Multi-omics analysis reveals drivers of loss of β-cell function after newly diagnosed autoimmune type 1 diabetes: An INNODIA‡ multicenter study

Background Heterogeneity in the rate of β-cell loss in newly diagnosed type 1 diabetes patients is poorly understood and creates a barrier to designing and interpreting disease-modifying clinical trials. Integrative analyses of complementary multi-omics data obtained after the diagnosis of T1D may provide mechanistic insight into the diverse rates of disease progression. Methods We collected samples in a pan-European consortium that enabled the concerted analysis of five different omics modalities in data from 97 newly diagnosed patients. In this study we used Multi-Omics Factor Analysis to identify molecular signatures correlating with post-diagnosis decline in β-cell mass measured as fasting C-peptide. Results Two molecular signatures were significantly correlated with fasting C-peptide levels. One signature showed a correlation to neutrophil degranulation, cytokine signaling, lymphoid and non-lymphoid cell interactions and G-protein coupled receptor signaling events that were inversely associated with rapid decline in β-cell function. The second signature was related to translation and viral infection were inversely associated with change in β-cell function. In addition, the immunomics data revealed a Natural Killer cell signature associated with rapid β-cell decline. Conclusion Features that differ between individuals with slow and rapid decline in β-cell mass could be valuable in staging and prediction of the rate of disease progression and thus enable smarter (shorter and smaller) trial designs for disease modifying therapies, as well as offering biomarkers of therapeutic effect. Funding This work is funded by the Innovative Medicine Initiative 2 Joint Undertaking (IMI2 JU) under grant agreement N° 115797 (INNODIA) and N° 945268 (INNODIA HARVEST). This Joint Undertaking receives support from the Union’s Horizon 2020 research and innovation program and ‘EFPIA’, ‘JDRF’ and ‘The Leona M. and Harry B. Helmsley Charitable Trust’. ### Competing Interest Statement CM serves or has served on the advisory panel for Novo Nordisk, Sanofi, Merck Sharp and Dohme Ltd., Eli Lilly and Company, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Medtronic, ActoBio Therapeutics, Pfizer, Imcyse, Insulet, Zealand Pharma, Avotres, Mannkind, Sandoz and Vertex. Financial compensation for these activities has been received by KU Leuven; KU Leuven has received research support for CM from Medtronic, Imcyse, Novo Nordisk, Sanofi and ActoBio Therapeutics; CM serves or has served on the speakers bureau for Novo Nordisk, Sanofi, Eli Lilly and Company, Boehringer Ingelheim, Astra Zeneca and Novartis. Financial compensation for these activities has been received by KU Leuven. S.Br. reports ownerships in Intomics A/S, Hoba Therapeutics Aps, Novo Nordisk A/S, Lundbeck A/S, ALK A/S and managing board memberships in Proscion A/S and Intomics A/S. MK reports ownership and managing board membership in Vactech Oy. ### Funding Statement This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115797 (INNODIA) and No 945268 (INNODIA HARVEST). This Joint Undertaking receives support from the Union's Horizon 2020 research and innovation programme, "EFPIA", "JDRF" and "The Leona M. and Harry B. Helmsley Charitable Trust". Novo Nordisk Foundation grants (NNF17OC0027594 and NNF14CC0001) to S.B. are also acknowledged. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: NHS Health Research Authority London - City & East Reasearch Ethics Committee gave ethical approval for this work (IRAS Project ID 210497) Subsequently, after translation of the participants' documentation, ethical approval was obtained from the local Ethic authorities throughout the entire INNODIA clinical network listed below. Commissie Medische Ethiek UZ KU Leuven / Onderzoek ga Ethikkommission Medizinische Universitat Graz Center for sundhed Videnskabsetisk Komite COMITE DE PROTECTION DES PERSONNES SUD MEDITERRANEE III Helsingen Ja Uudenmaan Sairaanhoitopiiri MHH Ethikkommission OE 9515 Ethik-Kommission der Bayerischen Landesarztenkammer Uulm Ethikkommission Comitato Etico Regionale per la Sperimentazione Clinica della Regione Toscana Comitato Etico delle Province di Chieti e Pescara Ospedala San Raffaele, il Comitato Etico Il comitato Etico Bambino Gesu Ospedale Pediatrico Comite National d`ethique de recherche Regional Ethics Committee Ethics Committee of Silesia in Katowice Republic of Slovenia, THE NATIONAL MEDICAL ETHICS COMMITTEESökande forskningshuvudman, Region Skåne I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data generated and analysed is person-sensitive and can be accessed in secure environments only. Access can be provided by application to the INNODIA Data Access Committee.