[Updated article about voluntary and involuntary genetic databases.
Plenty of CP/Politech relevence.]
_Science_ vol 298 pp 1158-1159
BIOBANKS:
Population Databases Boom, From Iceland to the U.S.
Jocelyn Kaiser
Countries and health providers are following Iceland's path and
combining health and genetic data on
large populations. They promise to deliver "personalized"
medicine, but will they?
In August, residents of the dairy country of central Wisconsin received
an unusual invitation from their local
health care provider: an opportunity to donate their DNA for research.
If they sign up, they will give blood and
talk with a clinic staffer about their family disease history, diet,
and exercise habits. The projected 40,000
participants will also give researchers extraordinary freedom to use
this information--including details of their
genetic makeup--to probe the complex interplay between genes,
environment, and disease.
Once researchers have amassed a bank of blood samples, they will scan
each subject's DNA for telltale
markers of increased risk for various diseases. Ultimately, these data
will be combined with the participants'
electronic health records in a powerful new type of database. With a
touch of a few keys, says Michael
Caldwell, director of the Marshfield Medical Research Foundation, which
will run the study, researchers will be
able to mine the confidential data for links between genes, lifestyle
factors, and illness. Caldwell's team hopes to
find disease genes that have so far proved elusive and to sort out
tricky epidemiologic questions, such as how
much a particular combination of genes and exposures--sunlight, say, or
drinking alcohol--is likely to raise the
risk of cancer or heart disease. "The consensus is that such databases
will be the key to unlocking the genetic
basis of common disease," Caldwell says.
The project puts the medical clinic in Marshfield, Wisconsin,
population 19,000, at the cutting edge of the new "genomic" medicine. It
is in the
vanguard along with countries such as Iceland and the United Kingdom,
which believe that these new population databases are a sure-fire way to
better health care. If the databases can find more disease genes and
quantify risks, doctors believe they can then give patients personalized
treatments and prevention plans. But ferreting out these links, say
researchers involved, requires huge DNA collections, bigger than any
gathered to
date--some projects aim to sample a million people--plus long-term
health data on each person who donates his or her DNA.
That's a dangerous combination, say some ethicists. They worry that
data won't remain confidential and suggest that companies, which will
play a
role in some projects, should not be allowed to profit from people's
genetic heritage. Indeed, Iceland's decision to give one biotech
company,
deCODE Genetics, exclusive rights to the nation's health records
ignited a firestorm of controversy 4 years ago that continues even now.
Heartland biobank. This volunteer's DNA will go into a database to be
probed by the Marshfield Clinic, which plans to study gene-environment
interactions among residents of central Wisconsin.
CREDITS: MARSHFIELD CLINIC
And although many geneticists agree that these databases will yield a
plethora of useful information, it is not clear that they will deliver
on their most
ambitious promises. "It's still mostly hype," says Stanford Law School
ethicist Henry Greely. Nobody knows for sure, for instance, that bigger
studies will be more successful at pinning down disease risks than
previous, smaller studies. Researchers are also split on the best way to
design
population databases. "There are many, many opinions and not a lot of
hard facts about this field," says human geneticist David Altshuler of
Harvard
Medical School in Boston and the Whitehead Institute in Cambridge,
Massachusetts.
But that's not dampening enthusiasm. Encouraged by their native
scientists, a half-dozen countries--as well as some U.S. health care
providers--are
laying plans to compile health information and collect DNA from a broad
swath of the population. All are grappling with similar scientific and
ethical
issues.
From families to populations
Small DNA studies sufficed when the target was easier: a single gene
that, when mutated, triggers a rare inherited disorder such as
Huntington's
disease. Common disorders such as arthritis or stroke--believed to be
caused by defects in multiple genes in combination with lifestyle
factors such
as diet and smoking--pose a trickier challenge. Because each gene
contributes just a small amount to overall risk, it emits a weaker
signal,
confounding efforts to find it. To compensate, researchers need to
study genetic profiles of many more people and also incorporate
information on
phenotype, or health data.
One of the best-known ventures is Iceland's deCODE Genetics, which 5
years ago made the startling announcement that it proposed, under a
contract with the Icelandic government, to put the health records of
all 270,000 citizens into a single database. This health
information--coded so it
could not easily be traced back to individuals--would then be combined
with Iceland's detailed genealogy and genetic data collected from
volunteers. Under deCODE's 12-year license, drug companies could access
the data for a fee; access would be free to academic researchers for
"noncommercial" projects. Icelanders wouldn't learn their test results;
the main benefit, supporters argued, was that the project would boost
the
country's economy.
Researchers within and outside Iceland strongly objected. Perhaps the
most contentious issue is that the project relies on "presumed consent":
Government health records on every citizen are included in the database
unless individuals specifically request otherwise. After safeguards were
added to ensure privacy--for example, two government-appointed bodies
will oversee encryption of data for research and database
operations--the
country voted to approve the project. About 7% of the population has
opted out of the study.
