Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Abstract

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine.

Why Patients Decline Genomic Sequencing Studies: Experiences from the CSER Consortium

“…This finding may have been influenced by protocol differences across studies. If, how, and what types of secondary findings were disclosed greatly varied by study (Green et al 2016), for example, the Pediseq project allowed participants to opt out of secondary findings that were determined to be not immediately medically actionable (Berg et al 2013). Regardless, recent research indicates that the majority of individuals who pursue GS express interest in secondary findings (Shahmirzadi et al 2014).…”

“…Enrollment in the other CSER projects took place between December 2011 and May 2016. More details about the CSER consortium and the individual site populations and goals, including information about the types of primary results reported by each CSER site and their reporting of secondary findings, are described elsewhere (Green et al 2016). …”

“…The National Institutes of Health (NIH)-funded Clinical Sequencing Exploratory Research (CSER) consortium is a group of research programs offering GS for a variety of indications (Green et al 2016). CSER sites collect data related to their individual project aims, including reasons potential participants choose to decline enrollment, and some sites have reported their project-specific findings in this area (Gilmore et al 2017; Robinson et al 2016; Scollon et al 2014).…”

Adapting crowdsourced clinical cancer curation in CIViC to the ClinGen minimum variant level data community‐driven standards

“…Clinical application of Next Generation Sequencing (NGS) has enhanced molecular profiling capacity (Kamps et al., 2017). NGS sequencing methods are now commonly used in personalized clinical cancer care (Chang et al., 2017; Green et al., 2016). However, NGS also yields increasing numbers of variants that predominantly are of unknown significance and compounds the challenge of variant interpretation (Good, Ainscough, McMichael, Su, & Griffith, 2014; Kamps et al., 2017).…”

Exploring the feasibility of delivering standardized genomic care using ophthalmology as an example

“…Demonstrable impacts on diagnostic rates and treatment have already been shown across a broad range of specialties. [1][2][3][4] In order to achieve widespread implementation of genomic care, it will be necessary to alter care pathways to incorporate early genomic testing and then expand the delivery of genetic and genomic care beyond clinical genetics and into mainstream clinical specialties. [5][6][7] A recent review of genetic service models has suggested that multidisciplinary clinics and coordinated services are key to delivering proper care in rare genetic disorders.…”