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3 JOURNAL OF LAW (3 THE POST) 99
FROM: THE FACULTY LOUNGE
ARE YOU READY FOR SOME
. . . RESEARCH?
UNCERTAIN DIAGNOSES, RESEARCH DATA
PRIVACY, & PREFERENCE HETEROGENEITY
Michelle N. Meyer†
s most readers are probably aware, the past few years have
seen considerable media and clinical interest in chronic
traumatic encephalopathy1 (CTE), a progressive, neuro-
degenerative condition linked to, and thought to result from, con-
cussions, blasts, and other forms of brain injury (including, im-
portantly, repeated but milder sub-concussion-level injuries) that
can lead to a variety of mood and cognitive disorders, including de-
pression, suicidality, memory loss, dementia, confusion, and aggres-
sion. Once thought mostly to afflict only boxers, CTE has more
recently been acknowledged to affect a potentially much larger
population, including professional and amateur contact sports play-
ers and military personnel.
CTE is diagnosed by the deterioration of brain tissue and tell-tale
patterns of accumulation of the protein tau inside the brain. Cur-
rently, CTE can be diagnosed only posthumously, by staining the
brain tissue to reveal its concentrations and distributions of tau.[1]
† Fellow, The Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics,
Harvard Law School. Original at www.thefacultylounge.org/2013/02/are-you-ready-for-
some-research-uncertain-diagnoses-research-data-privacy-preference-heterogeneity.html
(Feb. 3; vis. Apr. 15, 2013). The bracketed endnote calls in the text correspond to the
endnotes on pages 108-09. © 2013 The Faculty Lounge and Bill of Health, February 3,
2013, by Michelle N. Meyer.
1 www.bu.edu/cste/about/what-is-cte/.
A
MICHELLE N. MEYER
100 3 JOURNAL OF LAW (3 THE POST)
According to Wikipedia,2 as of December of 2012, some thirty-
three former NFL players have been found, posthumously, to have
suffered from CTE. Non-professional football players are also at
risk; in 2010, 17-year-old high school football player Nathan Styles
became the youngest person to be posthumously diagnosed with
CTE, followed closely by 21-year-old University of Pennsylvania
junior lineman Owen Thomas. Hundreds of active and retired pro-
fessional athletes have directed that their brains be donated to CTE
research upon their deaths. More than one of these players died by
their own hands, including Thomas, Atlanta Falcons safety Ray
Easterling, Chicago Bears defensive back Dave Duerson, and, most
recently, retired NFL linebacker Junior Seau. In February 2011,
Duerson shot himself in the chest, shortly after he texted loved ones
that he wanted his brain donated to CTE research. In May 2012,
Seau, too, shot himself in the chest, but left no note. His family de-
cided to donate his brain to CTE research in order “to help other
individuals down the road.”3 Earlier this month, the pathology re-
port revealed that Seau had indeed suffered from CTE. Many other
athletes, both retired and active, have prospectively directed that
their brains be donated to CTE research upon their death.[2] Some
4,000 former NFL players have reportedly joined numerous law-
suits against the NFL for failure to protect players from concussions.
Seau’s family, following similar action by Duerson’s estate, recently
filed a wrongful death suit4 against both the NFL and the maker of
Seau’s helmet.
The fact that CTE cannot currently be diagnosed until after death
makes predicting and managing symptoms and, hence, studying
treatments for and preventions of CTE, extremely difficult. Earlier
this month, retired NFL quarterback Bernie Kosar, who sustained
numerous concussions during his twelve-year professional career –
and was friends with both Duerson and Seau – revealed5 both that
2 en.wikipedia.org/wiki/Chronic_traumatic_encephalopathy.
3 espn.go.com/nfl/story/_/id/7889467/junior-seau-family-allow-concussion-study-brain.
4 usatoday30.usatoday.com/sports/!invesitgations%20and%20enterprise%20docs/seau_c
omplaint_-_superior_court.pdf.
