Part 3: Families Fight Back as Alzheimer’s Claws at Next Generation

When the leaders of the Dominantly Inherited Alzheimer’s Network met on September 27 in St. Louis, Missouri, they wrestled with the sensitive issue of genetic confidentiality when reporting data in scientific meetings and publications. The DIAN protocol has been constructed to allow participants to go through an intensive regimen of tests without having to know whether they have inherited their affected parent’s mutation. But as DIAN enters its fifth year, keeping this promise is becoming trickier as privacy is getting increasingly pitted against scientific learning. DIAN data are rolling in on all fronts—see part 2 of this series and AAIC Conference Story—and DIAN scientists across the globe have a dozen manuscripts in preparation or in press. As they are preparing to publish, they are confronting the prospect that anxious participants, or their curious relatives, will read the scientific paper and try to deduce their own mutation status from the presented data. In other instances, a participant might find out because their DIAN physician is obligated to tell them of an important unrelated medical finding they discovered in the course of the study assessments. In St. Louis last week, DIAN’s steering group and its external advisors sought ways to balance the need to publish meaningfully for the betterment of science—and scientists’ careers—with the need to maintain the cloak of confidentiality.

The concern is not hypothetical. When DIAN’s first data paper was published (Bateman et al., 2012), a participant’s spouse called the study’s principal investigator, John Morris of Washington University, St. Louis, to express chagrin at having purportedly discovered in a data figure that their spouse inherited the mutation causing Alzheimer’s disease in her family. It turned out that the person had misinterpreted the figure and the spouse’s status in fact remained blinded, but the situation illustrated how data presentation must be carefully considered to minimize any inadvertent opportunity for such deductions. Indeed, this has happened previously in AD genetics. Gary Reiswig, a member of the Volga German kindred, wrote in his book “The Thousand Mile Stare,” how in 1995 he discovered he had escaped the family’s presenilin 2 mutation when he read about the gene discovery in the New York Times and then located his spot in the family pedigree in the original paper in Science (see Alzforum book review). At the St. Louis meeting last month, the scientists were concerned that participants might find themselves in the position of puzzling out—rightly or wrongly—their mutation status. “Data are getting ready for publication. Some people will pore over the paper and try to find out which data point in a graph might be them. We need to think about how to protect patient privacy,” said Randall Bateman of WashU, who leads the clinical and trial components of DIAN.

DIAN scientists are exploring various ways of displaying data that avoid accidental disclosure. For one, they forgo scatter plots that show data points for individual people on an x axis labeled with how many years away a given person is from their expected age at onset. Those plots are established and most scientifically informative, but participants could try to find ‘themselves’ in them. Instead, scientists resort to graphs that connect data points into curves or shaded areas fitted to the distribution of the individual data points. That is not always quite sufficient, however. Scientific data reporting frequently requires tables and numbers. The curves and area plots used in the NEJM paper are adequate to display cross-sectional data, but not longitudinal data. For those, it is important also to show individual data that reflect a person’s baseline level of a given marker and how it changes from there, said WashU’s Anne Fagan, DIANs biomarker core director. Fagan solved the problem by retaining individual data points but removing the age labels from the x axis of a first cut of longitudinal CSF biomarker change she presented to the DIAN committees (see part 2). Disguising data is necessary not only for scientific publications but also in internal presentations, as the DIAN steering committee includes family members.

A similar study, the Alzheimer’s Prevention Initiative, bundled participants’ brain images into 5-year groups, or matched carriers and non-carriers by age, helping to prevent people from identifying their data. DIAN scientists have asked colleagues in other fields about how they handle this issue. In fact, most comparable studies make knowing one’s genetic status a condition of participating, said Virginia Buckles of WashU. “No other study has so many participants who do not want their mutation status to be known or disclosed, so no one has been able to give us their workable compromise between publishing real data and protecting privacy,” Buckles said.

Eric Reiman of the Banner Alzheimer’s Institute in Phoenix, Arizona, is a member of DIAN’s external advisory committee. “There is scientific value in looking at individual data points, and there are occasions in which some or all of the data can be shown in a manner that minimizes the risk of inadvertent disclosure,” Reiman said, adding, “I would recommend case-by-case flexibility over a one-size-fits-all policy. There is no magical answer at this point, but as we give thoughtful consideration to this important issue, we will learn as we go forward.”

After discussion, the DIAN leaders agreed to continue to explore alternate data displays while being upfront with participants that there is no absolute guarantee of indefinite privacy. Scientific papers could include a disclaimer reminding participants that their odds of carrying the family mutation are 50/50 and much higher if they are symptomatic. Prior to submission, DIAN checks all manuscripts to ensure nothing in it gives away more information than that. “You cannot totally eliminate a breach of confidentiality in the publication of research papers. Try your best to minimize it,” an anonymous family member on the steering committee told the scientists.

Accidental disclosure situations can also arise in the course of participants’ study visits. Every so often, a DIAN radiologist discovers an unrelated but medically important sign on a brain scan, such as a tumor or an aneurysm. This has happened. For example, Bateman showed an MRI scan of a DIAN participant that showed a finding that needs independent evaluation and might or might not be interpreted as being associated with the family’s AD mutation. Discussing his/her scan with the DIAN physician could theoretically prompt the participant to guess about their mutation status. This is a delicate situation for both physician and participant. In essence, a participant could arrive at a DIAN site unaware of their mutation status and thinking they are healthy, and return home thinking that they have the dread family disease and having heard about another medical issue that needs follow-up, too. What to do?

In these instances, the DIAN physicians have little choice. Institutional review boards (IRB) frown on research physicians withholding medically relevant information for any reason, and a doctor’s ethical obligation to disclose medically important findings generally prevails. DIAN’s informed consent states that mutation status could be revealed accidentally, though it does not specify that this might happen in the course of disclosing medically relevant information. In their discussion, the steering group proposed to update the consent form to include this possibility.

If a DIAN participant, at any point in the study, decides they want to know their status, then DIAN staff arranges and pays for genetic counseling and subsequent testing through commercial means. DIAN asks participants not to share their results with DIAN so that study staff can stay blinded. So far, only 20 of 290 DIAN participants have chosen this path. For others, anxiety about their mutation status remains intense. Some who are non-carriers firmly believe they have dementia symptoms and on this basis have been scored CDR 0.5, indicating very mild symptomatic disease, at their baseline exam, Morris said. By the second visit, those participants tend to revert to a score of CDR 0 (cognitively normal), as it is becomes clear that they do not have progressive disease.