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NIH

Clinical Sequencing Evidence-Generating Research (CSER)

CSER2

 

Program Rationale

Reports 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. Evidence regarding the most promising clinical applications and the specific diseases or individual susceptibilities most likely to be usefully addressed by a genomic sequencing approach still accumulating. Incorporation of comprehensive genomic sequence data into clinical care will require changes to institutional policies, standard procedures (including simplified analysis and interpretive tools), and improved  to integrating 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. Furthermore, research is needed to assess and improve the current processes of recruitment, testing, and follow-up of patients from diverse racial and ethnic groups, as well as those from the range of as-yet understudied clinical healthcare settings where genomic medicine might be put into practice.

In 2010, NHGRI, with co-funding from NCI, subsequently crafted the Clinical Sequencing Exploratory Research (CSER) initiative to: 1) leverage the Institute's long-standing experience in genomic sequencing and analysis to ease the adoption of these methods into clinical care, 2) guide the development and dissemination of best practices for the integration of clinical sequencing into clinical care, and 3) research the ethical, legal, and psychosocial implications (ELSI) of bringing broad genomic data into clinical decision-making including, for example, evaluation of the risks and potential benefits associated with the return of incidental findings or information on variants of uncertain effect. The CSER consortium added three more clinical sites and one Coordinating Center, and incorporated the nine projects formerly comprising the ELSI Return of Results Consortium in mid-2013. Investigators from NHGRI's Intramural ClinSeq® project also participate.  As of June, 2017, CSER investigators recruited over 6,900 participants.  Over 340 papers have been published, including 21 CSER-wide Working Group papers which disseminate best practices for genomic sequencing.

Beginning in August, 2017, NHGRI, NCI and the National Institute on Minority Health and Health Disparities (NIMHD) jointly funded a renewal of the CSER program. Phase II of the Clinical Sequencing Evidence-generating Research (CSER2) Program includes 6 clinical sites and one Coordinating Center who will work together to: 1) define, generate and analyze evidence regarding the clinical utility of genome sequencing; 2) research the critical interactions among patients, family members, health practitioners, and clinical laboratories that influence implementation of clinical genome sequencing; and 3) identify and address real-world barriers to integrating genomic, clinical, and healthcare utilization data within a healthcare system to build a shared evidence base for clinical decision-making. 

Crucial and complementary to these efforts are a continuing focus on ELSI and a dedicated focus on engaging stakeholders such as professional societies, payers, regulatory agencies and patient groups. Phase II of CSER will develop a Stakeholder Engagement Plan to solicit and be responsive to input regarding clinical utility measures or other relevant evidence to be generated and refined in CSER2. In turn, this process is anticipated to enhance the applicability of CSER evidence for decision-making by stakeholders, such as the establishment or refinement of best practices or implementation or reimbursement policies, or contribution to other evidentiary frameworks. Opportunities will continue for external collaborators, such as NHGRI ClinSeq® investigators and investigators with complementary ELSI or other expertise, to participate in CSER as affiliate members.

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Grantees of the Program

Clinical Sequencing Evidence-Generating Research (CSER2) Groups (2017-2021)
Institution Lead PI(s) Study Title

Clinical Focus

Baylor College of Medicine

Sharon Plon; Will Parsons, Amy McGuire

Evaluating utility and improving implementation of genomic sequencing for pediatric cancer patients in the diverse population and healthcare settings of Texas: The KidsCanSeq Study*
 

Pediatric cancer

Hudson-Alpha Institute for Biotechnology

Gregory Cooper, Gregory Barsh, Bruce Korf

Clinical sequencing across communities in the Deep South

Genetic disorders in newborns

Kaiser Foundation Research Institute

Katrina Goddard, Benjamin Wilfond

Exome sequencing in Diverse Populations in Colorado & Oregon

Cancer predisposition

Icahn School of Medicine at Mount Sinai

Eimear Kenny, Melissa Wasserstein, Carol Horowitz, Bruce Gelb

Incorporating genomics into the clinical care of diverse NYC children**

Pediatric undiagnosed disorders

University of California, San Francisco

Pui Kwok, Barbara Koenig, Mary Norton, Anne Slavotinek

Genomic sequencing to aid diagnosis in pediatric and prenatal practice: Examining clinical utility, ethical implications, payer coverage, and data integration in a diverse population.

