Clinical Sequencing Exploratory Research (CSER)
Program RationaleReports of genomic sequencing being applied to the medical care of individual patients are becoming more frequent, but much more needs to be done before the use of sequence data becomes routine. The potential range of clinical applications and the specific diseases or individual susceptibilities most likely to be usefully addressed by a genomic sequencing approach have yet to be determined. Furthermore, incorporation of comprehensive genomic sequence data into clinical care will require changes to institutional policies, standard procedures (including simplified analysis and interpretive tools), and the ability to integrate sequence information into the clinical workflow. The ethical, legal, and psychosocial implications of returning genomic variation data, with all of the caveats regarding statistical uncertainties, incomplete knowledge, and unanticipated findings, remain incompletely understood.
In 2010, NHGRI initiated a Clinical Sequencing Exploratory Research (CSER) program intended to support both the methods development needed to integrate sequencing into the clinic and the ethical, legal, and psychosocial research required to responsibly apply personal genomic sequence data to medical care. A U01 cooperative agreement mechanism was used to promote the development of a robust forum for scientific discussion as well as debate of issues, both practical and conceptual. In 2013, the program was extended for another funding cycle to bring in more diverse expertise and a larger number of clinical populations to support the goals of the consortium. The new awards (UM1s) are also cooperative agreements that encourage collaboration and discourse between disciplines under the banner of a common scientific goal. A CSER Coordinating Center at the University of Washington was also funded in 2013 to facilitate collaborative efforts among the CSER investigators and disseminate findings and approaches from the CSER program to the biomedical research community.
In addition to incorporating the UM1s, the CSER consortium was expanded in 2013 to include nine additional projects that formerly comprised the ELSI Return of Results Consortium. These studies (R01s and R21s), which incorporate both empirical and normative research methods, explore a broad range of ethical, legal and social implications relating to the return of research results in both research and clinical settings. The consolidation of these two consortia under the broader umbrella of CSER will make it possible for consideration of the ethical, legal, and psychosocial aspects of returning genomic results to better inform the implementation of genomic medicine.
In all, the CSER consortium supports nine multi-disciplinary projects, nine ELSI-specific projects, and a Coordinating Center that brings together clinicians, genomic researchers, bioinformaticians, ethicists and other investigators to research the challenges of utilizing genomic sequence data in the clinic in the routine practice of medicine. The challenges are many and not disease-specific. Important aims of the research include: generation of genomic sequence data on patients in a variety of clinical contexts; investigation of methods to interpret, translate and guide adoption of genomic data in a fashion and timescale that fits the normal clinical workflow; and study of the ethical, legal, and psychosocial implications of generating and returning genomic results, including returning incidental findings. The consortium of grantees will cooperate to evaluate best practices in this rapidly advancing field and communicate these to the community.
Grantees of the Program
Phase I Clinical Sequencing Exploratory Research Groups
|Institution||Lead PI(s)||Study Title||Clinical Focus|
|Baylor College of Medicine||Sharon Plon and D. Will Parsons||Incorporation of Genomic Sequencing into Pediatric Cancer Care*
||Childhood cancer patients with high-risk solid tumors and brain tumors|
|Brigham and Women's Hospital||Robert C. Green
||Integration of Whole Genome Sequencing into Clinical Medicine||Primary care patients, cardiomyopathy patients|
|Children's Hospital of Philadelphia||Ian Krantz and Nancy Spinner||Applying Genomic Sequencing in Pediatrics||Pediatric patients with one of four conditions - intellectual disability, sudden cardiac arrest/death, hearing loss, and mitochondrial disorders|
|Dana-Farber Cancer Institute||Levi Garraway and Pasi Janne||The Use of Whole-Exome Sequencing to Guide the Care of Cancer Patients||Lung and colorectal cancer patients|
|University of North Carolina, Chapel Hill||James P. Evans||NC GENES [ncgenes.org]||Patients from one of five clinical domains - cancer, cardiology, dysmorphology, neurodevelopmental and ophthalmology|
|University of Washington, Seattle||Gail Jarvik||Clinical sequencing in cancer: Clinical, ethical, and technological studies*||Patients who have clinical indications for colorectal cancer/polyposis (CRCP) genetic testing|
Phase II Clinical Sequencing Exploratory Research Groups
|Institution||Lead PI(s)||Study Title||Clinical Focus|
|Hudson-Alpha Institute for Biotechnology||Richard Myers
||Genomic Diagnosis in Children with Developmental Delay||Children with intellectual disability and/or developmental delay|