Maverick. DeCODE's Kari Stefansson started the trend in population
databases.
CREDIT: GINO DOMENICO/AP
DeCODE can't begin uploading medical records until it passes a final
hurdle, expected next year: an outside expert's test of the database
security
system, says Icelandic health official Gudridur Thorsteinsdottir.
But in the interim, the company has compiled proprietary genetic data
on a large chunk of Iceland's population by embarking on more
traditional,
although still ambitious, gene hunts for specific diseases. Through
referrals from clinicians, deCODE researchers have identified 80,000
volunteers
for these disease studies and have analyzed, or genotyped, their DNA
(tagging at least 1000 markers on each genome). Already, the company
says
it has mapped or identified genes involved in arthritis, stroke,
schizophrenia, and many other diseases and it is beginning to publish
these findings.
Once the full database is ready, it can be used for new types of
studies. "You will begin to see correlations you couldn't before,"
claims deCODE
CEO Kari Stefansson--for example, whether a gene for diabetes also
predisposes a carrier to hypertension or stroke.
Because Iceland's population is relatively homogeneous and has unique
genealogical data, its power to find new genes might never be matched,
says
geneticist Stephen Warren of Emory University in Atlanta. But findings
in Iceland won't necessarily apply directly to other ethnic groups and
more
diverse populations.
Beyond Iceland
Iceland's experience has informed the design of other population
databases, such as one in Estonia. In September, the government-founded,
nonprofit Estonian Genome Foundation began collecting DNA samples from
10,000 volunteers age 16 year and up. This 3-year pilot project,
funded with $2.5 million by EGeen International, a U.S.-based company,
will rely on a health questionnaire rather than medical records. Project
founder Andres Metspalu of the University of Tartu, Estonia, who
eventually hopes to enroll 1 million of the country's 1.4 million
people, says that
organizers have taken great pains to educate the public and allay
ethical concerns. Participants can ask to see their genetic profile. And
by feeding
back to participants data that can be used in health care, Metspalu
says, the project will give benefits "back to the people."
Giving back. Andres Metspalu notes that Estonia's population database
project will let participants see their own genetic profile.
CREDIT: ESTONIAN GENE BANK
The U.K.'s Medical Research Council (MRC) and the Wellcome Trust
charity are planning to spend $66 million on a large cohort study with
500,000 volunteers (Science, 3 May, p. 824). "We're very different from
Iceland in many ways," says Tom Meade of MRC.
Starting in 2004, BioBank UK plans to gather examination and interview
data from volunteers 45 to 69 years old and then track them for at least
10
years. By starting with middle-aged volunteers--who aren't promised any
direct benefit--the researchers expect to see enough cases of specific
diseases to verify and quantify links with candidate genes. Access to
BioBank UK will be open to "any bona fide researcher with a good idea,"
says
Meade.
"I think it's a very exciting project," says cancer geneticist
Nathaniel Rothman of the U.S. National Cancer Institute (NCI). He says
with 500,000
samples, BioBank UK will be the largest population database in the
world, and it will draw on resources--such as participants' national
health care
records for prescription histories and comprehensive disease
registries--that are "just not available in the U.S."
To the east in Latvia, researchers in June got parliamentary approval
for a planned pilot database. Even scientists in Germany, which has been
wary
of some areas of genetic research, are contemplating an Estonia-like
project, says Spiros Simitis, an ethics law professor at the University
of
Frankfurt. Researchers in Quebec are seeking funding for a $19 million,
5-year project that would initially enroll 50,000 adults, says Claude
Laberge of the University of Laval in Quebec City. And Singapore is
taking the first steps toward a population database with five new
disease
registries and a linked cancer tissue databank (Science, 30 August, p.
1470).
Pros and cons
Proponents believe these databases will be a gold mine for improving
health care. Identifying the genes involved in common diseases will
eventually
yield new treatments, they say. And quantifying genetic risks--for
instance, how much a certain combination of mutations ups the risks of
cancer--could help patients decide whether to have invasive procedures,
such as a colonoscopy. Companies could use these databases to design
drugs suited for an individual's genetic profile.
Some of these goals are out of reach today, database designers concede.
Finding new disease genes, for instance, requires scanning the entire
genome for markers. But the cost--10 cents per marker, when 50,000
markers per person might be needed--is prohibitive, says Metspalu. He
and
others are banking on technological advances--at least a year away--to
lower the cost to 1 cent per marker, as well as a new kind of genome map
that will reduce the number of markers needed.
Yale geneticist Kenneth Kidd sees another obstacle: The databases will
be only as good as the individual clinical or exposure information they
contain. "The quality of diagnosis is a sine qua non of doing these
kinds of studies," Kidd says. "Are these individuals going to be well
worked up?"
Opinions vary over whether a routine exam and a patient's health record
are sufficient, or whether more detailed measures are really
needed--such
as insulin metabolism tests to study diabetes.
Harvard epidemiologist Walter Willett has a more fundamental complaint.
