The Radboud Biobank: A Central Facility for Disease-Based Biobanks to Optimise Use and Distribution of Biomaterial for Scientific Research in the Radboud University Medical Center, Nijmegen

The Radboud Biobank offers disease-based biobanks a centralized facility to optimize the use and distribution of biomaterial for scientific research. Notably, two population biobanks are also included in this collection. All collections are professionally and sustainably maintained using high-quality and secure standardized protocols for ICT, legal-ethical aspects, sample collection, processing and storage, communication and distribution. The Radboud Biobank includes biomaterial (e.g. DNA, serum, plasma, tissue, urine and faeces – depending on the specific patient group), images, associated clinical data (patient, disease-specific and phenotypic data) and derived information (genotypic data, microarray gene expressions). Patient advocates and other relevant stakeholders are actively involved in the governance of the Radboud Biobank. Funding statement: The Radboud Biobank was implemented by the Radboudumc Executive Board as part of the university research infrastructure. It is a central facility for the Radboudumc, with guaranteed central support for at least 15 years. A governing strategic board, encompassing relevant stakeholder groups, oversees the operations of the Radboud Biobank. Two patient representatives are included in this strategic board, and one holds the position of chairperson.


Project description
The Radboud Biobank was established in 2012 with the aim of providing a centralized facility within the Radboud university medical center (Radboudumc) for the collection, storage and management of biomaterial, images and the corresponding clinical data. Its infrastructure is based on the Parelsnoer Institute model (PSI; [1]), which is a unique nationally representative biobanking partnership between the eight University Medical Centers (UMCs) in the Netherlands. It is expected that this infrastructure will serve as a conduit for generating robust scientific data, leading to improved health in patients as well as reinforcing the importance of biomedical research in the Radboudumc and abroad.
The Radboud Biobank was established to promote research for both prevalent and rare diseases (de novo biobanks, secondary use biobanks, remaining material from clinical trials and non-experimental follow-up studies). Such studies may be initiated by the founders of the sub-collection. However, biomaterial and clinical data from the Radboud Biobank are also available to other researchers with bona fide research protocols that directly or indirectly contribute to medical innovation. Each request for use of Radboud Biobank samples is reviewed by an institutional review board (IRB) and must be approved by the head of the sub-biobank.
The high requirements placed on quality, standardization and harmonization strengthen the research possibilities and both quality and quantity of the scientific output. Costs associated with patient inclusion and sample and data collection are covered by the participating department. The Radboud Biobank covers the costs of sample preparation, freezing, storage and sample management. For each issuance, investigators pay a fee to partly cover operational costs of the Radboud Biobank. The extent of the fee depends on the nature and quantity of the samples and the affiliation of the researcher with the Radboudumc.

Species
Homo sapiens.

Classification (2)
Clinical biobank: biological samples and associated data, clinical data.

Temporal coverage
Start data: January 2012. End date: not applicable (the intention is to include patients as long as possible, and thus there is no temporal limit); this implies that biomaterial and associated data will be stored without any time limitation.

Temporal coverage for accessibility
Radboud Biobank has not indicated a date for samples and data to be destroyed.

Steps
Samples are collected in a routine clinical care setting. Individual clinical departments are responsible for this part of the biobanking process. Once a sample arrives at the Department of Laboratory Medicine, Human Genetics or Pathology, responsibility for the material is transferred to the Radboud Biobank.
Sample handling and storage are based on standard operating procedures (SOPs). These procedures were established to ensure standardized sample collection and handling, and to guarantee a collection of samples of high and reproducible quality. Deviations from the SOPs are recorded as issues with haemolytic, lipemic, icteric, wrong tube, incorrect volume collected, deviation from time between sampling and storage, storage temperature deviation, incorrect sample handling (centrifugation, mixing/homogenization) storage problem or other deviation as free text. Figure 1 shows the schematic workflow of the Radboud Biobank. Table 1 gives an overview of procedures for collecting, processing and storing of samples defined in the Radboud Biobank's biomaterial protocol.

Type of long-term preservation
See

Shipping temperature from storage to research use
Body fluids or materials and fresh frozen tissue samples are shipped on an excess of dry ice (-80°C) and FFPE samples at room temperature. Shipment is carried out by various certified courier services. At the moment, data loggers are not used. However, each confirmation of receipt of a shipment attests that sufficient dry ice was still present in the package.

Quality assurance measures
The sample handling is embedded in the quality management system of all cooperating laboratories, i.e. Department of Laboratory Medicine, Human Genetics or Pathology. Process control is based on the department's detailed SOPs.

Source of associated data
The Radboud Biobank requires some basic data for the catalogue, however, the department responsible for a specific disease-based biobank has defined a minimal dataset. This dataset comprises patient information collected in the context of routine daily clinical practice, among which are base-line data (patient history, physical examination, diagnostic investigations, imaging, pharmacy) and data obtained during the follow-up treatment of the patient.
To facilitate follow-up, connections to existing medical registries are actively sought. This includes, for example, links to registries for vital status, cause of death, hospitalization, cancer diagnoses and pathology records.
The Radboud Biobank guarantees the privacy of the participants. Biomaterial and associated clinical data are stored using unique codes. The key connecting these codes to patient identifiers is kept by the owner of the specific disease-based biobank. The software package for the research database produces the unique code also noted on the application form accompanying the biomaterial. The Radboud Biobank laboratory technician enters the same code in the laboratory sample management software system. Each month, the Radboud Biobank functional manager synchronizes the research database and the sample management system using study numbers. Pseudonymisation is mandatory since hospital patient identifiers do not adequately protect patient privacy. In situations of external use, Radboud Biobank identifiers are encrypted by a Trusted Third Party using TRES (Trusted Reversible Encryption Services).