5 espn.go.com/nfl/story/_/id/8833397/bernie-kosar-former-cleveland-browns-quarterb
ack-finding-help-concussions.
ARE YOU READY FOR SOME . . . RESEARCH?
NUMBER!1!(2013)!101!
he, too, has suffered from various debilitating symptoms consistent
with CTE (but also, importantly, with any number of other condi-
tions) and also that he believes that many of these symptoms have
been alleviated by experimental (and proprietary) treatment pro-
vided by a Florida physician involving IV therapies and supplements
designed to improve blood flow to the brain. If we could diagnose
CTE in living individuals, then they could use that information to
make decisions about how to live their lives going forward (e.g.,
early retirement from contact sports to prevent further damage),
and researchers could learn more about who is most at risk for CTE
and whether there are treatments, such as the one Kosar attests to,
that might (or might not) prevent or ameliorate it.
Last week, UCLA researchers reported6 that they may have dis-
covered just such a method of in vivo diagnosis of CTE. In their very
small study, five research participants – all retired NFL players –
were recruited “through organizational contacts” “because of a histo-
ry of cognitive or mood symptoms” consistent with mild cognitive
impairment (MCI).[3] Participants were injected with a novel posi-
tron emission tomography (PET) imaging agent that, the investiga-
tors believe, uniquely binds to tau. All five participants revealed
“significantly higher” concentrations of the agent compared to con-
trols in several brain regions. If the agent really does bind to tau,
and if the distributions of tau observed in these participants’ PET
scans really are consistent with the distributions of tau seen in the
brains of those who have been posthumously-diagnosed CTE, then
these participants may also have CTE.[4]
That is, of course, a lot of “ifs.” The well-known pseudomymous
neuroscience blogger Neurocritic7 [5] recently asked me about the
ethics of this study. He then followed up with his own posts laying
out his concerns about both the ethics8 and the science9 of the study.
Neurocritic has two primary concerns about the ethics. First, what
are the ethics of telling a research participant that they may be
6 deadspin.com/5978074/new-study-reveals-that-cte-may-be-detectable-in-living-patients.
7 neurocritic.blogspot.com.
8 neurocritic.blogspot.com/2013/01/the-ethics-of-public-diagnosis-using.html.
9 neurocritic.blogspot.com/2013/01/is-cte-detectable-in-living-nfl-players.html.
MICHELLE N. MEYER
102 3 JOURNAL OF LAW (3 THE POST)
showing signs of CTE based on preliminary findings that have not
been replicated by other researchers, much less endorsed by any
regulatory or professional bodies? Second, what are the ethics of
publishing research results that very likely make participants identi-
fiable? I’ll take these questions in order.
UNCERTAIN DIAGNOSES &
RISK-BENEFIT HETEROGENEITY
n his blog, Neurocritic asks10:
“What are the ethics of telling [Wayne Clark,11 the only one of
the 5 participants who has experienced no symptoms except
age-consistent memory impairment,] that he has ‘signs of CTE’
after a undergoing a scan that has not been validated to accu-
rately diagnose CTE? It seems unethical to me. I imagine it
would be quite surprising to be told you have this terrible dis-
ease that has devastated so many other former players, especial-
ly if your mood and cognitive function are essentially nor-
mal. . . . I could be wrong about all of this and maybe [their
novel PET imaging agent] does provide a definitive diagnosis of
CTE (the definition of which may need amending). But don’t
you want to be sure before breaking the news to one of your
patients?”
One of the most contentious current debates in the law and eth-
ics of genetics and neuroimaging research is whether to offer to re-
turn individual research results (IRRs) to participants. Often, IRRs
are of uncertain analytical and/or clinical validity, and they may not
be clinically actionable. Some worry that returning such IRRs will
simply burden individuals with scary, but uncertain and relatively
useless, data. Others, by sharp contrast, view an offer to return
“their data” to research participants as akin to a human right. I’ve
tried to stake out a middle, participant-centered ground12 in this
polarized debate.
10 neurocritic.blogspot.com/2013/01/the-ethics-of-public-diagnosis-using.html.
