BBMRI.nl Brochure May 2023

ELSI SERVICE DESK

Conduit and supporter of debate

PROUD OF THE ‘ART OF SHARING’

‘If you don’t sustain the output, you’ll never build that up again’

BIOBANKING AT THE EUROPEAN FOREFRONT

‘Leaving ERIC would be a great loss for the Dutch research community’

Editorial

BBMRI.NL: booster of Dutch health research

More than a decade of BBMRI.nl has laid a crucial foundation for a national infrastructure for scientific health research in the Netherlands.

Health and healthcare are important values for individual citizens and society as a whole. To address the societal challenges of health and healthcare, scientific research is crucial. This type of research uses existing data from healthcare on the one hand, but on the other also generates new data from samples of body material – like blood, tissue, DNA – and images.

To obtain meaningful results from these efforts, studies are becoming increasingly large-scale; and as a consequence, these cannot be conducted properly and efficiently without excellent supporting infrastructure. This exactly is where BBMRInlL, the Dutch hub of the European Biobanking and BioMolecular Research Infrastructure (BBMRI-ERIC), has made major contributions.

Realizing such an infrastructure is an incredibly complex process, involving quality assurance of samples and data, biobank information systems, data standardization and interoperability, and resolving ethical, legal, and social issues (ELSI). To this end, establishing productive collaborations is key, for example among infrastructure builders, but also with other stakeholders such as governmental bodies, patient organizations, researchers, grant providers, hospitals, universities, population cohorts, companies, and many others. In this complex playing field BBMRI.nl has been very successful for more than a decade. In the first years, emphasis was on connecting research groups in the various Dutch centers, with the Genome of the Netherlands project as a great example. With the Dutch National Tissuebank Portal, a joint project of PALGA and the Dutch pathology laboratories, an important step was taken towards better and more secure use of pathology tissue archives – with residual material left over after diagnostics – for health research. A major enterprise of BBMRI.nl together with other European organizations, has been to influence the development of European privacy legislation General Data Protection Regulation (GDPR).

As a result, in the GDPR at the European level exemptions have been installed for using health data for research. Many countries

have adopted these exemptions in their national GDPR legislation, the Netherlands, however, unfortunately and incomprehensibly has failed to do so. In recent years, the focus has been on connecting and scaling up infrastructure initiatives. For example, in the second – granted – BBMRI.nl roadmap project, Population Imaging and CTMM-TraIT were co-applicants in addition to the original BBMRI.nl founders. This trend has continued with Health-RI, the national health data infrastructure for research and innovation.

One of the major challenges in the field is fragmentation across many initiatives. To promote defragmentation, since 2020 several initiatives have been incorporated in Health-RI, including Parelsnoer, Data4LifeSciences, TraIT, and the Dutch nodes of the European research infrastructures EATRIS, ELIXIR and BBMRI.nl. In particular, within the Biobanks & Collections theme within Health-RI, many BBMRI.nl activities have been sustained, as well as within the Architecture, ELSI, and FAIR data themes.

Within Health-RI’s Obstacle Removal Pathway, much emphasis is on ELSI aspects and important steps are currently being taken. Thanks to the Dutch National Growth Fund subsidy of 69 million euros for Health-RI, we now have a long-term perspective (through 2028) to develop and consolidate a research infrastructure for health research. At the European level, it is good to see that with the Alliance of Medical Research Infrastructures –a collaboration of BBMRI, ECRIN and EATRIS – a similar convergence has started, which is strongly encouraged from the Netherlands. With this, BBMRI.nl has laid an important foundation for an integrated national, and at the same time internationally interoperable, infrastructure to facilitate excellent scientific research. This will substantially contribute to improving health outcomes of Dutch citizens.

Gerrit Meijer

Proud of the ‘art of sharing’

Eline Slagboom and Dorret Boomsma, closely involved in the research side of BBMRI.nl from the very start, look back on ten years of BBMRI.nl and reflect together on the future of the assets that have emerged from the project.

