Methodological Advances in Patient-centered Rare Disease Research: the UTHealth Houston Turner Syndrome Society of the United States Research Registry

Methodological Advances in Patient-centered Rare Disease Research: the UTHealth Houston Turner Syndrome Society of the United States Research Registry | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Methodological Advances in Patient-centered Rare Disease Research: the UTHealth Houston Turner Syndrome Society of the United States Research Registry Sara Mansoorshahi, Cindy Scurlock, Scientific Advisory Board of the Turner Syndrome Research Registry, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3844775/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Mar, 2024 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted 5 You are reading this latest preprint version Abstract Background: Many different clinical specialists provide care to patients with Turner syndrome (TS), who have highly variable clinical manifestations. Therefore, a national TS registry is essential to inform a cohesive approach to healthcare and research. In 2015, the Turner Syndrome Society of the United States (TSSUS) created the Turner Syndrome Research Registry (TSRR) to engage directly with community participants who voluntarily provide longitudinal data about their experiences with TS. TSRR projects are collaborative partnerships between people with TS, TSSUS, and researchers. Results: To ensure that registry workflows conform to the data privacy choices of participants, TSSUS collaborated with UTHealth Houston in 2021 to create a new version of the TSRR that completely separates participant health data (stored at UTHealth) and personal identifiers (maintained at TSSUS). We developed an innovative Visual Basic (VB) script that, when embedded into Microsoft Outlook, redirects REDCap surveys through TSSUS to participants by matching registry IDs to participant email addresses. Additionally, the utilization of REDCap allows for portability of data as it is an open source platform. Conclusion: In this report, we will highlight three recent changes that more closely align the TSRR with this mission: a unique and equal collaborative partnership between UTHealth and TSSUS, an open-source platform, REDCap, that ensures data portability and compatibility across institutions, and an innovative survey routing system that retains participant confidentiality without sacrificing REDCap survey distribution capabilities to connect researchers with thousands of participants. Turner syndrome registry patient-centered research Figures Figure 1 BACKGROUND Turner Syndrome (TS) is caused by the absence of all or part of one X chromosome leading to developmental problems such as short stature, ovarian dysfunction, and heart malformations [ 1 , 2 ] Because TS involves multiple organ systems, it is often difficult to track the longitudinal trajectories of individuals as they navigate complex healthcare needs [ 3 ]. TS is also a rare condition (1 in 2500 females) and requires a coordinated nationwide effort to recruit large cohorts for research studies [ 4 ]. Clinical manifestations of TS are highly variable and occur throughout life, requiring long-term natural history studies [ 5 , 6 , 7 ]. Many different clinical specialists provide care to TS patients, presenting challenges to a cohesive approach to TS research [ 8 ]. Therefore, a national Turner Syndrome registry is essential to inform priorities for healthcare and research. To address these knowledge gaps, the Turner Syndrome Society of the United States (TSSUS) created the Turner Syndrome Research Registry (TSRR) in 2015 [ 9 ]. The purpose of the TSRR is to collect longitudinal data directly from participants about their lifelong experiences with TS. Data from TSRR surveys provides critical feedback about community priorities and facilitates recruitment for research [ 10 ]. In 2021, UTHealth Houston partnered with TSSUS to create an improved registry that more closely aligns the TSRR with these priorities. Version 2 of the TSRR is the product of an equal partnership between the TS community, TSSUS, and researchers. The new registry workflows maintain the highest level of data privacy and confidentiality by taking advantage of a lock and key model in which participant data and identifiers are kept separate. The unique REDCap-based structure of the TSRR also facilitates portability of data between participants, investigators, and institutions, fueling the virtuous cycle of TS research. METHODS The study protocol was reviewed and approved by the Committee for the Protection of Human Subjects at the University of Texas Health Science Center at Houston (IRB# HSC-MS-21-0384). The TSRR is managed using a version of Research Electronic Data Capture (REDCap) that is hosted at the McWilliams School of Biomedical Informatics at UTHealth Houston [ 11 ]. REDCap is a secure, web-based application designed to support data capture for research studies, providing 1) an intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to common statistical packages; and 4) procedures for importing data from external sources. The first version of the TSRR was hosted on the Platform for Engaging Everyone Responsibly (PEER, Genetic Alliance, Damascus, MD). To create TSRR