.

Progress and performance

Piloting of patient recruitment, sample collection, sequencing and data analysis was initiated in 2013 for both

the rare disease (4957 participants) and cancer programmes (1650 participants). The first patients from the

NHS GMCs were recruited in February 2015, with an average weekly recruitment of ~650 participants and

cumulative recruitment of 46,698 participants by October 2017 (fig e).

Sequencing at the 100,000 Genomes Project Sequencing centre in Hinxton commenced in March 2016; by

October 2017, a cumulative total of 36,083 WGS had been generated. Constitutional samples are being

sequenced to produce a minimum of 85 GB of data per sample (>300 million high quality, non-duplicated

sequencing reads per samples ensuring at least 15 sequencing read coverage for over 90% of the 3.2 billion

bases in each patient genome, figs f and g).

In March 2015, the first pilot results were returned to a family from Newcastle who had unexplained

autosomal dominant pattern renal failure: identification of a pathogenic INF2 mutation has enabled more

targeted blood pressure control in family members with early disease, whilst taking family members without

the mutation out of lifelong follow-up and anxiety. By October 2017, results had been returned to 4426 NHS

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participants with a preliminary diagnostic rate of 22%. This diagnostic yield (whole genome sequencing

following standard of care testing) is comparable to other sequencing projects but will likely further increase

following additional local clinical review of untiered variants and subsequent reporting of mutational classes

beyond small variants37 38

.

Challenges, hurdles and future directions

Hurdles initially limiting to recruitment have stimulated collaborative work to develop solutions and novel

approaches (box e). Fresh tumour tissue, while providing molecular results of dramatically higher quality (in

particular for whole genome sequencing), has to date almost exclusively been the preserve of research

studies. Acquisition, processing, storage and transport of fresh tumour tissue across the diverse cancer

pathways (involving theatres, out-patients, endoscopy, interventional radiology) has driven evolution of new

practices including vacuum-packing, tissue refrigeration, novel coolants and transport media. Furthermore,

significant simplification of consent within these complex pathways has been achieved through establishing a

joint statement that collection of fresh tissue as standard of care in modern cancer diagnostics, signed by the

Royal College of Pathology, NHS England, Genomics England, the Human Tissue Authority and Health Research

Authority39

.

This programme has required timely, accurate, complete submission of data on clinical features, sample

handling and sample tracking using unified data ontologies and models40 41

. Significant heterogeneity in the

quality of local data capture and storage has emerged, along with the degree of pressure upon local

informatics resource and expertise. Collaborative approaches across trusts working with NHS Digital, NHSE,

and the Farr Institute has driven solutions such as the GENIE system developed by the West Midlands NHS

GMC, which automates capture, collation and delivery of clinical and sample data from diverse systems42

. In

collaboration with the Association for Clinical Genetic Science, Genomics England and NHS England have co-led

development of cross-GMC multi-disciplinary expert working groups, which are evolving evidence-based, pan-

NHS standards for variant interpretation, technical validation, quality assurance and clinical reporting,

addressing substantial historical inconsistencies in these areas.

Genomics England and NHS England are co-leading transition working groups to evolve evidence-based

frameworks to direct NHS commissioning of genomic testing (including whole genome sequencing) post-2018.

Based on systematic clinical and health-economic evaluation, there will be directories of genetic tests linked to

a national ‘order-comms’ system, ensuring equity of patient access and consistency of testing provision.

Genomic testing will be delivered through (i) a centralised infrastructure for whole genome sequencing

established by Genomics England linked to (ii) a consolidated network of NHS England Genomic Laboratory

Regional Genetics Hubs, re-procurement of which is underway. This will be managed by a centralised NHS

England Genomics Coordinating Centre. Through evolution of these infrastructures, along with an expanded

specialist workforce and an upskilled general workforce, the Genomics England 100,000 Genomes Project will

have been a key catalyst to the delivery of a truly modernised UK genomics service43 44

.

