Overview of Web Site and Recruitment
Our Web site interface (http://www.kovlerdiabetescenter.org/registry/
) is part of the Kovler Diabetes Center at the University of Chicago, which is composed of integrated Web-based applications supported by a centralized MySQL database back end. The public pages allow for unrestricted viewing of our inclusion criteria and consent documents, with a secure registration form allowing for collection of contact information to facilitate subject telephone consent and enrollment (see schematic in
). The front-end engine that is currently utilized as the interface between approved registry staff users and the database back end is the Research Electronic Data Capture (REDCap) program, which provides an interface allowing for all data creation, retrieval, updates, and deletion. REDCap was created at Vanderbilt University to support data capture for research studies15
and is now available at no cost to participating Consortium members supported by the National Institutes of Health Clinical and Translational Science Awards program, such as our Institute for Translational Medicine supporting the Initiative in Biomedical Informatics (iBi) at the University of Chicago that hosts our REDCap database and related Kovler Diabetes Center Web sites.
Figure 1 Overview of enrollment and data collection for the U.S. Monogenic Diabetes Registry at the University of Chicago Kovler Diabetes Center (http://KovlerDiabetesCenter.org/Registry). DM, diabetes mellitus; CRC, Clinical Research Center.
Physicians who learn about the registry are asked to encourage potential patient participants to access the Web site directly (or alternatively may provide our telephone contact information to anyone without reliable Internet access). After being given the opportunity to review inclusion criteria and consent forms available for viewing or downloading on the Web site, the prospective research subject or parent/guardian may then enter his/her contact information, as well as that of his/her physician/diabetes provider, directly into the secure Web site form. Initially, this contact information was then sent by encrypted email to be decrypted on registry computers onto which the de-encryption key had been installed (open-source Gnu Privacy Guard encryption engine v1.2.1 using free software Windows Privacy Tools). The Web form is now being adapted to utilize a REDCap-provided application programming interface to allow subject-submitted information to be dumped directly into the MySQL centralized REDCap database back end as a temporary record. Upon consent, the record is converted to a permanent subject record or otherwise deleted if the prospective participant failed to meet inclusion criteria or decided not to enroll in our studies.
The institutional review board (IRB) of the University of Chicago has approved all studies, with approved registry consent forms freely available on our Web site to view, download, and print. Each Web site registrant is subsequently contacted by registry staff to arrange for telephone consent and review of inclusion criteria. Those without Internet access who contacted us directly may be provided with the consent forms through their physician or by mail. Those who agree to participate are then asked to sign the forms and mail them back to be signed by registry staff. All consent forms are then scanned and uploaded to the REDCap database, and a copy is mailed back to each participant. Given that the proposed research involves no greater than minimal risk to subjects, participation of children requires the written informed consent of one parent, with assent being requested from children aged 7 years or older. Because we propose to keep the collected data indefinitely, once any subject turns 18 years of age, reasonable effort is made to contact the subject to obtain informed written consent.
Data Collection and Surveys
Following consent, patient/parent participants are sent emails with a secure sockets layer (SSL)-encrypted link to surveys created through SurveyMonkey.com, where de-identified data may be stored on secure servers and downloaded with SSL encryption to registry computers for analysis. Because names and contact information were previously collected, the surveys do not ask for such protected health information. At any point, participants may elect to communicate directly with registry staff through email or by phone, and registry staff may also contact participants to clarify data elements and ensure completeness of data. For patients/families who prefer non-Internet interactions, surveys may be completed with registry staff by telephone. All surveys are now being adapted to utilize the REDCap Survey tool, which will soon allow for survey answers to be linked directly to existing databases.
The initial survey collects a wide range of information (
), while interval surveys collected at least annually will allow for brief updates of relevant information. Original medical records are also collected whenever possible, with medical record release forms being available on the Web site and collected during the consent process for this purpose. Key data elements may be confirmed by initial diabetes diagnosis hospital records, and in addition, physicians may also be contacted, whether or not they referred the patient to the registry. Ongoing clinic records, laboratory or radiology results, local neuro-developmental assessments, or other relevant information may be submitted by physicians, patients, or their families or requested directly in a manner compliant with The Health Insurance Portability and Accountability Act (HIPAA) of 1996. Quality-of-life information, adapted from validated measures, is also gathered.16
An overview of the data elements collected is provided in
Overview of Data Elements Collected in the Monogenic Diabetes Registry
Internet Discussion Groups
Participants are invited to join genetic-subtype-specific or general registry Web-based discussion groups, which are open only to consented participants and moderated by registry staff. In order to participate, parents/guardians or children who are 12–17 years of age must first have completed the consent process for the main study and are then asked to review and sign a separate discussion group consent form. Physicians/diabetes providers treating consented patient participants may also choose to consent to their own participation in the discussion groups by signing a separate consent form.