version 2, registry data were exported from PEER as a tab-delimited text file, transformed into a data frame using a custom python script, and imported into UTHealth Houston REDCap after quality control and de-identification (Supplementary Data). The initial data included a total of 957 participant records with two instruments: one foundational survey with 73 recoded variables and one instrument with participant contact and privacy preferences. The REDCap survey routing system was created by installing a custom macro in Microsoft Outlook Visual Basic for Apps (VBA, Supplementary Data). The VBA script redirects any incoming message with a subject line that matches the record ID of a TSRR participant to the corresponding personal email address in a linking log file that is maintained by TSSUS. RESULTS Enrollment Criteria and Registry Workflows All eligible participants with a clinical diagnosis of TS or caregivers of someone with TS are invited to enroll in the TSRR through a registration portal on the TSSUS website. Participants complete a foundational survey that requests information about demographics, medical history, and privacy options about their willingness to share their data for different types of research projects. TSSR researchers who wish to access TSRR participants or data must submit research proposals to the TSSUS Scientific Advisory Board (SAB) for review. The role of the SAB is to ensure that the research is of scientific merit and is consistent with the objectives of TSSUS. The SAB then works with researchers to promote selected projects to TSRR participants who consent to be contacted about new studies. TSSUS continuously updates a linking log of participant information whenever each new participant registers for the TSRR. Each row of the linking log contains the participant identifiers, registry ID, global universal identifier, and privacy options that were selected by the participant at registration. To complete the registration process, TSSUS exports the registry ID and privacy options, but not identifiers, to the UTHealth TSRR team as a templated text file that can be seamlessly imported into REDCap. The new REDCap TSRR platform promotes a virtuous cycle that expands the registry with each new project by automating the return of new data back into the registry when new surveys are created (Fig. 1 ). Partnership with TSSUS The TSRR is the first patient-powered registry that is entirely supported by an equal partnership between a nonprofit organization and an academic institution. TSSUS, the nonprofit organization, hosts all participant identifiers and is the gatekeeper to all interactions with participants, while UTHealth Houston manages the creation and distribution of surveys for TSRR projects. This lock and key model, where both organizations must cooperate in order to maintain the registry, is unique. The TSRR partnership amplifies the strengths and expertise of each organization and provides flexibility to adapt to changes in data ownership, data use, and privacy requirements. By remaining at the hub of TSRR communications, TSSUS can capitalize on contacts with the TS community that were developed over 30 years, while UTHealth Houston provides research infrastructure and expertise. Researchers who use the customizable REDCap survey system to launch projects benefit from this partnership, while returning new data to the TSRR to fulfill the ‘virtuous cycle.’ Portability Data in the TSRR is stored in REDCap instruments. REDCap is an open-source platform that has been widely adopted by academic partners across the United States. Therefore, it is simple to share data with collaborators by exporting de-identified REDCap data or by importing new data into the TSRR using customized REDCap instruments. This REDCap-based structure improves data security and portability to facilitate collaborative research. The TSRR is easy to sustain if institutions or investigators change because TSRR data can be easily exported to a new site while TSSUS retains complete sovereignty over the data. Data portability is also essential to maintain the virtuous cycle of the TSRR. The virtuous cycle refers to the process whereby researchers return new data or analysis to the TSRR. REDCap data import tools automate this process, removing the need for third-party custodial administration. Visual Basic Survey Routing System We developed an innovative Visual Basic (VB) script that, when embedded into Microsoft Outlook, redirects REDCap surveys through TSSUS to participants by matching registry IDs to participant email addresses. Therefore, participant identifiers are never accessible to UTHealth Houston registry support staff or researchers. To facilitate email redirection, we edited the outgoing message settings in the UTHealth TSRR REDCap project so that each participant ID is embedded into the subject line and the recipient email is set to a single address that is monitored by TSSUS personnel. The TSSUS Outlook VB script automatically scans for the participant ID in incoming messages, matches each participant ID to the corresponding email address in the linking log, and redirects outgoing messages to TSRR participants. Because the script automatically links participant IDs to identifiers, thousands of messages can be sent