Moving the genome into the clinic

The Clinical Sequencing Exploratory Research (CSER) Consortium, a national multi-site research program funded jointly by the National Human Genome Research Institute (NHGRI) and National Cancer Institute (NCI), conducts multidimensional, translational research to evaluate the integration of genome and exome sequencing into clinical care. Comprising of over 300 clinicians, scientists, ethicists, bioinformaticians, economists, and legal scholars, and recruiting over 5000 patients across diverse clinical indications, backgrounds, and age groups, CSER is well positioned to study the impacts and effectiveness of using genomic sequencing in clinical care. Through this expertise and research, CSER has and continues to develop and share innovations and best practices in areas such as variant classification, return of results, additional (incidental) findings, informed consent, and ethical, legal and social implications of sequencing.

CSER Tools for Genomic Medicine

CSER developed tools and resources to support the genomic medicine process.
Achievements

Key Contributions:

  • CSER consent forms, results report templates, and other research documents. CSER made available to the research community a wide range of documents developed in the course of the research conducted at individual clinical sites: https://cser-consortium.org/cser-research-materials
  • CSER Guide to Interpreting Genomic Reports, a reference guide for non-genetics practitioners to assist them in interpreting a genomic sequencing report: http://www.ashg.org/education/csertoolkit/index.html
  • Proband, an iPad app (with over 2500 downloads) for charting family pedigrees: https://probandapp.com/
  • Preferences Instrument for Genomic Secondary Results (PIGSR), a validated tool to help assess adult preferences for receiving secondary findings: http://www.pigsr.org/
  • ClinGen Pathogenicity Calculator. A pathogenicity calculated developed in collaboration with ClinGen to assess pathogenicity of genetic variants based on ACMG/AMP criteria1
  • Perceptions of Uncertainties in Genome Sequencing scale. A survey scale to evaluate perceived uncertainties in genome sequencing2
  • FACToR. A survey instrument based on the Multidimensional Impact of Cancer Risk Assessment (MICRA) questionnaire to elicit reactions to receiving genomic test results (in progress)

Footnotes

Process of Informed Consent

CSER provides guidance on informed consent practices in both pediatric and adult clinical sequencing.
Achievements

Key Contributions:

  • Investigating the consent processes when pediatric research participants reach the age of majority3
  • Illustrating challenging informed consent cases for genomic sequencing4
  • UPCOMING: Guidance on informed consent in clinical sequencing, studying participant engagement post-enrollment, and analysis of state laws on informed consent for clinical sequencing

Footnotes

  1. Brothers KB, Holm IA, Childerhose JE, Antommaria AH, Bernhardt BA, Clayton EW, Gelb BD, Joffe S, Lynch JA, McCormick JB, McCullough LB, Parsons DW, Sundaresan AS, Wolf WA, Yu JH, Wilfond BS; Pediatrics Workgroup of the Clinical Sequencing Exploratory Research (CSER) Consortium. When Participants in Genomic Research Grow Up: Contact and Consent at the Age of Majority. J Pediatr. 2016 Jan;168:226-31.e1. doi: 10.1016/j.jpeds.2015.09.020. No abstract available. PMID: 26477867.

Advance Understanding of Variant Classification Processes

CSER sought ways to increase concordance and standardize variant classification amongst different laboratories.
Achievements

Key Contributions:

  • Tested and clarified ACMG/AMP guidelines for variant pathogenicity classification5
  • Examined workflow and reporting procedures of various US laboratories interpreting genomic sequencing data to highlight shared practices and identify areas needing standardization6
  • Offered anticipatory guidance for laboratories and clinicians to do paired germline-tumor sequencing in cancer7
  • Evaluated effectiveness and need for tumor boards and reaching consensus on somatic sequencing results
  • ONGOING: Contributing CSER data into dbGAP (>1800 entries) and ClinVar (>3800 entries)
  • UPCOMING: Identified common poorly covered regions amongst sequencing technologies

Footnotes

Investigating Additional (Secondary) Findings

CSER identified the rate of actionable additional (secondary) findings and the impacts of returning such findings in both clinical and research settings.
Achievements

Key Contributions:

  • Identified patients prefer the term “additional findings” over "incidental finding"8
  • Coordinated with numerous investigators to estimate the rate of actionable additional findings9, 10
  • Led and collaborated with eMERGE on a consensus paper arguing that research investigators have no ethical obligation to actively search for additional findings11
  • Publicized CSER choices in identifying actionable genes to be reported as additional findings12
  • Conducted preliminary cost-effectiveness analyses of returning additional findings13
  • Collaborated with ACMG to develop a recommended list for returning additional findings14
  • Published commentary on the implications of conducting separate and deliberate search for additional findings in tumor sequencing contexts to clinical labs and clinicians15
  • UPCOMING: Participant responses to receiving additional findings and the impact on subsequent behaviors and healthcare resource utilization.