Ethics Statement
All new biobank initiatives are assessed by the IRB. This board also evaluates each specific request for use of the biomaterial and accompanying data in subsequent research proposals. The IRB handles ethical assessment of biobank-related issues with consideration given to both quality (i.e. principles of Good Research Practice) and efficiency (i.e. high frequency of meetings, digital procedure). A positive assessment is followed by an immediate authoritative decision and fast delivery of the material to the researcher. The head of a sub-biobank must also agree to the intended delivery.
In general, patients are asked to give broad consent. The biomaterial and associated clinical data that have been stored in the Radboud Biobank are released for research purposes only, after being approved by the IRB.

Constraints
Geographical: the Radboud Biobank collects biomaterial primarily collected at the Radboudumc, a tertiary care hospital with a catchment area predominantly, though not exclusively, from the eastern part of the Netherlands.

Bioresource location
The Radboud Biobank is the central biobanking facility at the Radboudumc, Nijmegen, the Netherlands. The Radboud Biobank was implemented by the Radboudumc Executive Board as part of the university research infrastructure. The

Bioresource type
The Radboud Biobank is a hospital integrated biobank, i.e. all disease groups and clinical departments are represented. It stores all types of disease samples (see Table 1). Table 2 gives an overview of the disease categories that are included (as of July 2017). The Radboud Biobank catalogue provides real time information about the content of the Radboud Biobank.
A number of biobanks have recently received approval from the IRB and will start including data in the near future; these new biobanks include Hemangioma and congenital vascular malformations [7]

Type of sampling
The Radboud Biobank is a central biobanking facility for both common and rare diseases and comprises all types of collections, thus defined: − De novo biobanks: after careful appraisal of the scientific ambitions and the consequences for the choice of specific patient categories, prospective inclusion of new patients with explicit consent to donate additional biomaterial and associated data, on top of that obtained for diagnostics, for future research purposes; − Secondary use biobanks: left over material obtained in the diagnostic or therapeutic process, for which the patients did not object to secondary use for purposes of future research; − Clinical trials and non-experimental follow-up studies: material of patients participating with full informed consent in studies with a specific research purpose; after completion of the trial, consent may be requested to keep the remaining material for future research.

Anatomical site
The disease-based biobanks that are part of the Radboud Biobank (see Table 2) cover several anatomic sites of the human body.

Disease status of patients/source
See Table 2.

Clinical characteristics of patients/source
A full clinical characterisation, including patient history, physical examination, diagnostic investigations, imaging, pharmacy and follow-up is specified for each diseasebased biobank.

Vital state of patients/source
All patients are alive at inclusion.

Size of the bioresource
Currently, the Radboud Biobank has more than 350,000 aliquots comprising different biomaterials (e.g. DNA, plasma, serum, urine, CSF, faeces and tissue) from over 32,000 participants. The current number of unique patients included per disease-based biobank is shown in Table 2.

Clinical diagnosis of patients/source
The disease-based biobanks that are part of the Radboud Biobank (see Table 2) cover various clinical diagnoses.

Pathology diagnosis
The clinical diagnosis is registered using standard vocabulary (e.g. ICD-10 or SNOMED CT).

Control samples
The Radboud Biobank also has samples available from the general population (n = 6,737 -Nijmegen Biomedical Study [8] and n = 535 from the human functional genomics project [5]). The Nijmegen Biomedical Study [8] is a populationbased survey conducted by the Department for Health Evidence and the Department of Laboratory Medicine at the Radboudumc. This population biobank consists of questionnaire data plus serum and DNA samples. The aim of the human functional genomics project is to characterise the interaction between the genetic background of the host and the consequences on an array of physiological functions and, in a subgroup of individuals, the cognitive function of the brain [5]. One section of the project investigates these relationships in healthy individuals (n = 535), while the second part of the project will assess the disturbance of this balance in specific cohorts of patients (see Table 2).

Biospecimen type
Currently, a variety of biomaterials are stored in the Radboud Biobank. DNA is sampled and stored in almost all instances (96.6%), but the specific collection of other materials depends on the category of disease.

Release date
Biomaterial and the matching clinical data are currently available.

Access criteria
Biomaterial and clinical data from the Radboud Biobank are available to researchers worldwide. Each research application is reviewed by the IRB. Criteria used by the IRB for approval of  applications are listed in Table 3. Access is open for investigators from the department that initiated the diseased-based biobank and for investigators who seek cooperation with them. Cooperation with external researchers, including those working in the health industry, is encouraged. After the IRB has approved the research application and the head of a sub-biobank also agrees to the intended delivery, the Radboud Biobank delivers the data and requested biomaterials to the researchers. Prior to the release, a standard Material (or Data) Transfer Agreement must be signed, which states that the biomaterial will not be used for other purposes than the original agreement, will not be delivered to third parties, remaining biomaterial will be destroyed, and that feedback will be Table 3: Criteria used by the institutional review board to review applications for the use of biobank material and the accompanying clinical data.
provided regarding the findings, profits and publications. Furthermore, new information that becomes available through scientific analyses will be added to the Radboud Biobank database. Researchers using the samples and clinical data pay a fee per sample, which is based on the nature and quantity of the requested samples, and on the affiliation of the applicants. In addition, a fixed administrative fee is charged for each delivery. All revenues are used as return of investment.

(4) Reuse potential
Biomaterial and clinical data are provided to researchers on a non-exclusive basis, therefore samples from the same participant may be used in several different projects.
Any new research data generated by the delivered biomaterial will be shared with the Radboud Biobank. This new information from scientific analyses will be added to the Radboud Biobank database to make it available for future non-commercial clinical, research and educational purposes.