simultaneously to TSRR participants, while TSRR data remains confidential. By editing automated REDCap survey invitation options, emails may be targeted to specific subgroups of recipients that meet prespecified criteria corresponding to variables in the registry such as age, diagnosis, or vital status. The survey distribution tools in REDCap are useful to generate real-time reports about survey completion by TSRR participants. DISSCUSSION Comparison with InsighTS Registry Inspiring New Science to Guide Healthcare in Turner Syndrome (InsighTS) is a contemporary TS registry that is administered at the University of Colorado Anschutz Medical Campus (unpublished data). InsighTS and the TSRR were intentionally designed to provide complementary snapshots of TS life experiences. InsighTS utilizes a provider-centered model for enrollment and research that primarily relies on data from medical records to build a traditional registry database. In contrast, the TSRR is based on direct survey data from participants that is most appropriate for qualitative research and direct community engagement. Future linkage of these datasets using a shared global universal identifier could eventually provide a more comprehensive longitudinal overview of care navigation and life transitions in TS. Limitations REDCap survey delivery requires TSSUS to maintain an accurate linking log with up-to-date participant contact information. Manual curation of the linking log in the current workflow is time consuming and prone to technical errors. Technical limitations in the current version of the visual basic app prevent sending reminder emails anonymously to survey recipients. We are currently revising the Visual Basic script and TSSUS webform to automate the registration process and optimize survey delivery. Research Progress The TSRR has currently enrolled more than 1,100 participants and successfully deployed two general health update surveys and three project-specific surveys (Supplementary Data). TSRR data has led to projects on skin concerns across the life spectrum and complications after cardiovascular surgeries [ 12 ]. Survey responses from these projects will be available to future researchers who apply for TSRR data. CONCLUSION The TSRR was designed to sustain a virtuous cycle of patient-powered research. In this report, we will highlight three recent changes that more closely align the TSRR with this mission: a unique and equal collaborative partnership between UTHealth and TSSUS, an open-source platform, REDCap, that ensures data portability and compatibility across institutions, and an innovative survey routing system that retains participant confidentiality without sacrificing REDCap survey distribution capabilities to connect researchers with thousands of participants. Declarations Ethics Approval and Consent to Participate Consent to participate was received from participants prior to enrollment in the research registry. The study protocol was reviewed and approved by the Committee for the Protection of Human Subjects at the University of Texas Health Science Center at Houston (IRB# HSC-MS-21-0384). Consent for Publication Not applicable. Availability of Data and Materials Data generated or analyzed during this study are included in this published article and its supplementary information files. If datasets of interest are not included in this study, they are available upon request to the corresponding author, Dr. Siddharth K. Prakash at [email protected] . Competing Interests The authors declare that they have no competing interests. Funding This work was supported in part by NIH/NCATS grants UL1 TR000445 and UL1 TR001105. Additionally, this study was supported in part by the Turner Syndrome Society of the United States (TSSUS). TSSUS had no role in study design, data collection, data analysis, or the decision to publish this study. Author Contributions SM: Data curation, Writing- Original draft preparation; CS: Software, Resources, Writing – Reviewing and Editing; SAB of the TSRR: Supervision, Writing – Reviewing and Editing; SP: Conceptualization, Methodology, Writing – Reviewing and Editing, Project administration. Acknowledgments This work was supported in part by the Turner Syndrome Society of the United States and NIH/NCATS grants UL1 TR000445 and UL1 TR001105. The authors are indebted to the members of the TSSUS Scientific Advisory Board, to Bobby Marsh and William J. Allen for informatics services, and to all TSRR participants for contributing their time and data to the registry. The Scientific Advisory Board of the TSRR is Siddharth K. Prakash, M.D., Ph.D. (chair), University of Texas Health Science Center at Houston, Cheryl Maslen, Ph.D., Oregon Health & Science University, G. Michael Silberbach, M.D., Oregon Health & Science University, Emilio Quezada, M.D., University of California San Francisco, Vaneeta Bamba, M.D., University of Pennsylvania, Melissa Crenshaw M.D., Johns Hopkins All Children's Hospital, Michelle Rivera-Davila, M.D., University of Texas Health Science Center at Houston, Aaron T. Dorfman, M.D., University of Pennsylvania, Rebecca C. Knickmeyer, M.D., Michigan State University, Gary A. Lorigan, M.D., Miami University. References Ford CE, Jones KW, Polani PE, De Almeida JC, Briggs JH. A sex-chromosome anomaly in a case of gonadal dysgenesis (Turner’s syndrome). Lancet. 