Blood Transcriptome Profiling Links Immunity to Disease Severity in Myotonic Dystrophy Type 1 (DM1)

We expect a to-the-point but comprehensive plan for use, which is aimed at the advancement of scientific and medical research. When publishing based on this data, you agree to acknowledge all those as outlined in the data access policy. Under no circumstance anything from this dataset may be shared with others that are not mentioned in the application. The access request form can be found as an appendix to the data access policy document.

Full blood mRNA sequencing of myotonic dystrophy patients after cognitive behavioural therapy: Access to Data General Policy principles Funded by the European Community's Seventh Framework Programme (FP7/2007–2013) the OPTIMISTIC consortium and in addition eRARE, the ReCognitION consortium (hereinafter also referred to as the “Project”, “Consortium” or “OPTIMISTIC”) has sequenced total blood RNA of 32 myotonic dystrophy type 1 (DM1) patients from four different European centers. The Project is led by Baziel van Engelen, Jeffrey Glennon and Peter-Bram ‘t Hoen from Radboud University Medical Centre in Nijmegen, the Netherlands (“Radboudumc”). The primary goal of OPTIMISTIC is to identify biomarkers for clinical response to cognitive behavioral therapy (CBT) and CBT in combination with graded exercise therapy (CBT + GET) in DM1. The Consortium is willing to consider applications from third party researchers for access to the anonymized RNA sequence and phenotype data generated by the Project. See also the Project website: https://optimistic-dm.eu/recognition/ Access to Project Data will be granted to qualified researchers for approved use and will be governed by the provisions laid out in the associated informed consent of individual data subjects for each cohort and/or of the associated ethics committee approval of the associated cohort, the Data Access Procedure set forth below and the terms of the Data Access Agreement attached hereto. A qualified researcher refers to a senior investigator who is employed or legitimately affiliated with an academic, non-profit or government institution and who has a track record in the field. Access to Project Data is available by application to the OPTIMISTIC Data Access Committee. Researchers granted access to Project Data must feedback the results of their research to OPTIMISTIC, after publication in accordance with the OPTIMISTIC publication policy set forth in the Data Access Agreement. Access is conditional upon availability of data and on signed agreement by the researcher(s) and the responsible employing institution to abide by the policies and conditions related to publication, data ownership, data return, intellectual property rights, data disposal, ethical approval, confidentiality and commercialization referred herein. Data Available The following Project Data are available: Full blood mRNA sequencing data: Blood drawn within the framework of the OPTIMISTIC trial (https://pubmed.ncbi.nlm.nih.gov/26002596/ and https://pubmed.ncbi.nlm.nih.gov/29934199/) was collected in Tempus blood RNA tubes (Life Technologies, NY, USA) and stored at -80 degrees for 5-6 years. Total RNA was extracted using MagMAX kit (Thermo Fisher Scientific, MA, USA), according to the manufacturer’s instructions. RNA samples were further quantified using the NanoDrop 1000 Spectrophotometer and Qubit Fluorometer (Thermo Fisher Scientific, MA, USA) and RNA integrity was assessed with the 2200 TapeStation Instrument (Agilent Technologies, CA, USA). Globin mRNAs and ribosomal RNAs were depleted using the Globin-Zero Gold rRNA Removal Kit (Illumina). Barcoded RNA libraries were generated according to the manufacturer’s protocol using the Ion Total RNA-Seq Kit v2 and the Ion Xpress RNA-Seq barcoding kit (Thermo Fisher Scientific). The size and concentration of the libraries were assessed using the 2200 TapeStation System. Sequencing templates were prepared on the Ion Chef System using the Ion PI Hi-Q Chef Kit (Thermo Fisher Scientific). Sequencing was performed on an Ion Proton machine using an Ion PI v3 chip (Thermo Fisher Scientific) according to the manufacturer’s instructions. Collected also during the OPTIMISTIC trial are the following genotype and patient characteristic data: AgeBaseline: age of the patient at the start of the trial (years) ePAL: estimated progenitor allele length V2Mode: modal CTG-repeat length at baseline CTGDiagnostic: CTG repeat length at diagnosis VariantRepeats: whether patient had a variant repeat (all 0=no variant repeat) Collected also during the OPTIMISTIC trial is the following phenotype data, consisting of clinical outcome measures at baseline and after 10 months of CBT: DM1ActivC: DM1ActivC MDHI: Myotonic Dystrophy Health Index INQOLQol: Individualized Neuromuscular Quality of Life Questionnaire. Domain: quality of life ASBQ: Adult Social Behavioral Questionnaire ICQ: Illness Cognition Questionnaire. Subscale: acceptance IMQ: Illness Management Questionnaire CISactivity: