18 July 2014  ●   Issue 7

Publication highlights

Over the past year, more than 30 articles citing or acknowledging RD-Connect have been published in journals such as Nature Reviews Genetics, The Lancet Oncology and the European Journal of Human Genetics. Articles range from basic research to policy and ethical, legal and social Issues and can be found in the Scientific Publication area of the RD-Connect website. 

The most recent publication to acknowledge RD-Connect comes from Boczonadi  et al., 2014 who published their original research article, EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia, in this month’s Nature Communications. Whole genome sequencing was used to identify homozygous mutations in EXOSC8 which codes for a protein belonging to the central component of the exosome in patients with profound infantile neurodegenerative disease combining features of cerebellar and corpus callosum hypoplasia, hypomyelination and spinal muscular atrophy.

In another articleIncidental findings: the time is not yet ripe for a policy for biobanksViberg et al., 2014 discuss the arguments for and against the disclosure of incidental findings in biobanks research. Similarly, in their short communication in Lancet Oncology, Hansson et al., 2013 discuss how simplifying the ethical review and consent procedures in rare disease research would result in benefits to patients (Patients would benefit from simplified ethical review and consent procedure).

Publications about the key resources and bioinformatics tools that are being integrated into the RD-Connect platform such as Yabi, COEUS and the Human Phenotype Ontology are also featured on the website.

In next month’s RD-Connect newsletter we will be starting a "Publication of the Month" feature to highlight the important research which is being produced from or by collaboration with RD-Connect. To submit or recommend an article please contact Louise Johnston

--Louise Johnston

Second RD-Connect jamboree focuses on variant calling and analysis

From 30 June to 2 July 2014 Christophe Béroud's team from Aix-Marseille University Medical School hosted 30 participants from Europe, the USA and Australia for the second RD-Connect data analysis jamboree. This year's event focused on whole exome sequencing variant analysis, in particular the development of a standard variant calling pipeline and the methods for analysis and prioritisation of variants towards finding causative mutations.

After a welcome by Christophe Béroud as host and an update on the International Rare Disease Research Consortium (IRDiRC) by Hanns Lochmüller (Newcastle), David Salgado (Marseille) and Sergi Beltran (Barcelona) presented the outcomes of a benchmarking process using NA12878, a well-known reference sample, which led to the implementation of the first version of the RD-Connect standard analysis pipeline. As a result of the benchmarking of systems in place in Leiden, Groningen, Marseille and Barcelona, the standard pipeline will now be further refined to further optimise the calling of both SNPs and indels. 

As part of the testing of the pipeline, RD-Connect made use of pilot data provided by the Neuromics project. The aligned BAM files from Neuromics were uploaded to the European Genome-phenome Archive (EGA), where they will be stored in perpetuity and will soon become available to any researcher wishing to reuse the Neuromics data. The files were transferred to RD-Connect (CNAG, Barcelona), where where they were converted to raw data FASTQ files and aligned against the reference genome with the first version of the standard analysis pipeline. The next step in the pipeline was to call variants and annotate them with publicly available tools and those newly developed in RD-Connect (Marseille). The results of this recalling procedure provided an opportunity for comparison against the original Neuromics calls

Victor de la Torre (Madrid) presented the central database for the reprocessed data and the current status of the user interface for the RD-Connect platform, and Mats Hansson (Uppsala) discussed ethical considerations for data sharing and the principles that should be incorporated into data sharing agreements.

The main focus of the jamboree then moved on to the methods for variant prioritisation and analysis, refining the data down from the hundreds of thousands of variants found in a single exome towards the single variant that is the cause of a monogenic disorder. The RD-Connect platform will provide a user-friendly interface for researchers to perform this type of analysis, enabling filtering and prioritisation by different methods and plugging in of various analysis tools, including commonly used tools and those being developed within RD-Connect. During the jamboree, 20 use cases from the Neuromics project were provided to participants for analysis. The cases included sibling pairs, families with several affected individuals, and trios. Some of these cases had already been solved by Neuromics investigators, while others are still unsolved. Using the data from the sequencing plus phenotypic information, participants were expected to show the methods they would use to solve the cases, and this allowed end-users from Neuromics and EURenOmics to clearly describe to the developers the features that the platform interface should have in order to facilitate their work. Further work in autumn 2014 will then enable these features to be implemented into the user interface, while a command line interface will also allow advanced users to perform their own queries. The first version of the user interface is planned to be ready by the time of the next RD-Connect annual meeting in March 2014.

