Harvard biostatistician Peter Kraft (co-author of an excellent recent article on genetic risk prediction in the New England Journal of Medicine) has just added an interesting comment on his experience of this week's Consumer Genetics Show:
The term "incidentalome" will probably sound somewhat familiar to clinicians; it's derived from the term "incidentaloma",
which refers to "a tumour found by coincidence without clinical
symptoms or suspicion", usually as a result of a whole-body scan. Such
tumours can often be perfectly benign, but nonetheless result in a whole
series of additional (and often invasive) tests to determine their
nature.
Any test that generates large amounts of potentially health-relevant data is prone to incidental findings (both genuine unexpected findings and spurious artefacts), and this will certainly be the case for whole-genome sequencing.
The first type of finding will be complete technical artefacts - false positives due to sequencing error - which will be a non-trivial problem over the next few years as the wrinkles are ironed out of rapid sequencing technologies, but will reduce in number as accuracy improves. Once sequencing accuracy is high enough these sorts of findings can be ruled out fairly easily through downstream validation assays (although there certainly is a need to design faster, cheaper and more readily customisable assays for novel sequence variants).
A much larger problem will be genuine sequence changes that would be predicted to seriously mess with the function of an important gene, but for which the health consequences are unknown. Accurate functional assays don't exist for most genes (and are cumbersome and imperfect even for well-studied genes such as BRCA1; hence the large numbers of *BRCA *mutations ending up in the "variants of uncertain significance" category), so it will often be difficult, expensive or simply downright impossible to get a handle on the effects of a newly discovered variant on disease risk.
Is this really a good argument against widespread genome sequencing, however, as some people have suggested? I don't think it's a compelling one; rather, it's a strong incentive for the medical establishment to start thinking hard about developing evidence-based strategies for dealing with uncertain genetic data and deciding which of the three strategies Kraft notes is most appropriate: do nothing, watch more carefully,
or intervene aggressively. Preventing people from getting access to genetic information is obviously not a productive long-term solution to the problem of incidental findings.
Kraft continues:
This is indeed an incredibly important (and astonishingly under-studied) field. I recently saw a presentation by Theresa Marteau describing her currently unpublished systematic literature review of studies looking at the effects of genetic testing results on behaviour. I was shocked at how little literature actually exists on this topic, but also intrigued by the general findings of the studies done so far: it seems as though testing results - even for serious diseases - actually have virtually no impact on long-term behaviour or quality of life.
There's clearly much more research to be done here, but if this general finding is confirmed it would be both good and bad news for personal genomics companies: good news in that it means that the wilder claims of critics (customers jumping off bridges after receiving news of an increased Alzheimer's risk) are overblown, but obviously bad news in that one of the primary stated motivations of companies like 23andMe is to motivate customers to improve their lifestyle.
Anyway, it sounds as though we will soon have a much clearer idea one way or the other about the effects of genetic data on behaviour. It will be good to see the discussion on this issue driven by data rather than protectionistic fear-mongering on one hand and commercial hype on the other.
