Patient Recruitment, Phenotyping and Disease Stratification
The development of a comprehensive PBC cohort and bioresource is the main goal of Workstrand 1. This will contain fully anonymised medical information on patients with PBC including symptoms, laboratory data and response to current treatments (disease stratification). The bioresource will contain clinical samples such as blood and DNA that can be used to identify markers that predict drug response and disease progression. By developing a large cohort of PBC patients we will be able to identify patients who can be recruited to clinical trials (Workstrand 3) as well as supporting laboratory studies (Workstrand 2) to develop potential new treatments.
Workstrand 1 therefore co-ordinates national patient recruitment with storage (biobanking) of serum, urine, stool and DNA to achieve a growing cohort of 5,700 patients. This group will also be grouped or stratified by their response to the commonest treatment for PBC, ursodeoxycholic acid (UDCA or “urso”). The genotyping of the Genome Wide Association Study (GWAS) of the entire cohort commenced in June 2017, allowing us to assess the pathways implicated in disease severity (genotyping will be to phenotype).
Workstrand 1 has developed the UK-PBC Database, which has been live for almost 2 years. This is a Microsoft® SQL database that is hosted on NHS servers and functions as a web-application restricted to the N3 network, enabling the safe electronic transfer (and storage) of patient identifiable information. Moreover, import of bulk data from several collaborating centres of the Consortium has already been completed and will support development of predictive algorithms over the next months. The database, therefore, now functions as a platform for clinical trials, focusing on the development of better care pathways for PBC (Workstrand 3).
These developments have been possible thanks to the hard work of the supporting teams of the UK-PBC Consortium, as well as, the engagement of participants. Some 60% of the 5,700 participants has signed the revised Informed Consent Form (ICF) of the UK-PBC Genetics Study (GS) that allows:
- Sharing of anonymised data and samples with independent third-party investigators;
- Direct invitation to further studies;
- Capture of linked bulk clinical data from electronic hospital records, as well as, national NHS Data Centres (e.g. NHS Digital, ISD, etc), and;
- Archiving of anonymised ‘omic datasets on publically accessible archives such as EGA.
Workstrand 1 also includes the UK-PBC Nested Cohort Study (NCS), which is actively recruiting PBC patients who will undergo more detailed study to understand at the cellular level why some patients do not respond to treatment. The Nested Cohort Study (NCS) is running at 35 centres across six regions and counts 400 recruited participants at the end of June 2017. While recruitment is ongoing, we will begin analysis of participant DNA in collaboration with the Sanger Institute in Cambridge. This will allow us to see whether NCS patients also carry the genes indicated as being significant in pre-disposing people to PBC. On the back of this project, in collaboration with Imperial College, London, we aim to expand the initial samples for metabonome-wide analysis and microbiome profiling, from 120 to 500, by the end of the Project. Participants in both GS and NCS are consented to data and sample sharing, as well as direct invitation to other studies.
Workstrand 1 is co-ordinated in the Academic Department of Medical Genetics, University of Cambridge in collaboration with Newcastle University and The Sanger Centre. These centres already have considerable experience in large scale genetic & clinical studies in PBC. The Workstrand 1 leaders in Cambridge are Dr Graeme Alexander (Consultant Hepatologist), Dr Richard Sandford (Consultant Clinical Geneticist) and Dr George Mells (Clinical Lecturer in Hepatology). Disease modelling and genetic analysis will be undertaken by Professor Heather Cordell (Newcastle University) and Dr Carl Anderson (Sanger Centre).
UK-PBC started in 2007 as a national effort to build a large patient cohort for genetic studies to understand whether genetic factors were important in the development of PBC. DNA samples from the cohort were used to identify variation in the human genome that were associated with PBC. These studies were undertaken as part of Wellcome Trust Case Control Consortium 3 and also supported by The Medical Research Council, The PBC Foundation, The Isaac Newton Trust and Addenbrooke’s Charitable Trust. Since 2008 the UK-PBC Genetics Study has been on the portfolio of the National Institute for Health Research (NIHR) Comprehensive Research Network (CRN) and is now a research network consisting of all NHS Trusts throughout the UK and forms an integral part of UK-PBC.