The jamboree also provided an opportunity for short update on associated bioinformatics tools: Christophe Béroud presented pathogenicity prediction results from UMD-Predictor and a prototype variant filtration tool developed in Marseille, while Matt Bellgard (Perth WA) presented the Yabi workflow environment and the second generation of their Rare Disease Registry Framework, and Andreas Zankl (Sydney) presented the BioLarK Archive and Skeletome Knowledge Base. Mark Thompson (Leiden) presented work done on integration of datasets from multiple sources using the COEUS tool to create semantic knowledgebases.

Finally, to update participants on progress towards the broader RD-Connect goals, Lucia Monaco (Milan) and Roxana Merino (Stockholm) presented the outcomes of the RD-Connect biobanking workpackage and the development of both a system for registering biobanks and registries and a sample catalogue using the MOLGENIS system. The sample catalogue will be integrated with the RD-Connect platform in order to allow individual omics datasets to be linked back to source samples for further research.

The jamboree organisers would like to thank all participants, in particular those from our collaborating projects Neuromics and EURenOmics, for their constructive feedback and collaborative spirit.

--Rachel Thompson & Sergi Beltran

RD-Connect Electronic Health Records workshop discusses extracting information from clinical records for use in research

Clinical research is currently challenged by disparate data and a long, costly and complex R&D phase. This results in a fragmented journey from basic research to therapies that would be vastly improved by access to coherently organised sets of health information or electronic health records (EHR). In the rare disease field, this is even more of an issue because of the limited number of patients and their distribution around the world. Therefore data sharing is essential to allow successful R&D.

RD-Connect organized an Electronic Health Records (EHR) workshop to investigate the feasibility of extracting information from clinically based systems in order to link it with datasets gathered in research projects. It gathered 20 participants from various backgrounds including key partners from the Electronic Health Records for Clinical Research (EHR4CR) and European Medical Information Framework (EMIF) IMI projects, which reported on their aims and achievements in this area. Both are major projects in the EHR field with substantial support from industry as well as from the European Union, and both are making progress on solutions towards the reuse of existing health data for research purposes. These projects deal with EHRs in general, in particular those from hospital systems, and do not have a specific focus on rare disease.

The workshop participants recognised that the key technical challenges were connectivity and interoperability, compliance with ethical, legal and privacy requirements from different countries and quality assurance of the data. They also concluded that although EHR might in future offer strong potential for information extraction related to rare diseases, many issues remain before this can become a reality. 

The workshop was an opportunity for rare disease experts to inform EHR experts about the specific issues faced in the rare disease field, in particular in areas such as semantic interoperability, disease coding systems and ontologies, which are often not appropriately specific for rare diseases. The use of ontologies such as the Human Phenotype Ontology and disease classifications such as the Orphanet Rare Disease Ontology are valuable solutions that are becoming widely used within the field but are not generally adopted in broader clinical practice.

The open discussions allowed RD-Connect, EHR4CR and EMIF to realise that they are facing similar issues with related goals and this constitutes the first step towards successful collaboration. Plans are now moving forward towards the development of a position paper setting out the specific needs of the rare disease field with regard to electronic health information systems, and communication between the projects will continue.

-- Caroline Graham, Gaëlle Blandin & Christophe Béroud

The NeurOmics project reaches a significant milestone in its data-sharing plans

NeurOmics is a consortium of European and worldwide experts in neuromuscular and neurodegenerative conditions, bioinformatics and –omics technologies. The project has 21 partners, is funded for 5 years under the EU FP7 scheme and is conducting cutting edge research into genetic causes, modifying factors, biomarkers and potential new therapies for neuromuscular and neurodegenerative diseases. Led by coordinator Professor Olaf Riess at Tübingen University and co-coordinators Professor Brunhilde Wirth (Cologne) and Professor Gert-Jan van Ommen (Leiden), NeurOmics has close ties with RD-Connect and the two teams are working together to help shape the rare-disease platform. NeurOmics is also providing some of the first data to be integrated into the RD-Connect platform and this process is now well underway with the first steps on the road to data-sharing being taken.

