Ethics and Genomic Research: ‘Genomethics’

Dr Anna Middleton is an Ethics Researcher and Registered Genetic Counsellor, based at the Wellcome Trust Sanger Institute. She leads the ethics component of the Deciphering Developmental Disorders study, a collaborative project involving WTSI and the 23 National Health Service Regional Clinical Genetics Services in the UK. This project involves searching for the genetic cause of developmental disorders, using array-CGH, SNP genotyping and exome sequencing, in ~12,000 children in the UK who currently have no genetic diagnosis.

One of the issues raised by this, and many other research projects, is what should happen to ‘incidental’ findings, i.e. potentially interesting results from genomic analyses that are not directly related to the condition under study.  Here Anna discusses the research she is conducting on this topic as part of the DDD study, and provides a link to the DDD Genomethics survey where you can share your own views (I should also disclose here that both Caroline and I also work on the DDD study).[KIM]

Whole genome studies have the ability to produce enormous volumes of valuable data for individuals who take part in research. However, as a consequence of analysing all 20,000+ genes, whole genome studies unavoidably involve the discovery of health related information that may have actual clinical significance for the research participant.  Some of this will be considered a ‘pertinent finding’, i.e. directly related to the phenotype under study (e.g. the child’s developmental disorder); some of this will be considered an ‘incidental or secondary finding’ in that it is not directly linked to the phenotype under study or the research question that the genomic researchers are trying to answer.

There is no universally accepted definition of what an ‘incidental finding’ is, with some feeling it should only relate to clinically significant, even only actionable conditions, whereas others feel it relates to any genomic data, including that which reveals non-paternity or ancestry information.  What should be done with this potentially useful data?  What obligations do genomic researchers have to research participants and what might research participants want to know?

Many feel it is unethical to withhold incidental findings that have the potential to affect health decisions. ‘Even pure scientists can and should advance research subjects well-being and respect their autonomy by making appropriate disclosures of potentially significant incidental findings’ (Miller, Mello et al. 2008). Others feel it is too soon to be offering such information, particularly in a research context, where clinical interpretation may be difficult.

There has been much published on the attitudes of lay members of the public, researchers and health professionals towards the sharing of genetic information pertaining to single genes.  However, as whole genome research is so new there are limited equivalent social sciences studies that evaluate how genomic information should be shared and communicated.

There is knowledge and experience from the medical imaging arena to guide us on the practice of sharing incidental findings and indeed clinical geneticists have been working with incidental findings, for example from karyotyping and latterly from array CGH, for quite a while.  What marks genomic research as different is the potential for hundreds of different findings of varying interest and significance (and which we have varying ability to interpret accurately), all potentially available in one go.

The debate amongst genomic researchers, health professionals, policy makers and ethicists about what genomic data could, or even should, be shared with research participants and how such sharing might work in reality is far from being resolved.  Much of this discussion has, to date, been based on opinion, conjecture and anecdotes; as yet, there are no large-scale empirical studies that assess the attitudes of the various stakeholders about the sharing of genomic data within a research context.

We aim to address this by exploring these issues within a new ethics and genomics research study (‘genomethics’) that is being conducted as part of the ‘Deciphering Developmental Disorders’ (DDD) project. Anyone is free to participate: members of the public, genomic researchers, genetic health professionals, laboratory staff and families recruited to the DDD project.  An independent film-maker has been employed to create the films that provide information about genomics, these are integrated into the questionnaire and make for an interesting questionnaire-completion experience.

If you are reading this blog, you are eligible to participate! 

The online questionnaire is here:

Feel free to discuss any of the issues raised by the questionnaire in the comments below.

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15 Responses to “Ethics and Genomic Research: ‘Genomethics’”

  • Daniel MacArthur

    Thanks Anna and Kate – this is incredibly important research. The return of incidental findings is shaping up to be the defining topic of genomics ELSI in 2012, and it will be great to have some real data on views from all the key interest groups (researchers, clinicians, participants and parents) to inform that discussion.

