Author Correction: Leveraging European infrastructures to access 1 million human genomes by 2022.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Leveraging European infrastructures to access 1 million human genomes by 2022.

Human genomics is undergoing a step change from being a predominantly research-driven activity to one driven through health care as many countries in Europe now have nascent precision medicine programmes. To maximize the value of the genomic data generated, these data will need to be shared between institutions and across countries. In recognition of this challenge, 21 European countries recently signed a declaration to transnationally share data on at least 1 million human genomes by 2022. In this Roadmap, we identify the challenges of data sharing across borders and demonstrate that European research infrastructures are well-positioned to support the rapid implementation of widespread genomic data access.

Contextual factors influencing the equitable implementation of precision medicine in routine cancer care in Belgium.

BACKGROUND: Precision medicine represents a paradigm shift in health systems, moving from a one-size-fits-all approach to a more individualized form of care, spanning multiple scientific disciplines including drug discovery, genomics, and health communication. This study aims to explore the contextual factors influencing the equitable implementation of precision medicine in Belgium for incorporating precision medicine into routine cancer care within the Belgian health system. METHODS: As part of a foresight study, our approach evaluates critical factors affecting the implementation of precision oncology. The study scrutinizes contextual, i.e. demographic, economic, societal, technological, environmental, and political/policy-related (DESTEP) factors, identified through a comprehensive literature review and validated by a multidisciplinary group at the Belgian Cancer Center, Sciensano. An expert survey further assesses the importance and likelihood of these factors, illuminating potential barriers and facilitators to implementation. RESULTS: Based on the expert survey, five key elements (rising cancer rates, dedicated healthcare reimbursement budgets, increasing healthcare expenditures, advanced information technology solutions for data transfer, and demand for high-quality data) are expected to influence the equitable implementation of precision medicine in routine cancer care in Belgium in the future. CONCLUSIONS: This work contributes to the knowledge base on precision medicine in Belgium and public health foresight, exploring the implementation challenges and suggesting solutions with an emphasis on the importance of comparative analyses of health systems, evaluation of health technology assessment methods, and the exploration of ethical issues in data privacy and equity.

Genetic counselling legislation and practice in cancer in EU Member States.

BACKGROUND: Somatic and germline genetic alterations are significant drivers of cancer. Increasing integration of new technologies which profile these alterations requires timely, equitable and high-quality genetic counselling to facilitate accurate diagnoses and informed decision-making by patients and their families in preventive and clinical settings. This article aims to provide an overview of genetic counselling legislation and practice across European Union (EU) Member States to serve as a foundation for future European recommendations and action. METHODS: National legislative databases of all 27 Member States were searched using terms relevant to genetic counselling, translated as appropriate. Interviews with relevant experts from each Member State were conducted to validate legislative search results and provide detailed insights into genetic counselling practice in each country. RESULTS: Genetic counselling is included in national legislative documents of 22 of 27 Member States, with substantial variation in legal mechanisms and prescribed details (i.e. the 'who, what, when and where' of counselling). Practice is similarly varied. Workforce capacity (25 of 27 Member States) and genetic literacy (all Member States) were common reported barriers. Recognition and/or better integration of genetic counsellors and updated legislation and were most commonly noted as the 'most important change' which would improve practice. CONCLUSIONS: This review highlights substantial variability in genetic counselling across EU Member States, as well as common barriers notwithstanding this variation. Future recommendations and action should focus on addressing literacy and capacity challenges through legislative, regulatory and/or strategic approaches at EU, national, regional and/or local levels.

Poor Antibody Response to BioNTech/Pfizer Coronavirus Disease 2019 Vaccination in Severe Acute Respiratory Syndrome Coronavirus 2-Naive Residents of Nursing Homes.