Box a: Landmarks in UK genomic research

1903: pioneering studies of early inborn errors of metabolism by Archibald Garrod at University

College London, later Oxford

1951: X-ray diffraction studies reveal 3D structure of DNA, Rosalind Franklin, King’s College

London

1953: elucidation of the structure of the double helix by James Watson and Francis Crick,

Cambridge University

1954: description of the structure and synthesis of nucleotides and nucleosides by Alexander

Todd, Cambridge University

1977: ‘chain-termination’ sequencing by synthesis is developed by Frederick Sanger and Alan

Coulson, Cambridge University

1990: scientists from Wellcome Trust Sanger Centre lead UK Human Genome Project effort

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Confidential: For Review Only1995: development of solid phase colony next-generation sequencing technology at Cambridge

University

Box b: Application of genomics for healthcare improvement

• Diagnosis of rare and/or inherited diseases: whole genome or exome sequencing for a child

with rare disease within the first weeks or months of life enables provision of a precise

molecular genetic diagnosis. This offers opportunity for early administration of the

interventions and therapies most likely to be effective, improved estimation of prognosis, pre-

emption of complications and, if timely, facilitates reproductive decision-making for

subsequent pregnancies. Historically diagnosis in rare disease took, on average, seven years.

A ‘diagnostic odyssey’ was typical, involving investigation of multiple organ systems by

different medical specialists and, even once referred to a geneticist, prolonged, serial testing

of individual genes.

• Non-invasive pre-natal testing: analysis of fetal DNA circulating in the maternal bloodstream

is transforming population screening for conditions such as Down’s syndrome. Genetic testing

in pregnancy for known conditions can also be undertaken non-invasively, avoiding the risk of

amniocentesis or CVS (chorionic villus sampling).

• Newborn screening: newborn screening has to date relied on assay of relevant metabolites to

detect severe inherited diseases. Sequencing of the relevant genes may enable earlier and

more accurate detection at a population level of childhood diseases.

• Testing for carrier status for genetic diseases: identification in the population of individuals

or couples at high risk of having a child with a severe genetic disease enables reproductive

options such as preimplantation genetic diagnosis to be offered.

• Risk stratified cancer screening: identification in the population of well individuals at high

inherited genetic risk of developing cancer allows targeting of early interventions such as

intensive screening, preventative drugs and risk-reducing surgery.

• Drug sensitivity and metabolism: analysis for ‘pharmacogenomic’ variants can enable

avoidance of life-threatening toxicity from chemotherapeutic drugs and precision dosing in

widely-used drugs such as warfarin45.

• Early detection of cancer: analysis of peripheral blood for circulating tumour DNA (ctDNA) is

offering new opportunities for non-invasive surveillance for cancer recurrence. Large scale

research programmes are underway to evaluate the role of ctDNA in primary population

screening for cancer36.

• Precision oncology and targeted cancer treatments: growth and replication of cancer cells

can be driven by mutated oncogenes (‘oncogene addiction’)46

. Small molecules or monoclonal

antibodies switching off the over-active protein can yield dramatic response (targeted drugs).

However, the response is often time-limited as the tumour typically evolves a ‘resistance

mutation’.

• Rapid detection of pathogens and characterisation of resistance: sequencing of viral and

bacterial genomes enables delineation of species taxonomy, virulence, transmission and anti-

microbial resistance47.

Box c: Key objectives of the 100,000 Genomes Project

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Confidential: For Review Only1. To bring benefit to NHS patients through transformation of NHS genomics services

2. To create an ethical and transparent programme based on consent

3. To enable new scientific discovery and medical insights

4. To kick start the development of a UK genomics industry

Box d: Major funding support for the 100,000 Genomes Project

Government/NIHR: £300 million

MRC: £24 million - for computing infrastructure, plus £12.1 million supporting the devolved

nations

Wellcome Trust: £27 million-for the 100,000 Genomes Project Sequencing Centre

NHSE: £20 million

Box e: 100,000 Genomes Project: examples of early steps in catalysing complex change

1) Complexity around consent. As per introduction to the NHS of any paradigm-shifting

technology, this programme is a hybrid of clinical care and research, causing tensions around

consent. Research consent addresses sharing data with researchers from industry as well as

life-long data storage and linkage, both areas of potential public concern. Impact on insurance

and longer-term diminution in mental capacity need to be covered when enrolling participants.