Checklist Individual Strength. Subscale: activity 6MWT: Six-minute walk test L5ENMO: Activity during the 5 least active hours of the day (negative control) M5ENMO: Activity during the 5 most active hours of the day MeanENMO: Accelerometery, mean of euclidian norm minus one PreBORG: Borg Scale measurement after SMWT FDSS: Fatigue and Daytime Sleepiness Scale CISFatigue: Checklist Individual Strength. Subscale: fatigue JFCS: Jacobsen Fatigue Catastrophizing Scale TMT: Trail Making Test (TMTB/TMTA) StroopInterference: Stroop colour-word interference score ((60 - stroopCardIIIErrors/60) / stroopCardIIITime /(60 - stroopCardIIErrors)/60) / stroopCardIITime McGillPain: McGILL Pain Questionnaire: short version BDIFs: Beck Depression Inventory: fast screen SSLD: Social Support: Discrepancies SSLI: Social Support: Interactions SSLN: Social Support: Negative Interactions AEScScore: Apathy Evaluation Scale: clinical version Data Access Committee Applications for access to Project Data must be made to the ReCognitION Data Access Committee (DAC). The OPTIMISTIC DAC consists of Baziel van Engelen, Peter-Bram ‘t Hoen, Jeffrey Glennon, Guillaume Bassez, Benedikt Schoser and Grainne Gorman. Data Access Procedure 1. Application for Access The handling of applications, the issue of Project Data and any associated operations, administration and audits will be performed by the Radboudumc on behalf of the Consortium. Applications for Access to Project Data must be submitted using the online EGA data request procedure and using the form in Appendix 1. The information disclosed in the application will be treated as confidential and will only be disclosed to the persons evaluating the application. All incoming applications will be documented, including any conjunct agreements with the applicants. Unless explicitly consented for by the applicant, this information will not be used for purposes other than evaluation of the application. The research topic of the applications which have been granted will be published on the website of the Project. Applications which have not been granted will not be published. In cases where an application contains classified plans, know-how or trade secrets, the applicant may request the conclusion of a separate confidentiality agreement. 2. Multiple applications Applicants agree to use the Project Data for the approved purpose and project described in the application; use of the data for a new purpose or project will require a new application and approval. The DAC will consider applications that include named collaborators, but each Institution must sign a separate Data Access Agreement. In the event an applicant wishes to share the data with additional collaborators not previously approved, these additional collaborators must make a separate application for access to the Project Data. In the event two or more applications overlap, the DAC may propose the respective applicants to align their applications. 3. Assessment criteria Applications which seek to reserve Project Data for unspecified research goals will not be taken into consideration. Applications for access to Project Data must be Specific, Measurable, Attainable, Resourced and Timely (SMART). Specifically, the OPTIMISTIC DAC will assess each application to determine whether: i. it has been submitted by a qualified researcher or researchers, who is employed by or legitimately affiliated with a recognized research institution that can provide institutional responsibility for appropriate research governance; ii. its proposed use of the Project Data is in accordance with and meets the objectives of the OPTIMISTIC trial Project and the objectives of the associated cohorts and collections; iii. its proposed use of the Project Data constitutes research in the context of the individual sample donor consent process, and is likely to be understood as such by the individual sample donors; iv. it would breach any of the ethical permissions or restrictions in the consent forms for any component cohort; v. all required ethico-legal approvals, restrictions and commitments for the proposed use of the Project Data have been obtained and adhered to; vi. the proposed research has any adverse potential impact, specifically whether the proposed research could affect minorities; vii. the nature of the funding of the application and the applicant; viii. the research proposal has been peer-reviewed, and, if not, whether the proposal satisfies applicable scientific standards; ix. the requested data are, quantitatively and qualitatively, suitable and not excessive for the applicant’s proposed research; x. there are any similar applications pending or granted; xi. the proposed use of the Project Data has the potential to produce information that will enable identification of the individual sample donors. xii. In the event the applicant(s)’ proposed use of Project Data involves use of his/their your own data the applicant has warranted that he has obtained all required ethico-legal approvals, restrictions and commitments, without limitation his data subject consent and approval of his pertinent medical ethical review board, for his proposed use of his data in combination with the Project Data, as appropriate. 