BACKGROUND: Residents of nursing homes (NHs) are at high risk of coronavirus disease 2019 (COVID-19)-related disease and death and may respond poorly to vaccination because of old age and frequent comorbid conditions. METHODS: Seventy-eight residents and 106 staff members, naive to infection or previously infected with severe acute respiratory syndrome coronavirus (SARS-CoV-2), were recruited in NHs in Belgium before immunization with 2 doses of 30 µg BNT162b2 messenger RNA (mRNA) vaccine at days 0 and 21. Binding antibodies (Abs) to SARS-CoV-2 receptor-binding domain (RBD), spike domains S1 and S2, RBD Ab avidity, and neutralizing Abs against SARS-CoV-2 wild type and B.1.351 were assessed at days 0, 21, 28, and 49. RESULTS: SARS-CoV-2-naive residents had lower Ab responses to BNT162b2 mRNA vaccination than naive staff. These poor responses involved lower levels of immunoglobulin (Ig) G to all spike domains, lower avidity of RBD IgG, and lower levels of Abs neutralizing the vaccine strain. No naive residents had detectable neutralizing Abs to the B.1.351 variant. In contrast, SARS-CoV-2-infected residents had high responses to mRNA vaccination, with Ab levels comparable to those in infected staff. Cluster analysis revealed that poor vaccine responders included not only naive residents but also naive staff, emphasizing the heterogeneity of responses to mRNA vaccination in the general population. CONCLUSIONS: The poor Ab responses to mRNA vaccination observed in infection-naive NH residents and in some naive staff members suggest suboptimal protection against breakthrough infection, especially with variants of concern. These data support the administration of a third dose of mRNA vaccine to further improve protection of NH residents against COVID-19.

The genetic structure of the Belgian population.

BACKGROUND: National and international efforts like the 1000 Genomes Project are leading to increasing insights in the genetic structure of populations worldwide. Variation between different populations necessitates access to population-based genetic reference datasets. These data, which are important not only in clinical settings but also to potentiate future transitions towards a more personalized public health approach, are currently not available for the Belgian population. RESULTS: To obtain a representative genetic dataset of the Belgian population, participants in the 2013 National Health Interview Survey (NHIS) were invited to donate saliva samples for DNA analysis. DNA was isolated and single nucleotide polymorphisms (SNPs) were determined using a genome-wide SNP array of around 300,000 sites, resulting in a high-quality dataset of 189 samples that was used for further analysis. A principal component analysis demonstrated the typical European genetic constitution of the Belgian population, as compared to other continents. Within Europe, the Belgian population could be clearly distinguished from other European populations. Furthermore, obvious signs from recent migration were found, mainly from Southern Europe and Africa, corresponding with migration trends from the past decades. Within Belgium, a small north-west to south-east gradient in genetic variability was noted, with differences between Flanders and Wallonia. CONCLUSIONS: This is the first study on the genetic structure of the Belgian population and its regional variation. The Belgian genetic structure mirrors its geographic location in Europe with regional differences and clear signs of recent migration.

Policy brief Belgian EBCP mirror group Artificial Intelligence in cancer care.

Artificial Intelligence (AI) is already a reality in health systems, bringing benefits to patients, healthcare providers, and other stakeholders in the health care. To further leverage AI in health, Belgium is advised to make policy-level decisions about how to fund, design and undertake actions focussing on data access and inclusion, IT-infrastructure, legal and ethical frameworks, public and professional trust, in addition to education and interpretation. EU initiatives, such as European Health data space (EHDS), the Genomics Data Infrastructure (GDI) and the EU Cancer Imaging Infrastructure (EUCAIM) are building EU data infrastructures. To continue these positive developments, Belgium should continue to invest and support existing European data infrastructures. At the national level, a clear vision and strategy need to be developed and infrastructures need to be harmonized at the European level.

Policy brief - cancer research in Belgium.