Footnotes

  3. Dorschner M, Amendola LM, Turner EH, Robertson PD, Shirts BH, Gallego CJ, Bennett RL, Jones KL, Tokita MJ, Bennett JT, Kim JH, Rosenthal EA, Kim DS; National Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing Project, Tabor HK, Bamshad MJ, Motulsky AG, Scott CR, Pritchard CC, Walsh T, Burke W, Raskind WH, Byers P, Hisama FM, Nickerson DA, Jarvik GP.. Actionable, Known Pathogenic Incidental Findings in 1000 Subjects. American Journal of Medical Genetics. PMID: 24055113.
  5. Berg JS, Amendola LM, Eng C, Van Allen E, Gray SW, Wagle N, Rehm HL, DeChene ET, Dulik MC, Hisama FM, Burke W, Spinner NB, Garraway L, Green RC, Plon S, Evans JP, Jarvik GP; Members of the CSER Actionability and Return of Results Working Group.. Processes and preliminary outputs for identification of actionable genes as incidental findings in genomic sequence data in the Clinical Sequencing Exploratory Research Consortium. Genet Med. 2013 Nov;15(11):860-7. doi: 10.1038/gim.2013.133. Review. Erratum in: Genet Med. 2014 Feb;16(2):203. PMID: 24195999.

Develop best practices for responsible results return

CSER developed and tested best practices for both geneticist and non-geneticist clinicians to responsibly returning sequencing results to patients, families, and the EHR, in both adult and pediatric settings.
Achievements

Key Contributions:

  • Offered illustrative case examples highlighting challenges and responsibilities in results return across different clinical contexts16
  • Investigated how sequencing data is reported into EHRs17, 18 and identified areas for improvement
  • Highlighted processes involved in developing a Genome Report to report medically relevant findings19, 20
  • Developed a reference Guide to aid non-geneticist clinicians in interpreting genetics reports (http://www.ashg.org/education/csertoolkit/index.html)
  • Provided an ethical framework to guide and evaluate the professional disclosure of sequencing results to pediatric patients21
  • Provided consensus recommendations on the return of results to relatives22 and gauged participant preferences for results disclosure to relatives in the event of their death23
  • Developed guidelines for returning research results from pediatric genome studies24
  • UPCOMING: Examination of return of results experiences from genetic counselors and clinicians in returning results of genomic sequencing

Footnotes

  5. Vassy JL, McLaughlin HM, MacRae CA, Seidman CE, Lautenbach D, Krier JB, Lane WJ, Kohane IS, Murray MF, McGuire AL, Rehm HL, Green RC. A one-page summary report of genome sequencing for the healthy adult. Public Health Genomics. 2015;18(2):123-9. doi: 10.1159/000370102. Erratum in: Public Health Genomics. 2015 Apr;18(3):191. McLaughlin, Heather L [corrected to McLaughlin, Heather M]. PMID: 25612602.

Nidus for Building Policy Consensus

CSER’s combined diversity in clinical indications and population demographics has swayed policy, illustrated different processes involved in clinical sequencing research, and identified high priorities for future efforts.
Achievements

Key Contributions:

  • Developed a summary paper describing CSER25
  • Investigated disclosure of results in carrier testing26
  • Produced numerous site papers describing a range of research methodologies27, 28, 29, 30
  • Extensive ongoing work identifying new areas of focus, such as the need for greater population diversity, the technological limitations of current sequencing technologies, the need for greater attention to the economic aspects of clinical sequencing31, and emerging ELSI issues

Footnotes

  1. Green RC, Goddard KA, Amendola LM, Appelbaum PS, Berg JS, Bernhardt BA, Biesecker LG, Biswas S, Blout CL, Bowling KM, Brothers KB, Burke W, Caga-Ana CF, Chinnaiyan AM, Chung WK, Clayton EW, Fullerton SM, Garraway LA, Garrett JR, Gray SW, Henderson GE, Hindorff LA, Hutter CM, Janne PA, Jarvik GP, Joffe S, Kaufman D, Knoppers BM, Koenig BA, Krantz ID, Manolio T, McCullough L, Myers RM, Nickerson DA, Ou J, Parsons DW, Petersen GM, Plon SE, Rehm HL, Roberts JS, Robinson D, Salama J, Scollon S, Sharp RR, Shirts B, Spinner NB, Tabor HK, Tarczy-Hornoch P, Veenstra DL, Wagle N, Weck K, Wilfond BS, Wilhelmsen K, Wolf SM, Wynn J, Yu JH, for the CSER Consortium.. The Clinical Sequencing Exploratory Research Consortium: Accelerating the Evidence-Based Practice of Genomic Medicine. Am J Hum Genet. 2016 May 12. pii: S0002-9297(16)30106-9. doi: 10.1016/j.ajhg.2016.04.011. PMID: 27181682.
  5. Gallego CJ, Bennette CS, Heagerty P, Comstock B, Horike-Pyne M, Hisama F, Amendola LM, Bennett RL, Dorschner MO, Tarczy-Hornoch P, Grady WM, Fullerton SM, Trinidad SB, Regier DA, Nickerson DA, Burke W, Patrick DL, Jarvik GP, Veenstra DL. Comparative effectiveness of next generation genomic sequencing for disease diagnosis: design of a randomized controlled trial in patients with colorectal cancer/polyposis syndromes. Contemp Clin Trials. 2014 Sep;39(1):1-8. doi: 10.1016/j.cct.2014.06.016. PMID: 24997220.