In order to achieve the desired aims of sharing data within the NeurOmics consortium and then more widely with RD-Connect, partners across NeurOmics have agreed and signed up to a data-sharing policy which both protects patient confidentiality and allows secure flow of data between those who need access in order to advance research into rare disease. In the first instance this policy means that data generated within the NeurOmics project is private to the individual investigator for the first 6 months and then becomes available across the consortium.

The 16th July 2014 marked the end of the 6 month ‘private’ period for the first batch of NeurOmics data. This sees both the deep-phenotyping information which has been entered into a bespoke, secure database using the PhenoTips system and raw sequencing data generated by whole-exome sequencing at deCODE becoming available to all NeurOmics partners. This is crucial in order to allow the comparison of results between different conditions with phenotypic overlap and to provide a larger set of sequencing data in which to check for variants which may or may not be associated with those phenotypes.

This is a significant milestone for the NeurOmics project and demonstrates partners' absolute commitment to collaboration and pooling of data in order to advance research together. The implications for RD-Connect are important too – the next phase of the data-sharing process means that after a further 12 months, this first batch of NeurOmics data will become securely available to the wider rare-disease community via the RD-Connect platform and the European Genome-phenome Archive (EGA). Access to this data will always be overseen by a data-access committee who have the mandate to grant access to any legitimate researcher. The use of this important dataset by other researchers for the benefit of research into these conditions will be actively promoted. Even before the "official" release, many NeurOmics datasets have already been made available to RD-Connect to test the variant calling and analysis pipelines and some new candidate genes have been identified and are being followed up.

RD-Connect coordinator Professor Hanns Lochmüller said, "RD-Connect enthusiastically welcomes the successful achievement of this first and crucial step in Neuromics’ data-sharing. The willingness of the consortium’s partners to collaborate in this way and the infrastructure that the project has established to enable easy but secure access to each other’s data is extremely encouraging and bodes well for the future of data-sharing in rare disease and indeed for the RD-Connect rare-disease platform itself."

For further information about the project or for details on the data-sharing process in NeurOmics, please visit www.rd-neuromics.eu or contact Cathy Turner. 

-- Cathy Turner

Innorare (Innovation and Research Acceleration for Rare Diseases) - a new application to the EU's Horizon 2020 Infrastructures Programme 

Innorare (Innovation and Research Acceleration for Rare Diseases) is the title of an application to be submitted to the INFRAIA-1-2014/15-integrating activity call in Horizon 2020 which is being assembled by RD-Connect WP7 leader Kate Bushby and her team at Newcastle University. By bringing together the existing research infrastructures offering services in the biomedical sphere with rare disease experts, Innorare aims to build a new resource that will add value to clinical translational research in rare diseases by assembling and streamlining the tools and resources offered by the existing infrastructures and where necessary improving their specificity to rare disease. If funded, Innorare aims to launch in April 2015.

To disseminate information while the project is still in its planning stages, an Innorare holding website has been developed. The website provides further background about the project and lists the partners. The team are keen to reach out to members of the rare disease community who will be the users of the infrastructure resources that Innorare will establish and would like to invite interested parties to join the Innorare User Group. To register your interest for Innorare, please click here.

--Emma Heslop

3Gb-TEST / ESHG / EuroGentest: Clinical and quality issues when introducing new technologies in genomics - Milan, Italy

A satellite meeting dedicated to discussing the clinical and quality issues when introducing new technologies in genomics was jointly organized by the European Society for Human Genetics, the 3Gb-TEST consortium, and EuroGentest in Milan, Italy on 30 May 2014.