|Kaiser Foundation Research Institute||Katrina Goddard and Benjamin Wilfond||Clinical Implementation of Carrier Testing Using Next Generation Sequencing (NGS)
||Women and their partners seeking pre-conception carrier testing|
|University of Michigan, Ann Arbor||Arul Chinnaiyan||Exploring Precision Cancer Medicine for Sarcoma and Rare Cancers*||Patients with advanced sarcoma or other rare cancers|
|University of Washington, Seattle||Gail Jarvik||CSER Centralized Support Coordinating Center||The coordinating center is responsible for facilitating the scientific work of the CSER consortium and its working group by providing logistical and scientific expertise. It will also be a key partner in disseminating findings and approaches from the CSER program to the biomedical research community.|
Ethical, Legal, and Social Implications-specific ProjectsFormerly comprising the Return of Results Consortium
|Institution||PI||Study Title||Grant Type|
|Cleveland Clinic||Richard Sharp||Presenting diagnostic results from large-scale clinical mutation testing||R01|
|Columbia University||Paul S. Appelbaum||Challenges of informed consent in return of data from genomic research||R21|
|Columbia University||Wendy K. Chung||Impact of return of incidental genetic test results to research participants in the genomic era||R01|
|Children's Hospital Boston||Ingrid A. Holm||Returning research results in children: Parental Preferences and Expert Oversight||R01|
|Children's Mercy Bioethics Center||Jeremy R. Garrett||The presumptive case against returning individual results in biobanking research||R21|
|Johns Hopkins University||Michelle Huckaby Lewis||Return of research results from samples obtained for newborn screening||R21|
|University of California, San Francisco||Barbara Koenig||Disclosing genomic incidental findings in a cancer biobank: An ELSI experiment*||R01|
|University of Washington School of Medicine||Holly K. Tabor||Innovative Approaches to Returning Results in Exome and Genome Sequencing Studies||R01|
|Vanderbilt University||Ellen Wright Clayton||Returning research results of pediatric genomic research to participants||R21|
Working GroupsInformed Consent & Governance
Chairs: Paul Appelbaum and Joon-Ho Yu
Mission: Discuss emerging issues and develop new and creative approaches related to informed consent in the context of clinical sequencing; compare and, to the extent feasible, develop standardized consent language and protocols. Discuss and compile experience with institutional governance of genomic data in research and clinical settings; where appropriate integrate governance recommendations with best practice and/or model language for informed consent.
Actionable Variants and Return of Results
Chairs: Laura Amendola and Wendy Chung
- Define the principles and processes guiding the definition of an 'actionable' gene across the consortium, highlighting common outcomes and the rationale underlying discrepancies.
- Explore overlap regarding the classification process of identified variants in these actionable genes, and develop resources to support decisions with respect to pathogenicity.
- Coordinate with other CSER working groups to develop best practices for the process of returning genomic findings, including the informed consent process, analysis of sequence variants, storage in the medical record, and communication of results to the patient.
Chair: Levi Garraway and Brian Shirts
Mission: Develop and share technical standards for sequencing in a clinical context (for example, minimum coverage and quality metrics, turnaround time, data formats, CLIA); develop best practices for variant validation.
Electronic Reports/Medical Records
Chair: Peter Tarczy-Hornoch and Brian Shirts
Mission: Understand and facilitate cross site collaboration nationally around informatics work as related to variant annotation, prioritization, integration into electronic medical record, and integration into decision support.
Analysis and Phenotype Measures
Chairs: Ian Krantz and Peter White
Mission: Assess overlap in phenotype and disease measures; explore minimal set of phenotypes useful for clinical sequencing.
Outcomes and Measures
Chairs: Christine Rini and Staci Gray
Mission: Coordinate development of instruments to measure psychosocial outcomes related to returning results.
Chairs: Kyle Brothers and Ben Wilfond
Mission: Explore and attempt to develop standardized approaches to addressing the unique ethical, legal, and practical challenges relating to returning results in studies involving pediatric populations.
Chair: Will Parsons
Misson: Explore the unique technical, interpretive and ethical challenges and considerations involved in clinical sequencing of cancer genomes (e.g. identification of somatic variants) and to attempt to develop best practices for these tests.
Chairs: Denise Lautenbach and Sarah Scollon
Mission: Discuss site-specific experiences with issues related to genetic counseling. Work on publications and educational materials, and function as a sounding board to new groups.
NHGRI Program DirectorsLucia Hindorff, Ph.D., M.P.H.
Division of Genomic Medicine
Jean McEwen, J.D., Ph.D.
Division of Genomics and Society
Carolyn Hutter, Ph.D.
Division of Genomic Medicine
National Cancer Institute (NCI) Program DirectorsCharlisse Caga-anan, J.D.
Sheri Schully, Ph.D.
NHGRI Program AnalystsKathie Sun
Last Updated: April 1, 2014