Children and teenagers are alerted that they will require re-consenting on turning 18. We are

also piloting return of secondary findings (genetic variants identified which are not related to

the condition under investigation but which are informative to the risk of unrelated but serious

medical conditions)48 49. The time required offer informed consent for all these complex

aspects, along with collecting all clinical/phenotype data, has rendered infeasible recruitment

within a routine outpatient setting.

2) Tensions between data protection and federation. Only through comparing across patients’

phenotypes and their genomes in cases of rare disease can we correctly narrow down from the

millions of variants in the genome to the single causative pathogenic rare variant. Therefore,

sharing data across the ‘virtual laboratory of the NHS’ is essential; sharing internationally

through clinical networks such as DeCIPHER50 51 and Matchmaker52 53 further increases

opportunity for ‘matching’ genotypes with other patients with similar vanishingly rare disease.

3) Collection of phenotype data. Genomic interpretation and/or subsequent research for

individuals with rare disease requires detailed capture of phenotypic elements in a universal

hierarchical ontology, for which the HPO (Human Phenotype Ontology) has largely been

adopted internationally40 54. Preliminary systems for capturing HPO terms have been

implemented for this project (fig h), but are otherwise currently entirely lacking within routine

electronic medical records and other NHS data systems.

4) ‘Mainstreaming’ and democratisation of the genome. Germline genetic testing has to date

largely been the preserve of Clinical Geneticists. This programme has catalysed the expansion

of genomics into other medical specialties, but highlighted that judicious oversight across this

larger and more diverse range of clinicians will be required to ensure the appropriate genomic

test is applied to a patient/family, along with detailed and accurate capture of phenotyping

and proportionate interpretation of complex genomic results.

5) Unpicking genotype-phenotype inferences. Large-scale genomic sequencing applied to

broader patient groups is disrupting established genotype-phenotype paradigms, derived from

targeted gene sequencing in original families ascertained with classical phenotypes. A

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Confidential: For Review Onlypathogenic variant may be detected on WGS, but careful clinical review is required to establish

the degree to which the variant explains the phenotype in the patient and any additional

implications for health. The programme has triggered development of specialty genomic-

MDMs in areas such as ophthalmology, cardiology and neurology at which laboratory clinical

scientists, clinical geneticists, disease specialists and expert researchers convene.

6) Molecular pathology. Routine acquisition of fresh frozen tissue (surgical and biopsy) along

with pathology evaluation for sample tumour purity has required re-engineering of hundreds

of cancer ‘pathways’, which vary tumour type-to-tumour type and trust-to-trust.

7) Tumour Sequencing Boards (TSBs). GMCs are establishing Tumour Sequencing Boards for

review of cancer WGS with representation from molecular pathology, molecular oncology and

clinical trialists. Sophisticated hub-and-spoke networks have evolved to facilitate information

flow from molecular experts to tumour-types-specific MDT meetings, across complex

geography in a time-scales relevant to cancer management.

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Figure a: The decrease in cost of sequencing against time

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Figure b: 13 Genomic Medicine Centres have been established, each with a lead

organisation, encompassing >85 NHS trusts. Roles of GMCs include:

• identification of patients eligible for whole genome sequencing, with equity

of access through established eligibility

• criteria

• consenting of patients and collection of clinical data.

