UK Infrastructure for Large-scale Clinical Genomics Research

Background
The UK 100,000 Genomes Project will accelerate the application of whole genome sequencing (WGS) into routine care for the National Health Service. The genome is the genetic material of an organism (either in DNA or, for many types of viruses, in RNA). WGS provides the most comprehensive inventory of an individual's genetic variation. By incorporating this into routine care it will transform the health services people receive, changing the processes of diagnosis and management. The UK 100,000 Genomes Project seeks to drive this change by sequencing 100,000 genomes of individuals affected by rare diseases and cancer (and their families) and infectious disease pathogens.

Vision
The UK Infrastructure for Large-scale Clinical Genomics Research will provide the infrastructure which, using the information from the 100,000 Genomes project, will develop the UK as an international centre of excellences for the analysis of very large and complex biomedical datasets. As a national resource for the development of new knowledge it will provide transformative advances in the speed and range of research into the causes and consequences, prevention and treatment of disease. This proposal presents a unique opportunity for UK clinical research that will enable the discovery of new diagnostics, test complex approaches to stratified medicine, and drive therapeutic innovation.

Rare diseases
There are between 6,000 and 8,000 rare diseases and while each one only affects a small number of people, overall they affect the lives of 3 million people in England. Only 50% of rare diseases have an existing molecular (genetic) diagnosis. Through the scale of the 100,000 Genomes Project and by having a focus on unmet need, this infrastructure will create significant opportunities for scientific innovation, helping to assist in the interpretation of genetic findings whose clinical significance is currently unknown or uncertain.

Cancer
Cancer is, fundamentally, a genetic disorder where mutations lead to uncontrolled cell growth. The clinical impact of sequencing technologies has already enabled precise definitions of disease, uncovered insights into how cancer develops and has helped identify therapeutic targets from which to develop treatments. The importance of around 200 key genes across cancer types is known but focusing only on these alone in clinical care will not be enough to significantly impact upon the majority of individuals with cancer. Due to the scale of the 100,000 Genomes Project it offers the best opportunity to drive forward our understanding.

Pathogens and Infectious Disease.
WGS for pathogens - both viruses and bacteria is being adopted for routine management of infectious diseases, providing information on transmission and antibiotic resistance and creating tremendous opportunities for clinical research.

Output
This proposal is to fund the core hardware and software components of a data and computing infrastructure for genomics and clinical genomics research, this includes adapting existing software developed by UK partners who are international leaders in this field. The proposed infrastructure will be innovative in terms of content, technology, and scientific collaboration. It will contain clinical, health, and WGS data on large numbers of patients and pathogens in a range of key therapeutic areas. The data will be collected prospectively and will be extended with regular updates from clinical care. Available to clinicians, patients, industry and academia it will: encourage and enable engagement and collaboration in research, provide a platform for trials recruitment, and increase the depth and quality of the data obtained.

This proposal to the MRC will establish a shared, secure, high performance data and compute infrastructure as a platform for large-scale clinical genomics research based on the data flows of the UK 100,000 Genomes project.

Samples and data from patients with cancer and rare, inherited disorders will be provided by NHS England, working in collaboration with Cancer Research UK and programmes funded by the NIHR and the MRC. Genomics England, a company wholly owned by the Department of Health, will pay for the generation of whole genome sequence data.

Genomics England will pay also for the generation of summary reports, based upon clinical annotations of this data, and will return these to the NHS to support patient care. Genomics England will make anonymised, redacted versions of the data available for industrial research strictly within a secure, managed environment.

The proposed infrastructure will provide a similar environment for academic research, with a more comprehensive collection of genomic and patient data, including the read-level data used for the generation of variant calls and summary reports. The infrastructure will include software tools to support the production of 'research-ready' data sets, the effective management of patient and genomic data, and the delivery of collaborative clinical research.

The project partners have experience in infrastructure development and clinical genomics research, and will be able to re-use designs, procedures, and software developed and tested within existing programmes and organisations, including UK Biobank and the European Bioinformatics Institute.

A formal mechanism will be established for engagement with public, charitable, and philanthropic funders, and with the clinical research projects that they fund. Subject to capacity constraints, projects that add appropriate value to the Genomics England programme will be provided with access to the compute infrastructure at no charge.

The 100,000 Genomes Project is the most ambitious and most advanced of its kind. It's aim is to accelerate the application of whole genome sequencing into routine care for NHS patients with rare diseases, cancer, and infectious diseases, transforming the processes of diagnosis and management. Similar programmes are under development in America, in the Middle East and in South Asia. MRC support for the creation of a research infrastructure, alongside the existing £50m MRC investment in the Farr Institute of Health Informatics Research, will add considerably to the quality and value of the data collected; maximizing the translational research potential of the 100,000 Genomes Project.

The programme presents a unique opportunity for UK clinical research that will enable the discovery of new diagnostics, test complex approaches to stratified medicine, and drive therapeutic innovation. The economic and commercial impact is likely to be large, both in terms of the potential utility to pharma and the impetus to small and medium biotech companies.

The 100,000 Genomes Project is already providing the focal point for the creation of a community for engagement, dialogue and debate with government, regulators, policy makers and the public. A key part of this dialogue in developing public trust, understanding and confidence through ongoing active engagement will be the benefits realised from the research infrastructure.

Through the Genomic England Clinical Interpretation Partnership (GECIP) it is aimed to stimulate specific dedicated programmes funded by GECIP partners (the funders) through response mode or specific calls. These will be led by GECIP researchers whom it is expected will form and lead appropriate national and international consortia to maximise the value of the dataset by maximising the understanding of this highly complex data. The impact arising from the creation of GECIP, which will be built on the proposed research infrastructure, may include, but are not limited to:

- Enhanced clinical interpretation focused on rare inherited disease, including clinically- or genomically-driven deeper phenotyping, novel approaches to interpretation and annotation, validation and functional characterisation of variants, identification of novel therapeutic targets, or repurposing of existing therapies.
- Innovative clinical interpretation in cancer, including multi-omic datasets (e.g. transcriptomics, epigenetics, proteomics), analysis of circulating tumour DNA, sequential biopsy to address the genetic architecture of cancer, validation and characterisation of variants, identification of novel therapeutic targets, or repurposing of existing therapies.
- Improved clinical interpretation in infectious disease, focussing upon individuals with severe outcomes in sepsis, or - in partnership with Public Health England - greater understanding of the spread of antimicrobial resistance and phylogenetic tracking of transmission across the whole of the health economy.
- Expanding the programme to include other disease areas, to address specific research questions and opportunities to develop stratified approaches. The Genomics England infrastructure will be designed to facilitate expansion and re-use, and GECIP partnership can be extended to programmes with funding outwith the 100,000 Genomes Programme.
- Health records research, such as that exemplified by the rapidly-developing capacity of the Farr Institute, can build upon and add value to the combination of clinical, laboratory, and health records data, linked to variant call data, held securely within the proposed data and compute infrastructure.
- Algorithms, models, and tools for clinical genomics research, data quality assurance, and the annotation, interpretation, and presentation of genomic, clinical, and laboratory data in combination, may be developed, evaluated, used, and shared within the proposed infrastructure.