ScATtEred Rare Disease Biobanks: a Model of Sample/Data Collection With susTainablE and Shared Criteria

Specific aim 1. Establishment of the Scattered RD Biobank. The aim of our project is to create the Scattered RD biobank as a network of novel dedicated and already existing biobank in order to overcome RD biological sample scarcity and to make high quality material available for future collaborative studies in national and international cooperation. The network will include mainly biobanks focused on cardiovascular and neurological RDs. It will be organized according to a bidirectional Hub\&Spoke model in which each RD biobank serves as a centralised hub for samples and data collected from RD patients who refer to its own Institution/Centre and as a spoke for the other RD biobanks of the network. Each biobank will serves as hub for sample/data collection from RD patients who refer to other RD reference centres scattered throughout the territory and which do not have organized biobank according to the modern definition of biobank. This approach will favours the connection of different biobanks geographically spread through the Country and will avoid patient migration towards the biobank of interests. Two principal hubs will be defined: the Northern Hub to which the RD biobanks and RD Reference Centres of northern Italy will refer; and the Southern Hub to which the RD biobanks and RD Reference Centres of central and Southern Italy will refer. A Biospecimen Inventory Catalogue will be created and the description of all the procedures used for these collections (SOPs, sample associated data, ethical and legal documents) will be related to each sample and data.

Specific aim 2. Harmonization, Standardization and Network Governance. According to ISO 20387 that illustrates the general requirements for biobanking, Standard Operating Procedures (SOPs) will be defined to ensure consistency and standardization of practice (collection, preparation, storage and distribution of biological material as well as related information and data) in each single biobank. The biological samples from RD patients collected in the Scattered RD Biobank will be obtained following the specific SOPs generated for the collection of RD biological samples suitable for Omics approaches. SOPs will be generated for every stages of the pre-analytical process from collection to storage and more for the sharing of samples. The creation of the Scattered RD Biobank as biobank network needs of a rigorous Quality Management System (QMS) which is necessary to minimize inter-laboratory and intercentre variation and to guarantee the quality of the sample to be distributed in the collaborative projects. The QMS includes: (1) Quality Assurance to standardize all stages of the biobanking process, (2) Quality Controls (QC) on samples in order to validate the sample management process, to ensure reproducible quality and to the reliability of the storage procedures and the stability of the samples over time. QC will be performed both on the historical and new collections of RD biological samples to maximize experiment success and reliable interpretation of results. Sample QC will give valuable information to take preventive or corrective measures early, saving costs and reducing the risk of experimental errors. The most appropriate tools (markers and assays) that can be used to assess pre-analytical variations for both fluid and solid tissuederived samples will be defined for a better standardization between RD biobank laboratories. Data on biological samples and clinical information corresponding to the samples will be collected using a common database. The objective will be to harmonize and standardize the rules of communication between RD biobanks on the level of information about the donor and to facilitate sample location and access. To address these issues, a communication protocol according to MIABIS will be designed for the minimum information required to initiate collaborations among biobanks and to enable the exchange of biological samples. To facilitate harmonization of the different biobanks in the network, common regulations and fundamental ethical and legal documents will be also elaborated. Moreover, a website of the biobank network will be created to increase the visibility of the tool and to share all the elaborated documents. The website will include a \"virtual biobank\", an online catalogue of biological specimens stored in the biobanks. The virtual biobank will quickly and efficiently help investigators to find biospecimens that are located in different biobanks and will promote transparent sharing of bioresources in order to facilitate national and international collaborations. Specific aim 3.RD biobank upgrading and creation of novel RD biobanks. The already existing RD biobanks in the network will be implemented in terms of numerosity of samples collected and organization of the sample collections according to the common SOPs. All samples will be linked to relevant personal and health information, including health records, family history and lifestyle. They will be further characterized through genome data analysis and the phenotype regularly updated through follow-up visits. Novel biobanks will be established and dedicated to biological material and associated data deriving from subjects carrying Huntington disease (HD) mutations, Marfan Syndrome (MS), Hereditary Angioedema (HAE) and Congenital Heart Diseases (CHD). HD is a rare genetic neurodegenerative condition that today affects 1 out over 10,000 persons in Europe. The disease affects more than 6,000 people in Italy and around 40,000 people are considered \'at risk\' of developing symptoms later in life. Although the disorder is well studied and characterized, much remains to be investigated on the diversity of symptoms among patients even within the same family. To this regard, the Centre for Rare Diseases of IRCCS Neuromed and the Untà Ricerca e Cura Huntington e Malattie Rare of IRCCS CSS are both recognized as reference centers for the disease at a national and international level. LIRH Foundation is a European HD Network site connected with HD family organizations across the Country. Its collaboration will guarantee the collection of clinical data which will be stratified according to disease stage and origin of samples from all over Italy. MS is a rare genetic condition happening in about 1 in 5,000 people and it is caused by a mutation in a gene called FBN1. MS affects connective tissue but it damages the blood vessels, heart, eyes, skin, lungs, and the bones of the hips, spine, feet and rib cage. Some complications of MS can be very serious, like an aneurysm (bulge) of the aorta. HAE is a rare, genetic disease characterized by unpredictable, recurrent episodes of skin and mucosal swelling most commonly caused by C1-inhibitor deficiency. The prevalence of HAE is estimated to be approximately 1 in 50,000 people worldwide. IRCCS Policlinico San Donato is a member of the ERN Guard Heart network, member of ITACA (Italian Network for Hereditary and Acquired Angioedema) and the headquarters of Cardio Vascular Genetics Centre. The establishment of a dedicated biobanks, will be an innovative and valuable tool for exploring genotype-phenotype correlations and molecular mechanisms underlying such a large variability. The establishment of these novel RD biobanks, will significantly impact on the national and international competitiveness of Italian biomedical research. The advantage of creating this kind of biobanks will result in having the possibility to collect multiple biological samples over the time during disease progression for each single subject. The function of the Scattered RD Biobank as research resource calls into question the processes and practices for recruitment, participation and engagement. The role of biobank participants is often passive after the initial enrolment and sample collection. However, to improve transparency and to demonstrate trustworthiness of the biobanks of the network, participants will be actively involved beyond the initial face-to-face towards more interactive dialogues with the research teams. Considering biobanking as a service for patients, a collaboration between RD biobanks of the network and Patient Organisations will be defined promoting dedicated meetings, round-tables and focus groups. A strong collaboration between RD biobanks and Patient Organisations will be also crucial to achieve the integration of sample data stored in biobanks and clinical data stored in registries or clinical databases.

