2.1. Purpose of Registry
The goals of the Registry are to assist researchers in the recruitment of patients into clinical studies, to develop an extensive database of de-identified patient information, and to allow for the analysis of data related to the pathophysiology and clinical spectrum of disease manifestations in DM and FSHD.
2.2. Organization and leadership
The Registry is funded by the National Institute of Arthritis, Musculoskeletal, and Skin Diseases and the National Institute of Neurological Disorders and Stroke. Registry leadership consists of two NIH Project Officers, an Internal Steering Committee (principal and co-investigators based at the University of Rochester), and an External Steering Committee. The Internal and External Steering Committees comprise the Scientific Advisory Committee, and its members include scientists and clinicians who are recognized experts in neuro-muscular medicine as well as patient advocates. Principal and co-investigators have presented and shared information about the Registry with colleagues in Australia, Peru, Canada, Germany, Italy, Netherlands, and the United Kingdom [32
]. In addition, the principal investigator of the Registry currently serves as an advisory member for the Office of Rare Diseases Research initiatives to establish a Global Rare Diseases Patient Registry and Data Repository, and most recently served as one of the key-note speakers at a workshop about model informed consents. Proceedings from this meeting will be published as guidelines for obtaining informed consents from subjects enrolled in registries (http://rarediseases.info.nih.gov/PatientRegistry.aspx
2.3. Patients and data collection
The Research Subjects Review Board at the University of Rochester Medical Center reviews and approves all Registry materials and activities. Patients in the United States are recruited to join the Registry through a variety of methods including a public website (www.dystrophyregistry.org
). Patients, investigators, and physicians also learn about the Registry through recruitment letters sent annually to neuromuscular disease specialists, advertisements through patient advocacy groups, advertisements on NIH-affiliated and patient support group websites, and presentations at national and international research and medical conferences. In accordance with NIH and World Health Organization guidelines, the Registry is listed on ClinicalTrials.gov (http://clinicaltrials.gov/ct2/show/NCT00082108
), which is a website that “describes federally and privately supported clinical trials conducted in the United States and around the world.”
Patients can obtain Registry forms from neuromuscular clinics, by printing forms from the Registry website, or by contacting the Registry staff (e.g., email, toll-free phone call) and requesting that an application packet be mailed to them. The application packet to join the Registry includes:
- Patient Information Form, a disease-specific questionnaire that captures patient-reported information such as demographics, education and employment, use of assistive devices, physical limitations, medical history, diagnostic tests, rehabilitation therapies received, and other medical problems (http://www.urmc.rochester.edu/neurology/nih-registry/join/index.cfm).
- Release of Medical Information Form, which allows the Registry to obtain medical records to confirm applicants’ diagnoses.
- Consent Form, which describes the purpose of the Registry and the benefits and risks of participation.
All the forms associated with the Registry are paper-based. Patients complete each of the forms listed above and send the application packet to Registry staff in a postage paid envelope. Submitted applications are reviewed by Registry staff to ensure that all forms have been completed adequately. Once an application is complete, medical records for the patient are requested from the patient’s care providers and reviewed by Registry staff and investigators.
2.4. Eligibility and classification of enrollees
Eligibility is determined when the Principal Investigator or Co-investigators have confirmed an enrollee’s consent, reviewed their Patient Information Form, and verified a diagnosis through medical record review. In order to increase recruitment opportunities, genetic confirmation of the disease is not required for enrollment in the Registry. The clinical and genetic criteria for enrollment are outlined in a disease-specific Physician Checklist Form to facilitate determination of eligibility (www.urmc.rochester.edu/neurology/nih-registry/research/investigators.cfm
). Members of the Registry are classified as:
- Definite DM or FSHD: Individuals with diagnostic genetic testing according to current guidelines for DM and FSHD [32,34,35] are classified as “definite” DM or FSHD.
- Probable DM or FSHD: Individuals without genetic testing but who meet the defined clinical criteria [1,2,23,35–37] are classified as “probable” DM or FSHD.
- Possible DM or FSHD: Individuals with symptoms suggesting DM or FSHD but without detailed clinical and genetic testing information are classified as possible DM or FSHD.
- Unaffected Family: Unaffected blood relatives and spouses complete an abbreviated Patient Information Form that collects demographic information, family history, and documents if any diagnostic tests have been completed to rule out DM or FSHD.
The Physician Checklist Forms were developed by the Scientific Advisory Committee and capture information on the patient’s pattern of muscle weakness, diagnostic muscle tests (e.g., electromyography and muscle biopsy results), and diagnostic genetic testing. Several categories are used to classify enrollees because of the variety and complexity of symptoms, onset and subtypes of DM and FSHD, variability in clinical and diagnostic procedures, regional health care differences, the quality of medical records available for review, and the inclusion of unaffected family members. A member’s classification is updated if additional diagnostic information becomes available through follow-up data collection.
