BioSocieties

, Volume 12, Issue 3, pp 439–458 | Cite as

Narrating uncertainty: Variants of uncertain significance (VUS) in clinical exome sequencing

  • Stefan Timmermans
  • Caroline Tietbohl
  • Eleni Skaperdas
Original Article

Abstract

Exome sequencing is an innovative next-generation sequencing technology that examines the majority of disease-causing genes with a single test. Physicians and patients resort to exome sequencing to probe for a genetic cause of disease. The technology produces about 20,000 variants and many are of uncertain clinical relevance. Drawing from ethnographic field notes and audio recordings of over 1,500 patient cases discussed at genetic data board meetings over a three-year period, this article reports on how a collective of laboratory scientists and clinicians contend practically and conceptually with variants of uncertain significance (VUS). Rather than standardizing the inclusion criteria for a VUS, the collective contextualizes each VUS with its own evidentiary narrative. The VUS then becomes subject to revision based on evolving evidence, further testing, and updated interpretations. We argue that the epistemic uncertainty of VUS becomes productive; it indicates future causality and suggests that genetic causes can explain patients’ symptoms even if no known pathogenic variants could be located.

Keywords

uncertainty bioclinical collective standardization narrative exome sequencing next-generation sequencing genetic testing laboratory 

Notes

Acknowledgements

The authors thank Ruth Baxter, Tanya Stivers, the reviewers, editors, and members of the UCLA Medical Sociology working group for helpful comments. The manuscript consists of original material not under review elsewhere. The research received IRB approval. The research was funded by an NSF Grant (SES-1256874). The authors do not have a financial interest in the research presented.

