Available on the American Society of Human Genetics' education resources is a CSER-developed Guide to Interpreting Genomic Reports, a just-in-time resource for non-geneticist physicians when receiving a genomic test report. This Toolkit's work was led by Sharon Plon from Baylor and Kelly East from HudsonAlpha, with support from the CSER Practitioner Education working group.
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
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
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ClinGen Pathogenicity Calculator: a configurable system for assessing pathogenicity of genetic variants. Genome Med. 2017 Jan 12;9(1):3. doi: 10.1186/s13073-016-0391-z. PMID: 28081714. -
PUGS: A novel scale to assess perceptions of uncertainties in genome sequencing. Clin Genet. 2016 Dec 7. doi: 10.1111/cge.12949. [Epub ahead of print]. PMID: 27925165.
Process of Informed Consent
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
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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. -
Not Tied Up Neatly with a Bow": Professionals' Challenging Cases in Informed Consent for Genomic Sequencing. J Genet Couns. 2016 Feb;25(1):62-72. doi: 10.1007/s10897-015-9842-8. PMID: 25911622.
Advance Understanding of Variant Classification Processes
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
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Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium. Am J Hum Genet. 2016 Jun 2;98(6):1067-76. doi: 10.1016/j.ajhg.2016.03.024. PMID: 27181684. -
A survey of current practices for genomic sequencing test interpretation and reporting processes in US laboratories. Genet Med. 2016 Nov 3. doi: 10.1038/gim.2016.152. [Epub ahead of print]. PMID: 27811861. -
Germline Findings in Tumor-Only Sequencing: Points to Consider for Clinicians and Laboratories. J Natl Cancer Inst. 2015 Nov 20;108(4). doi:pii: djv351. 10.1093/jnci/djv351. Print 2016 Apr. PMID: 26590952.
Investigating Additional (Secondary) Findings
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
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Is "incidental finding" the best term?: a study of patients' preferences. Genet Med. 2017 Feb;19(2):176-181. doi: 10.1038/gim.2016.96. PMID: 27490114. -
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. Genome Res. 2015 Mar;25(3):305-15. doi: 10.1101/gr.183483.114. PMID: 25637381. -
Actionable, Known Pathogenic Incidental Findings in 1000 Subjects. American Journal of Medical Genetics. PMID: 24055113. -
Return of genomic results to research participants: the floor, the ceiling, and the choices in between. Am J Hum Genet. 2014 Jun 5;94(6):818-26. doi: 10.1016/j.ajhg.2014.04.009. PMID: 24814192. -
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. -
The cost-effectiveness of returning incidental findings from next-generation genomic sequencing. Genet Med. 2015 Jul;17(7):587-95. doi: 10.1038/gim.2014.156. PMID: 25394171. -
ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013 Jul;15(7):565-74. doi: 10.1038/gim.2013.73. PMID: 23788249. -
Clinical tumor sequencing: an incidental casualty of the American College of Medical Genetics and Genomics recommendations for reporting of incidental findings. J Clin Oncol. 2014 Jul 20;32(21):2203-5. doi: 10.1200/JCO.2013.54.8917. No abstract available. PMID: 24958819.
Develop best practices for responsible results return
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
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Illustrative case studies in the return of exome and genome sequencing results. Per Med. 2015;12(3):283-295. PMID: 26478737. -
A survey of informatics approaches to whole-exome and whole-genome clinical reporting in the electronic health record. Genet Med. 2013 Oct;15(10):824-32. doi: 10.1038/gim.2013.120. PMID: 24071794. -
CSER and eMERGE: current and potential state of the display of genetic information in the electronic health record. J Am Med Inform Assoc. 2015 Nov;22(6):1231-42. doi: 10.1093/jamia/ocv065. PMID: 26142422. -
A systematic approach to the reporting of medically relevant findings from whole genome sequencing. BMC Med Genet. 2014 Dec 14;15:134. doi: 10.1186/s12881-014-0134-1. PMID: 25714468. -
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. -
Professionally Responsible Disclosure of Genomic Sequencing Results in Pediatric Practice. Pediatrics. 2015 Oct;136(4):e974-82. doi: 10.1542/peds.2015-0624. PMID: 26371191. -
Returning a Research Participant's Genomic Results to Relatives: Analysis and Recommendations. J Law Med Ethics. 2015 Fall;43(3):440-63. doi: 10.1111/jlme.12288. PMID: 26479555. -
Patients' Choices for Return of Exome Sequencing Results to Relatives in the Event of Their Death. J Law Med Ethics. 2015 Fall;43(3):476-85. doi: 10.1111/jlme.12290. PMID: 26479557. -
Guidelines for return of research results from pediatric genomic studies: deliberations of the Boston Children's Hospital Gene Partnership Informed Cohort Oversight Board. Genet Med. 2014 Jul;16(7):547-52. doi: 10.1038/gim.2013.190. PMID: 24406460.
Nidus for Building Policy Consensus
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
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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. -
Genome sequencing and carrier testing: decisions on categorization and whether to disclose results of carrier testing. Genet Med. 2017 Jan 12. doi: 10.1038/gim.2016.198. [Epub ahead of print]. PMID: 28079899. -
Design of a randomized controlled trial for genomic carrier screening in healthy patients seeking preconception genetic testing. Contemp Clin Trials. 2017 Feb;53:100-105. doi: 10.1016/j.cct.2016.12.007. PMID: 27940182. -
The MedSeq Project: a randomized trial of integrating whole genome sequencing into clinical medicine. Trials. 2014 Mar 20;15:85. doi: 10.1186/1745-6215-15-85. PMID: 24645908. -
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. -
The NCGENES project: exploring the new world of genome sequencing. N C Med J. 2013 Nov-Dec;74(6):500-4. PMID: 24316776. -
Assessing the Costs and Cost-Effectiveness of Genomic Sequencing. J Pers Med. 2015 Dec 10;5(4):470-86. doi: 10.3390/jpm5040470. Review. PMID: 26690481.