Prenatal and pediatric undiagnosed developmental disorders

University of North Carolina, Chapel Hill

Jonathan Berg, Christine Rini, Bradford Powell

North Carolina Clinical Genomic Evaluation by Next-gen Exome Sequencing 2

Multiple adult and pediatric diseases

University of Washington

Gail Jarvik, Peter Tarczy-Hornoch, David Veenstra, Stephanie Fullerton, Deborah Nickerson

Evolving Our Partnership: The CSER2 Centralized Support Coordinating Center

Coordinating Center

* Co-funded by NCI

** Co-funded by NIMHD

Phase I Clinical Sequencing Exploratory Research Groups (2011-2017)
Institution Lead PI(s) Study Title Clinical Focus
Baylor College of Medicine Sharon Plon, Will Parsons and Amy McGuire Evaluating utility and improving implementation of genomic sequencing for pediatric cancer patients in the diverse population and healthcare settings of Texas: The KidsCanSeq Study
 
Pediatric cancer
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

Hudson-Alpha Institute for Biotechnology

Greg Cooper and 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 North Carolina, Chapel Hill James Evans,
Jonathan Berg and
Gail Henderson

 
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
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 Projects (through 2017)

Formerly 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 Gloria Peterson, Barbara Koenig, and Susan Wolf
 
Disclosing genomic incidental findings in a cancer biobank: An ELSI experiment* R01
Seattle Children's Hospital 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

* Co-funded by NCI

Phase II CSER2 Working Groups will be convened in Fall 2017
Clinical Utility, Health Economics, and Policy (CUHEP)

Co-Chairs: Bruce Gelb (Mt Sinai) and Kristen Lich (UNC)

Mission: This transdisciplinary group acknowledges that key outcomes of interest to payers, administrators and policymakers include those related to clinical outcomes, healthcare utilization, and health economics. Initial activities would include planning collaborative cross-consortium analyses informed by common measures of clinical utility and healthcare utilization. To maximize usefulness for payers and other policymakers, these measures could be collected using a standardized data model for coding health outcomes. This group could also convene meetings with payers and policymakers, to ensure we are including outcome measures they are interested in. This group would include experts in clinical care, health economics, cost effectiveness, health policy, health IT systems, and administration as well as our traditional genomics and health outcomes researchers. This WG will also work with other groups for input on an overall framework defining clinical utility (including granular definitions of different types of personal utility), and how different outcomes would be mapped into this framework.

Education and Return of Results (Edu/ROR)

Co-Chairs: Anne Slavotinek (UCSF) and Sarah Scollon (Baylor)

Mission: Since each CSER site is returning diagnostic results and incidental findings to patients, there are opportunities to discuss and collaborate on efforts to educate patients and providers about genomics, genetics and genetic testing methods for returning results. This would include some continuation of CSER topics as needed, as well as patient and provider education to ensure information is accessible, understandable and actionable. Thus, we would be bringing together clinical geneticists (MD and GC), other medical providers and researchers so that all perspectives and tools are used to develop, implement and evaluate this process. This WG will also investigate implications of secondary findings (with input from the SADY and CUHEP WGs), family-related factors relevant for ROR, and clinical decision support. Edu/ROR will also collaborate with Measures and Outcomes to discuss measures of downstream impact of ROR method.

ELSI and Diversity

Co-Chairs: Amy McGuire (Baylor) and Sara Knight (HudsonAlpha)

Mission: Given the focus on diversity, it is natural that this group would likely tackle more issues in the "social" implications category that are not addressed by other WGs, which encompasses the challenges of implementing genomics in diverse populations and how racial, ethnic and socioeconomic diversity might impact the informed consent and return of results process, and the delivery of genomic medicine more broadly. Although diversity will be a major focus, this WG will also take on other ELSI-related issues beyond diversity. This WG will also address common measures of ancestry, enrollment-related measures (consent, enrollment barriers, etc.) with input from the M&O WG, discuss disparities in genomic medicine and public health, and identify ELSI issues related to emerging health IT innovations. Measures of difference not addressed by the M&O WG will also be discussed.

Sequence Analysis and Diagnostic Yield (SADY)

Co-Chairs: Bradford Powell (UNC) and Pui Kwok (UCSF)

Mission: All CSER sites are recording some measure of diagnostic yield, since it provides a proximal measure of clinical usefulness (or at least sets a cap on potential clinical utility). This group would need to harmonize or at least understand differences among sites to make cross-consortium comparisons, including phenotype/disease categories, sequencing performance metrics, variant calling/annotation/interpretation, case-level reporting criteria, and secondary findings. This WG would also address issues related to laboratory-provider interactions. This WG will also discuss sharing sequencing data sharing among sites, sharing technical improvements, adding founder mutations to databases, and reanalyzing VCFs to assess impact on yield and cost.