Research is central to achieving Europe's Beating Cancer Plan, and is the key focus of the European Commission's Mission on Cancer. To successfully tackle the challenges we face in cancer research, a coordinated effort of the entire Belgian scientific community is needed. It is for this reason the Belgian Cancer Research Alliance was proposed. The aim of BeCRA is to bring together various Belgian research institutes and associated care institutions and position them optimally at the EU level, with respect to the many research initiatives launched in the EBCP within the EU4Health program, the Mission on Cancer, Digital Europe programs and other EU projects. Members of BeCRA collaboratively plan the participation in certain cancer research activities to ensure optimal use of investment and sustained excellence of Belgian cancer research. Belgium cancer research has an excellent track record in fundamental, translational research and phase I, II, III clinical trials. However, translating outcomes from research to patients in the Belgian healthcare system has been less successful. Gaps in the collaboration between actors in the research field, have led to fragmentation hampering the development of fundamental and translational research. Moreover, actors from multi-disciplinary background, such as behavioural or psycho-social fields, are not systematically included in cancer research. More efficient coordination between the aforementioned actors is necessary. Academic hospitals and universities should be incentivized to collaborate across regions, as well as to put sufficient focus on research activities with a virtuous spiral ("bed-to bench" and "bench to bed" process), while supporting researchers focusing on patient-driven research. There is an urgent need for Belgium to determine how best to ensure it remains an attractive market so that patients have access to innovative care. This could include streamlining regulatory complexity, while establishing lean and harmonized clinical trial designs, procedures and networks.

Unlocking the genomic landscape: Results of the Beyond 1 Million Genomes (B1MG) pilot in Belgium towards Genomic Data Infrastructure (GDI).

Genomic medicine has great potential to offer insights into how humans' genetic variation can affect their health, prevention options and treatment responses. The Beyond 1 Million Genomes (B1MG) project was kicked off in 2020 with the aim of building a federated network of genomic data in Europe, in which Belgium took part as a piloting country. B1MG developed a framework to enable all interested countries to self-evaluate the level of maturity of national genomic medicine practices following a common matrix, called Maturity Level Model (MLM), that contained 49 indicators across eight domains: I. Governance and strategy; II. Investment and economic model; III. Ethics, legislation and policy; IV. Public awareness and acceptance; V. Workforce skills and organisation; VI. Clinical organisation, infrastructure and tools; VII. Clinical genomics guidelines and infrastructure; and VIII. Data management, standards and infrastructure. The ongoing Genomic Data Infrastructure (GDI) project aims to capitalise on the experience of B1MG piloting countries and their MLM results. In this paper, we present the qualitative and quantitative outcomes of B1MG MLM assessment in Belgium and discuss their relevance to GDI. The insights gained from this study can be helpful for steering future policy directions and interventions on genomics in Belgium and beyond.

Tackling the implementation gap for the uptake of NGS and advanced molecular diagnostics into healthcare systems.

Next-generation sequencing (NGS) and liquid biopsy (LB) showed positive results in the fight against different cancer types. This paper aims to assess the uptake of advanced molecular diagnostics/NGS for quick and efficient genetic profiles of tumour cells. For that purpose, the European Alliance for Personalised Medicine conducted a series of expert interviews to ascertain the current status across member states. One stakeholder meeting was additionally conducted to prioritize relevant factors by stakeholders. Seven common pillars were identified, and twenty-five measures were defined based on these pillars. Results showed that a multi-faceted approach is necessary for successful NGS implementation and that regional differences may be influenced by healthcare policies, resources, and infrastructure. It is important to consider different correlations when interpreting the results and to use them as a starting point for further discussion.

Demographic Analysis of Cancer Research Priorities and Treatment Correlations.

Understanding the diversity in cancer research priorities and the correlations among different treatment modalities is essential to address the evolving landscape of oncology. This study, conducted in collaboration with the European Cancer Patient Coalition (ECPC) and Childhood Cancer International-Europe (CCI-E) as part of the "UNCAN.eu" initiative, analyzed data from a comprehensive survey to explore the complex interplay of demographics, time since cancer diagnosis, and types of treatments received. Demographic analysis revealed intriguing trends, highlighting the importance of tailoring cancer research efforts to specific age groups and genders. Individuals aged 45-69 exhibited highly aligned research priorities, emphasizing the need to address the unique concerns of middle-aged and older populations. In contrast, patients over 70 years demonstrated a divergence in research priorities, underscoring the importance of recognising the distinct needs of older individuals in cancer research. The analysis of correlations among different types of cancer treatments underscored the multidisciplinary approach to cancer care, with surgery, radiotherapy, chemotherapy, precision therapy, and biological therapies playing integral roles. These findings support the need for personalized and combined treatment strategies to achieve optimal outcomes. In conclusion, this study provides valuable insights into the complexity of cancer research priorities and treatment correlations in a European context. It emphasizes the importance of a multifaceted, patient-centred approach to cancer research and treatment, highlighting the need for ongoing support, adaptation, and collaboration to address the ever-changing landscape of oncology.