"We already know that most variation in human disease is due to diet and
lifestyle factors," he says, and quantifying how the risks vary with
one's genetic makeup usually won't change the solution: encouraging
healthier
lifestyles. Willett worries that the zeal for genomic medicine will
divert resources from prevention (Science, 26 April, p. 695).
Willett is also part of a camp that argues that new population studies
could be reinventing the wheel, because existing studies with DNA
samples
could provide similar information (see table). Funded by NCI, he and
colleagues are pooling data from many large cohort studies, such as
Harvard's
nurses and physicians studies and EPIC, a European cancer study; the
combined database will have more than 1 million DNA samples for cancer
research. True, there are hurdles to studying additional diseases:
Participants might have to be tracked down for fresh DNA samples or new
informed consent. But Willett thinks that these efforts, as well as new
population databases, should be supported.
SOME PROPOSED POPULATION DATABASES
Project
Company
DNA Sample Size
Budget
Status
Icelandic Health Sector Database
deCODE Genetics
280,000
$212M
Health database in 2003?; 80,000 DNA samples
genotyped
Estonian Genome Project
EGeen International
1,000,000
$150M
3-year, $2.5M pilot (10,000 donors) began fall
2002
BioBank UK
?
500,000
$66M
Full enrollment in 2004
Marshfield Personalized Medicine
40,000
$3.8M+
Enrolling this fall
National Children's Study
100,000
?
Full study begins in 2004
Latvian Genome Database
?
60,000 pilot
$1.7M
Law passed in June; seeking funding
Quebec CARTaGENE
?
50,000+
$19M
Seeking funding
EXISTING BIOBANKS AND/OR HEALTH RECORDS
Vdsterbotten, Sweden
UmanGenomics
80,000
Data use agreement with county in 2002
Mayo Clinic
?
100,000
Prototype health database completed in July
EPIC
350,000
Pooling data for cancer studies through consortium
Nurses' Health Study
63,000
Pooling data for cancer studies through consortium
American Cancer Society CPS-II
110,000
Pooling data for cancer studies through consortium
CDC NHANES III
7300
Proposals to use individual data requested fall
2002
And 4 years after deCODE sparked international debate on population
databases, ethical questions still loom large. One issue is "how much of
a
blanket consent you can create" for studying unspecified diseases, says
Wylie Burke of the University of Washington, Seattle. Meade says there
is
"still a lot of discussion" about whether BioBank UK participants
should be able to give consent only for specific diseases. Estonia and
Marshfield
will rely on ethics review boards to decide if new informed consent is
needed to undertake potentially controversial studies--on behavior, for
instance.
Despite claims to the contrary, some critics charge that privacy is
still not assured. Jane Kaye, a doctoral student at the University of
Oxford, U.K.,
says that although Iceland's data system is "quite tight," BioBank UK
has not yet outlined a plan that will adequately protect data. The role
of
companies, which is still in flux, remains contentious: The advocacy
group Human Genetics Alert, for instance, is opposed to allowing
companies to
patent findings from BioBank UK.
Biobanks, American style
Genomics leaders in the United States think the benefits of population
databases will likely outweigh these risks. But federally funded
projects are
still in the early planning stages. At the National Institutes of
Health, officials are thinking about a project like BioBank UK but even
bigger, says Lisa
Brooks of the genome institute there: "Something that looks at a lot of
people and a lot of diseases. Something that's big and pretty
comprehensive."
The obvious way to create a large population database in a country
without a national health care system is to work with health care
providers, as
Marshfield is doing on a small scale, says Stanford geneticist Neil
Risch. Indeed, in some ways, the Marshfield Personalized Medicine
Research
Project is out in front, because Marshfield Clinic--whose research
foundation is conducting the study--already has electronic health
records on more
than 1.2 million patients and began collecting DNA samples this fall.
Patients won't learn their results, but they will help advance health
care in
general, the clinic tells donors. The project has strong support in
Wisconsin, where the state has contributed $2 million of $3.8 million in
initial
funding. Although the nonprofit clinic expects to patent discoveries,
it will funnel any profits back into research or donate them. Companies
will not
be directly involved: "The hope is to keep funding in the public domain
and have this become a national resource," Caldwell says.
Bottleneck. The cost of sequencing DNA samples like these has to drop
considerably before gene-discovery studies in large populations will be
affordable.
CREDIT: MARSHFIELD CLINIC
Some other health care providers are also moving ahead on their own:
The Mayo Clinic is building a database of the health records for 4
million of
its patients and members; it plans eventually to add genetic data
stored in the clinic's many tissue banks. A research database is also
"in the early
discussion stages" at Kaiser Permanente's division in Northern
California, which has 3.1 million members, says Kaiser Permanente
epidemiologist
Cathy Schaefer.
But U.S. researchers are proceeding cautiously, wary of running into
the controversy that Iceland's deCODE and other projects have
encountered.
Says Risch: "We're not going to have many opportunities. It will be
very expensive, and it really needs to be done right."