References

  1. Abbott, A. (1988) The System of Professions. Chicago: The University of Chicago Press.Google Scholar
  2. Armstrong, D. (2002) Clinical autonomy, individual and collective: The problem of changing doctors’ behaviour. Social Science and Medicine 55: 1771–1777.CrossRefGoogle Scholar
  3. Atkinson, P. (1984) Training for certainty. Social Science and Medicine 19: 949–956.CrossRefGoogle Scholar
  4. Beckert, J. (1996) What is sociological about economic sociology? Uncertainty and the embeddedness of economic action. Theory and Society 25: 803–840.CrossRefGoogle Scholar
  5. Biesecker, L.G. and Green, R.C. (2014) Diagnostic clinical genome and exome sequencing. New England Journal of Medicine 370: 2418–2425.CrossRefGoogle Scholar
  6. Bourret, P. (2005) BRCA patients and clinical collectives: New configurations of action in cancer genetics practices. Social Studies of Sciecne 35: 41–68.CrossRefGoogle Scholar
  7. Cox, H. and Webster, A. (2013) Translating biomedical science into clinical practice: Molecular diagnostics and the determination of malignancy. Health (London) 17: 391–406.CrossRefGoogle Scholar
  8. Duster, T. (1990) Backdoor to Eugenics. New York: Routledge.Google Scholar
  9. Eggington, J.M., Bowles, K.R., Moyes, K., Manley, S., Esterling, L., Sizemore, S., Rosenthal, E., Theisen, A., Saam, J., Arnell, C., Pruss, D., Bennett, J., Burbidge, L.A., Roa, B. and Wenstrup, R.J. (2014) A comprehensive laboratory-based program for classification of variants of uncertain significance in hereditary cancer genes. Clinical Genetics 86: 229–237.CrossRefGoogle Scholar
  10. Eyal, G. (2013) For a sociology of expertise: The social origins of the autism epidemic. American Journal of Sociology 118: 863–907.CrossRefGoogle Scholar
  11. Green, R.C., Berg, J.S., Grody, W.W., Kalia, S.S., Korf, B.R., Martin, C.L., Mcguire, A.L., Nussbaum, R.L., O’daniel, J.M., Ormond, K.E., Rehm, H.L., Watson, M.S., Williams, M.S. and Biesecker, L.G. (2013) ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genetics in Medicine 15: 565–574.Google Scholar
  12. Han, P.K., Klein, W.M.P. and Arora, N.K. (2011) Varieties of uncertainty in health care: A conceptual taxonomy. Medical Decision Making 31: 828–838.CrossRefGoogle Scholar
  13. Hedgecoe, A.M. (2003) Expansion and uncertainty: Cystic fibrosis, classification and genetics. Sociology of Health and Illness 25: 50–70.CrossRefGoogle Scholar
  14. Hughes, E. (1945) 1971 The Sociological Eye: Selected Papers. Chicago: Aldine-Atherton.Google Scholar
  15. Jutel, A. (2009) Sociology of diagnosis: A preliminary review. Sociology of Health and Illness 31: 278–299.CrossRefGoogle Scholar
  16. Keller, E.F. (2000) The Century of the Gene. Cambridge, MA: Harvard University Press.Google Scholar
  17. Lampland, M. and Star, S.L. (eds.) (2009) Standards and Their Stories: How Quantifying, Classifying, and Formalizing Practices Shape Everyday Life. Ithaca, NY: Cornell University Press.Google Scholar
  18. Lee, H., Deignan, J.L., Dorrani, N., Strom, S.P., Kantarci, S., Quintero-Rivera, F., Das, K., Toy, T., Harry, B., Yourshaw, M., Fox, M., Fogel, B.L., Martinez-Agosto, J.A., Wong, D.A., Chang, V.Y., Shieh, P.B., Palmer, C.G., Dipple, K.M., Grody, W.W., Vilain, E. and Nelson, S.F. (2014) Clinical exome sequencing for genetic identification of rare mendelian disorders. JAMA 312(18): 1880–1887Google Scholar
  19. Lippman, A. (1991) Prenatal genetic testing and screening: Construcing needs and reinforcing inequalities. American Journal of Law and Medicine 17: 15–50.Google Scholar
  20. Lock, M. (2011) Learning to live again with uncertainty: Social repercussions of molecular genomics. In Maheu, L. and Macdonald, R.A. (eds.) Challenging Genetic Determinism: New Perspectives on the Gene and its Multiple Environments. Montreal: McGill-Queen’s University Press.Google Scholar
  21. Navon, D. (2011) Genomic designation: How genetics can delineate new, phenotypically diffuse medical categories. Social Studies of Science 41: 203–226.CrossRefGoogle Scholar
  22. Nelson, N.C., Keating, P. and Cambrosio, A. (2013) On being ‘actionable’: Clinical sequncing and hte emerging contours of a regime of genomic medicine in oncology. New Genetics and Society 32: 405–428.CrossRefGoogle Scholar
  23. Novas, C. and Rose, N. (2000) Genetic risk and the birth of the somatic individual. Economy and Society 29: 485–513.CrossRefGoogle Scholar
  24. Porter, T. (1996) Trust in Numbers: The Pursuit of Objectivity in Science and Public Life, Princeton: Princeton University Press.CrossRefGoogle Scholar
  25. Rabeharisoa, V., Callon, M., Filipe, A.M., Nunes, J.A., Paterson, F. and Vergnaud, F. (2014) From ‘politics of numbers’ to ‘politics of singularisation’: Patients’ activism and engagement in research on rare diseases in France and Portugal. Biosocieties, 9: 194–217.CrossRefGoogle Scholar
  26. Radley, D.C., Finkelstein, S.N. and Stafford, R.S. (2006). Off-label prescribing among office-based physicians. Archives of Internal Medicine 166: 1021–1026.CrossRefGoogle Scholar
  27. Richards, C.S., Bale, S., Bellissimo, D.B., Das, S., Grody, W.W., Hegde, M.R., Lyon, E. and Ward, B.E. (2008) ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genetics in Medicine 10: 294–300.CrossRefGoogle Scholar
  28. Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W.W., Hegde, M., Lyon, E., Spector, E., Voelkerding, K. and Rehm, H.L. (2015) Committee ALQA (2015) standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine 17: 405–424.CrossRefGoogle Scholar
  29. Sarangi, S. and Clarke, A. (2002) Zones of expertise and the management of uncertainty in genetics risk communication. Research on Language and Social Interaction 35: 139–171.CrossRefGoogle Scholar
  30. Shostak, S. (2013) Exposed Science: Genes, the Environment and the Politics of Population Health. Berkeley, CA: University of California Press.CrossRefGoogle Scholar
  31. Somers, M.R. (1994) The narrative constitution of identity – A relational and network approach. Theory and Society 23: 605–649.CrossRefGoogle Scholar
  32. Tavory, I. and Timmermans, S. (2014) Abductive Analysis: Theorizing Qualitative Research. Chicago: University of Chicago Press.CrossRefGoogle Scholar
  33. Timmermans, S. (2015) Trust in standards: Transitioning clinical exome sequencing from bench to bedside. Social Studies of Science 45: 77–99.CrossRefGoogle Scholar
  34. Van Zuuren, F.J., Van Schie, E.C. and Van Baaren, N.K. (1997) Uncertainty in the information provided during genetic counseling. Patient Education and Counseling 32: 129–139.CrossRefGoogle Scholar

Copyright information

© Macmillan Publishers Ltd 2016

Authors and Affiliations

  • Stefan Timmermans
    • 1
  • Caroline Tietbohl
    • 1
  • Eleni Skaperdas
    • 1
  1. 1.Department of SociologyUCLALos AngelesUSA

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