Next generation sequencing (NGS) technologies can produce large volumes of human genome sequence data inexpensively. Carrier testing identifying individuals who carry one copy of a variant in a gene for a disease that requires two copies to be expressed is a prime candidate for clinical implementation of NGS technology. We will investigate the clinical implementation of carrier testing using whole genome sequencing to aid reproductive decision-making in adults. The study population will include women and their partners requesting pre-conception testing for cystic fibrosis (CF) carrier status, or other conditions. We propose three interrelated projects. In Project 1, we will conduct a Randomized Clinical Trial within the Kaiser Permanente Northwest (KPNW) health plan to test clinical implementation of whole genome sequencing and the integration of this screening within the electronic medical record (EMR), as well as measure outcomes from patient and physician perspectives. We will evaluate the comparative outcomes of adding genome sequencing versus usual care or versus a targeted genomic test panel. In Project 2, we will perform genome sequencing of the laboratory test samples, including validation and interpretation of the identified variants to identify "actionable variants" deemed worthy of reporting to doctors and patients. This will include using a Return of Results Committee (RORC). In Project 3, we will evaluate the ethical and psychosocial implications of expanded carrier screening for the return of carrier status and secondary findings from whole genome sequencing, and evaluate the downstream healthcare utilization and costs. This project will have a far-reaching impact and will inform discussions about the advantages and disadvantages of returning preconception carrier status results from whole genome sequencing. Carrier testing represents a high proportion of genetics services delivered, meaning this program can be readily translated to a large number of patients. Our focus on patients seeking preconception carrier status will allow us to rapidly assess the potential impact of using NGS for carrier status. Our access to real world patients and clinical settings will make our research broadly generalizable.

Public Health Relevance

We will offer whole genome testing to would-be parents in an HMO who want to know if they carry genes for diseases that would affect their child. We will compare couples who get whole genome testing to couples who get usual care. We will identify which test results are meaningful enough to return to patients, return those results to patients, and then survey doctors and patients about whether they learned what they wanted to know and how it affected their choices. DESCRIPTION (provided by applicant): Next generation sequencing (NGS) technologies can produce large volumes of human genome sequence data inexpensively. Carrier testing identifying individuals who carry one copy of a variant in a gene for a disease that requires two copies to be expressed is a prime candidate for clinical implementation of NGS technology. We will investigate the clinical implementation of carrier testing using whole genome sequencing to aid reproductive decision-making in adults. The study population will include women and their partners requesting pre-conception testing for cystic fibrosis (CF) carrier status, or other conditions. We propose three interrelated projects. In Project 1, we will conduct a Randomized Clinical Trial within the Kaiser Permanente Northwest (KPNW) health plan to test clinical implementation of whole genome sequencing and the integration of this screening within the electronic medical record (EMR), as well as measure outcomes from patient and physician perspectives. We will evaluate the comparative outcomes of adding genome sequencing versus usual care or versus a targeted genomic test panel. In Project 2, we will perform genome sequencing of the laboratory test samples, including validation and interpretation of the identified variants to identify actionable variants deemed worthy of reporting to doctors and patients. This will include using a Return of Results Committee (RORC). In Project 3, we will evaluate the ethical and psychosocial implications of expanded carrier screening for the return of carrier status and secondary findings from whole genome sequencing, and evaluate the downstream healthcare utilization and costs. This project will have a far-reaching impact and will inform discussions about the advantages and disadvantages of returning preconception carrier status results from whole genome sequencing. Carrier testing represents a high proportion of genetics services delivered, meaning this program can be readily translated to a large number of patients. Our focus on patients seeking preconception carrier status will allow us to rapidly assess the potential impact of using NGS for carrier status. Our access to real world patients and clinical settings will make our research broadly generalizable.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Project with Complex Structure Cooperative Agreement (UM1)
Project #
5UM1HG007292-02
Application #
8680280
Study Section
Special Emphasis Panel (ZHG1-HGR-N (J2))
Program Officer
Hutter, Carolyn
Project Start
2013-06-14
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$1,980,930
Indirect Cost
$388,066
Name
Kaiser Foundation Research Institute
Department
Type
DUNS #
150829349
City
Oakland
State
CA
Country
United States
Zip Code
94612
Amendola, Laura M; Jarvik, Gail P; Leo, Michael C et al. (2016) Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium. Am J Hum Genet 98:1067-76
Leo, Michael C; McMullen, Carmit; Wilfond, Benjamin S et al. (2016) Patients' ratings of genetic conditions validate a taxonomy to simplify decisions about preconception carrier screening via genome sequencing. Am J Med Genet A 170:574-82
Rasmussen, Luke V; Overby, Casey L; Connolly, John et al. (2016) Practical considerations for implementing genomic information resources. Experiences from eMERGE and CSER. Appl Clin Inform 7:870-82
O'Daniel, Julianne M; McLaughlin, Heather M; Amendola, Laura M et al. (2016) A survey of current practices for genomic sequencing test interpretation and reporting processes in US laboratories. Genet Med :
Korngiebel, Diane M; McMullen, Carmit K; Amendola, Laura M et al. (2016) Generating a taxonomy for genetic conditions relevant to reproductive planning. Am J Med Genet A 170:565-73
Green, Robert C; Goddard, Katrina A B; Jarvik, Gail P et al. (2016) Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine. Am J Hum Genet 98:1051-66
Schneider, Jennifer L; Goddard, Katrina A B; Davis, James et al. (2016) "Is It Worth Knowing?" Focus Group Participants' Perceived Utility of Genomic Preconception Carrier Screening. J Genet Couns 25:135-45
Brothers, Kyle B; Holm, Ingrid A; Childerhose, Janet E et al. (2016) When Participants in Genomic Research Grow Up: Contact and Consent at the Age of Majority. J Pediatr 168:226-31.e1
Amendola, Laura M; Lautenbach, Denise; Scollon, Sarah et al. (2015) Illustrative case studies in the return of exome and genome sequencing results. Per Med 12:283-295
Wilfond, Benjamin S; Goddard, Katrina Ab (2015) It's complicated: criteria for policy decisions for the clinical integration of genome-scale sequencing for reproductive decision making. Mol Genet Genomic Med 3:239-42

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