1959;1(7075):711–3. Zinn AR, Page DC, Fisher EM. Turner syndrome: the case of the missing sex chromosome. Trends Genet. 1993;9(3):90–3. Campbell IM, Shaw CA, Stankiewicz P, Lupski JR. Somatic Mosaicism: Implications for Disease and Transmission Genetics. Trends Genet. 2015;31(7):382–92. Cui X, Cui Y, Shi L, Luan J, Zhou X, Han J. A basic understanding of Turner syndrome: Incidence, complications, diagnosis, and treatment. Intractable Rare Dis Res. 2018;7(4):223–8. Gravholt CH, Andersen NH, Conway GS, Dekkers OM, Geffner ME, Klein KO et al. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol. 2017;177(3):G1–70. Viuff M, Skakkebaek A, Nielsen MM, Chang S, Gravholt CH. Epigenetics and genomics in Turner syndrome. Am J Med Genet C Semin Med Genet. 2019;181(1):68–75. Zhong Q, Layman LC. Genetic considerations in the patient with Turner syndrome–45,X with or without mosaicism. Fertil Steril. 2012;98(4):775–9. Lin AE, Prakash SK, Andersen NH, Viuff MH, Levitsky LL, Rivera-Davila M, et al. Recognition and management of adults with Turner syndrome: From the transition of adolescence through the senior years. Am J Med Genet A. 2019;179(10):1987–2033. Prakash SK, Lugo-Ruiz S, Rivera-Dávila M, Rubio N, Shah AN, Knickmeyer RC, et al. The Turner syndrome research registry: Creating equipoise between investigators and participants. Am J Med Genet C Semin Med Genet. 2019;181(1):135–40. Sandberg DE, Singer D, Bugajski B, Gebremariam A, Scerbak T, Maley KLD, et al. Research Priorities of People Living with Turner Syndrome (TS). Am J Med Genet C Semin Med Genet. 2019;181(1):43–51. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377–81. Ribe L, Shihadeh FD, Afifi RO et al. Outcomes of cardiothoracic surgery in women with Turner syndrome. Annals of Cardiothoracic Surgery 2023; in press. Supplementary Files Mansoorshahi.Prakash.TSRR.DataDictionary1.xlsx Cite Share Download PDF Status: Published Journal Publication published 11 Mar, 2024 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted Editorial decision: Major revision 08 Feb, 2024 Reviewers agreed at journal 20 Jan, 2024 Reviewers invited by journal 10 Jan, 2024 Editor assigned by journal 10 Jan, 2024 First submitted to journal 07 Jan, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3844775","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":266504259,"identity":"78f2c668-d608-4ae9-b01d-84401d8375c6","order_by":0,"name":"Sara Mansoorshahi","email":"data:image/png;base64,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","orcid":"https://orcid.org/0009-0002-9668-5640","institution":"The University of Texas Health Science Center at Houston","correspondingAuthor":true,"prefix":"","firstName":"Sara","middleName":"","lastName":"Mansoorshahi","suffix":""},{"id":266504260,"identity":"5c91be35-55e4-4158-8ea0-6ec10543c4bb","order_by":1,"name":"Cindy Scurlock","email":"","orcid":"","institution":"Turner Syndrome Society of the United States","correspondingAuthor":false,"prefix":"","firstName":"Cindy","middleName":"","lastName":"Scurlock","suffix":""},{"id":266504261,"identity":"906b82a2-5811-4ac0-b4ae-ae66d111899f","order_by":2,"name":"Scientific Advisory Board of the Turner Syndrome Research Registry","email":"","orcid":"","institution":"Turner Syndrome Society of the United States","correspondingAuthor":false,"prefix":"","firstName":"Scientific","middleName":"Advisory Board of the Turner Syndrome Research","lastName":"Registry","suffix":""},{"id":266504262,"identity":"27e2512a-f737-4cb4-acda-6c7ae101a4ea","order_by":3,"name":"Siddharth K. Prakash","email":"","orcid":"https://orcid.org/0000-0001-6341-9624","institution":"The University of Texas Health Science Center at Houston","correspondingAuthor":false,"prefix":"","firstName":"Siddharth","middleName":"K.","lastName":"Prakash","suffix":""}],"badges":[],"createdAt":"2024-01-08 07:19:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3844775/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3844775/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13023-024-03120-1","type":"published","date":"2024-03-11T15:01:03+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":49645461,"identity":"379d2cc9-8ae3-4192-8852-40f2c73d9bb9","added_by":"auto","created_at":"2024-01-15 20:57:39","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":120867,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eStructure of the Turner Syndrome Research Registry (TSRR). The flow diagram illustrates how surveys can be distributed from the UTHealth Houston REDCap registry to participants, and how self-reported data is returned to REDCap. The Turner Syndrome Society of United States (TSSUS) is the sole gatekeeper of participant information.