11 www.nfl.com/player/wayneclark/2511579/profile.
12 papers.ssrn.com/sol3/papers.cfm?abstract_id=2106135.
O
ARE YOU READY FOR SOME . . . RESEARCH?
NUMBER!1!(2013)!103!
On one hand, participants need to understand what they’re get-
ting into when they join a study like this. Information, once learned,
cannot be unlearned (thus, the relatively new concept of the “right
not to know”). Among other things, Wayne Clark and the other
participants should have been told (by which I mean, throughout,
meaningfully made to understand) why they were recruited – name-
ly, that their history of head trauma, combined with their MCI
symptoms, made researchers suspect that they may well have CTE.
In 64-year-old Clark’s case, it should have been made additionally
clear to him that, although his only current symptom is age-
appropriate memory loss, that investigators might come to suspect
that this is a symptom of a neurodegenerative condition rather than
normal aging. And all participants should have been told that they
would effectively have no choice but to have their IRRs “returned”
to them: a CTE study involving five retired NFL players, released
shortly before the Super Bowl and amidst lots of media coverage
about the future of contact sports was bound to go (and has gone)
viral. Finally, they should have been told that virtually nothing can
be concluded from a study of just five individuals with various addi-
tional design limitations. We can’t know, of course, whether the
informed consent process in this case was adequate. Readers of the
study are told that “[i]nformed consent was obtained in accordance
with UCLA Human Subjects Protection Committee procedures” –
and also told that UCLA owns the patent to the method used in the
study, and that some of the investigators are inventors who stand to
collect royalties. We should have additional concerns about in-
formed consent, given that the participants by definition all suffer
from some level of MCI.
That said, it is not inherently unethical to give people uncertain
information – even when the information is potentially devastating
and even if it’s not “clinically actionable.” Extremely inconvenient
though it often is, life is filled with uncertainties. Information rarely
carries with it tags that read 0% or 100%. This is about as true in
medical practice, by the way, as it is in biomedical research – in part
because huge swaths of “standard practice” are not evidence-based,
for a variety of reasons; in part because even a solid evidence base is
MICHELLE N. MEYER
104 3 JOURNAL OF LAW (3 THE POST)
typically based on the effects of an intervention on narrowly select-
ed research participants in highly controlled circumstances which
may not generalize to individual patients in real life; and in part be-
cause medicine, even at its best, often remains probabilistic. So alt-
hough most of us, most of the time, would prefer certainty to un-
certainty, where certainty is out of reach, the question becomes
whether it’s better, relative to the status quo ante, to obtain (addi-
tional) probabilistic information or not.
The answer is that it depends. Learning probabilistic information
(here I assume that the study isn’t completely without probative
value) about oneself can be risky. But it can also carry potential ben-
efits. Just how risky and/or potentially beneficial it is – and whether
this expected risk-benefit profile is “reasonable” (as IRBs must find)
– depends on a variety of factors, most obvious among them the
kind of information at issue, the degree of uncertainty, and – as I
have been at pains to emphasize in my work – the individual’s pref-
erences and circumstances. Sometimes people who suffer from MCI
are relieved to learn that they may have a diagnosis, and perhaps a
culprit, and that their symptoms aren’t mere figments of their imag-
ination. Other participants, especially those who have lost friends to
CTE, may feel so strongly that something needs to be done to ad-
vance our knowledge of CTE that they are willing to assume the
risks of psychosocial discomfort and privacy invasions in order to
contribute to that effort even in a small way.
Heterogeneity in stakeholder preferences implies a prima facie
case against any one-size-fits-all law, policy, or ethical code govern-
ing risk-benefit trade-offs. (My forthcoming law review article on
this “heterogeneity problem” in risk-benefit decision-making by cen-
tral planners is here;13 a tl;dr version of some of the take-home
points is here.14) Sometimes, of course, one-size-fits-all is the best
we can do in law and policy; but where we can improve upon it,
especially with little or no cost, we should. The presence of hetero-
geneity tends to recommend private ordering, nudges, federalism,
13 papers.ssrn.com/sol3/papers.cfm?abstract_id=2138624.