Asked about the most important results that emerged from BBMRI.nl, Dorret Boomsma (professor of biological psychology at the Vrije Universiteit Amsterdam) and Eline Slagboom (professor of molecular epidemiology at Leiden University Medical Center) – leaders of BBMRI.nl’s molecular data and research work package from the start – point to the special collaboration between a great many groups in the Netherlands. ‘This has led to an ever-expanding omics dataset that now and in the years to come will be used for health and behavioral questions by a wide range of stakeholders’, Boomsma says.

Specifically, she mentions GoNL (Genome of the Netherlands), which maps the DNA sequences of 250 family trios (two parents and a child). It is, so to speak, the first genetic profile of the Netherlands. Boomsma: ‘That’s not only going to help establish links between genetic variation and disease, but also provides insight

into the major population migrations in our history.’

An even larger number of participants were catalogued, including information on gene expression and epigenetics. Based on this, large genetic association studies were carried out. Later, the catalog was expanded to include many more cohorts in which metabolomics data were jointly generated. Via Internet questionnaires, the catalog was further enriched with food preferences and data on depression.

‘The metabolomics datasets made it possible to conduct large international studies on disease risk. On that basis, health scores could be created to determine vulnerability in the elderly. Those scores are used in follow-up studies in the clinic and for lifestyle interventions’, Slagboom says. ‘These are the large, high-profile projects, but in addition there are numerous smaller projects that have made it possible to train young people on this data. There is also a lot of new research based on these datasets, and many successful new grant applications.’

Cohort research in the Netherlands is of a very high level, Boomsma and Slagboom agree. There are many large chohorts with long follow-up times and with rich data collections. Many cohorts also include new,

© Jordi Huisman

often younger, participants in their research, such as the children of their original participants. Cohort data are also widely used by biomedical researchers. Data sharing in clinical research is more complicated; that is still in its infancy in terms of regulations, and rests within Health-RI on the shoulders of BBMRI.

However, societal dilemmas mostly take place outside the clinic, and to find answers to them, maintaining cohorts and enriching them with innovative data collections is very important. Clinical communities and cohort communities integrate within Health-RI, but the cohort research itself is not covered. Also, the maintenance of the BBMRI data collection, computational capacity (largely invested in SURF), and joint solving of methodological problems, are not secured within Health-RI.

To partly overcome this, the cohort community has established the Netherlands Cohort Consortium, chaired by Dr. Miranda Schram. It specifically addresses the sustainability of cohort research. Nevertheless, Slagboom and Boomsma are concerned. ‘There is real urgency for this to succeed. There’s an incredible amount of output from lots of national and international users from lots of disciplines, but if you don’t sustain this, you’ll never build that up again.’

The successes of BBMRI.nl are not trivial. If you ask Boomsma and Slagboom for some examples, they again stress the high level of cooperation, which has led to large, harmonized datasets (see separate text

box), new project applications and fruitful, continuing collaborations. ‘This has produced a lot of knowledge in the form of numerous scientific publications, but very practically also beautiful biomarkers that are now increasingly being discussed in the clinic’, Slagboom says. Boomsma adds: ‘The community is using omics more than ever in health and behavioral research. That data, methodology and knowledge is being shared like never before.’

They look back on ten years of BBMRI.nl with great pleasure and pride. ‘We owe a lot to professor Gertjan van Ommen, who started BBMRI fourteen years ago. We are proud of “the art of sharing” that we have put into practice together.’

Dividends of a decade of sharing

> 370 granted data requests on the shared data.

Cloud-based data-analysis platform with ready-to-use summarized experiments, saved with FAIR principlesi n mind in public repositories.

>160 peer-reviewed papers based on BBMRI.nl-omics data since 2014, that have been cited over 21.000 times.

11 software tools.

22 comprehensive omics atlases to browse through the results.

6 workshops to train researchers in optimal use of the data infrastructure.

Apps about different topics and analyses for clinicians, researchers, and the general public.

Interactieve PDF for highschool students.

Dutch Data Prize 2018.