4. Access decision The DAC will decide on an application within a reasonable period of time after it has received all pertinent information. If the DAC grants an application, additional agreements may be made regarding authorships along the lines set forth in the Publication Policy attached to the Data Access Agreement. Rejections of applications will be motivated. Mode of Access to Data; restrictions and authentication The Consortium will make the pseudonymised Project Data available through the European Genome Phenome Archive (EGA), hosted at the European Bioinformatics Institute. Issue of Project Data may be subject to restrictions pursuant to data subject’s or ethics committee’s consent. The issue of Project Data and the Data Access Agreement will be administered by Radboudumc. Data Access Conditions Access to Project Data is conditional on prior receipt by the Consortium of the Data Access Agreement attached as Appendix 2 hereto, signed and dated by the applicant(s) and the responsible employing Institution(s). Authors who use Project Data must: 1. Acknowledge the OPTIMISTIC Consortium using the following wording: "This study makes use of data generated by the OPTIMISTIC Consortium. A full list of the investigators is available from https://optimistic-dm.eu/recognition/. Funding for the project was provided by European Community's Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 305697 (OPTIMISTIC). In addition, funding has been received under the European Community's E-RARE programme under grant agreement no. 18-038 (ReCognitION) “ 2. Acknowledge, by reference, the OPTIMISTIC trial where the samples and Project Data have been derived from: Okkersen K, Jimenez-Moreno C, Wenninger S, Daidj F, Glennon J, Cumming S, Littleford R, Monckton DG, Lochmüller H, Catt M, Faber CG, Hapca A, Donnan PT, Gorman G, Bassez G, Schoser B, Knoop H, Treweek S, van Engelen BGM; OPTIMISTIC consortium. Cognitive behavioural therapy with optional graded exercise therapy in patients with severe fatigue with myotonic dystrophy type 1: a multicentre, single-blind, randomised trial. Lancet Neurol. 2018 Aug;17(8):671-680. doi: 10.1016/S1474-4422(18)30203-5. Epub 2018 Jun 19. PMID: 29934199. 3. Cite the relevant primary OPTIMISTIC publication by Nieuwenhuis, Widomska, Blom, the OPTIMISTIC consortium, van Engelen, ‘t Hoen and Glennon (details of which can be found on the project website: https://optimistic-dm.eu/recognition/). Application Form for Access to OPTIMISTIC Data PLEASE SUBMIT COMPLETED, SIGNED AND DATED FORM BY EMAIL TO: peterbram.thoen@radboudumc.nl 1. Name and position of the Applicant(s), including employment or affiliation with any organization Please ensure that a full postal and email address is included for each applicant. 2. Title of the study In less than 30 words. 3. Research Question Please describe the study in no more than 750 words. Include: a. outline of the study design; b. an indication of the methodologies to be used; c. proposed use of the Project Data; d. preceding peer-reviews of the study (if any present); e. specific details of what you plan to do with the Project Data; f. timeline; g. key references.   4. Consent and Approvals Does your proposed use of Project Data involve use of your own data? Yes […..] No […..] If Yes, with signing this document you confirm the following: ‘I confirm that I have obtained all approvals required by the rules and regulations of my jurisdiction, including my institution’s institutional rules, and the consent of my data subjects, for my use of my own data in combination with the Project Data in the study.’ 5. Resources, Feasibility & Expertise Please confirm that you have secured funding for your proposed use of the Project Data and that you will carry out your research within a reasonable period of time after the granting of this application: by ticking the following box: Yes, we will □. Please describe your experience and expertise, and that of your collaborators, and how this will be applied to the proposed study (in 250 words). Please provide a list of recent publications (max. 10). Appendix 2 Data Access Agreement This agreement governs the terms on which access will be granted to the Project Data generated by the OPTIMISTIC Project. In signing this agreement, You are agreeing to be bound by the terms and conditions of access set out in this agreement. For the sake of clarity, the terms of access set out in this agreement apply both to the User and the User’s Institution (as defined below). User Institution and User are referred to within the agreement as “You” and “Your” and shall be construed accordingly. Definitions: “Consortium” refers to the OPTIMISTIC Consortium, comprising Radboud University Medical Center, Newcastle University, Ludwig-Maximilians-University Munich, l’Assistance