NHGRI has initiated a Clinical Sequencing Exploratory Research program intended to support both the methods development needed to integrate sequencing into the clinic and the ethical and psychosocial research required to responsibly apply personal genomic sequence data to medical care. The program will also provide a forum for the development and dissemination of innovative and best practices in this area.

The Clinical Sequencing Exploratory Research program supports multi-disciplinary projects that bring together clinicians, bioinformaticians, and ethicists 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: development of technical specifications and standards for sequencing in a clinical setting, investigation of methods to transmit genome-scale data to physicians in a fashion and timescale that fits the normal clinical workflow, exploration of regulatory requirements for applying genomic sequence data to patient care, and study of the ethical implications of returning unintended findings.

A U01 cooperative agreement mechanism is being used to promote the development of a robust forum for debate of issues, practical and philosophical. Also, 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

The currently funded groups are:

Baylor College of Medicine, Houston: Sharon Plon and D. Will Parsons

Incorporation of Genomic Sequencing into Pediatric Cancer Care
The goal of this project is to integrate CLIA-certified germ line and tumor exome sequencing information into the care of childhood cancer patients with high-risk solid tumors and brain tumors. The group is assessing the impact of whole exome sequence data reported by a novel web-based platform with links to existing data for each variant reported and presented through a graphical display that will facilitate physician disclosure of complex data to parents. Quantitative analysis of physician communication in disclosure of genome-scale data is to be performed, and parental understanding and preferences for receiving genome scale data will be assessed.

Brigham and Women’s Hospital, Boston: Robert C. Green

Integration of Whole Genome Sequencing into Clinical Medicine
This group plans to explore and compare the impact of using whole genome sequencing (WGS) in clinical conditions that model forms of General Genomic Medicine and Disease-Specific Genomic Medicine approaches. The team is conducting an exploratory clinical trial randomizing physicians and their patients within each of these models to receive clinically meaningful information derived from WGS versus current standard of care. This initiative will significantly accelerate the use of genomics into clinical medicine by creating and safely testing novel ways of integrating information from WGS into physician care of patients.

Children’s Hospital of Philadelphia: Ian Krantz and Nancy Spinner

Applying Genomic Sequencing in Pediatrics
This group is bringing genomic sequencing into pediatric clinical settings. They are studying effects of genomic sequencing for 5 groups of pediatric disorders that are genetically heterogeneous. They expect to develop tools for identifying and consenting patients for study, carrying out and interpreting the sequencing data, and reporting useful information to patient families. This will be a unique study which will allow researchers to work with families, scientists, and ethicists up front to determine how patients should be counseled and educated before testing, what data should be provided back to individual families, and what educational tools will help in understanding the implications of the testing.

Dana-Farber Cancer Institute, Boston: Levi Garraway and Pasi Janne

The Use of Whole-Exome Sequencing to Guide the Care of Cancer Patients
The intention of this project is to define a scalable model for the integration of clinical sequencing into cancer care. The group is establishing a robust framework for generation, interpretation, and clinical implementation of cancer whole exome sequencing. Upon completion of the project, they will have configured a clinical formalism through which oncologists incorporate genomic information into their management plan and report the results to cancer patients and their families.

University of North Carolina, Chapel Hill: James P. Evans and others

NC GENES
The aim of this project is to establish a set of best practices to guide future implementation of robust genomic technologies for the practical improvement of human health. To achieve this, the group is exploring the use of whole exome sequencing as a diagnostic tool in the care of a broad array of patients, including traditionally underrepresented populations, evaluate its performance, identify critical clinical characteristics which can guide its application, and measure the impact of such information on patients and providers. In addition, educational materials will be developed to enable patients to make decisions about appropriate return of results and the impact of collateral information will be assessed at the level of the provider, laboratory, and patient.

University of Washington, Seattle: Gail Jarvik

Clinical Sequencing in Cancer: Clinical, Ethical, and Technological Studies
This group is investigating aspects of using exomic data clinically through a randomized controlled trial of usual care vs. the addition of exome analysis in patients who have clinical indications for colorectal cancer/polyposis (CRCP) genetic testing. The group is evaluating effectiveness of this technology for the identification of clinically relevant CRCP gene mutations, cost, and patient derived measures. An important component of the work will be the determination of which results to return and how to best incorporate genomic data into official medical records. CLIA certified results will be returned to the participants and the experiences of patients will be evaluated. In addition, the group expects to perform CRCP gene discovery studies for families without identifiable CRCP mutations.

Clinical Sequencing Exploratory Research Working Groups

Informed Consent & Governance (with the Return of Results Consortium)
Chairs: Paul Appelbaum and Malia Fullerton
Affiliations: Columbia University, University of Washington
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: Jonathan Berg and Gail Jarvik
Affiliations: UNC, University of Washington
Mission:

1. Define the principles and processes guiding the definition of an ‘actionable’ gene across the consortium, highlighting common outcomes and the rationale underlying discrepancies.
   1. The process will be considered for variants related to the reason for study and for those actionable variants unrelated to the reason for study (incidental findings). The context dependence of incidental findings will be considered given the wide range of diagnoses and patient ages, ranging from adult cancer screening to congenital disorders in the pediatric population.
2. Develop a consensus regarding the classification process of identified variants in these actionable genes, and develop resources to support decisions with respect to pathogenicity.
3. Coordinate with other CSER and ROR consortium 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.’

Sequencing Standards
Chair: Levi Garraway
Affiliations: Dana-Farber Cancer Institute/Harvard
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
Affiliations: University of Washington
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
Affiliations: CHOP
Mission: Inventory and harmonize outcomes where useful, to maximize cross-study sample sizes; share and review approaches to genotype-phenotype analysis.

Outcomes and Measures (with the Return of Results Consortium)
Chairs: Amy McGuire and Gail Henderson
Affiliations: Baylor College of Medicine, UNC
Mission: Coordinate development of instruments to measure psychosocial outcomes related to returning results.

Pediatrics (with the Return of Results Consortium)
Chairs: Ellen Clayton and Larry McCullough
Affiliations: Vanderbilt, Baylor College of Medicine
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.