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-3844775/v1/046bdbb3d96ff8ae41dd49ef.png"},{"id":52907206,"identity":"e84e739a-a00e-4561-9027-a6e233212e8e","added_by":"auto","created_at":"2024-03-18 15:11:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":420836,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3844775/v1/7ed9cc60-6cb4-4c62-a812-ea9f75134bc8.pdf"},{"id":49645462,"identity":"b1738aa8-5fc2-45db-a57d-4f32fe153379","added_by":"auto","created_at":"2024-01-15 20:57:39","extension":"xlsx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":26963,"visible":true,"origin":"","legend":"","description":"","filename":"Mansoorshahi.Prakash.TSRR.DataDictionary1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3844775/v1/cfc64218e4d0be72bee6a154.xlsx"}],"financialInterests":"","formattedTitle":"Methodological Advances in Patient-centered Rare Disease Research: the UTHealth Houston Turner Syndrome Society of the United States Research Registry","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eTurner Syndrome (TS) is caused by the absence of all or part of one X chromosome leading to developmental problems such as short stature, ovarian dysfunction, and heart malformations [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] Because TS involves multiple organ systems, it is often difficult to track the longitudinal trajectories of individuals as they navigate complex healthcare needs [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. TS is also a rare condition (1 in 2500 females) and requires a coordinated nationwide effort to recruit large cohorts for research studies [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Clinical manifestations of TS are highly variable and occur throughout life, requiring long-term natural history studies [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Many different clinical specialists provide care to TS patients, presenting challenges to a cohesive approach to TS research [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Therefore, a national Turner Syndrome registry is essential to inform priorities for healthcare and research.\u003c/p\u003e \u003cp\u003eTo address these knowledge gaps, the Turner Syndrome Society of the United States (TSSUS) created the Turner Syndrome Research Registry (TSRR) in 2015 [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The purpose of the TSRR is to collect longitudinal data directly from participants about their lifelong experiences with TS. Data from TSRR surveys provides critical feedback about community priorities and facilitates recruitment for research [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn 2021, UTHealth Houston partnered with TSSUS to create an improved registry that more closely aligns the TSRR with these priorities. Version 2 of the TSRR is the product of an equal partnership between the TS community, TSSUS, and researchers. The new registry workflows maintain the highest level of data privacy and confidentiality by taking advantage of a lock and key model in which participant data and identifiers are kept separate. The unique REDCap-based structure of the TSRR also facilitates portability of data between participants, investigators, and institutions, fueling the virtuous cycle of TS research.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e The study protocol was reviewed and approved by the Committee for the Protection of Human Subjects at the University of Texas Health Science Center at Houston (IRB# HSC-MS-21-0384). The TSRR is managed using a version of Research Electronic Data Capture (REDCap) that is hosted at the McWilliams School of Biomedical Informatics at UTHealth Houston [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. REDCap is a secure, web-based application designed to support data capture for research studies, providing 1) an intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to common statistical packages; and 4) procedures for importing data from external sources.\u003c/p\u003e \u003cp\u003eThe first version of the TSRR was hosted on the Platform for Engaging Everyone Responsibly (PEER, Genetic Alliance, Damascus, MD). To create TSRR version 2, registry data were exported from PEER as a tab-delimited text file, transformed into a data frame using a custom python script, and imported into UTHealth Houston REDCap after quality control and de-identification (Supplementary Data). The initial data included a total of 957 participant records with two instruments: one foundational survey with 73 recoded variables and one instrument with participant contact and privacy preferences.\u003c/p\u003e \u003cp\u003eThe REDCap survey routing system was created by installing a custom macro in Microsoft Outlook Visual Basic for Apps (VBA, Supplementary Data). The VBA script redirects any incoming message with a subject line that matches the record ID of a TSRR participant to the corresponding personal email address in a linking log file that is maintained by TSSUS.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eEnrollment Criteria and Registry Workflows\u003c/h2\u003e \u003cp\u003eAll eligible participants with a clinical diagnosis of TS or caregivers of someone with TS are invited to enroll in the TSRR through a registration portal on the TSSUS website. Participants complete a foundational survey that requests information about demographics, medical history, and privacy options about their willingness to share their data for different types of research projects. TSSR researchers who wish to access TSRR participants or data must submit research proposals to the TSSUS Scientific Advisory Board (SAB) for review. The role of the SAB is to ensure that the research is of scientific merit and is consistent with the objectives of TSSUS. The SAB then works with researchers to promote selected projects to TSRR participants who consent to be contacted about new studies.