14
www.forbes.com/sites/davidshaywitz/2013/01/24/personalized-regulation-more-than-
just-personalized-medicine-and-urgently-required/.
ARE YOU READY FOR SOME . . . RESEARCH?
NUMBER!1!(2013)!105!
and ex post regulation (rather than ex ante licensing). You’ll find
libertarians who are sympathetic to this line of argument, of course.
But you’ll also find welfare liberals like Cass Sunstein agreeing (in
his Storrs Lecture, no less) that15 “While some people invoke auton-
omy as an objection to paternalism, the strongest objections are
welfarist in character. Official action may fail to respect heterogene-
ity . . . .” And so one answer to Neurocritic’s query about “the eth-
ics” of revealing this information is that there is no singular “ethics”
of this situation, at least not in terms of substantive outcomes, as
opposed to an appropriate process for allowing individualized deci-
sion-making.
(RE)IDENTIFIABILITY OF RESEARCH DATA &
RISK-BENEFIT HETEROGENEITY
eurocritic’s second concern is about the privacy implications
of participating in the CTE study. Of the five participants, two
have spoken on the record to the media about the study – voluntari-
ly, I’ll assume. One hopes that they were told that, even if they are
okay with the public learning about their results, they can’t always
control the way the public interprets those results. For instance,
Wayne Clark’s Wikipedia page16 has already been updated to indi-
cate, inaccurately, that “[a]fter his career, Clark was discovered to
have chronic traumatic encephalopathy,” citing to an article whose
headline declares breathlessly: “Scans show CTE in living ex-
players; could be breakthrough.”17 (See also “Researchers find CTE
in living former NFL players,”18 “Scientists discover ‘holy grail’ of
concussion-linked CTE research,”19 and “Holy Grail Breakthrough in
CTE Brain Damage Research.”20) Scientists have a responsibility to
15 papers.ssrn.com/sol3/papers.cfm?abstract_id=2182619.
16 en.wikipedia.org/wiki/Wayne_Clark_(American_football).
17 www.nflevolution.com/article/Scans-show-CTE-in-living-ex-players-could-be-breakthr
ough?ref=4026.
18 www.cbssports.com/nfl/blog/eye-on-football/21599368/researchers-find-cte-in-living
-former-nfl-players.
19
www.ctvnews.ca/health/scientists-discover-holy-grail-of-concussion-linked-cte-research
-1.1125840.
20 www.theblend.ie/lifestyle-2/health-fitness/holy-grail-breakthrough-in-cte-brain-damag
N
MICHELLE N. MEYER
106 3 JOURNAL OF LAW (3 THE POST)
carefully and accurately communicate all science, but especially sen-
sitive or controversial science. They should go out of their way to
avoid hype, and should affirmatively correct the record when neces-
sary. When neuroscience is at issue, investigators should avoid brain
porn21 – pretty pictures of brain scans designed to look as dramati-
cally different from the “control” brain scan as possible, and which
exploit our tendency to believe that being able to point to some-
thing in the brain makes it more “real” than otherwise. In this case,
in addition to plenty of pretty pictures of brain scan, the journal
article contains plots of nice-looking correlations between concus-
sions and tau, but these graphics are easily misinterpreted, since
results from just five observations will be very sensitive to the influ-
ence of outliers.
What of the other three participants, who have not been identi-
fied? They may nevertheless be identifiable, given the information
about them that has been published in the journal article and in the
press (e.g., age, position played in the NFL, concussion history,
MCI symptoms). One can’t help but be reminded of another recent
study, published in Science22 just a week or so before the CTE study
appeared. That paper reported that computer informatics and ge-
netics researchers were able to re-identify five men who had partici-
pated in both the 1000 Genomes Project23 – an international public-
private consortium to sequence (as it turns out, 2500) genomes
from “unidentified” people from about 25 world populations and
place that sequence data, without phenotypic information, in an
open online database – and a similar study of Mormon families in
Utah, which did include some phenotypic information. Although
this “DNA hacking” made a huge splash, the fact that de-identified
genetic information can fairly easily be re-identified is not news; it’s
happened before to research samples (although, importantly, always
by researchers simply attempting to show that it can be done, rather
than by actors with nefarious motives). NIH, which funds both pub-
e-research/.
