Methodological advances in patient-centered rare disease research: the UTHealth Houston Turner Syndrome Society of the United States research registry

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. Every participant is assigned a global universal identifier (GUID) that consists of pseudonymized data. Each row of the linking log contains the participant identifiers, GUID, and privacy options that were selected by the participant at registration. To complete the registration process, TSSUS exports the GUID and privacy options, but not identifiers, to the UTHealth TSRR team as a templated text file that can be seamlessly imported into REDCap. This workflow ensures that personal identifiers are physically separated from the registry data on two independent encrypted servers. 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).

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.’

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. Data sharing with collaborators is simple: de-identified data can be exported from one REDCap project and imported into another REDCap project using customized REDCap instruments. REDCap adheres to worldwide data privacy standards such as HIPAA and GDPR [11, 12]. The UTHealth server where TSRR data is stored is encrypted and backed up regularly. Therefore, the REDCap-based structure of the TSRR 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.

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 (Supplemental Data). 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.

By February 2024, the TSRR had enrolled 1,380 participants and successfully deployed two general health update surveys and three project-specific surveys. The project-specific surveys were designed collaboratively by independent investigators and the TSSUS Scientific Advisory Board to address research priorities that were identified by people with Turner syndrome and stakeholders in the TS community. Eligible TSRR participants who responded to project-specific surveys completed consent forms authorizing study investigators to contact them for interviews or retrieval of health record information. Data from these follow up studies were stored in separate REDCap projects and exported to the TSRR after de-identification. Using this approach, TSRR investigators identified health disparities in access to guideline-recommended medical care for Spanish speakers with TS [13]; characterized the increased prevalence of dermatologic diseases in TS [14]; and described risk factors for postoperative complications after cardiovascular surgeries in young adults with TS, which occur more frequently than expected [15].