\u003c/p\u003e \u003cp\u003eTSSUS continuously updates a linking log of participant information whenever each new participant registers for the TSRR. Each row of the linking log contains the participant identifiers, registry ID, global universal identifier, and privacy options that were selected by the participant at registration. To complete the registration process, TSSUS exports the registry ID and privacy options, but not identifiers, to the UTHealth TSRR team as a templated text file that can be seamlessly imported into REDCap. The new REDCap TSRR platform promotes a virtuous cycle that expands the registry with each new project by automating the return of new data back into the registry when new surveys are created (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003ePartnership with TSSUS\u003c/h2\u003e \u003cp\u003eThe TSRR is the first patient-powered registry that is entirely supported by an equal partnership between a nonprofit organization and an academic institution. TSSUS, the nonprofit organization, hosts all participant identifiers and is the gatekeeper to all interactions with participants, while UTHealth Houston manages the creation and distribution of surveys for TSRR projects. This lock and key model, where both organizations must cooperate in order to maintain the registry, is unique.\u003c/p\u003e \u003cp\u003eThe TSRR partnership amplifies the strengths and expertise of each organization and provides flexibility to adapt to changes in data ownership, data use, and privacy requirements. By remaining at the hub of TSRR communications, TSSUS can capitalize on contacts with the TS community that were developed over 30 years, while UTHealth Houston provides research infrastructure and expertise. Researchers who use the customizable REDCap survey system to launch projects benefit from this partnership, while returning new data to the TSRR to fulfill the \u0026lsquo;virtuous cycle.\u0026rsquo;\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003ePortability\u003c/h2\u003e \u003cp\u003eData in the TSRR is stored in REDCap instruments. REDCap is an open-source platform that has been widely adopted by academic partners across the United States. Therefore, it is simple to share data with collaborators by exporting de-identified REDCap data or by importing new data into the TSRR using customized REDCap instruments. This REDCap-based structure improves data security and portability to facilitate collaborative research.\u003c/p\u003e \u003cp\u003eThe TSRR is easy to sustain if institutions or investigators change because TSRR data can be easily exported to a new site while TSSUS retains complete sovereignty over the data. Data portability is also essential to maintain the virtuous cycle of the TSRR. The virtuous cycle refers to the process whereby researchers return new data or analysis to the TSRR. REDCap data import tools automate this process, removing the need for third-party custodial administration.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eVisual Basic Survey Routing System\u003c/h2\u003e \u003cp\u003eWe developed an innovative Visual Basic (VB) script that, when embedded into Microsoft Outlook, redirects REDCap surveys through TSSUS to participants by matching registry IDs to participant email addresses. Therefore, participant identifiers are never accessible to UTHealth Houston registry support staff or researchers. To facilitate email redirection, we edited the outgoing message settings in the UTHealth TSRR REDCap project so that each participant ID is embedded into the subject line and the recipient email is set to a single address that is monitored by TSSUS personnel. The TSSUS Outlook VB script automatically scans for the participant ID in incoming messages, matches each participant ID to the corresponding email address in the linking log, and redirects outgoing messages to TSRR participants. Because the script automatically links participant IDs to identifiers, thousands of messages can be sent simultaneously to TSRR participants, while TSRR data remains confidential. By editing automated REDCap survey invitation options, emails may be targeted to specific subgroups of recipients that meet prespecified criteria corresponding to variables in the registry such as age, diagnosis, or vital status. The survey distribution tools in REDCap are useful to generate real-time reports about survey completion by TSRR participants.\u003c/p\u003e \u003c/div\u003e"},{"header":"DISSCUSSION","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eComparison with InsighTS Registry\u003c/h2\u003e \u003cp\u003eInspiring New Science to Guide Healthcare in Turner Syndrome (InsighTS) is a contemporary TS registry that is administered at the University of Colorado Anschutz Medical Campus (unpublished data). InsighTS and the TSRR were intentionally designed to provide complementary snapshots of TS life experiences. InsighTS utilizes a provider-centered model for enrollment and research that primarily relies on data from medical records to build a traditional registry database. In contrast, the TSRR is based on direct survey data from participants that is most appropriate for qualitative research and direct community engagement. Future linkage of these datasets using a shared global universal identifier could eventually provide a more comprehensive longitudinal overview of care navigation and life transitions in TS.