The groups are not guided by registry staff, but rather provide a forum for discussion of various aspects related to the subtypes of monogenic and/or neonatal diabetes for those with these rare conditions or those treating them. Moderators of the discussion groups attempt to provide clarification of what is known or unknown regarding the disorders and their treatment and provide editorial clarifications if any misleading or inaccurate information is posted. Participants are always strongly encouraged to discuss any possible modifications to their treatment regimen with their physician/provider before making any changes. Patient/parent participants are warned of the risk of loss of confidentiality, particularly if they choose to share identifying information. Physicians/diabetes providers are reminded to adhere to HIPAA guidelines. Participants are informed that the investigators may choose to publish findings related to the discussion groups, e.g., by quoting from the discussion. In such instances, every effort is made to protect the confidentiality of participants.
In addition to a private Facebook discussion group for all participants in the Neonatal Diabetes Registry, participants may choose to join various subtype-specific email distribution lists hosted through the University of Chicago, e.g., subjects whose diabetes is treatable with glyburide instead of insulin, subjects with transient neonatal diabetes, or subjects with insulin gene mutations. The list mechanism ensures that all participants receive all emails but also protects the confidentiality of subjects who may not wish to participate actively. Participants are reminded that their email address will be visible whenever they choose to email the group and that they should be careful to share only the information that they are comfortable discussing with others. Subjects may unsubscribe at any time.
An optional additional segment of the Neonatal Diabetes Registry involves screening assessment of neuro-development, behavior and sleep, through collection of age-appropriate validated survey instruments by study staff over the telephone, through mailings, or in person whenever possible.
While our registry data were originally maintained using standard spreadsheet software, we subsequently transferred all data to the secure, Web-based REDCap application. The multiple forms in our REDCap database are tailored to our inter-related research studies, facilitating organized, validated data collection with audit trails. The online editor has allowed our forms to be completely customized to collect specific detailed data elements regarding diabetes diagnosis and medical history, family history, as well as interval medical history to be collected longitudinally using REDCap Survey. Consent to our multiple related studies is logged for each subject with uploading of all scanned consent forms as well as any medical records, and other forms allow for sample inventory and tracking as well as capture of detailed sequencing and related research testing information. REDCap also unifies records and enables all research staff to access identical data, and as a Web-based tool, REDCap is fully portable, allowing multiple users to access, add, and update records simultaneously. REDCap has built-in tools for data cleaning and evaluation that allow for immediate and repeated graphical representation and descriptive statistics on all data, including missing data. Furthermore, data can be quickly and repeatedly interrogated by building an unlimited number of reports on any combination of variables that remain available for online viewing or easy export to Microsoft Excel or any statistical software for more detailed analysis.
Supporting Hardware Architecture and Security
The Bioinformatics Research Development Facility and iBi of the Biological Sciences Division at the University of Chicago are fully compliant with HIPAA requirements and standards, including personnel compliance training. All servers are located in a locked, well-ventilated building in downtown Chicago, with monitored cooling and power. Physical security is maintained by an electronic alarm system with window and door contacts, motion detectors, and keycard access entry to the building, with all entry logged and monitored via video surveillance. Servers employ power-on and user passwords, virus protection, and battery backup systems. Authorized users have restricted access to files requiring sophisticated rotating passwords. Operating system and security patches are current. Servers are constantly monitored for break-in attempts or other illegal activity. Only gateway machines or bastion hosts are accessible outside the firewall. All other systems are behind the monitored firewall. The Oracle, DB2, MySQL, and other database servers are not directly accessible from the Internet. The iBi currently supports and maintains multiple instances of REDCap in Redhat Enterprise Linux 5 (RHEL 5) to ensure a secure deployment. All Web servers are secured behind a Web proxy that requires authentication to access any Web applications, including REDCap. Intrusion detection software and certified SSL encryption is available for Web transactions, such as the registration Web form of participant contact information. Backups to tape are maintained nightly, and full-backups are conducted monthly with periodic transfer to an offsite location for storage.
Collection of DNA Samples for Related Genetics Studies
Any eligible subject who does not have a known genetic diagnosis is also given the option of consenting to participate in our IRB-approved genetic studies. Although providing a blood sample is one option, it has been particularly efficient and convenient to collect saliva samples directly from participant probands and relevant family members (typically both parents, if available, and any other family members with diabetes). Oragene® DNA sample collection kits (http://DNAGenotek.com
) have generally provided a high-quality DNA sample, including from infants (who use a modified kit with swabs).