Patient, Community, and Clinical Stakeholder Engagement

Co-Chairs: Galen Joseph (Kaiser) and Mimsie Robinson (Mt. Sinai)

Mission: Stakeholders at the various CSER sites will represent diverse patient SES, demographic, geographic and disease groups, advocates, and clinicians from diverse specialties and clinical settings. These are likely to be very different, based on the study population and geographic location. This group can discuss these activities and address common challenges and outcomes, and measure levels and impact of engagement. This WG will discuss the feasibility of identifying CSER-wide metrics to assess quality and impact of engagement and plan a stakeholder engagement session at each in person meeting.

Survey Measures and Outcomes (M&O)

Co-Chairs: Katrina Goddard (Kaiser) and Kelly East (HudsonAlpha)

Mission: Similar to the CSER1 Outcomes and Measures Working Group, this group will focus on patients' and family members' knowledge, attitudes, beliefs, behaviors and psychological outcomes. In keeping with the focus of CSER, we would also study provider knowledge, attitudes, beliefs and behaviors, including diagnostic thinking and management planning. This can include mixed methods-qualitative interviews, surveys, and abstracting clinical records. This WG will also address issues related to patient/providers surveys with input from the CUHEP, ELSI/diversity, and Edu/ROR WGs; common measures related to demographics and socioeconomic status (other than ancestry) with input from the ELSI/diversity WG; and a cross-CSER decliner survey.

CSER Working Groups (through 2017)

Working Groups

Informed 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
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.
  2. Explore overlap 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 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: Nick Wagle and Donna Muzny
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 Health 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.

Outcomes and Measures
Chairs: David Veenstra and Stacy Gray
Mission: Coordinate development of instruments to measure psychosocial outcomes related to returning results.

Pediatrics
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.

Genetic Counseling
Chairs: Julia Wynn 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.

Tumor
Chair: Will Parsons and Dan Robinson
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.  

Practitioner Education
Chairs: Sharon Plon and Kelly East
Mission: Develop ideas, tools and resources that can help inform non-genetic medical practitioners of the use of genomic sequencing in the clinic. 

CSER Website
https://cser-consortium.org/ 

Funding Announcements and Press Releases

RFA-HG-10-017: [grants.nih.gov] Clinical Sequencing Exploratory Research (U01)

RFA-HG-11-003: [grants.nih.gov] Development of a Preliminary Evidence Base to Inform Decision-making about Returning Research Results to Participants in Genomic Studies (R01)

RFA-HG-11-004: [grants.nih.gov] Ethical, Legal, and Social Implications of Returning Research Results to Genomic Research Participants (R21)

RFA-HG-12-008: [grants.nih.gov] Clinical Sequencing Exploratory Research Coordinating Center (U01)

RFA-HG-12-009: [grants.nih.gov] Clinical Sequencing Exploratory Research (UM1)

RFA HG-16-010: [grants.nih.gov] Clinical Sequencing Evidence-Generating Research (CSER2) - Clinical Sites (U01)

RFA HG-16-011: [grants.nih.gov] Clinical Sequencing Evidence-Generating Research (CSER2) - Clinical Sites with Enhanced Diversity (U01)

RFA HG-16-012: [grants.nih.gov] Clinical Sequencing Evidence-Generating Research (CSER2) - Coordinating Center (U24)

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Meetings, Workshops and Webinars

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Program Contacts

NHGRI Program Directors

Lucia Hindorff, Ph.D., M.P.H.
Division of Genomic Medicine
E-mail: hindorffl@mail.nih.gov

Dave Kaufman, Ph.D.
Division of Genomics and Society
E-mail: dave.kaufman@nih.gov

Ebony Madden, Ph.D., M.G.C.
Division of Genomic Medicine
Email: ebony.madden@nih.gov

NHGRI Program Analysts

Melpi Kasapi 
Division of Genomic Medicine
E-mail: melpomeni.kasapi@nih.gov

National Cancer Institute (NCI) Program Directors

Charlisse Caga-anan, J.D.
E-mail: cagaananef@mail.nih.gov

Kelly Filipski, Ph.D., M.P.H.
E-mail: kelly.filipski@nih.gov 

National Institute on Minority Health and Health Disparities (NIMHD) Program Director

Benyam Hailu, M.D., M.P.H.
E-mail: benyam.hailu@nih.gov

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Last Updated: July 3, 2018