\u003c/p\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eREDCap survey delivery requires TSSUS to maintain an accurate linking log with up-to-date participant contact information. Manual curation of the linking log in the current workflow is time consuming and prone to technical errors. Technical limitations in the current version of the visual basic app prevent sending reminder emails anonymously to survey recipients. We are currently revising the Visual Basic script and TSSUS webform to automate the registration process and optimize survey delivery.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eResearch Progress\u003c/h2\u003e \u003cp\u003eThe TSRR has currently enrolled more than 1,100 participants and successfully deployed two general health update surveys and three project-specific surveys (Supplementary Data). TSRR data has led to projects on skin concerns across the life spectrum and complications after cardiovascular surgeries [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Survey responses from these projects will be available to future researchers who apply for TSRR data.\u003c/p\u003e \u003c/div\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThe TSRR was designed to sustain a virtuous cycle of patient-powered research. In this report, we will highlight three recent changes that more closely align the TSRR with this mission: a unique and equal collaborative partnership between UTHealth and TSSUS, an open-source platform, REDCap, that ensures data portability and compatibility across institutions, and an innovative survey routing system that retains participant confidentiality without sacrificing REDCap survey distribution capabilities to connect researchers with thousands of participants.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsent to participate was received from participants prior to enrollment in the research registry. The study protocol was reviewed and approved by the Committee for the Protection of Human Subjects at the University of Texas Health Science Center at Houston (IRB# HSC-MS-21-0384).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData generated or analyzed during this study are included in this published article and its supplementary information files. If datasets of interest are not included in this study, they are available upon request to the corresponding author, Dr. Siddharth K. Prakash at\u0026nbsp;\u003ca href=\"mailto:[email protected]\"\[email protected]\u003c/a\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported in part by NIH/NCATS grants UL1 TR000445 and UL1 TR001105.\u0026nbsp;Additionally, this study was supported in part by the Turner Syndrome Society of the United States (TSSUS). TSSUS had no role in study design, data collection, data analysis, or the decision to publish this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSM: Data curation, Writing- Original draft preparation;\u0026nbsp;CS: Software, Resources, Writing \u0026ndash; Reviewing and Editing; SAB of the TSRR: Supervision, Writing \u0026ndash; Reviewing and Editing; SP:\u0026nbsp;Conceptualization, Methodology, Writing \u0026ndash; Reviewing and Editing, Project administration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported in part by the Turner Syndrome Society of the United States and NIH/NCATS grants UL1 TR000445 and UL1 TR001105. The authors are indebted to the members of the TSSUS Scientific Advisory Board, to Bobby Marsh and William J. Allen for informatics services, and to all TSRR participants for contributing their time and data to the registry.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e The Scientific Advisory Board of the TSRR is Siddharth K. Prakash, M.D., Ph.D. (chair), University of Texas Health Science Center at Houston, Cheryl Maslen, Ph.D., Oregon Health \u0026amp; Science University, G. Michael Silberbach, M.D., Oregon Health \u0026amp; Science University, Emilio Quezada, M.D., University of California San Francisco, Vaneeta Bamba, M.D., University of Pennsylvania, Melissa Crenshaw M.D., Johns Hopkins All Children\u0026apos;s Hospital, Michelle Rivera-Davila, M.D., University of Texas Health Science Center at Houston, Aaron T. Dorfman, M.D., University of Pennsylvania, Rebecca C. Knickmeyer, M.D., Michigan State University, Gary A. Lorigan, M.D., Miami University.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eFord CE, Jones KW, Polani PE, De Almeida JC, Briggs JH. A sex-chromosome anomaly in a case of gonadal dysgenesis (Turner\u0026rsquo;s syndrome). Lancet. 1959;1(7075):711\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZinn AR, Page DC, Fisher EM. Turner syndrome: the case of the missing sex chromosome. Trends Genet. 1993;9(3):90\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCampbell IM, Shaw CA, Stankiewicz P, Lupski JR. Somatic Mosaicism: Implications for Disease and Transmission Genetics. Trends Genet. 