Publique-Hôpitaux de Paris, The University of Glasgow, University of Dundee, Concentris research management. “Project” refers to the OPTIMISTIC project as described in the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 305697 (OPTIMISTIC) “Project Data” refers to the human genomic data generated by the Project. “Data Subject” refers to the person whose sample has been used to generate Project Data. “User” refers to a researcher who has successfully applied for access to Project Data. “Publications” refers to, without limitation, articles published in print journals, electronic journals, reviews, books, posters and other written and verbal presentations of research. “User Institution” refers to the organization with which the User is employed, affiliated or enrolled. Terms and Conditions: In signing this Agreement: 1. You agree to use Project Data only for the advancement of scientific and medical research. 2. You agree not to use, and not to allow use of, Project Data or any part thereof for the creation of products or services for sale or for any commercial purpose, whether sale by You or by third parties. 3. You acknowledge that the Project Data You receive is pseudonymised and that the Consortium will under no circumstances provide You with any means to identify any Data Subject. You agree not to use Project Data to identify or contact individual Data Subjects. You agree to preserve, at all times, the confidentiality of information and Project Data. In particular, You undertake not to use, or attempt to use Project Data to compromise or otherwise infringe the confidentiality of information on Data Subjects and their right to privacy. 4. You agree to disclose Project Data only to those of Your employees who strictly need access to it for the purpose of your approved study (Authorized Recipients), and who are bound by a duty of confidentiality which is at least as strict as provided for in this agreement. 5. You agree to ensure that any Authorized Recipient who has access to Project Data is advised of the confidentiality of Project Data. Upon request by the Consortium, you agree to furnish the Consortium the names of all Authorized Recipients who have gained access to Project Data. You agree that You are responsible for all breaches of confidentiality and of the terms of this agreement by your Authorized Recipients. 6. You agree to store Project Data on a computer with adequate security controls that prevent unauthorized access to or loss of Project Data and to maintain appropriate control over the Project Data. You represent and warrant that You have in place, and You agree that You will keep having in place, state of the art technical and organizational security measures preventing unauthorized access and loss of Project Data or other forms of unlawful processing of Project Data, including without limitation, physical security measures, access controls, security and privacy technologies, security checks in relation to personnel, security incident response management and audit arrangements. You agree to notify forthwith the administrator of the Project, Radboudumc, of any violations of the foregoing. 7. You represent and warrant that you have obtained and adhered to all required ethico-legal approvals, restrictions and commitments, without limitation data subject consent and approval of the pertinent medical ethical review board, for Your proposed use of Your data in combination with the Project Data. 8. In the event the Project Data is issued to You subject to any Data Subject’s restrictions, you hereby assume the obligation to abide by these restrictions as Your own obligation towards the Data Subject. You agree that Data Subjects can enforce such restrictions as well as any pertinent provisions of this agreement as third-party beneficiaries and, in the event they choose to do so, that You will not object to Data Subjects being represented by an association or other bodies if they so wish. You agree that a Data Subject who has suffered damage(s) as a result of any violation by You of pertinent provisions in this Agreement or of applicable legislation, is entitled to receive compensation from You for the damage(s) suffered. You agree that, in the event of such a violation, the Data Subject may bring an action before a court within the Data Subject’s jurisdiction against You. 9. You agree not to attempt to link Project Data to other information or archive data available for the data sets provided to You under this agreement, even if access to that data has been formally granted to you, or it is freely available without restriction, without the required consents and approvals. You agree to retain control over Project Data, and NOT TO DISTRIBUTE (individual-level or aggregated) Project Data provided under this agreement, in any form, to any entity or individual. 10. You agree not to transfer, share or disclose Project Data, in whole or in part, to or with anybody else, whether or not he or she is affiliated with Your institution, unless he or she is a named and approved collaborator under the OPTIMISTIC Data Access Procedure. 