The NHS in the genomics era

Mark BaleDepartment of Health

100,000 Genomes Project

“It is crucial that we continue to push the boundaries and this new plan will mean we are the first country in the world to use DNA codes in the mainstream of the health service”

The Rt Hon David Cameron MPThe Prime Minister10 December 2012

Genetics White PaperGenetics White Paper

The rate of change• Sequencing costs are dropping rapidly and new sequence data consequently rising• Research is advancing at a rapid rate, but understanding of the role of genes in health and disease is still in its infancy•Applications in some areas (such as cancer) are already here and the NHS must start to adapt for the advent of genomic medicine •Benefits in reduced diagnostic time, better precision and possible savings from other (futile) treatment options•Capacity challenges and bottlenecks in data storage and interpretation•Concerns that investment unlikely piecemeal under current assumptions – industry and other private investment

The UK Strategy for Rare Disease

• Launched November 2013• 51 commitments across all 4

devolved administrations

5 themes:

1. Empowerment2. Diagnosis3. Prevention & early intervention4. Better coordination of care5. Research and development

Rare inherited diseases

Deciphering Developmental Disorders (DDD)

https://decipher.sanger.ac.uk 7

NIHR Rare Diseases Translational Research Collaboration (RD-TRC)

• >7,000 rare diseases (fewer than 5 in 10,000) have been identified

• The UK is at the cutting edge of research in rare diseases internationally

• ‘Deep’ phenotyping information combined with data on genomic abnormalities will increase research opportunities, enable faster diagnosis and support improved management and treatment of rare diseases

• RD-TRC will provide world-class NHS research infrastructure as a key element to harness the unique strength of the NHS to support fundamental discoveries and translational research on rare diseases

• Co-chaired by John Bradley (Cambridge BRC) and Patrick Chinnery (Newcastle BRC)

NIHR BioResource - Rare DiseasesSequencing Projects

NIHR BioResource Rare Diseases: Approved BRIDGE~ sequencing projects per 30 November 2013

Rare Disease/Condition

Lead Investigator

Biomedical Research Centre/Unit

Capacity allocated

Participants recruited

No. of WESin pipeline/ completed

No. of WGS in pipeline/ completed

Bleeding and Platelet Disorders

Prof Willem H Ouwehand

Cambridge 1000 800 658/524* 0/0

Steroid Resistant Nephrotic Syndrome

Dr Ana Koziell Guy’s and St Thomas’

500 8 0/0 0/0

Pulmonary Arterial Hypertension

Prof Nick Morrell

Cambridge 1000 360 47/0 96/0

Primary Immune Disorders

Prof Ken Smith Cambridge 1000 283 47/0

48^/0

Intrahepatic Cholestasis of Pregnancy

Prof Catherine Williamson

Guy’s and St Thomas’

270 0 - -

Specialist Pathology: Evaluating Exomes in Diagnostics

Dr Lucy Raymond

Cambridge 1000 550 94/0 192/0

Primary Membranoproliferative Glomerulonephritis

Dr Daniel Gale UCL 93 70 0/0 48^/0

Ehler-Danlos (ED) and ED-like Syndromes

Prof Tim Aitman

Imperial 400 10 0/0 0/0

Multiple Primary Malignant Tumours

Prof Eamon Maher

Cambridge 700 0 - -

Cancer

Vogelstein et al. Science 339, 1546 (2013)

Signal transduction pathways affected by mutations in human cancer

• Disease of disordered genomes – over 200 drivers known

• Stratified medicine and targeted therapy

• Drug metabolism• Immunological targets

• International Cancer Genomes Consortium- the Cancer Genome Atlas

• Optimise Molecular Pathology

Incidence v survival at 5 years

Lung cancer before and after Gefitinib

BRAF inhibitors for Melanoma

Antimicrobial resistance

A vision for NHS genomicsHuman Genomics Strategy Group (2012)•By 2020, the NHS will be a world leader in the development and use of genomic technology in the areas of healthcare and public health. It will be seen as a first-choice partner for industry, academia and research, contributing substantially to the global genomics knowledge base by supporting and facilitating innovation and novel research. •Genomic information and clinical genetic testing will be used equitably across the NHS, improving diagnosis and treatment decisions by identifying the right therapies to maximise efficacy and reducing adverse effects.•Healthcare providers within the NHS will confidently use genomic information within their roles•Effective public engagement will increase awareness of the role of genomic information in healthcare; how it can inform health choices; and the need for consent to access, study and use genomic data for the greater good.•There will be a vibrant SME sector and large life sciences company investment in and around our best universities and genomics hubs.