Benefits to patients who join the Registry include receiving notification of research studies, learning about advances in the knowledge of their disease, and connecting with experts in neuromuscular disease.
2.5. Data entry, annually updated forms, and security
Data from the two disease groups are stored in separate Microsoft Access databases. These databases are very similar in structure, yet contain some differences due to the capture of disease-specific information. After initial contact is made with applicants, Registry staff enter demographic data and the dates the application and medical records were received. After the Principal and Co-investigators have reviewed the medical records and completed the Physician Checklist Form to determine eligibility, Registry staff enter information from both the Patient Information Form and the Physician Checklist Form into the Registry database.
Annual update forms are sent to members and include information reported in the member’s baseline Patient Information Form and changes from any previously returned forms. Each year members can record changes in their symptoms and any significant milestones in their lives on these forms, which are mailed back to the Registry in a postage paid envelope. These follow-up data allow investigators to track disease-related changes from year to year and enable investigators to have the most up-to-date information available to target recruitment.
The database of the Registry is stored on file servers maintained by the University of Rochester Information Systems Division. This group is responsible for the security of all University network servers, including firewalls, virus checking, network and workstation access passwords, and backup and disaster recovery. In addition to these security layers, the University of Rochester Neuromuscular Center further safeguards data privacy by requiring individual application passwords and restricting access of confidential data to only those staff members with a direct need. Individual identifiers are limited to a single data table. All other files are linked by a non-informative, random identifier.
The underlying source documents (consent, medical records, patient forms) are similarly protected. They are locked in file cabinets in secured areas. File folders are stored in ID number order (rather than by name) to further protect them from unauthorized access.
2.6. Review of research applications and release of information
Investigators are required to submit a brief research protocol and application form to analyze de-identified data from the Registry database or to recruit members of the Registry to participate in clinical studies. These application forms are available on the Registry website or by contacting Registry leaders or staff. Investigators must also submit confirmation of necessary approvals from their Institutional Review Board. Submitted applications are then reviewed anonymously by members of the Scientific Advisory Committee to determine the scientific merit, feasibility, and safety of the study.
Once an application is approved, Registry staff and leadership work closely with the investigator to facilitate their research plans. To assist recruitment for an approved project, a list of Registry members potentially eligible to participate is compiled based upon the inclusion and exclusion criteria submitted by the researcher. The Registry then sends a letter to each potentially eligible member of the Registry to describe and provide contact information for the study. Registry members are invited to contact the investigator if they have questions or if they are interested in participating in the study. The Registry does not provide any identifiable patient data directly to investigators. At the conclusion of the study, researchers are required to report the number of participants that were recruited through the Registry and to acknowledge the Registry if results are published. Results may not be published for studies or surveys that are not research (e.g., surveys to improve clinic experience or educational outreach) or if manuscripts are rejected.
To provide investigators with de-identified data for an approved research application, Registry staff review the inclusion and exclusion criteria in the protocol and develop data reports based upon all eligible members in the Registry. Registry staff can provide assistance with clarifying the data and highlighting variables that may correspond to the specific objectives in the research protocol, but the statistical analysis and summaries are performed by the investigator. Researchers are required to acknowledge the Registry if the results are published.
2.7. Analyses of data at time of enrollment and after follow-up period
We analyzed data from all members of the Registry who have been classified with the following diagnostic categories from the Physician Checklist Form: definite, probable, congenital, and juvenile DM1; definite and probable DM2; and definite and probable FSHD. Congenital DM1 was defined as onset of DM symptoms at age<4 weeks based on retrospective chart review [1
]. Juvenile or childhood DM1 was defined as onset of DM symptoms at age<10 years and an uneventful prenatal and neonatal history, and normal physical development in the first year based on retrospective chart review [38
Select burdens of disease were analyzed at enrollment and at follow-up for members who met the following criteria: a.) 18 yrs and older, b.) returned at least one annual update form; and c.) met the inclusion criteria noted above from the Physician Checklist Form. Juvenile and congenital DM members were excluded from these analyses. Variables analyzed were use of assistive devices (cane, leg brace, and wheelchair/scooter); use of therapies (occupational, physical, and psychological counseling); and psychosocial burdens (reduced employment, disability due to disease manifestations, and psychological problems).
Short-term progression of these burdens of disease was determined by comparing information collected at enrollment to information reported by patients on their most recently completed annual update form. We report the mean length of time and the range for the follow-up period (in years). Data are summarized as the percentage of patients who reported: 1.) no change; and 2.) increased values (for example, requiring a new assistive device).
Data are reported as means±standard deviations, frequencies, and percentages. We used T-tests and chi-square tests to compare results among disease groups. Comparisons were made between DM1 and DM2 patients, DM1 and FSHD patients, and DM2 and FSHD patients. Pearson correlations were used to examine the associations between genetic testing results and clinical characteristics. Significance was set at α = 0.05.