The GMOseek matrix: a decision support tool for optimizing the detection of genetically modified plants.

BACKGROUND: Since their first commercialization, the diversity of taxa and the genetic composition of transgene sequences in genetically modified plants (GMOs) are constantly increasing. To date, the detection of GMOs and derived products is commonly performed by PCR-based methods targeting specific DNA sequences introduced into the host genome. Information available regarding the GMOs' molecular characterization is dispersed and not appropriately organized. For this reason, GMO testing is very challenging and requires more complex screening strategies and decision making schemes, demanding in return the use of efficient bioinformatics tools relying on reliable information. DESCRIPTION: The GMOseek matrix was built as a comprehensive, online open-access tabulated database which provides a reliable, comprehensive and user-friendly overview of 328 GMO events and 247 different genetic elements (status: 18/07/2013). The GMOseek matrix is aiming to facilitate GMO detection from plant origin at different phases of the analysis. It assists in selecting the targets for a screening analysis, interpreting the screening results, checking the occurrence of a screening element in a group of selected GMOs, identifying gaps in the available pool of GMO detection methods, and designing a decision tree. The GMOseek matrix is an independent database with effective functionalities in a format facilitating transferability to other platforms. Data were collected from all available sources and experimentally tested where detection methods and certified reference materials (CRMs) were available. CONCLUSIONS: The GMOseek matrix is currently a unique and very valuable tool with reliable information on GMOs from plant origin and their present genetic elements that enables further development of appropriate strategies for GMO detection. It is flexible enough to be further updated with new information and integrated in different applications and platforms.

GMOMETHODS: the European Union database of reference methods for GMO analysis.

In order to provide reliable and harmonized information on methods for GMO (genetically modified organism) analysis we have published a database called "GMOMETHODS" that supplies information on PCR assays validated according to the principles and requirements of ISO 5725 and/or the International Union of Pure and Applied Chemistry protocol. In addition, the database contains methods that have been verified by the European Union Reference Laboratory for Genetically Modified Food and Feed in the context of compliance with an European Union legislative act. The web application provides search capabilities to retrieve primers and probes sequence information on the available methods. It further supplies core data required by analytical labs to carry out GM tests and comprises information on the applied reference material and plasmid standards. The GMOMETHODS database currently contains 118 different PCR methods allowing identification of 51 single GM events and 18 taxon-specific genes in a sample. It also provides screening assays for detection of eight different genetic elements commonly used for the development of GMOs. The application is referred to by the Biosafety Clearing House, a global mechanism set up by the Cartagena Protocol on Biosafety to facilitate the exchange of information on Living Modified Organisms. The publication of the GMOMETHODS database can be considered an important step toward worldwide standardization and harmonization in GMO analysis.

Development, Testing, and Implementation of the Belgian Patient Reported Experience Measure for Pancreatic Cancer Care (PREPARE) Project: Protocol for a Multi-Method Research Project.

