June 19, 2013
OrphaNews Europe: What was the aim of developing DECIPHER? What were the factors that helped in creating this database?
Dr. Helen Firth: The DECIPHER project was conceived as a clinical and research tool to:
• Aid in the interpretation of data from genome-wide analyses eg. Differentiation between pathogenic and polymorphic genomic variants
• Utilise the human genome reference sequence via Ensembl and other genome browsers to define which genes are involved in a specific copy number variant (microdeletion / microduplication) and for sequence variants, whether they are positioned within a gene or regulatory element.
• Facilitate research into the study of genes that affect human health and development to improve diagnosis, management and therapy of rare diseases.
The main factors that helped in creating the DECIPHER database were the proximity of the genomics, programming, web expertise and bioinformatics resources at the Wellcome Trust Sanger Institute and European Bioinformatics Institute, Hinxton.
OrphaNews Europe: What is the current focus of this project?
Dr. Helen Firth: With the launch of DECIPHER Sequence earlier this month, our current focus is the integration of sequence variation with structural variation. Due to the historical legacy of microscopy based chromosome analysis and single gene Sanger-based sequence analysis, genomic variation has been categorized into large structural aberrations and nucleotide-based sequence variants. In reality, there is a continuous spectrum of genomic variation from copy number variants to sequence variants and DECIPHER now reflects that biological reality.
OrphaNews Europe: What are the key features of DECIPHER?
Dr. Helen Firth: DECIPHER brings together a suite of genomic resources that enable visualisation of a genomic variant in its correct location on the human genome map together with the associated phenotype. The DECIPHER display includes separate tracks of normal variation and pathological variation that together help in determining the significance of a variant identified in a patient.
DECIPHER is unique in capturing information from copy number variants (CNVs) and sequence variants (SNVs) ie across the scale from Megabases to single nucleotide changes. DECIPHER is a global resource containing data on >20,000 patients with consent for data sharing in >8,000 patients.
DECIPHER now has an integrated, scrollable and zoomable browser enabling simultaneous display of CNVs and SNVs. It also has a report function enabling production of a customisable PDF report that can be printed for the patient record.
To facilitate collaboration, members of the consortium have an email link to the submitting centre. External users can contact DECIPHER who will forward their email request to the submitting clinician. DECIPHER has been instrumental in facilitating >260 publications relating genotype with phenotype.
OrphaNews Europe: Can you describe some of the challenges you encountered during the creation of DECIPHER?
Dr. Helen Firth: At the start of the project, the main challenge in developing DECIPHER related to the diversity of arrays in use and the need to catalogue and map every clone in an array to enable users to display their data. This was overcome by the move to deposition by base-pair position a few years ago once arrays had reached a sufficiently high level of resolution to enable this. A second challenge has been remapping all of the data to the reference sequence with new releases of the reference genome. A third challenge has been building an international collaboration of academic genetics centres. This was facilitated by the annual DECIPHER symposia from 2004-11 and latterly by the annual Genomic Disorders meeting held at Hinxton.
OrphaNews Europe: How long have you been involved in this project?
Dr. Helen Firth: I have been involved with DECIPHER since its inception in 2004. I came up with the initial concept of DECIPHER and have had the good fortune to work with a very talented and committed team at the Wellcome Trust Sanger Institute whose creativity and vision have helped the project to flourish and to develop in scope and ambition.
OrphaNews Europe: Who are your key collaborators?
Dr. Helen Firth: Dr Matt Hurles of the Wellcome Trust Sanger Institute is the Lead Scientist for the DECIPHER project. More than 200 academic centres of clinical genetics worldwide are members of the DECIPHER consortium. Patients and their families are key participants in the project and they are represented on the Scientific Advisory Board for the project by Dr Beverly Searle, CEO of the Rare Chromosome Disorder support group ‘Unique’ www.rarechromo.org.
OrphaNews Europe: What are your main funding sources?
Dr. Helen Firth: The DECIPHER project is funded by the Wellcome Trust Sanger Institute at Hinxton, UK.
OrphaNews Europe: How does DECIPHER help catalogue common copy number changes?
Dr. Helen Firth: DECIPHER helps catalogue copy number changes by providing a way for clinicians and scientists to share rare and novel variants and their associated phenotype and inheritance. This approach has facilitated the identification of some of the recurrent microdeletion/duplication disorders. It enables patients with rare conditions to be evaluated against the global experience of these conditions that is essential in improving diagnosis and care for patients with rare disorders in such a rapidly evolving field.
As DECIPHER now incorporates SNVs, this increases the opportunity to identify causative genes for rare disease by leveraging the synergy between haploinsufficiency caused by gene deletion in CNVs with loss of function SNVs.
OrphaNews Europe: How do you decide who can contribute to the database? Do the contributing centers have to fulfil certain criteria?