‘There’s an incredible amount of output, but if you don’t sustain this, you’ll never build that up again’

Biobanking at the European forefront through BBMRI-ERIC

The fact that BBMRI.nl 2.0 is coming to an end may have implications for the Netherlands’ involvement in the overarching European initiative BBMRIERIC. Folkert van Kemenade is an ardent supporter of remaining closely involved in it through Health-RI.

As professor of pathology, Folkert van Kemenade has a special interest in large, well-structured, and easily accessible biobanks with a multitude of pathological samples and associated data. It should therefore come as no surprise that he has been intensively involved in BBMRI.nl for years as the representative of this Dutch node of BBMRI-ERIC, the European research infrastructure for biobanking. How does Van Kemenade see the future of the international embedding of the Dutch biobanking infrastructure after BBMRI.nl? It becomes clear in our conversation that much still appears uncertain. ‘This ERIC (headquarters in Graz, Austria, ed.) is paid for just over half from fees from the member states’,

he says. ‘We have always paid that from the BBMRI. nl grants, but of course that ends. In accordance with National Growth Fund rules, Health-RI cannot pay the 130,000 euros or so in remittance. We probably need alternative sources of funding, and the main issue is what we get in return.’

Initially that was clear, because the Netherlands contributed a lot to ERIC’s IT infrastructure through BBMRI.nl in the beginning, says Van Kemenade. For example, the Netherlands built the directory – the catalog – where the 600+ European biobanks can be found, and then co-developed the negotiator – the software that connects applicant with the biobank. In addition, there were important Dutch contributions to the development of the ELSI activities. Van Kemenade emphasizes that even now there is still added value from the ERIC membership: the IT infrastructure is continuously being developed, the quality of samples has improved, there has been more harmonization of biobanks, and important lobbying work has been done around the GDPR legislation. ‘ERIC has been instrumental in taking the edge off the GDPR legislation for scientific research. This can hardly be underestimated. Everyone in the field benefits from that every day.’

There are more countries struggling with the question of what the return on investment is of participating in BBMRI-ERIC. Major countries such as France and Britain have dropped out of this ERIC, although Spain and the Baltic states, for example, have joined; currently ERIC has 23 member countries. ‘So, the field is quite dynamic’, says Van Kemenade. What does not help is that there is now a lot of overlap threatening other European initiatives, including EATRIS, ELIXIR and ECRIN, making it more difficult for ERIC to stand out.

Another major challenge is the great diversity in biobanks and cohorts, and the differences in development between member states. Some countries have one biobank for the whole country, while Sweden already has an entire infrastructure of biobanks for cancer care, paid for by the government. ‘To us, this is still far away, although we are now trying to achieve that in the Netherlands with Health-RI. This is an excellent initiative and really the way to go. If you bring research infrastructures together, you avoid duplication and you can operate more easily as one party.’

In this regard, Van Kemenade sees Health-RI as a European example. ‘ERIC is having a hard time, because ultimately they are under the control of politics. Health-RI is an initiative from the scientific and biobank community. Health-RI could therefore be a template for the research infrastructures as united Europe-wide under EUAMRI (European Alliance of Medical Research Infrastructure, ed.). For example, when it comes to sample exchange between member states, there are still several legal challenges. As a result, in my opinion, there is currently an underuse of data. This is where Health-RI has a wonderful and challenging task.’

It should be clear by now that Van Kemenade hopes that the Netherlands will remain in ERIC. ‘We have contributed so much to the IT infrastructure, the ELSI aspects, and the outreach activities, among others. And let’s not forget that if we leave, we will of course no longer have access to ERIC’s directory and negotiator. That would be a great loss for the Dutch research community.’

‘Leaving ERIC would be a great loss for the Dutch research community’

© La Loes Fotografie

ransition to Health-RI

Clickable map to navigate the building blocks of BBMRI.nl that will find a new home under Health-RI.