BACKGROUND: Patients with pancreatic cancer do not feel involved in the development of their treatment and care plans. In Belgium, these plans are decided on during multidisciplinary team meetings. However, limited time is spent on the discussion of the preferences of the patient during these meetings. This research project aims to develop a patient-reported experience measure (PREM) for pancreatic cancer and assess if its use can support collaborative treatment decision-making. OBJECTIVE: This paper aims to outline the protocol for a multi-method research project to improve person-centered pancreatic cancer care in Belgium. Three subobjectives are pursued: (1) to develop a PREM to assess the experiences of care-related aspects in pancreatic cancer care, (2) to validate the PREM, and (3) to develop and evaluate an educational intervention to support the use of the PREM's results. METHODS: For the development of the PREM, an exploratory mixed methods study design will be used. The study will start with a survey followed by a telephone interview involving patients with pancreatic cancer and digestive oncology health care professionals. Study two is the testing of the content and construct validity of the PREM. Study three involves the implementation study according to the Medical Research Council framework of a complex intervention introducing the PREM in practice. The effectiveness of the intervention will be investigated using a pragmatic randomized controlled trial study design. RESULTS: The protocol presents the entire structure of the research project. Ethics approval to conduct the exploratory mixed methods study (objective 1) has been obtained, and recruitment has started since January 2022. CONCLUSIONS: The poor prognosis of patients with pancreatic cancer should not be considered a hurdle to not study this patient population group. Involving patients in the research and decision-making processes early on is key. This project aims to realize a scientifically sound research process providing research outputs that can easily and timely be implemented in the care trajectory of patients with pancreatic cancer. This research project will also lead to recommendations on how to involve patients with pancreatic cancer and how the methodology of this research project can be translated to other patient groups. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/29004.

Risk-Adjusted Cancer Screening and Prevention (RiskAP): Complementing Screening for Early Disease Detection by a Learning Screening Based on Risk Factors.

Background: Risk-adjusted cancer screening and prevention is a promising and continuously emerging option for improving cancer prevention. It is driven by increasing knowledge of risk factors and the ability to determine them for individual risk prediction. However, there is a knowledge gap between evidence of increased risk and evidence of the effectiveness and efficiency of clinical preventive interventions based on increased risk. This gap is, in particular, aggravated by the extensive availability of genetic risk factor diagnostics, since the question of appropriate preventive measures immediately arises when an increased risk is identified. However, collecting proof of effective preventive measures, ideally by prospective randomized preventive studies, typically requires very long periods of time, while the knowledge about an increased risk immediately creates a high demand for action. Summary: Therefore, we propose a risk-adjusted prevention concept that is based on the best current evidence making needed and appropriate preventive measures available, and which is constantly evaluated through outcome evaluation, and continuously improved based on these results. We further discuss the structural and procedural requirements as well as legal and socioeconomical aspects relevant for the implementation of this concept.

Application of the modular approach to an in-house validation study of real-time PCR methods for the detection and serogroup determination of verocytotoxigenic Escherichia coli.

European Commission regulation 2073/2005 on the microbiological criteria for food requires that Escherichia coli is monitored as an indicator of hygienic conditions. Since verocytotoxigenic E. coli (VTEC) strains often cause food-borne infections by the consumption of raw food, the Biological Hazards (BIOHAZ) panel of the European Food Safety Authority (EFSA) recommended their monitoring in food as well. In particular, VTEC strains belonging to serogroups such as O26, O103, O111, O145, and O157 are known causative agents of several human outbreaks. Eight real-time PCR methods for the detection of E. coli toxin genes and their variants (stx(1), stx(2)), the intimin gene (eae), and five serogroup-specific genes have been proposed by the European Reference Laboratory for VTEC (EURL-VTEC) as a technical specification to the European Normalization Committee (CEN TC275/WG6). Here we applied a "modular approach" to the in-house validation of these PCR methods. The modular approach subdivides an analytical process into separate parts called "modules," which are independently validated based on method performance criteria for a limited set of critical parameters. For the VTEC real-time PCR module, the following parameters are being assessed: specificity, dynamic range, PCR efficiency, and limit of detection (LOD). This study describes the modular approach for the validation of PCR methods to be used in food microbiology, using single-target plasmids as positive controls and showing their applicability with food matrices.

New approaches in GMO detection.

