Discovery Genomics - Duke Clinical Research Institute

DaviD GolDstein
Director, center for Human
Genome variation
Director, Discovery Genomics
at tHe Duke clinical
researcH institute
tHe ricHarD anD Pat JoHnson
DistinGuisHeD university
Professor
Dr. David Goldstein is professor of
molecular genetics & microbiology and
director of the Center for Human Genome
Variation at Duke University. He received
his PhD in biological sciences from
Stanford University in 1994, and from
1999–2005 was Wolfson Professor of
Genetics at University College London.
Dr. Goldstein is the author of more than
150 scholarly publications in the areas of
population and medical genetics. His work
focuses on the genetics of human disease
and treatment response, with a concentration
on neuropsychiatric disease and host
determinants of response to infectious
diseases. He is the recipient of one of
the first seven nationally awarded Royal
Society/Wolfson research merit awards
in the UK, and was awarded the Triangle
Business Journal Health Care Heroes Award
in 2008 for his work on host determinants
of control of HIV-1. Most recently, he
was appointed the co-chair and chair of
the Gordon Research Conference meeting
on human genetics and genomics for 2011
and 2013.
cHGv siGnificant accomPlisHments
----------------------------------------------------------------------------
• Identification of genetic variants that predict drug-induced clearance of hepatitis C
• Identification of genetic variants that are predictive of drug-induced anemia in patients
treated for hepatitis C
• Identification of a Mendelian disease gene by whole-genome sequencing of one individual
• Identification of genetic risks factors in epilepsy and schizophrenia
• Identification of genetic variants of viral control of HIV-1
For more information
Suzanne Pfeifer
Director, Business Development
Duke Clinical Research Institute
919.668.8196
suzanne.pfeifer@duke.edu
http://dcri.org/our-services/discovery-genomics/
Darcy McMullin, PhD
Project Planner
Center for Human Genome Variation
919.684.7573
darcy.mcmullin@duke.edu
http://humangenome.duke.edu
DCRI Communications
August 2010
Discovery Genomics
Identifying relevant and biologically informative genetic variation
related to therapeutic response

tHe imPortance of
PHarmacoGenomics
in clinical trials
--------------------------------------------------
In today’s competitive environment, optimizing
the drug development process in terms of cost,
safety, and efficacy is perhaps more important
than ever before. Pharmacogenomic studies
increasingly are being integrated into clinical
trials for this purpose as technologies and
analysis techniques have rapidly advanced. By
understanding how genetic variation impacts
variability in drug response, pharmacogenomic
studies can be used to make more informed
decisions about how best to proceed with the
development of a drug.
Responders
Non-responders
Toxic responders
All patients receiving
same treatment
An especially powerful use of pharmacogenomic
studies is to identify subpopulations having
unexpected adverse events or subpopulations
of poor responders negatively affecting overall
efficacy data. These subpopulation data can
then be used as the basis for a companion
diagnostic to screen patients, optimize dosing,
and enhance the safety and efficacy profile
of the drug. In some cases, this review may
help salvage compounds that would not
otherwise be viable. In other cases, it may
help strategically differentiate the drug and
position it for greater market penetration and
premium pricing.
Treat with conventional
drug or dose
Treat with alternative
drug or dose
tHe Discovery Genomics offerinG
--------------------------------------------------
The Duke Clinical Research Institute (DRCI)
offers a comprehensive, integrated solution for
incorporating pharmacogenomic studies into
clinical trials, providing sponsors with an
“insurance option” to quickly investigate
genetic association with adverse events or
efficacy after clinical trial completion.
The DCRI provides:
• Assistance with informed consent to ensure
that collected samples can be properly
analyzed after study completion
• A dedicated, 40,000-square-foot purpose-
built facility providing cost-effective,
high-quality sample storage if storage
is required
• A single point of contact for kit development,
supply and re-supply, and sample collection to
streamline workflow
• Scientific expertise and cutting-edge
infrastructure for pharmacogenomic
testing analysis through the DCRI’s
David Goldstein, PhD, and the Center for
Human Genome Variation (CHGV) within
the Duke University School of Medicine
• Clinical expertise and guidance on
how to implement findings
WHat you Will receive
--------------------------------------------------
• A detailed description of the methodology
used in the genetic and statistical analysis
• A detailed description of the results
generated from the genetic analysis
• Guidance on how to apply the findings in
the clinical setting and in future
development studies
• Recommendations for possible follow-up
genotyping work or functional
follow-up studies
• A final study manuscript suitable for
submission for publication
• A timely turnaround, specified in advance
and based on project-specific activities
Genetic testinG caPabilities
anD exPertise
-----------------------------------------------
Pharmacogenomic testing and analysis is
performed by the Center for Human Genome
Variation (CHGV). The CHGV is capable
of fully supporting a wide range of genetic
studies in all phases of clinical research. While
each project is customized, the CHGV typically
follows a two-stage approach, starting with
a genome-wide association (GWA) study to
examine common genetic variation and
proceeding, if needed, with whole-genome
or whole-exome sequencing to identify
rare variants.
Our expectation is that for studies of efficacy
involving large numbers of patients, analyses
would normally begin with GWA studies,
moving on to whole-exome or whole-genome
sequencing as needed. Studies of rare adverse
drug reactions normally involve whole-exome
or whole-genome sequencing.
cost-effective sequencinG
noW a reality
-----------------------------------------------
The CHGV provides particular expertise
in sequencing to investigate rare drug
events occurring in less than 5% of patients.
The CHGV can perform whole-genome or
whole-exome sequencing studies in a timely,
cost-effective manner using a small number
(20–50) of patient samples, in
part because it has compiled
a large and growing reference
database that already contains
over 200 control genomes that
have been sequenced at high
coverage. The availability of
these control genomes means
that for rare adverse reactions,
it is possible to sequence only
those individuals with the
adverse reactions and to use
existing control data for
comparison, saving on costs.
analytic exPertise Drives
novel Discovery
-----------------------------------------------
The CHGV excels at analyzing large amounts
of genetic data. Many software applications
developed by CHGV bioinformaticians are
now used by leading research labs to help
transform genetic data into a usable format
and enable efficient discovery activities. This
expertise in analytics has already resulted
in a remarkable stream of novel, useable
discoveries, including the identification of a
variant in the IL28B gene that is associated
with response to peginterferon-a combined
with ribavirin for treatment of hepatitis C.
Many software
applications developed
by CHGV bioinformaticians
are now used by
leading research labs to
help transform genetic
data into a usable format
and enable efficient
discovery activities. This
screenshot shows the
discovery of SNPs having
genome-wide significance
with response to hepatitis
C treatment (adapted
from Ge et al. (2009)
Nature 461doi:10.1038/
nature08309)