  • Not the ethicome? Ethicomics?

    Thanks though, will have a look later.

  • GenEthics

  • Gholson Lyon

    I and my colleagues have discussed this issue in a published paper in June 2011, which we put into an open-access journal, so that anyone in the world can read it, without having to pay $15-35 to some publisher. The link is below.

    Also, I presented at CSHL Personal Genomes on October 2, 2011, where I discussed that “There is nothing “incidental” about unrelated findings”. This is the subject of a commentary currently in press. I am hoping very much that the genomics world will consider no longer using this word “incidental” to describe unrelated or unanticipated results. The argument expanding on this will be in the commentary when it publishes.

  • Brian P. Swann

    This work should reference back to the Nuffield Council on Bioethics Report of 2010 on Personalised Medicine and Healthcare and the working group there. Many of these issues were considered by the distinguished group of folk there.

    It is important that the wheel is not rediscovered – and we have endless International Conferences. This has the potential to become as big as Rowe versus Wade.

    Also Sir Tim Montgomery, former Head of the Huamn Genetics Committee, before its abolition in David cameron’s “Bonfire of the Quagos” has re-emgred as the new Chair of the Nuffield Council on Bioethics.

  • Anna Middleton

    The debate about terminology is interesting. I had a long chat with several in the field at ICHG in Montreal last year about the pros and cons of using ‘incidental’ versus ‘unrelated’ versus ‘secondary finding’. For our team in the UK we decided to stick with incidental as in lay language we felt this made the most sense for the research participant and it is also a term that is widely recognised in the literature. I acknowledge though that it is an imperfect term.

    The Nuffield Council on Bioethics have covered some very useful and relevant issues but as with many of these groups and the policies that come from them, they are still largely based on thoughtful discussion from a small group of people. So, whilst we don’t need to keep reinventing the wheel, it would nevertheless be helpful to actually gather some large-scale, international data from multiple social sciences projects that give us a proper idea of how real people (members of the public, genomic researchers, health professionals) want to use genomic data. This has, so far been missed from the debate.

  • Bob Fowler

    Hasn’t this situation existed for some time in a more defined area? In routine evaluation of fetal karyotypes of older mothers where the main goal is to look for trisomies 13, 18, and 21, other chromosome abnormalities often turn up. These include aneuploidy for the sex chromosomes and various aberrations and they have variable phenotypic consequences and sometimes unknown phenotypic consequences. How has this situation being handled presently and can it help in the future situations discussed here?

  • Bob – people like Ron Zimmern at the PHG Foundation – – have been arguing for years that there is nothing new in the ethical challenges thrown up by genetics and genomics: more a matter of scale. One difference, though, is who is throwing up these “incidental” findings. Previously it would be a radiologist, pathologist or ultrasound technician under the direct guidance of a physician of some kind, with the subject being a patient and under a duty of care. So, if the doctor thought it really mattered, she could tell the patient. If the patient didn’t want to know, he could say so on the procedure’s consent form. Now, more research-oriented scientists are making discoveries, where no duty of care has been established, and where feedback was not anticipated in the consent process. But that way, paternalism lies – with doctors acting as the gatekeepers to all health-related information.

    PS: “incidentalome”? You may have to pay to read the paper …

  • Gholson Lyon

    Here is the definition of the word “incidental”:
    adj \ˌin(t)-sə-ˈden-təl\
    a : being likely to ensue as a chance or minor consequence b : minor 1
    : occurring merely by chance or without intention or calculation

    In this current world of most people placing more value on actual publications, versus just blog entries, I am waiting for my full-length commentary on this subject to publish. Bottom line though is that there is nothing “incidental” about proving causality of any mutation found intentionally in someone’s genome. The use of the word “incidental” to describe a genetic finding is just not appropriate, in my opinion.

  • Anna Middleton

    Just thinking more about definitions and enjoying the debate….
    Here is (one of many) definitions for ‘unrelated’
    1. Not connected by kinship or marriage

    For the average patient or research participant engaging with whole genome technologies, it is so vital not to assume that a term which makes sense to researchers and health professions has the same meaning for non-professionals.

