October 2016  ●   Issue 23




Growing interest in making rare disease registries linkable at the source

Report on the 3rd RD-Connect BYOD Workshop to Link Rare Disease Registries held at the National Centre of Rare Diseases Istituto Superiore di Sanità (ISS-CNMR) in Rome

The third ‘Bring Your Own Data workshop’ (BYOD) for rare disease registries in Rome (29-30 of September 2016) brought more registries with more data than ever before. The workshop took place with support from RD-Connect, ISS-CNMR, and ELIXIR, and was addressed for people directly involved in managing a rare disease registry or are establishing a new rare disease registry. Participants learned how to make registries Findable, Accessible, Interoperable and Reusable (FAIR) for humans and computers at the source and a general "FAIRification" procedure was customized for the case at hand in the working sessions.

It is widely agreed that rare disease patient registries should be international and more FAIR for humans and computers, and the procedures to collect and exchange data should be harmonised. The BYOD workshop introduces a FAIRification protocol by bringing together Linked Data experts and, in this case, registry experts, including Mark Wilkinson, one of the authors of the FAIR guiding principles. For the third time, ISS-CNMR and DTL/Elixir-NL  organised an RD-Connect BYOD to Link Rare Disease Registries. For the second time, the workshop was joint with the International Summer School on Rare Disease and Orphan Drug Registries (4th edition, 26–28 September 2016).

The two days long BYOD program consisted of theoretical and practical parts. After an introduction to the data linkage approach and FAIR principles, participants, in groups, worked with Linked Data experts on making their data samples FAIR. We also partially addressed authorization issues. The participants defined questions across resources that are difficult to answer for non-FAIR resources. In a friendly environment, attendees exchanged information with other registries and experienced how preparing data for linking makes difficult queries easy. The exercise on self–sketching the FAIRification workflow, a novel BYOD element, clarified doubts regarding IT.

FAIR maximizes the use of a registry, but also requires IT expertise, for which the participants have requested further guidance, such as the DTL’s blueprints for FAIR data projects. Registry creation tools can further mitigate the IT bottleneck. This is part of future development and the topic for the next BYOD (25-27 October, 2016).

The interest in the workshop was so high that more data sets were brought to the workshop than the linked data experts had time to work on. The organisers will address this issue in the BYOD follow-up.

We thank all the organisers, attendees, registry experts and Linked Data experts, who gave life to a highly interactive edition of this BYOD.

~ Claudio Carta, National Centre for Rare Diseases Istituto Superiore di Sanità, Rome, Italy & Marco Roos, Leiden University Medical Centre, Leiden, Netherlands


4th International Summer School on Rare Disease and Orphan Drug Registries

The 4th Edition of the International Summer School on Rare Disease and Orphan Drug Registries on the 26–28 September 2016 in Rome was organised by the National Centre for Rare Diseases and External Relations Office of Istituto Superiore di Sanità. The event was endorsed by the International Conference on Rare Diseases & Orphan Drugs (ICORD).
The number of places was limited and the participants were selected based on the their background and role in registry activities.

The event promoted the establishment of Rare Disease registries in compliance with the International Rare Diseases Research Consortium (IRDiRC) and EU Recommendations. It aimed at supporting cooperation among different registry stakeholders and coordination with the rare diseases registries developed within National Plans in the EU.

The list of speakers included a number of RD-Connect members:

• Manuel Posada with two presentations on “quality assurance” and “patient unique identifier”;

• Sabina Gainotti with a presentation on informed consent;

• Yllka Kodra with an interactive session “Strategies for Data Quality”;

• Paola Torreri with a presentation in the interactive session “Experiences with building and managing a registry; and

• Marco Roos, who in the interactive session on “Modern techniques and tools for data sharing” showed the data linkage approach and a set of guiding principles to make data Findable, Accessible, Interoperable, Reusable (FAIR).

The objectives were to make attendees able to describe:

• the resources needed for the establishment of a clinical research registry;

• the features of successful strategies to ensure long term sustainability of the registry, including registry purposes, data use, data sharing, dissemination activities, and the role of patient organisations; and

• the main steps for planning a registry and keeping control on its operations.

