IMS Magazine - Summer 2012 edition in PDF format - Institute of ...

FEATURE
seling on a WGS test, which examines over
20,000 genes and many of which have known
pathogenic variants. That said, counseling is
critically important within the WGS context;
however, the information needs to be more
general in nature, analogous to the research
setting. Healthcare providers need to educate
patients about genomic testing using theory
and case-based examples, identify any likely
clinical implications of WGS, and discuss
the general risks and benefits of undergoing
WGS in order for patients to make an
informed decision as to whether they want
their genome sequenced.
Return of results
Whether researchers have a duty to return
individual research results in genetic studies
has been the subject of much debate. Should
research be purely for research sake? This debate
is especially important within the WGS
context since the likelihood of identifying
pathogenic variants is high. Fortunately, a
consensus is emerging. The World Health
Organization has identified three conditions
to be met before disclosure should occur: (1)
the data should be clinically beneficial; (2)
disclosure should avert or minimize significant
harm; and (3) there is no indication that
the individual in question would prefer not
to know 8 . Consistent with this approach, Canadian
research ethics guidelines outline an
obligation to disclose any material incidental
findings or unanticipated discoveries made
during the course of research that are interpreted
as having a significant welfare implication
for the participant 9 .
Different strategies have been suggested to
manage the return of clinically relevant research
results in the WGS context. One approach
would categorize human genes according
to clinical parameters10. In such a
scheme, all gene mutations that are medically
actionable are labeled as “Bin 1” genes
and would trigger an automatic return of the
result. “Bin 2” genes are defined as gene mutations
associated with human disease that
could not be acted upon medically. Finally,
“Bin 3” contains all other genes whose association
with human disease is unknown. It has
been estimated that there are currently only
100 “Bin 1” genes in the human genome 10 .
The ClinSeq project at the National Institutes
of Health (NIH) has taken a different
approach that is more research-subject-centered
and engages research subjects to determine
the type and extent of information
they would find useful 11 . In the NIH project,
all pathogenic variants can be returned to research
subjects, provided consent is obtained
for disclosure. Additionally, they have set up
an independent panel to periodically review
any new evidence linking variants to human
disease and to determine if the evidence is
sufficient to warrant disclosure.
With all the effort spent on identifying variants
associated with human disease, new
clinically relevant variants will no doubt be
identified in the future. This reality necessitates
a long-term plan to deal with stored
sequences. Researchers returning individual
research results could implement software
that can reanalyze past genomes and flag new
clinically relevant data. Alternatively, if such
a measure was not possible, research subjects
should be informed during the informed
consent process that reanalysis will not occur
and that any results returned would only reflect
current knowledge.
It is generally understood that test results are
returned to patients, however, it is unclear
what should be returned to patients when
WGS is used as a genetic test. While any results
that inform the original differential diagnosis
seem appropriate to disclose, many
other variants of known and unknown significance
may also be detected that have nothing
to do with the original query. A “binning”
mechanism or a patient-guided approach
may be borrowed from the research context
described above. Lastly, the issue of clinical
reanalysis was addressed in a recent article
by the head of the NIH clinical sequencing
project mentioned previously, Leslie Biesecker
describes WGS as a resource not a genetic
test 12 . As such, a WGS dataset can be “interrogated
by the patient and clinician in situations
where it could be of potential use to
the patient, when both agree to this use” 12 .
This type of integration would also solve the
issue of reanalysis. If treated as a one off test,
the physician who ordered it would not have
a legal or ethical obligation to periodically
reanalyze each of her patient’s genome for
any new medical information. If comprehensively
integrated into primary care, a patient’s
whole genome could be part of the transformation
of healthcare Francis Collins and Bill
Clinton predicted over a decade ago.
Concluding remarks
While it is still unclear exactly how informed
consent and return of results are going to
look in the future context of WGS, many of
the research projects employing WGS have
an integrated ethics component, which includes
research subject engagement. As
such, I am confident we will establish ethical
best practices when it comes to WGS in
clinical and research settings. Furthermore,
as WGS is exploited clinically, opportunities
and challenges will be created for researchers
and clinicians. Clinical WGS datasets could
provide a rich source of data for researchers,
provided that appropriate informed consent
and privacy safeguards are put in place. This
environment would represent a paradigm
shift in which clinical medicine and research
could occur using the same platform, facilitating
knowledge exchange.
References
1. Lander ES, et al. Initial sequencing and analysis of the
human genome. Nature. 2001; 409(6822): 860-921.
2. Wade NA. Decade Later, Genetic Map Yields Few New
Cures, in New York TImes.2010: New York.
3. Tucker TM, et al. Massively parallel sequencing: the
next big thing in genetic medicine. Am J Hum Genet.
2009; 85(2): 142-54.
4. Tabor HK et al. Genomics really gets personal: how
exome and whole genome sequencing challenge the ethical
framework of human genetics research. Am J Med
Genet A. 2011; 155A(12): 2916-24.
5. Human T.-C.P.S.E.C.f.R.I. 1998 Aril 9, 2009]; Available
from: http://pre.ethics.gc.ca/eng/index/.
6. Beauchamp TL and Childress JF. Principles of biomedical
ethics. 6th ed. 2009, New York: Oxford University
Press. xiii, 417.
7. Singer PA and Viens AM. The Cambridge textbook
of bioethics. 2008, Cambridge ; New York: Cambridge
University Press. xvi, 538 p.
8. Organization, W.H. Genetic databases: assessing the
benefits and impact on human and patient rights. 2003
[cited 2009 December 15]; Available from: http://www.
law.ed.ac.uk/ahrb/publications/online/whofinalreport.
doc.
9. Canadian Institutes of Health Research, N.S.a.E.R.C
.o.C.a.S.S.a.H.R.C.o.C., Tri-Council Policy Statement:
Ethical Consult for Research Involving Humans, 2010.
10. Evans JP and Rothschild BB. Return of results: not
that complicated? Genet Med. 2012; 14(4): 358-60.
11. Biesecker LG et al. The ClinSeq Project: piloting
large-scale genome sequencing for research in genomic
medicine. Genome Res. 2009; 19(9): 1665-74.
12. Biesecker LG. Opportunities and challenges for the
integration of massively parallel genomic sequencing
into clinical practice: lessons from the ClinSeq project.
Genet Med. 2012; 14(4): 393-8.
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