An interconnected data infrastructure to support large-scale rare disease research
Authors: Johansson Lennart F , Laurie Steve , Spalding Dylan , Gibson Spencer , Ruvolo David , Thomas Coline , Piscia Davide , de Andrade Fernanda , Been Gerieke , Bijlsma Marieke , Brunner Han , Cimerman Sandi , Dizjikan Farid Yavari , Ellwanger Kornelia , Fernandez Marcos , Freeberg Mallory , van de Geijn Gert-Jan , Kanninga Roan , Maddi Vatsalya , Mehtarizadeh Mehdi , Neerincx Pieter , Ossowski Stephan , Rath Ana , Roelofs-Prins Dieuwke , Stok-Benjamins Marloes , van der Velde K Joeri , Veal Colin , van der Vries Gerben , Wadsley Marc , Warren Gregory , Zurek Birte , Keane Thomas , Graessner Holm , Beltran Sergi , Swertz Morris A , Brookes Anthony J ,   Solve-RD consortium, Riess Olaf , Haack Tobias B , Graessner Holm , Zurek Birte , Ellwanger Kornelia , Ossowski Stephan , Demidov German , Sturm Marc , Schulze-Hentrich Julia M , Schüle Rebecca , Xu Jishu , Kessler Christoph , Kellner Melanie , Synofzik Matthis , Wilke Carlo , Traschütz Andreas , Schöls Ludger , Hengel Holger , Lerche Holger , Kegele Josua , Heutink Peter , Brunner Han , Scheffer Hans , Hoogerbrugge Nicoline , Hoischen Alexander , ’t Hoen Peter A C , Vissers Lisenka E L M , Gilissen Christian , Steyaert Wouter , Sablauskas Karolis , de Voer Richarda M , Kamsteeg Erik-Jan , van de Warrenburg Bart , van Os Nienke , te Paske Iris , Janssen Erik , de Boer Elke , Steehouwer Marloes , Yaldiz Burcu , Kleefstra Tjitske , Brookes Anthony J , Veal Colin , Gibson Spencer , Maddi Vatsalya , Mehtarizadeh Mehdi , Riaz Umar , Warren Greg , Dizjikan Farid Yavari , Shorter Thomas , Töpf Ana , Straub Volker , Bettolo Chiara Marini , Manera Jordi Diaz , Hambleton Sophie , Engelhardt Karin , Clayton-Smith Jill , Banka Siddharth , Alexander Elizabeth , Jackson Adam , Faivre Laurence , Thauvin Christel , Vitobello Antonio , Denommé-Pichon Anne-Sophie , Duffourd Yannis , Bruel Ange-Line , Peyron Christine , Pélissier Aurore , Beltran Sergi , Gut Ivo Glynne , Laurie Steven , Piscia Davide , Matalonga Leslie , Papakonstantinou Anastasios , Bullich Gemma , Corvo Alberto , Fernandez-Callejo Marcos , Hernández Carles , Picó Daniel , Paramonov Ida , Lochmüller Hanns , Gumus Gulcin , Bros-Facer Virginie , Rath Ana , Hanauer Marc , Lagorce David , Hongnat Oscar , Chahdil Maroua , Lebreton Emeline , Stevanin Giovanni , Durr Alexandra , Davoine Claire-Sophie , Guillot-Noel Léna , Heinzmann Anna , Coarelli Giulia , Bonne Gisèle , Evangelista Teresinha , Allamand Valérie , Nelson Isabelle , Yaou Rabah Ben , Metay Corinne , Eymard Bruno , Cohen Enzo , Atalaia Antonio , Stojkovic Tanya , Macek Milan , Turnovec Marek , Thomasová Dana , Kremliková Radka Pourová , Franková Vera , Havlovicová Markéta , Lišková Petra , Doležalová Pavla , Parkinson Helen , Keane Thomas , Freeberg Mallory , Thomas Coline , Spalding Dylan , Robinson Peter , Danis Daniel , Robert Glenn , Costa Alessia , Patch Christine , Hanna Mike , Houlden Henry , Reilly Mary , Vandrovcova Jana , Efthymiou Stephanie , Morsy Heba , Cali Elisa , Magrinelli Francesca , Sisodiya Sanjay M , Rohrer Jonathan , Muntoni Francesco , Zaharieva Irina , Sarkozy Anna , Timmerman Vincent , Baets Jonathan , de Vries Geert , De Winter Jonathan , Beijer Danique , de Jonghe Peter , Van de Vondel Liedewei , De Ridder Willem , Weckhuysen Sarah , Nigro Vincenzo , Mutarelli Margherita , Morleo Manuela , Pinelli Michele , Varavallo Alessandra , Banfi Sandro , Torella Annalaura , Musacchia Francesco , Piluso Giulio , Ferlini Alessandra , Selvatici Rita , Gualandi Francesca , Bigoni Stefania , Rossi Rachele , Neri Marcella , Aretz Stefan , Spier Isabel , Sommer Anna Katharina , Peters Sophia , Oliveira Carla , Garcia-Pelaez Jose , Barbosa-Matos Rita , José Celina São , Ferreira Marta , Gullo Irene , Fernandes Susana , Garrido Luzia , Ferreira Pedro , Carneiro Fátima , Swertz Morris A , Johansson Lennart , van der Velde Joeri K , van der Vries Gerben , Neerincx Pieter B , Ruvolo David , Abbott Kristin M , Frederikse Wilhemina S Kerstjens , Zonneveld-Huijssoon Eveline , Roelofs-Prins Dieuwke , van Gijn Marielle , Köhler Sebastian , Metcalfe Alison , Verloes Alain , Drunat Séverine , Heron Delphine , Mignot Cyril , Keren Boris , de Sainte Agathe Jean-Madeleine , Rooryck Caroline , Lacombe Didier , Trimouille Aurelien , De la Paz Manuel Posada , Sánchez Eva Bermejo , Martín Estrella López , Delgado Beatriz Martínez , de la Rosa F Javier Alonso García , Ciolfi Andrea , Dallapiccola Bruno , Pizzi Simone , Radio Francesca Clementina , Tartaglia Marco , Renieri Alessandra , Furini Simone , Fallerini Chiara , Benetti Elisa , Balicza Peter , Molnar Maria Judit , Maver Ales , Peterlin Borut , Münchau Alexander , Lohmann Katja , Herzog Rebecca , Pauly Martje , Macaya Alfons , Cazurro-Gutiérrez Ana , Pérez-Dueñas Belén , Munell Francina , Jarava Clara Franco , Masó Laura Batlle , Marcé-Grau Anna , Colobran Roger , Osorio Andrés Nascimento , de Benito Daniel Natera , Lochmüller Hanns , Thompson Rachel , Polavarapu Kiran , Grimbacher Bodo , Beeson David , Cossins Judith , Hackman Peter , Johari Mridul , Savarese Marco , Udd Bjarne , Horvath Rita , Chinnery Patrick F , Ratnaike Thiloka , Gao Fei , Schon Katherine , Capella Gabriel , Valle Laura , Holinski-Feder Elke , Laner Andreas , Steinke-Lange Verena , Schröck Evelin , Rump Andreas , Başak Ayşe Nazlı , Hemelsoet Dimitri , Dermaut Bart , Schuermans Nika , Poppe Bruce , Verdin Hannah , Mei Davide , Vetro Annalisa , Balestrini Simona , Guerrini Renzo , Claeys Kristl , Santen Gijs W E , Bijlsma Emilia K , Hoffer Mariette J V , Ruivenkamp Claudia A L , Boztug Kaan , Haimel Matthias , Maystadt Isabelle , Cordts Isabell , Deschauer Marcus , Zaganas Ioannis , Kokosali Evgenia , Lambros Mathioudakis , Evangeliou Athanasios , Spilioti Martha , Kapaki Elisabeth , Bourbouli Mara , Striano Pasquale , Zara Federico , Riva Antonella , Iacomino Michele , Uva Paolo , Scala Marcello , Scudieri Paolo , Cilio Maria-Roberta , Carpancea Evelina , Depondt Chantal , Lederer Damien , Sznajer Yves , Duerinckx Sarah , Mary Sandrine , Depienne Christel , Roos Andreas , May Patrick 
Published: September 2024

Abstract
The Solve-RD project brings together clinicians, scientists, and patient representatives from 51 institutes spanning 15 countries to collaborate on genetically diagnosing (“solving”) rare diseases (RDs). The project aims to significantly increase the diagnostic success rate by co-analyzing data from thousands of RD cases, including phenotypes, pedigrees, exome/genome sequencing, and multiomics data. Here we report on the data infrastructure devised and created to support this co-analysis. This infrastructure enables users to store, find, connect, and analyze data and metadata in a collaborative manner. Pseudonymized phenotypic and raw experimental data are submitted to the RD-Connect Genome-Phenome Analysis Platform and processed through standardized pipelines. Resulting files and novel produced omics data are sent to the European Genome-Phenome Archive, which adds unique file identifiers and provides long-term storage and controlled access services. MOLGENIS “RD3” and Café Variome “Discovery Nexus” connect data and metadata and offer discovery services, and secure cloud-based “Sandboxes” support multiparty data analysis. This successfully deployed and useful infrastructure design provides a blueprint for other projects that need to analyze large amounts of heterogeneous data.