21 neurocritic.blogspot.com/2012/12/the-mainstreaming-of-neurocriticism.html.
22 www.sciencemag.org/content/339/6117/321.
23 www.1000genomes.org.
ARE YOU READY FOR SOME . . . RESEARCH?
NUMBER!1!(2013)!107!
lic genetic databases, responded, as it had following a similar inci-
dent in 2008,24 by reducing the richness of the Utah dataset by elim-
inating the ages of participants to make re-identification more diffi-
cult. In this case, that was likely appropriate, since participants
probably had consented to a different risk-benefit profile. But what
to do going forward? Should participants be allowed to donate their
data to open access science, knowing that ensuring anonymity is
impossible? We can, of course, make research data available to only
a limited circle of those with approved access, as is typically done.
And we can render our datasets less and less rich, to reduce the risk
of re-identification. But both privatizing and watering down data
sets impede knowledge production.
A different – and neglected – approach is the one taken by the
Personal Genome Project25 (PGP), led by Harvard Medical School
geneticist George Church.26 The PGP posts on the Internet partici-
pants’ whole genome sequences (WGS), along with as rich a pheno-
type dataset as participants are willing to provide. The first ten par-
ticipants[6] (the PGP ultimately wants to recruit 100,000) identified
themselves by name, occupation, and photo,27 and provided medical
and other personal data.28 Since then, participants generally have not
explicitly identified themselves by name, but they have agreed to
make their DNA sequence and often huge amounts of personal in-
formation available to researchers and to the general public – all
with the express understanding and agreement that their anonymity cannot
be guaranteed. (Disclosure: I’m a PGP participant; indeed, my ge-
nome is being sequenced as I write.) Rather than making what are,
it has for some time now been clear, fairly empty promises of de-
identification, the PGP’s “open consent”29 model requires partici-
pants to be “information altruists.”
It is, perhaps, the idiosyncratic person such as myself whose net
preferences yield a willingness to give such “open consent.” But the-
24 gwas.nih.gov/pdf/Data%20Sharing%20Policy%20Modifications.pdf.
25 www.personalgenomes.org.
26 www.hms.harvard.edu/dms/BBS/fac/church.php.
27 www.personalgenomes.org/pgp10.html.
28 my.personalgenomes.org/users.
29 arep.med.harvard.edu/pdf/Lunshof08.pdf.
MICHELLE N. MEYER
108 3 JOURNAL OF LAW (3 THE POST)
se people do exist, they may be more numerous than many believe,
and they have perfectly rational (if difficult to quantify) reasons to
want to sacrifice their informational privacy, including altruism,
intellectual curiosity, novelty, and a desire to be part of something
bigger than themselves. To help ensure that these really are partici-
pants’ considered preferences, the PGP requires that prospective
participants obtain a 100% score on a genetic test that includes
questions about the limits of information privacy. Rather than Har-
vard’s IRB or a state or federal regulator imposing a one-size-fits-all
privacy rule, this approach accommodates both heterogeneous risk-
benefit preferences and heterogeneity among individuals in their
comprehension of the study’s risks.
Were the five retired NFL players who participated in the CTE
study knowing information altruists who gave open consent? I don’t
know, because I don’t know what they were told and, of that, what
they understood and appreciated. But I think they should have been
allowed to be.
[Disclaimer: I am not involved in this,30 and the views expressed
here are entirely my own.]
Cross-posted at Bill of Health.
