Jean E. McEwen

Integrating common and rare genetic variation in diverse human populations.

Despite great progress in identifying genetic variants that influence human disease, most inherited risk remains unexplained. A more complete understanding requires genome-wide studies that fully examine less common alleles in populations with a wide range of ancestry. To inform the design and interpretation of such studies, we genotyped 1.6 million common single nucleotide polymorphisms (SNPs) in 1,184 reference individuals from 11 global populations, and sequenced ten 100-kilobase regions in 692 of these individuals. This integrated data set of common and rare alleles, called ‘HapMap 3’, includes both SNPs and copy number polymorphisms (CNPs). We characterized population-specific differences among low-frequency variants, measured the improvement in imputation accuracy afforded by the larger reference panel, especially in imputing SNPs with a minor allele frequency of ≤5%, and demonstrated the feasibility of imputing newly discovered CNPs and SNPs. This expanded public resource of genome variants in global populations supports deeper interrogation of genomic variation and its role in human disease, and serves as a step towards a high-resolution map of the landscape of human genetic variation.

Community Engagement and Informed Consent in the International HapMap Project

The International HapMap Consortium has developed the HapMap, a resource that describes the common patterns of human genetic variation (haplotypes). Processes of community/public consultation and individual informed consent were implemented in each locality where samples were collected to understand and attempt to address both individual and group concerns. Perceptions about the research varied, but we detected no critical opposition to the research. Incorporating community input and responding to concerns raised was challenging. However, the experience suggests that approaching genetic variation research in a spirit of openness can help investigators better appreciate the views of the communities whose samples they seek to study and help communities become more engaged in the science.

Evolving approaches to the ethical management of genomic data

The ethical landscape in the field of genomics is rapidly shifting. Plummeting sequencing costs, along with ongoing advances in bioinformatics, now make it possible to generate an enormous volume of genomic data about vast numbers of people. The informational richness, complexity, and frequently uncertain meaning of these data, coupled with evolving norms surrounding the sharing of data and samples and persistent privacy concerns, have generated a range of approaches to the ethical management of genomic information. As calls increase for the expanded use of broad or even open consent, and as controversy grows about how best to handle incidental genomic findings, these approaches, informed by normative analysis and empirical data, will continue to evolve alongside the science.

The Ethical, Legal, and Social Implications Program of the National Human Genome Research Institute: Reflections on an Ongoing Experiment*

For more than 20 years, the Ethical, Legal, and Social Implications (ELSI) Program of the National Human Genome Research Institute has supported empirical and conceptual research to anticipate and address the ethical, legal, and social implications of genomics. As a component of the agency that funds much of the underlying science, the program has always been an experiment. The ever-expanding number of issues the program addresses and the relatively low level of commitment on the part of other funding agencies to support such research make setting priorities especially challenging. Program-supported studies have had a significant impact on the conduct of genomics research, the implementation of genomic medicine, and broader public policies. The programs influence is likely to grow as ELSI research, genomics research, and policy development activities become increasingly integrated. Achieving the benefits of increased integration while preserving the autonomy, objectivity, and intellectual independence of ELSI investigators presents ongoing challenges and new opportunities.

Abstract 4888: Clinical sequencing in the National Institute of Health's Clinical Sequencing Exploratory Research (CSER) Program

To evaluate best uses of and support the integration of genomic sequencing into the clinical workflow, the National Human Genome Research Institute and National Cancer Institute co-fund the Clinical Sequencing Exploratory Research (CSER) project. This initiative aims to 1) leverage NHGRI9s experience in genomic sequencing and analysis to facilitate adoption of these methods into patient care, 2) develop and disseminate best practices for the integration of genomic sequencing into clinical care, and 3) research the ethical, legal, and psychosocial (ELSI) implications of bringing broad genomic data into the clinic. The CSER Consortium includes nine multi-disciplinary projects, nine ELSI-specific projects, a Coordinating Center and NHGRI9s Intramural ClinSeq program. Four of the multi-disciplinary projects and one ELSI project have a specific focus on cancer settings and outcomes: CanSeq (Dana-Farber Cancer Inst.), BASIC3 (Baylor College of Med.), ONCOSEQ (Univ. of Michigan), and NEXT Medicine (Univ. of Washington) are developing robust frameworks for the integration of whole exome sequencing (WXS) in tumor and germline samples. By measuring the effectiveness of novel platforms for returning results, analyzing the costs and benefits of using sequencing technology to identify rare variants, and evaluating patient experiences, these projects will help define best practices for incorporating WXS into cancer management. As of August 2014, these projects had collected WXS data from 415 patients (269 adults and 146 children). The CSER consortium also has nine working groups that strive to advance best practices and communicate lessons learned to the community regarding the use of genomic sequence data in the clinical workflow. The Tumor Working Group explores the unique technical, interpretive, and ethical challenges involved in clinical sequencing of both somatic and germline cancer genomes. This presentation will highlight progress to date, anticipated products and results, and the relationship between these cancer sequencing projects and broader CSER consortium efforts. Citation Format: Catherine Crawford, Charlisse Caga-Anan, Dave Kaufman, Alexander Lee, Jean Mcewen, Sheri Schully, Carolyn Hutter, Lucia Hindorff. Clinical sequencing in the National Institute of Health9s Clinical Sequencing Exploratory Research (CSER) Program. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4888. doi:10.1158/1538-7445.AM2015-4888