2015;31(7):382\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCui X, Cui Y, Shi L, Luan J, Zhou X, Han J. A basic understanding of Turner syndrome: Incidence, complications, diagnosis, and treatment. Intractable Rare Dis Res. 2018;7(4):223\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGravholt CH, Andersen NH, Conway GS, Dekkers OM, Geffner ME, Klein KO et al. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol. 2017;177(3):G1\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eViuff M, Skakkebaek A, Nielsen MM, Chang S, Gravholt CH. Epigenetics and genomics in Turner syndrome. Am J Med Genet C Semin Med Genet. 2019;181(1):68\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhong Q, Layman LC. Genetic considerations in the patient with Turner syndrome\u0026ndash;45,X with or without mosaicism. Fertil Steril. 2012;98(4):775\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLin AE, Prakash SK, Andersen NH, Viuff MH, Levitsky LL, Rivera-Davila M, et al. Recognition and management of adults with Turner syndrome: From the transition of adolescence through the senior years. Am J Med Genet A. 2019;179(10):1987\u0026ndash;2033.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePrakash SK, Lugo-Ruiz S, Rivera-D\u0026aacute;vila M, Rubio N, Shah AN, Knickmeyer RC, et al. The Turner syndrome research registry: Creating equipoise between investigators and participants. Am J Med Genet C Semin Med Genet. 2019;181(1):135\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSandberg DE, Singer D, Bugajski B, Gebremariam A, Scerbak T, Maley KLD, et al. Research Priorities of People Living with Turner Syndrome (TS). Am J Med Genet C Semin Med Genet. 2019;181(1):43\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRibe L, Shihadeh FD, Afifi RO et al. Outcomes of cardiothoracic surgery in women with Turner syndrome. Annals of Cardiothoracic Surgery 2023; in press.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Turner syndrome, registry, patient-centered, research","lastPublishedDoi":"10.21203/rs.3.rs-3844775/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3844775/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Many different clinical specialists provide care to patients with Turner syndrome (TS), who have highly variable clinical manifestations. Therefore, a national TS registry is essential to inform a cohesive approach to healthcare and research. In 2015, the Turner Syndrome Society of the United States (TSSUS) created the Turner Syndrome Research Registry (TSRR) to engage directly with community participants who voluntarily provide longitudinal data about their experiences with TS. TSRR projects are collaborative partnerships between people with TS, TSSUS, and researchers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e To ensure that registry workflows conform to the data privacy choices of participants, TSSUS collaborated with UTHealth Houston in 2021 to create a new version of the TSRR that completely separates participant health data (stored at UTHealth) and personal identifiers (maintained at TSSUS). We developed an innovative Visual Basic (VB) script that, when embedded into Microsoft Outlook, redirects REDCap surveys through TSSUS to participants by matching registry IDs to participant email addresses. Additionally, the utilization of REDCap allows for portability of data as it is an open source platform.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e In this report, we will highlight three recent changes that more closely align the TSRR with this mission: a unique and equal collaborative partnership between UTHealth and TSSUS, an open-source platform, REDCap, that ensures data portability and compatibility across institutions, and an innovative survey routing system that retains participant confidentiality without sacrificing REDCap survey distribution capabilities to connect researchers with thousands of participants.\u003c/p\u003e","manuscriptTitle":"Methodological Advances in Patient-centered Rare Disease Research: the UTHealth Houston Turner Syndrome Society of the United States Research Registry","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-15 20:57:34","doi":"10.21203/rs.3.rs-3844775/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2024-02-08T23:19:24+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-01-20T16:01:27+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-01-10T16:10:23+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-01-10T12:18:28+00:00","index":"","fulltext":""},{"type":"submitted","content":"Orphanet Journal of Rare Diseases","date":"2024-01-07T18:37:04+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0f24b4a3-d7b9-49aa-bc57-f5f4ef1744de","owner":[],"postedDate":"January 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-03-18T15:04:12+00:00","versionOfRecord":{"articleIdentity":"rs-3844775","link":"https://doi.org/10.1186/s13023-024-03120-1","journal":{"identity":"orphanet-journal-of-rare-diseases","isVorOnly":false,"title":"Orphanet Journal of Rare Diseases"},"publishedOn":"2024-03-11 15:01:03","publishedOnDateReadable":"March 11th, 2024"},"versionCreatedAt":"2024-01-15 20:57:34","video":"","vorDoi":"10.1186/s13023-024-03120-1","vorDoiUrl":"https://doi.org/10.1186/s13023-024-03120-1","workflowStages":[]},"version":"v1","identity":"rs-3844775","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3844775","identity":"rs-3844775","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}