CMO priorities for genomics in the NHS – 20121. Reconfigure NHS laboratories around genomic technologies for single gene and

gene panel diagnostic testing2. Ensure fast, high quality testing services for high penetrance genetic

variants of common diseases such as cardiac, eye and metabolic disorders

3. Develop a “discovery diagnostic” network of excellence for rapid translation into the clinic

4. Commission appropriate genome diagnostics on all children from specialist units where a diagnosis is unclear

5. Improve pathways for genetic testing or sequencing of cancers to build on current stratified medicines initiatives

6. Align standards and architecture to collect genomic data and phenotypes

7. Facilitate a network of clinical bioinformatics, with powerful computing and data analysis

8. Review the role of sequencing in antenatal and adult screening, for example new developments in fetal DNA testing and cervical screening

Genetic Services in the NHS: What is likely to change

Genetic services in the NHS at present are primarily focused on testing for rare monogenic disorders, via specialist genetic service fundamental shift in approach

FACTOR CURRENT SITUATION EMERGING TREND

Nature of tests

Relatively limited number of tests provided, primarily for relatively rare single gene disorders*

Many more tests - including for monogenic forms of common diseases, pharmacogenetic tests and genome-wide tests for risks of common diseases

Nature of information

Few data points, clinical implications usually clear (single genes with large effects)

Large volume of complex, risk-based information; clinical significance often less clear cut

How the information is used

Primarily to diagnose those identified as at risk (due to family history) of inherited genetic disorders

Increasingly to select most appropriate treatment strategy. In the longer term, potential shift to prevention based on risk-based information

Workforce requirements

Genetic testing provided via specialist clinical geneticists and genetic counsellors

Genetics will increasingly enter into mainstream care – with requirement for professionals across NHS to be trained in genetics and its implications

Consumer expectations

Relatively low level of awareness of genetics amongst general population – beyond those affected by genetic disorders

Increasing access to information sources on-line and to direct-to-consumer testing is likely to see increased awareness and demand

*According to UKGTN second report (Nov 2010), between Apr 2008 and Mar 2010 the NHS Directory of Genetic Testing contained 503 diseases and 688 associated tests

Discovery DiagnosticsDiagnosis from research studies using genomic technologies in a clinical translation research setting:

DDD (UK)Analysed first 1,133 families, with a diagnostic rate of aprox 30%, discovered 12 new genes

Gilissen etal (2014) – Nijmegen

42% diagnosis rate of 50 children with severe intellectual disability using WGS

Beaulieu etal (2014) – FORGE Canada Consortium

45-95% diagnosis rate of 264 patients using whole exome sequencing

WGS500 ResultsMENDELIANOf 95 families, to date•23 families have new diagnosis

• pre-screened for known genes • result will increase with follow-up

•74 families in follow up studies •Over 50% of these have strong lead candidate

• 7 Novel genes for disease

• 6 Novel phenotypes for known genes

• 2 pathogenic regulatory variants in or

downstream of known candidate genes

• 6 genes missed by prior Sanger Sequencing

• Specialist genetics, pathology and specialist clinical workforce in Genomic Medicine

• Increase in specialised scientific training fellows funded over 3/5 years:

• Molecular Pathology including Infections and Pathogens• Genetics / genomics • Bioinformatics

• Commission bioinformatics workshops in conjunction with partners

• Develop specialist on line on-line learning and an MSc in Genomic Medicine

• Develop an MSc in Genomic Medicine

• CPD access to MSc modules for specialist practitioners

Genomic medicine

Conclusion

• Genomic Medicine is here

• Time for translation is now

• Prime therapies or repurpose treatments

• It needs further optimisation

• Together we can transform Genomic Medicine in the NHS