SAMPLES, IMAGES, DATA

Find & access

Catalogue biobanks/images/data collections (>200)

PODIUM Portal request & tracking application

RESEARCH TOOLS Capture, Integrate & Analyse Data Capture Data Integration Analysis Omics & Images

ETHICAL, LEGAL AND SOCIETAL IMPLICATIONS Support

ELSI Servicedesk Patient & Public Advisory Council

Public Website biobanken.nl

KNOWLEDGE

Share Scientific papers Guides For biobank research

Not all assets from BBMRI.nl will be transferred to Health-RI. Some are transferred to other projects, some are discontinued. Within Data Capture and Data Integration, only a part of the infrastructural solutions will be transferred to Health-RI. For more information, please visit www.health-ri.nl and www.bbmri.nl.

ELSI Service conduit and supporter

‘One desire remains: to improve regional support around ELSI questions from our national position’

© Arnold Reyneveld

Service Desk: supporter of debate

Susanne Rebers is project manager of the ELSI Service Desk, which she says ‘clearly meets a need’. The future of the Service Desk is therefore guaranteed within Health-RI now that BBMRI.nl is ending.

Personalized medicine and next-generation sequencing, both rapidly emerging in healthcare, bring with them issues regarding privacy and the handling of secondary findings. Such questions about Ethical, Legal and Social Issues – ELSI for short – can be answered by the national ELSI Service Desk, a service developed by BBMRI.nl, Health-RI, Lygature, COREON and the Antoni van Leeuwenhoek Hospital.

According to project leader Susanne Rebers, the desk meets a clear need. ‘There are many ethical, legal and social questions surrounding scientific research with data and bodily material, for example about collection, sharing, archiving and analysis. People in the field can find information on the website and ask us their questions. These people include researchers, but also healthcare providers, patient representatives and policy makers. Our specialists, such as ethicists and health lawyers, offer answers. The questions and answers will also become available to other interested parties via the website as soon as possible.’

Health-RI is the national infrastructure for health data, images and samples, complete with provisions for their optimal use. It is a natural place to house the ELSI Service Desk now that BBMRI.nl is ending, Rebers believes. ‘Health-RI is pushing for well integrated, sectoral legislation, among other things, with a socalled obstacle removal process. And on transparency and a national control register to give citizens and patients control around sharing their health data for scientific research and innovation. We share current information and knowledge with the field and can give back to our colleagues within Health-RI what is going on. What is working well and what is not, and how can we use this practical knowledge for improvements, also within the obstacle removal process?’

Each month, the ELSI Service Desk website is viewed about 2,000 times. These are mainly researchers, but also people in support positions, such as science coordinators or data managers. ‘We get an average of six questions a month’, Rebers says. ‘Think of requests for a template for agreements on what you can do with certain material, who can use it and when it must be returned to where it was acquired. Currently, there are many questions about COREON’s revised Health Research Code of Conduct. How do you deal with control of study participants? Can you use material and data for research other than that for which informed consent was obtained? People also knock on the door with social or ethical questions. Think of the issue of how to deal with secondary findings.’

The ELSI Service Desk clearly meets a need, and the approach of answering questions and making the collected knowledge widely available works well, Rebers believes. ‘One wish is still to improve regional support around ELSI questions from our national position, in line with the structure of Health-RI with their central hub and eight regional hubs. We are currently discussing how we can best assist the regional ELSI coordinators to improve harmonization.’ In this way, the ELSI Service Desk aims to expand its reach and further expand services.

‘In this field, we agree that more harmonization is needed’, Rebers concludes. ‘In the real world, we run into differences in interpretation of legislation. Multicenter research in particular is difficult if each party draws different conclusions after careful consideration. This makes data sharing very complicated. My main lesson: it is crucial to continue taking steps together to further accelerate harmonization.’

This interview by Marc van Bijsterveldt appeared in expanded form in October 2022 on ZonMw’s website:

April 2023 | content created by Lygature. All rights reserved. Sharing and distribution of the content in this magazine is encouraged, provided the source is mentioned. Please let us know if you intend to do so: robin.verjans@lygature.org