DIAN Part 3: Genetic and Data Protection for Volunteers
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DIAN asks a lot of its study volunteers. Much like in ADNI, repeated clinical, neurological, and neuropsychometric testing are only part of their to-do list at every visit. In addition, they will have blood drawn for genetics analyses, enter a brain scanner at least three times (for PIB-PET amyloid imaging, FDG-PET metabolic imaging, and MRI structural and functional imaging), and will be asked to undergo a lumbar puncture to donate a CSF sample. All this adds up to a three-day stay. DIAN pays for travel and accommodation, and study staff handles the necessary arrangements.
Participants will have the option to see a genetic counselor and, if they wish, obtain formal genetic testing to find out if they inherited their affected parent’s mutation or not. This is strictly optional; family members can also participate in the entire six-year study without ever knowing their genetic status if they prefer. DIAN pays for genetic counseling and/or testing, if desired. Because families with eFAD are so few and far between, and themselves often scattered across cities and states, most DIAN participants may have to travel to the nearest DIAN site for study visits. In practice, this means DIAN participants, many of whom will be middle-aged working adults and/or parents of young children, must arrange for days off and childcare.
Concern that all this would place too great a burden on family members and overstretch the coordination capacity on the part of study staff has held back the formation of such a large network in the past. However, in previous research with smaller groups of potential DIAN volunteers at individual sites, scientists were struck by how motivated these volunteers proved to be. For example, Randy Bateman’s ongoing eFAD study at WashU, which requires a four- to five-day visit complete with a 36-hour hospital stay during which CSF samples are collected hourly from an indwelling catheter, has seen a determined response from participants. Bateman will lead the clinical core of DIAN. In another eFAD study at WashU, 27 of 28 eligible family members participated in all assessments ranging from imaging to lumbar puncture, Morris wrote.
Lumbar puncture is a concern, because fears about it are pervasive. But in ADNI, too, researchers initially expected that a fifth of participants would consent to a lumbar puncture, and then were surprised to discover that more than half did, prompting an add-on study to the original protocol to accommodate people’s willingness to participate fully. “Never underestimate the patient,” Clifford Jack noted about this experience. Jack, of the Mayo Clinic in Rochester, Minnesota, heads not only the ADNI MRI core but will also oversee MRI quality control for DIAN’s MRI scans. Growing up, prospective participants in DIAN have watched autosomal-dominant AD decimate their families, and therefore many of them have an abiding interest in helping advance research. Reisa Sperling, who leads DIAN’s Boston site, noted that many relatives of affected families know exactly what may lie ahead of them, and that some are waiting for a comprehensive study that directly addresses their situation. (See also interview with eFAD carrier.)
At present, the 10 DIAN centers together follow roughly 400 candidate research participants for the network. In addition, some families do not know if they are candidates for DIAN because their family has not conducted testing for a causative mutation. In some of these situations, DIAN will support what’s called “discovery genetic testing,” i.e., a scan for a pathogenic mutation in APP and PS1 (PS2 mutations are exceedingly rare) in an affected parent with AD. However, this can only be done in rare pedigrees where the pattern of inheritance is truly autosomal-dominant, not every time AD clusters in a family. Other risk factors, most prominently ApoE4, can drive up a family’s risk, but DIAN is only for those mostly stringently genetic cases where an asymptomatic mutation carrier faces near certainty to develop AD.
DIAN is currently funded to enroll 300 participants and follow them for six years. Cognitively healthy and very mildly symptomatic people can enter DIAN. Relatives with more advanced disease cannot enter the study because DIAN’s primary goal is to characterize the asymptomatic period; however, they are encouraged to consider consenting to an autopsy and donating samples of brain tissue to DIAN’s neuropathology core, headed by Nigel Cairns at WashU. This would not only confirm the genetic and clinical diagnosis of AD in the family, but also ensure a uniform neuropathological examination of DIAN families.
The DIAN investigators expect to enroll about as many carriers as non-carriers. Importantly, participants need not know their genetic status, and study staff as well will stay blinded to a person’s mutation status wherever possible. How often study participants will visit their DIAN site depends on how many years away in age they are from their family’s average age at onset. Those who are more than 10 years younger will only come once every five years. Those between 10 and three years younger will come every two years. They will also talk on the phone once a year with study staff, and if that call triggers concern, or if their spouse/partner/sibling believes that their cognition appears to have declined, they will be invited for annual visits. Those between three years younger and three years older than average family age at onset will come once a year, and those who are more than three years older will have annual phone calls with study staff.
One point of pride for ADNI lies in the broad access to its data and the ease of data sharing. Open access was a decision from the get-go, and ADNI’s informatics leader Art Toga at UCLA and his group have built informatics systems that make it possible for all qualified scientists around the world to download its research data for their own analyses. DIAN’s data will also become widely accessible but not in the same instant open-access fashion, Morris wrote. This is partly because families with eFAD are considered a special population who require heightened sensitivity for privacy; hence de-identification of the data will have to be done with extra care. Partly, DIAN investigators want quality control before data are shared. And partly, DIAN investigators will be encouraged to use the data first; once they do, the data will become more publicly available. The details of access to DIAN data are still being worked out, Morris wrote. Dan Marcus, who leads DIAN’s informatics core, is a neuroinformatics researcher at WashU with a commitment to data sharing. Marcus directs development of an open source data management platform called the Extensible Neuroimaging Archive Toolkit (XNAT), as well as the public data sharing project OASIS (see ARF related news story). While DIAN preparations continue, this group has set up www.dian-info.org, which will post public information about DIAN, much as www.adni-info.org does for that initiative. At this initial stage, the group is focusing on developing the tools necessary for data management within the research network and for building DIAN’s integrated database. —Gabrielle Strobel.
This concludes a three-part series. See also Parts 1 and 2.
References
News Citations
- Changes In Cortical Thickness Mirror Loss of Network Connectivity in AD
- DIAN: Registry for eFAD to Chart Alzheimer’s Preclinical Decade
- DIAN Part 2: The Science, Inner Workings of the Network
Other Citations
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