The meeting started with a series of talks and discussions around the introduction of new technologies such as next generation sequencing (NGS) into the diagnostic setting. Presenters demonstrated that NGS technologies in particular have the potential to double the diagnostic yield in rare diseases. Nevertheless, they also warned that guidelines and protocols should be developed to clearly distinguish between the use of NGS in research and diagnostic environments. There were discussions around reporting and the issue of re-contacting patients following reclassification of variants. Participants agreed that the latter will be near impossible to do. The session finished off with a presentation on  cross-border testing. This could be offered to countries where NGS facilities are not available yet.

Practical workshops were held to discuss emerging NGS guidelines and to find out what is actually happening in laboratories at the moment. Discussions focused on whole genome analysis (NGS and microarray), variant calling parameters, quality control, confirmation / follow up and predicting the functional effects of DNA variants to laboratory report findings. It emerged that current guidelines contain discrepancies. For example, the instructions on reporting unsolicited findings differ considerably between the US and Europe. Currently, the majority of laboratories still use Sanger sequencing to confirm NGS findings. Good quality requires consensus on calling parameters, variant confirmation procedures, functional tests and proper exclusion of sample swaps. Ethical issues relating to diagnostic NGS are not new to genetics, but occur at a much larger scale.

 A 4-day 3Gb-TEST workshop on NGS will take place in Athens, Greece from 8-11 September. This course will also include an evening symposium organised by Jan Traeger-Synodinos: “Next-generation sequencing and genomic applications in disease and health: has the future arrived?” Further details can be found here.

-- Bart Janssen, Ellen Thomassen & Louise Johnston


Upcoming events

For further information on future events please visit the events page on the RD-Connect website.


September 7 - September 10, Strasbourg Convention Centre, France

ECCB’14 is the 13th edition of the ECCB conference series, which in 2014 will take place in the historic city of Strasbourg in the north-east of France. ECCB’14 will incorporate JOBIM, the annual French bioinformatics conference. An inter-regional and cross-border Organizing Committee has been formed, joining the Champagne-Ardennes (Reims), Lorraine (Nancy), and Alsace (Strasbourg) regions in France together with Belgium (Leuven), Germany (Saarbrücken), Luxembourg, and Switzerland (Basel). We are all looking forward to welcoming you in Strasbourg for ECCB’14 !

2014 Golden Helix Summer School

September 11 - September 15, Aegina, Greece

The 2014 Golden Helix Summer School will be held in the beautiful island of Aegina, close to Athens, Greece, 11-15 September 2014. The theme of the 2014 Golden Helix Summer School is “Pharmacogenomics and Genomic Medicine: Bridging research and the clinic” and will revolve around the most important disciplines of Genomic Medicine.

International Summer School "Rare diseases and orphan drug registries"

September 15 - September 19, Rome, Italy

The School will take the participants through the main concepts and methodological steps that must be undertaken in the establishment and management of a rare disease registry and to ensure its usefulness, scientific soundness and sustainability.

Who should attend: researchers, clinicians, experts in statistics, experts in bioinformatics, health authorities,policy makers, academics, other relevant experts, students and patient organizations, who are involved or intend to establish a rare disease patient registry.

No registration fees.

Further information will be available soon at: www.iss.it/cnmr (Section “In rilievo”).

15th International Conference on Human Genome Variation and Complex Genome Analysis (HGV2014)

September 17 - September 19

HGV2014 will bring together approximately 180 delegates (selected on the basis of their abstract submission) in a workshop-style atmosphere, with 25 internationally recognized speakers, in the Culloden Estate and Spa in Belfast, Northern Ireland from 17th – 19th September 2014.

Scientific topics include:
• Clinical NGS (including cancer genomics and rare disease diagnosis)
• Epigenomic variation (including that found in the single cell)
• Large scale population studies of human disease
• Stratified and Personalised medicine
• Data and knowledge sharing/discovery (including the Global Alliance for Genomics and Health)
• Biomedical informatics
• Genomic evolution
• Genomic technology advances
• Human mosaicism & aging

This residential conference provides opportunities for interactions with an unrivalled international faculty in an environment which promotes discussion and consideration of the key technologies and advances that will inform the development of this important discipline over the coming years.

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