    This reminds me of a discussion I had with a colleague a few years ago when I worked clinically as a genetic counsellor. He had done a consultation with two parents of a disabled child and had spent a long time describing what a ‘terminal deletion’ was – this related to a lab report pertaining to the child’s diagnosis. The mother burst into tears, all she heard was the word ‘terminal’ and automatically assumed the geneticist was telling her the child was going to die.

    Whilst ‘unrelated finding’ is suitably descriptive and yet, so too is ‘incidental’ until we actually know what patients and research participants understand by these terms, it is all a little bit academic. For the time being, I’m happy to stick with ‘incidental finding’ as it is in common parlance amongst scientists and has been used for many years, for example in the imaging world. As this whole area evolves we may naturally align with other terms and so introducing ‘unrelated finding’ into the debate is very valuable. But before we collectively say one term is the definitive one over another we really must ask patients first what is most meaningful to them.

  • Gholson Lyon

    I am mainly suggesting to get rid of this term “incidental finding”, as it makes no sense to the general public in this context. Other alternatives might be “unrelated” or “unanticipated” results, where the words have definitions that the general public understands. In my own polling of many research participants, most think of “incidental findings” as something found by chance or by accident. This does not do justice to how much time and effort ought to go into searching for unrelated findings and proving causality for any mutation. Just because our radiology colleagues choose to use this term for a very different thing in their field does not mean that we have to use the term in the genomics world. My main point here is that most people (at least in America) have zero idea how the word “incidental” applies to an unrelated and important finding found in their genome. How would you like it if someone found a highly penetrant mutation in BRCA2 in your family and reported it simply as an “incidental finding”? There is nothing incidental about finding a mutation that could cause death in you or your children AND going to the trouble of proving penetrance/causality and counseling the family appropriately. This is in the same vein as “terminal deletion”, which I agree should not be used with research subjects or patients.

  • Gholson Lyon:

    The unanticipated finding you report in your paper, was in a subject with extant disease, for which a genetic cause was suspected, in a gene already implicated in other versions of his disease. I would argue that this is at one (very worthwhile) end of the spectrum of “unanticipated” – gluing together a proper diagnosis for a patient – but I and perhaps others here are more worried about the other end – giving sentences of doom to healthy research subjects.

    In the absence of a family history or symptoms to motivate a test, the penetrance of even well known mutations is complicated – see e.g.:
    Cox DG et al (2011)
    Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers.
    Hum Mol Genet. 2011 Dec 1;20(23):4732-47. Epub 2011 Sep 2.

    So, in your BRCA2 situation above what advice would it be: if you have a family history of breast cancer, go see your physician? I think I would give that advice with or without knowing the mutation.

  • Gholson Lyon

    Hello, my first response is that the article you cite is not open-access, so it will cost $32 for anyone to read the article, unless they are so lucky as to belong to an institution with a library paying huge fees to a publisher, in order that they can access the article. So, to make your argument, I would think that one should refer readers to open-access articles, given that most people in the world cannot afford closed-access fees.

    Second, I did not not talk about giving anyone a “sentence of doom”. I simply believe that families would want to be made aware of any highly penetrant mutations that they have which are known to carry major elevated (>10%) risk of a disease, so that they can incorporate that knowledge with their family history and act accordingly. We are moving more and more toward a world of open data-sharing (including hopefully more open-access publishing), so why shouldn’t research participants have access to their own genomes after all? It is also time to increase genetic counseling services, so that participants can better understand their own genomes.

    I realize these are contentious issues, however, so this is simply my opinion.

  • Gholson Lyon

    Ok, my commentary finally published on this issue that I discuss above. See here. I welcome any comments or feedback.

    There is nothing ‘incidental’ about unrelated findings
    Gholson J Lyon
    Personalized Medicine, March 2012, Vol. 9, No. 2, Pages 163-166.

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