_________________________________________________
[1] All neurodegenerative diseases can be diagnosed definitively only on autopsy. This is
true, for instance, of Alzheimer’s. You likely know at least one person who has been diag-
nosed with Alzheimer’s while they were still living. That’s because, after much research, a
professional consensus has been reached about the clinical diagnostic features of, and objec-
tive biomarkers for, Alzheimer’s which allow clinicians to make a differential diagnosis of
“probable Alzheimer’s” as opposed to some other form of dementia. Any in vivo diagnostic
for CTE would likely have implications for the (probably much bigger) Alzheimer’s diag-
nosis market.
[2] For a graphic description of this process, which suggests one reason why families often
wrestle with the decision to permit their loved ones’ bodies to be donated to science,
especially when the deceased hasn’t indicated his or her wishes, see a few paragraphs down
in this article31 about the brain donation of hockey player Derek Boogaard, who was found
to have had CTE.
30 blogs.law.harvard.edu/billofhealth/2013/01/30/petrie-flom-center-to-work-with-nfl-
players-association/.
31 www.nytimes.com/2011/12/06/sports/hockey/derek-boogaard-a-brain-going-bad.ht
ml?pagewanted=1&hp.
ARE YOU READY FOR SOME . . . RESEARCH?
NUMBER!1!(2013)!109!
[3] The investigators were led through “organization contacts” to 19 retirees known to have
“MCI-like symptoms.” Of these, 11 were lost to “non-response or disinterest” [sic], 2 to
being too young, and 2 to “medical illness.” This was not, then, a representative sample of
professional football players, football players who have experienced concussions, or even
football players who have experienced concussions and MCI-like symptoms. Moreover,
investigators chose controls that were as similar as possible in relevant ways (e.g., age,
BMI) to players but, of the 35 eligible controls, investigators chose 5 and averaged their
PET scans, rather than averaging data from all 35 eligible controls – a potentially question-
able decision to jettison statistical power.
[4] Neurocritic notes that tau deposits observed in the participants’ PET scans may not, in
fact, match observed patterns of tau in deceased individuals diagnosed with CTE.
[5] As profiled in this recent New York Times piece,32 Neurocritic is one of a “gaggle of ener-
getic and amusing, mostly anonymous, neuroscience bloggers – including Neurocritic,
Neuroskeptic, Neurobonkers and Mind Hacks – [who] now regularly point out the lapses
and folly contained in mainstream neuroscientific discourse.” If I recall correctly, I first got
on Neurocritic’s radar back when Charlie Sheen was “winning.” I took his side in a Twitter
war over the professional ethics of diagnosing celebrities. At the time, various people (Dr.
Drew, I’m looking at you) were rushing before the television cameras to make all manner
of “diagnoses” of Sheen’s mental health. No one who isn’t (a) medically qualified, (b) treats
or knows the individual well, and (c) has said individual’s permission to discuss his diagno-
sis publicly has any business doing so. This is not a hard question. Neurocritic’s interlocu-
tor argued that since there’s no shame in having mental health issues, there’s nothing
wrong without “outing” someone. There should indeed be no shame in having mental
health issues, which should be seen as on par with physical disabilities. But that is not re-
motely the world in which we live. Elyn Saks’s story is inspiring, and her willingness to
share it33 – after tenure, in the way she chooses – is wonderful. But that’s her decision to
make, not someone else’s. So I agreed then, and still agree now, with Neurocritic about
the importance of sound diagnoses, of patient privacy, and generally of avoiding imposing
upon individuals even accurate diagnoses when they are unwanted. The rest of this post
explains why I think the present situation is – at least potentially – entirely different.
[6] Small world alert: PGP-10 member James Sherley is none other than “Sherley” from
Sherley v. Sebelius.34 //
32
www.nytimes.com/2012/11/25/opinion/sunday/neuroscience-under-attack.html?hp&
_r=0.
33 www.nytimes.com/2013/01/27/opinion/sunday/schizophrenic-not-stupid.html?_r=0.
34 www.thefacultylounge.org/2012/08/finally-an-endfor-nowto-dickey-wicker-sticky-wic
kets-on-stem-cell-research-and-chevron-deference.html.