The steady rate of development and diffusion of genetically modified plants and their increasing diversification of characteristics, genes and genetic control elements poses a challenge in analysis of genetically modified organisms (GMOs). It is expected that in the near future the picture will be even more complex. Traditional approaches, mostly based on the sequential detection of one target at a time, or on a limited multiplexing, allowing only a few targets to be analysed at once, no longer meet the testing requirements. Along with new analytical technologies, new approaches for the detection of GMOs authorized for commercial purposes in various countries have been developed that rely on (1) a smart and accurate strategy for target selection, (2) the use of high-throughput systems or platforms for the detection of multiple targets and (3) algorithms that allow the conversion of analytical results into an indication of the presence of individual GMOs potentially present in an unknown sample. This paper reviews the latest progress made in GMO analysis, taking examples from the most recently developed strategies and tools, and addresses some of the critical aspects related to these approaches.

A theoretical introduction to "combinatory SYBRGreen qPCR screening", a matrix-based approach for the detection of materials derived from genetically modified plants.

The detection of genetically modified (GM) materials in food and feed products is a complex multi-step analytical process invoking screening, identification, and often quantification of the genetically modified organisms (GMO) present in a sample. "Combinatory qPCR SYBRGreen screening" (CoSYPS) is a matrix-based approach for determining the presence of GM plant materials in products. The CoSYPS decision-support system (DSS) interprets the analytical results of SYBRGREEN qPCR analysis based on four values: the C(t)- and T(m) values and the LOD and LOQ for each method. A theoretical explanation of the different concepts applied in CoSYPS analysis is given (GMO Universe, "Prime number tracing", matrix/combinatory approach) and documented using the RoundUp Ready soy GTS40-3-2 as an example. By applying a limited set of SYBRGREEN qPCR methods and through application of a newly developed "prime number"-based algorithm, the nature of subsets of corresponding GMO in a sample can be determined. Together, these analyses provide guidance for semi-quantitative estimation of GMO presence in a food and feed product.

NGS for (Hemato-) Oncology in Belgium: Evaluation of Laboratory Performance and Feasibility of a National External Quality Assessment Program.

Next-generation sequencing (NGS) is being integrated into routine clinical practice in the field of (hemato-) oncology to search for variants with diagnostic, prognostic, or therapeutic value at potentially low allelic frequencies. The complex sequencing workflows used require careful validation and continuous quality control. Participation in external quality assessments (EQA) helps laboratories evaluate their performance and guarantee the validity of tests results with the ultimate goal of ensuring high-quality patient care. Here, we describe three benchmarking trials performed during the period 2017-2018 aiming firstly at establishing the state-of-the-art and secondly setting up a NGS-specific EQA program at the national level in the field of clinical (hemato-) oncology in Belgium. DNA samples derived from cell line mixes and artificially mutated cell lines, designed to carry variants of clinical relevance occurring in solid tumors, hematological malignancies, and BRCA1/BRCA2 genes, were sent to Belgian human genetics, anatomic pathology, and clinical biology laboratories, to be processed following routine practices, together with surveys covering technical aspects of the NGS workflows. Despite the wide variety of platforms and workflows currently applied in routine clinical practice, performance was satisfactory, since participating laboratories identified the targeted variants with success rates ranging between 93.06% and 97.63% depending on the benchmark, and few false negative or repeatability issues were identified. However, variant reporting and interpretation varied, underlining the need for further standardization. Our approach showcases the feasibility of developing and implementing EQA for routine clinical practice in the field of (hemato-) oncology, while highlighting the challenges faced.

Is there any benefit to particles over photon radiotherapy?

Particle, essentially, proton radiotherapy (RT) could provide some benefits over photon RT, especially in reducing the side effects of RT. We performed a systematic review to identify the performed randomised clinical trials (RCTs) and ongoing RCTs comparing particle RT with photon therapy. So far, there are no results available from phase 3 RCTs comparing particle RT with photon therapy. Furthermore, the results on side effects comparing proton and carbon ion beam RT with photon RT do vary. The introduction of new techniques in photon RT, such as image-guided RT (IGRT), intensity-modulated RT (IMRT), volumetric arc therapy (VMAT) and stereotactic body RT (SBRT) was already effective in reducing side effects. At present, the lack of evidence limits the indications for proton and carbon ion beam RTs and makes the particle RT still experimental.