Dr. Helen Firth: The DECIPHER consortium is a global network of >200 academic genetics centres. When centres apply to join the consortium they are asked to complete a brief questionnaire. We evaluate the web-site of the institution, the availability of both clinical and laboratory expertise in genetics and the number of relevant publications together with other parameters in order to reach a decision regarding membership in order to ensure that high quality data with good phenotype is deposited in DECIPHER. Much of the utility of DECIPHER is freely available to non-members including a comprehensive search facility and access to Syndrome reports.
OrphaNews Europe: What are the benefits of having a source like DECIPHER for clinicians and patients in the rare disease community?
Dr. Helen Firth: In 2012 alone, DECIPHER data was referenced in over 160 international peer-reviewed publications. It has been a real delight to see the number of publications using DECIPHER data to advance scientific knowledge and a great privilege to experience at first hand the real difference DECIPHER can make to patients in the clinic when we can find a ‘match’ for them with patients from another centre and work collaboratively to understand the biological basis of their disorder.
OrphaNews Europe: How does being a part of IRDiRC help you in furthering your needs?
Dr. Helen Firth: IRDiRC brings DECIPHER into contact with an international network of clinicians and scientists who share our aims to improve diagnosis and treatment for patients with rare disease so we are delighted with this partnership. We would be very pleased for DECIPHER to be adopted by IRDiRC for sharing of genomic variant and phenotype data and would be delighted to facilitate this. Please contact us at email@example.com to discuss how we can provide help for individual projects or collaborations within IRDiRC.
OrphaNews Europe: How is DECIPHER planning to contribute to reaching the goals of IRDiRC by 2020?
Dr. Helen Firth: By becoming the first global resource integrating copy number and sequence variant data with phenotype and inheritance data we hope that DECIPHER can catalyse data sharing within IRDiRC and enable it to reach and indeed surpass its goal of the means to diagnose most rare diseases and develop 200 new therapies by 2020.
OrphaNews Europe: What do you think might be some of the ethical issues faced by DECIPHER and databases such as this one? How do you plan to address these dilemmas?
Dr. Helen Firth: We have been very mindful of ethical and privacy issues in the design and development of DECIPHER. A medical ethicist and an expert in privacy law have been part of our advisory board from the start of the project. Within the UK a Research Ethics Committee has approved the project.
There is a clear tension between the need for wide data sharing to facilitate rapid progress in rare disease research and maintaining privacy and confidentiality for individuals with rare diseases. DECIPHER is a secure database using https (ie the same level of security used for banking and financial transactions). DECIPHER’s web security is audited by external independent auditors to confirm its compliance. Only logged-in members of the consortium are able to discover the submitting centre for a given patient, other users do not know the global location of the patient and can only access the submitting centre through contact with DECIPHER which will then forward their request to the submitting clinician so that they can judge whether to share more information. The link between the DECIPHER number and patient identifiable information is held within the academic genetics service who has legitimate access to that information and an obligation to keep that information secure. This design maintains a balance that enables effective data sharing whilst retaining privacy and confidentiality.
OrphaNews Europe: Do you think the proposed changes to the privacy laws in Europe would affect DECIPHER? If yes, can you tell us how?
Dr. Helen Firth: DECIPHER has always maintained a position of explicit consent for broad data sharing so the current structure of the project would not be threatened by the proposed changes to the privacy laws in Europe. However these changes would impact on and constrain our proposed development to facilitate data sharing by managed data access that are designed to promote research in rare disorders in situations where individual patient consent is not possible.
OrphaNews Europe: What are the future goals (long term and/or short term goals) of DECIPHER?
Dr. Helen Firth: Opening the project to research teams to deposit data. As genomics moves into mainstream medicine, broadening the range of centres that are eligible to join the consortium so that centres specialising for example in cardiac genetics or neurological genetics can utilise the resource to share data.
1. Firth, H.V., Richards, S.M., Bevan, A.P., Clayton, S., Corpas, M., Rajan, D., Van Vooren, S., Moreau, Y., Pettett, R.M. and Carter, N.P. (2009) DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am. J. Hum. Genet., 84, 524-533. Consult the PubMed abstract
2. Corpas, M., Bragin, E., Clayton, S., Bevan, P. and Firth, H.V. (2012) Interpretation of genomic copy number variants using DECIPHER. Current protocols in human genetics / editorial board, Jonathan L. Haines [et al.], Chapter 8, Unit 8 14. Read the open access chapter
3. Swaminathan, G.J., Bragin, E., Chatzimichali, E.A., Corpas, M., Bevan, A.P., Wright, C.F., Carter, N.P., Hurles, M.E. and Firth, H.V. (2012) DECIPHER: web-based, community resource for clinical interpretation of rare variants in developmental disorders. Hum. Mol. Genet., 21, R37-44. Consult the PubMed abstract
Helen Firth on behalf of the DECIPHER development team.
Visit the website for more information on DECIPHER