WP1. Hub\&Spoke model. The Scattered RD biobank will be created as a network of already existing and novel dedicated biobank mainly focused on cardiovascular and neurological RDs, according to a bidirectional Hub\&Spoke model. The model will include two principal hubs, the Northern Hub and the Southern Hub , which already have experience in establishing of biobank networks. The objectives of these principal hubs will be: 1. To coordinate the creation of the Scattered RD biobank through the standardization and harmonization of all the procedures of the biobanking process.

Standard Operating Procedures (SOPs) for collection, processing and storage, quality control management, Ethical Legal Social Issue (ELSI) and uniformity in governance will be generated since biobanks will act as a single entity. 2. To manage and facilitate the connection of different biobanks and RD Reference Centres geographically spread through the Country. Virtual and in presence meetings between the representatives of the biobanks and of the RD Reference Centres will be periodically organized. 3. To be reference biobanks for RD Reference Centres scattered throughout the territory which do not have the facilities to collect samples and data for research studies, or for RD Reference Centres which have already collected samples and data but do not have a modern defined biobank and wish to be part of the Scattered RD biobank.

OU1 will be reference biobank of RD Reference Centres of Northern Italy and OU3 of RD Reference Centres of Central and Southern Italy. 4. To coordinate the creation of a Biospecimen Inventory Catalogue of samples/data collections already present in the biobanks of the network. A questionnaire will be generated and shared among the Units participating to this project and to the new biobanks or RD Reference Centres that desire to be part of the network. Questions will regard both information on the biobank infrastructures and facilities of the institution where the collection are stored and on the historical samples/data collections (SOPs developed and used for the collection, processing and storage, type of samples and associated data collected, number of patients involved, ethical and legal documents used, Quality Assurance policies). Moreover, the bidirectional model will plan that each Unit will be a centralised hub for historical and new collections from RD patients who refer to its own Institution/Centre and will be also a spoke for the network. Each Unit will collect and store new biological samples and associated data of patients with RDs and syndromes according to the SOPs and to the policies elaborated. Each Unit will be responsible of their own samples/data collection and will manage them according to the network governance.

WP2. Quality Manual: i) procedures for samples processing (e.g. aliquoting, storage and QC), supplies, equipment, instruments, reagents and labels; ii) procedures for obtaining informed consent and withdrawal of consent from participants; iii) management policies, including access control, backup systems, clinical annotation, document maintenance and archiving; iv) procedures for sample sharing and receiving, including methods and equipments; v) procedures for cost recovery; vi) organizational requirements (governance).

WP2.1 SOPs for the biobanking workflow according to official guidelines: 1. pre-analytical conditions (collecti