The interactive sessions consisted of plenary presentation and discussions and/or practical small-group exercises employing the Problem-Based Learning (PBL) methodology. PBL is a highly interactive and learner-centred approach, which uses a problem as a didactic stimulus. Participants, in small groups assisted by a facilitator, learn by working on the solution of an earlier presented problem. PBL is typically implemented in seven steps:

• 1) clarification of terms/concepts;

• 2) definition of the core issues;

• 3) analysis of the problem, formulation of hypotheses;

• 4) categorisation of hypotheses;

• 5) formulation of learning objectives needed to explain/solve the problem;

• 6) individual study, documents, lectures;

• 7) problem solution.

After an individual study of the topics, group discussions and plenary lectures, the participants presented their questions to the speakers. Finally, the groups provided their solutions, which were then discussed with the speakers. The participants’ performance were evaluated based on the work group solutions followed by discussion with the speakers.

We would like to take the opportunity to thank speakers and participants for the highly interactive edition of the International Summer School on Rare Disease and Orphan Drug Registries.

~ Claudio Carta and Paola Torreri, National Centre for Rare Diseases Istituto Superiore di Sanità, Rome, Italy


EURORDIS webinar on genome editing

Due to an intense interest from patient groups on the recent development in genome editing technology, EURORDIS held an interactive webinar to discuss current scientific advances and related ethical issues. This webinar aimed to start informing and engaging rare disease patient representatives on the complex topic of genome editing. It included presentations from:

• Professor Fulvio Mavilio, Scientific Director of Généthon, France, who explained some of the science behind the therapeutic potentials for rare genetic diseases and

• Dr Heidi Howard, bioethicist at Uppsala University, Sweden who focused her talk on the ethical and social considerations relating to the use of genome editing in clinical application.

While genome editing tools have existed for a number of years, the most recent generation is considered by many experts as a breakthrough in genetics. Indeed, genome editing tools have enabled scientists to identify novel disease-causative genes and to develop cell and animal models to study genetic diseases more quickly and efficiently. The impact on genetic diseases is potentially significant and so are the related ethical questions which need to be thoroughly discussed before any decision regarding clinical applications of the technology. Around 40 people, mostly patient representatives from rare disease organisations; joined the webinar on Tuesday 20th October and were able to actively participate by asking questions directly to the experts.

EURORDIS together with a dedicated working group on genome editing comprising several members of the Patient Advisory Council of RD-Connect, have organised a follow up workshop on 4th November in Paris for rare disease patient representatives across Europe to participate in an open discussion with experts on several aspects of gene therapy and genome editing specifically on scientific progress and its relevance for rare diseases, associated ethical, legal and social issues as well as on the perspectives from the regulatory and biotech sectors. Following the workshop, EURORDIS will work on publishing a position paper based on the feedback from patient groups.

To watch the webinar, visit the EURORDIS TV website.


CORBEL launches 1st Open Call for research projects

CORBEL – Coordinated Research Infrastructures Building Enduring Life-science services – is an European Commission Horizon2020 project uniting 11 Biological and Medical Science Research Infrastructures. In CORBEL, the participating research infrastructures expand their cooperation in order to harmonize researchers’ access to their cutting-edge technologies and services by establishing a sustainable platform of aligned services that will enable faster admission to and a wider portfolio of technologies and services to boost research projects.

The CORBEL Open Call invites researchers to apply to access technologies and services from more than 15 facilities from eight different research infrastructures across Europe. Selected projects will be allocated to so-called Access Tracks and gain unprecedented opportunities to utilize a wide range of high-end technologies and services. These include state-of-the-art offers from the fields of advanced imaging, biobanking, curated databases, marine model organisms, mouse mutant phenotyping, screening and medicinal chemistry, structural biology as well as systems biology.

Projects will be supported at every stage, with CORBEL project managers on hand to help scientists navigate between different service providers and exploit the full potential of the offers available.

Learn more about the CORBEL Open Call on the CORBEL website.


Featured publications


Correlation of SIN3A genomic variants with β-hemoglobinopathies disease severity and hydroxyurea treatment efficacy

Gravia A, et al., (2016)

In haemoglobinopathies, especially in β-thalassemia and sickle cell disease, the symptom severity and efficacy of hydroxyurea treatment strongly differ between the individual patients. Those differences dependent on the elevated foetal haemoglobin levels in the blood. Understanding what makes foetal haemoglobin levels increase is crucial for the development of new, more effective therapies.

Certain proteins, such as protein KLF10, can modify foetal haemoglobin production via different mechanisms. In this study, supported by RD-Connect, the researchers investigated whether SIN3A, a partner protein of KLF10, also works as a modifier of foetal haemoglobin production. The analyses indeed confirmed that small differences in the gene encoding SIN3A contribute to differences in symptom severity and efficacy of hydroxyurea treatment between the β-haemoglobinopathies patients. These results suggest that SIN3A is a potential candidate for a modifier of foetal haemoglobin production that might eventually be used to treat β-haemoglobinopathies.