• collection of biological samples (blood/tumour tissue/saliva)

• sample processing, DNA extraction and quality control checks

• sample dispatch to the central sample biorepository

• interpretation and technical validation of clinically important variants

• return of genomic findings to patients and implementation of management

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Rare Disease Cancer Cross-cutting

• Cardiovascular

• Dermatology

• Endocrine and

Metabolism

• Gastroenterology and

Hepatology

• Haematology

• Hearing and Sight

• Immunology

• Inherited Cancer

Predisposition

• Musculoskeletal

• Neurology

• Paediatric sepsis

• Paediatrics

• Renal

• Brain Tumours

• Breast Cancer

• Cancer of Unknown Primary

• Childhood Solid Cancers

• Colorectal Cancer

• Haematological Malignancy

• Head and Neck Cancer

• Lung Cancer

• Melanoma

• Neuroendocrine Tumours

• Ovarian and Endometrial Cancers

• Pan-Cancer

• Prostate Cancer

• Renal and Bladder Cancers

• Sarcoma

• Testicular Germ Cell Tumours

• Education and Training

• Electronic Health Records

• Enabling Rare Disease

Translational Genomics

via Advanced Analytics

and International

Interoperability

• Ethics and Social Science

• Functional Cross-Cutting

• Functional Effects

• Health Economics

• Machine Learning,

Quantitative Methods

and Functional Genomics

• Population Genomics

• Stratified Medicine and

Therapeutic Innovation

Figure c: The Genomics England Clinical Interpretation Partnership: Researchers have grouped themselves

into 41 “domains” and will work within these groups to analyse the genomic and clinical data to make

additional diagnoses in patients and advance overall genomic understanding

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Figure d: Data flow in the 100,000 Genomes Project

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Figure e: Current total families recruited to the Rare Disease arm of the Project, by disease category

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Figure f: Number of WGS returned to Genomics England from Illumina from the beginning of the Project.

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Figure g: per base sequencing coverage for constitutional (blood) from a sample of sequences

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Figure h: Number of overall and positive HPO terms per participant, for all participants in the rare disease

arm of the programme with at least one HPO term entered.

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Figure i:

(a) Number of HES records by date for all current project participants.

(b) Total HES records for all project participants, by source (log scale).

(c) Total records held for project participants, by external data set (log scale).

(HES: Hospital Episode Statistics; DID: Diagnostic Imaging Dataset; PROMs: Patient Reported Outcome

Measures; ONS: Office for National Statistics)

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Confidential: For Review OnlyContribution

The manuscript was drafted by CT with support from MC, FBP, RS, ET, DH, LJ, AR, KS, TH and JM. All

authors contributed to the project and reviewed the final manuscript.

Conflicts of interest

We have read and understood the BMJ Group policy on declaration of interests and declare the

following interests: none.

License

Clare Turnbull, The Corresponding Author has the right to grant on behalf of all authors and does

grant on behalf of all authors, an exclusive licence (or non exclusive for government employees) on a

worldwide basis to the BMJ Publishing Group Ltd ("BMJ"), and its Licensees to permit this article (if

accepted) to be published in The BMJ's editions and any other BMJ products and to exploit all

subsidiary rights, as set out at: http://www.bmj.com/about-bmj/resources-authors/forms-policies-

and-checklists/copyright-open-access-and-permission-reuse.

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Figure e: Current total families recruited to the Rare Disease arm of the Project, by disease category

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Figure f: Number of WGS returned to Genomics England from Illumina from the beginning of the Project

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Figure h: Number of overall and positive HPO terms per participant, for all participants in the rare disease arm of the programme with at least one HPO term entered

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Figure i: (a) Number of HES records by date for all current project participants. (b) Total HES records for all project participants, by source (log scale).

(c) Total records held for project participants, by external data set (log scale). (HES: Hospital Episode Statistics; DID: Diagnostic Imaging Dataset; PROMs: Patient Reported Outcome

Measures; ONS: Office for National Statistics)

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the genomics england 100,000 genomes project...2005/10/17 · nevin-ridley1, olivia niblock1,...

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