11. You agree to use Project Data for the purpose and project described in your application (nr.____________________), as approved by the OPTIMISTIC Data Access Committee; use of the data for a new purpose or project or by another researcher will require a new application and approval. Substantive modification of the original application requires submission of an amendment to the original application. 12. You agree to, when analyses result in newly estimated variables at an individual level (e.g. haplotypes), submit these new variables for archiving with the Consortium. This should be done no later than that the related paper will be submitted for publication. 13. You accept that Project Data will be reissued from time to time, with suitable versioning. If the reissue is at the request of sample donors and/or subject to other ethical scrutiny, You will destroy earlier versions of the Project Data. 14. You agree to destroy the Project Data after the resulting paper has been published. To meet journals’ requirements for availability of Project Data for reviewers to see and readers to use, you agree to refer to the availability of the Project Data as deposited with EGA, under the terms hereof. You agree that the availability of the data resulting from your study of the Project Data for reviewers to see and readers to use is subject to this Access Policy, Procedure and this Data Access Agreement. 15. You agree to acknowledge in any work based in whole or in part on Project Data, the published paper from which the Project Data derives, the version of the data, and the role of the Consortium and the relevant primary collectors and their funders, as per the wording provided in the paragraph “Data Access Conditions”. 16. You accept that the Consortium, the original Project Data generators and the funders of the Project Data: a) bear no legal responsibility whatsoever for the accuracy, completeness or comprehensiveness of the Project Data; and b) accept no liability for direct, indirect, consequential or incidental, damages or losses arising from any use of Project Data by anyone, including without limitation any clinical use and any commercial use thereof, or arising from the unavailability of, or break in access to, the Project Data for whatever reason. 17. You understand and acknowledge that Project Data are protected by copyright, database right and other intellectual property and proprietary rights, and that duplication, sale, licensing or any other form of disposing or distribution or making available, of all or part of the Project Data on any media is not permitted. 18. You acknowledge that the Project Data are made available to you under this agreement on the title of unassignable, non-exclusive “loan”. You recognize that nothing in this agreement shall operate to transfer to You any rights, including but not limited to intellectual property rights and database rights, in or relating to Project Data. 19. You accept that this agreement will terminate immediately upon any breach of this agreement by You and You will be required to destroy any Project Data held. 20. You accept that it may be necessary for the Consortium or its appointed agent to alter the terms of this agreement from time to time in order to address new concerns. In this event, the Consortium or its appointed agent will contact You to inform You of any changes and You agree that Your continued use of Project Data shall be dependent on the parties entering into a new version of the agreement. 21. You agree that You will submit a report to the Consortium Data Access Committee, if requested, on completion of your study of the Project Data. Such report will include the data resulting from your study of the Project Data. The Consortium Data Access Committee agrees to treat the report and all information, data, results, and conclusions contained within such report as confidential information. 22. You accept that Project Data may be protected by and subject to national and international laws and that You are responsible for ensuring compliance with any such applicable law. The Consortium Data Access Committee reserves the right to request and inspect Your data security and management documentation to ensure the adequacy of data protection measures in countries that have no national laws comparable to that which pertain in the European Economic Area (EEA). 23. This agreement shall be construed, interpreted and governed by the laws of the Netherlands. Signed by: ……………………………………………………………. ………………………………….……………………………………. Name of Applicant: Legal representative of Applicant’s Institution: Affiliation of Applicant with Institution: Name of Applicant’s Institution: ……………………………………………………………. ……………………………………………………………………….. Place:………………………………………………….. Place:……………………………………………………………… Date:…………………………………………………… Date:……………………………..……………………………….. Stamp or Seal of Applicant’s Institution: ………………………………………………………………………..