These findings confirm that foetal haemoglobin production depends on a complex interplay of various factors and individual differences in genes encoding haemoglobin and protein modifiers determine the disease severity and response to medication. Understanding these complex interactions will allow to adjust treatment to individual patients based on the genetic variants they carry.

Integration of targeted metabolomics and transcriptomics identifies deregulation of phosphatidylcholine metabolism in Huntington’s disease peripheral blood samples

Mastrokolias A, et al., (2016)

Metabolic alterations are often found in Huntington’s disease (HD) patients. Blood sampling is the least invasive way to detect them since brain and other tissue samples are difficult to collect. In this study, the researchers analysed the levels of 163 metabolites in blood serum of Huntington’s disease patients and controls to identify metabolic changes related with the disease. They analysed them jointly with the previously published sequencing data from the same patients, to reveal the links between changes in gene expression and metabolism.

The analysis identified alterations of three phosphatidylcholine metabolites in Huntington’s disease and eight additional ones that are associated with the symptom severity. By integrating metabolomics data with gene expression data, the researchers discovered that deregulated levels of four genes related to phosphatidylcholine metabolism (ALDH1B1, MBOAT1, MTRR and PLB1) were associated with altered metabolite concentrations in the blood of the patients.

This study identified the links between metabolic changes in Huntington’s disease and altered gene expression that could underlie them. The study, financially suported by RD-Connect and its partner project NeurOmics, demonstrates how integrating various types of data, such as from sequencing and blood sampling, can help the researchers understand the mechanisms of genetic diseases.


From Wet‐lab to Variations: Concordance and Speed of Bioinformatics Pipelines for Whole Genome and Whole Exome Sequencing

Laurie S., et al., (2016)
Human Mutation

As whole genome sequencing is becoming cheaper and faster, it will become a standard practice in research and diagnostics and will gradually substitute older approaches for genomic analysis. Although the costs of sequencing are rapidly decreasing, the costs and speed of computational analysis are not. Therefore, robustness and computation-performance cost ratio should be considered when deciding which bioinformatic tools to use for analysis.

In this study, the authors compared six combinations of commonly used bioinformatic tools (three read aligners and three variant callers) used for analysis of genetic variants in whole genome and whole exome sequencing data.

They found that in some steps of the process the computing speed could be up to 20 times differenct between the tools. They have also observed that detection of SNVs (single nucleotide variants) and to a lesser extent InDel (nucleotide insertions or deletions), was highly consistent in the most – 70% - of the genome. However, it was less reliable in 20% and almost impossible in 10% of the genome.

The study was conducted by RD-Connect partners with financial support from RD-Connect. By helping the researchers select the tools best meeting their needs, these findings will make analysis of genome sequencing data more efficient and contribute to better research and diagnosis of genetic diseases.


Interoperability and FAIRness through a novel combination of Web technologies

Wilkinson MD., et al., (2016)
PeerJ Preprints

Data in the life sciences are extremely diverse and are stored in various types of repositories – some of them designed for particular data types (such as KEGG for pathway data or UniProt for protein data) and some for general-purpose (such as FigShare, Zenodo, or EUDat). Different types of data differ with respect to sensitivity and security considerations. Clinical data concerning genetic mutations in patients are highly sensitive, in contrast to the data on other species. In addition, data in different repositories are not interoperable. It means they cannot be easily exchanged between repositories due to differences in data format, structure and metadata (information about the data). In consequence, data integration cannot be automatized and is therefore work- and time-consuming.

This article explores resource-oriented Web design patterns that could be used by general as well as specialised repositories to help users find and reuse their data collections. According to the authors, existing technologies provide simple ways to make data interoperable even to the level of an individual spreadsheet cell. This is in line with the FAIR Principles  (Findability, Accessibility, Interoperability and Reusability), which define the requirements that allow data in repositories to be found and used both automatically and manually. The authors show that once data become interoperable, the other FAIR principles - Findability, Accessibility, and Reusability – can be easily achieved. The authors believe the proposed interoperability design patterns can facilitate discovery and integration of both new and existing data. They use RD-Connect as an example of how implementing the FAIR approach can help communities find, access, and reuse their valuable data holdings.


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