A new model for genetic privacy: you don't have any

In a perspective piece in Nature Reviews Genetics (subscription required, I think), Personal Genome Project leader George Church and colleagues advocate a revolutionary new approach to research subject privacy. Essentially, they argue that "the reality of the new genetics and genomics urges us to abandon the traditional concept of medical confidentiality". In other words, research participants must learn to accept the fact that the privacy of their genetic and health information cannot be guaranteed.

When I first heard of this concept in the context of the Personal Genome Project it struck me as pure insanity - who would volunteer for a project if there is a significant risk of your genetic and health information being accessed by (say) insurance companies? Having thought it over, though, the need for such an approach is becoming more and more clear to me. The basic argument goes something like this:

1. Your DNA sequence (or any sufficiently large set of genetic markers, like those used in modern genome-wide association studies) is enough by itself to unambiguously identify you.

2. Thus even "anonymous" participants in large-scale genetic studies are vulnerable to having their identity revealed - all it would take is someone to have a sample of your DNA, and access to the individual data-points from the study, and they would then have access to any health or life-style information recorded about you as part of that study.

3. As such, there simply cannot be guarantees of anonymity given to participants in such studies, fundamentally undermining the traditional model of confidentiality.

4. The best solution to this problem is to abandon the illusion of research subject privacy, and instead recruit participants with the explicit condition that all of the data collected about them as part of the study may in fact be revealed to the public.

The authors aren't advocating a complete dump of participant genetic and health records on a publically accessible website - although volunteers in the Personal Genome Project have the option of doing just that, should they choose to. Rather, they argue for a strategy of "maximizing data protection while informing people about its limits". In other words, doing your best to limit disclosure of individual health data, while clearly informing participants of the fact that their privacy can't be guaranteed.

It certainly is an audacious paradigm shift, and I'm having trouble predicting its consequences. For instance, will such a policy discourage people with a clear family history of genetic disease from participating in large-scale cohort studies (for insurance reasons), thus reducing the power of such studies to detect disease-associated variants? Will it create a generation gap in research participation, with conservative older people shunning studies while the children of the Facebook era - who engage in public disclosure of information with a wilfulness that seems shocking to their elders - embrace participation? I don't know, but I guess we'll all find out sooner rather than later...

Anyone interested in the Personal Genome Project (which is calling for volunteers for whole-genome sequencing, by the way) should check out their informative web-site. Misha Angrist, one of the "First Ten" participants who will have their genomes sequenced by the PGP, also has a blog that's well worth adding to your RSS reader.

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The moral manipulation of Gattaca

A man is given strong medical evidence that he will die from a heart attack if exposed to the exertions of space travel, thus risking his own life and the lives of his crewmates. Ignoring this evidence, he fakes his way into astronaut training - and inexplicably, we cheer him on. How did the makers of Gattaca steer us towards this bizarre response? Philosopher Neven Sesardic explains, in a fascinating essay (PDF) that touches on issues highly relevant to personal genomics.

One quote to chew over:

Contrary to what the movie is trying to tell us, a more detached analysis leads us back to the common sense belief that a more detailed knowledge of our genetic predispositions would indeed severely narrow our choices. Were this kind of information to become massively available, it would be rational for many people to abandon their previous career plans and reconsider what they want to do with their lives.

Obviously we don't know enough yet about genetics to be advising people on future careers based on a genome scan - but at some point, it's likely that we'll be able to make at least some probabilistic inferences about predispositions and skills very early in life based on genetic information. So long as we ensure that we rely only on accurate information, this isn't a bad thing. It simply means that people will have more information with which to make important decisions.

HT: Black Belt Bayesian.

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The ethical challenges of whole-genome sequencing part 1

A recent perspective article in Nature Reviews Genetics (sorry, subscriber only!) discusses the issues arising from the advent of individual whole-genome sequencing. The authors discuss three major issues facing researchers using this new technology: the return of data to participants, obligations to participants' relatives, and potential future uses of samples and data. Although I don't agree with all of the authors' arguments, it's great to see some informed discussion of these issues in advance of whole-genome sequencing technologies becoming widely available.

I'll start with a bit of a background on whole-genome sequencing technology and discuss the first of these ethical challenges today; I plan to discuss the other two problematic areas in a separate post.

The power of whole-genome sequencing
It's important to remember just how difficult it was for us humans to obtain the first (almost) complete sequences of the DNA that resides within each of our cells - the sequences generated by the public Human Genome Project and by the private company Celera, both published in 2001. It took almost a decade and cost somewhere in the vicinity of $3 billion to obtain the public human genome sequence, a vast amount of money by any standards.

Over the last seven years the price of genome sequencing has plummeted. A private company, Knome, will now sequence your genome for the comparatively paltry sum of $350,000, and the notion that we will see a $1000 genome sequence within the next decade has become a cliché. Over the last year we saw the publication of several brand new genome sequences: those of James Watson (right) and J. Craig Venter, as well as a Chinese volunteer analysed by the Beijing Genomics Institute.

The advantages of whole-genome sequencing (WGS) for research and for medicine are enormous. Your full genome sequence - including both the nuclear DNA you inherited from both your parents, and the mitochondrial DNA you inherited from your mother - contains all of the genetic information that resulted, through a complex process of interaction with your environment, in your adult form. This gives researchers a complete catalogue of the genetic differences between you and the people around you, a far superior data-set to the limited collection of common variants provided by genotyping methods (like those employed by 23AndMe and deCODEme). This is because at least some of the differences between people are due to rare variations, perhaps found only in them and their immediate family, that simply won't show up at all on even the densest genotyping chips but will be revealed by complete sequencing.

How important are those rare variants? It's still difficult to say, but at least for some traits these uncommon genetic quirks probably play a major role. For instance, we know that variation in height is around 80% determined by our genes, but the common variants identified by recent (and quite well-powered) genome-wide scans for height differences explain only about 1% of this variation. It's likely that much of the residual variation is made up of less common variants that each confer only a small proportion of the total effect.

The same is likely to be true for many common diseases, for which genome scans to date have uncovered only a fraction of the total genetic risk. Such rare, small-effect variants could only realistically be identified by sequencing, either of a selected set of "candidate genes", or - more comprehensively - by whole-genome sequencing.

Return of genome data to participants
I suspect that the majority of the three readers of this blog (one of whom is me) would be very interested in getting a free copy of their own genome sequence, should we be fortunate enough to be part of a study in which this was generated. Indeed, the authors of the NRG review drily note that in the age of 23AndMe and hugely popular genetic ancestry sites, "the desire for information and the expectations of research participants for receiving their results are likely to increase."

However, they also note that "in most jurisdictions there are still no definitive research ethics policies regarding the return of research results." In practice, there are a number of logistical and ethical hurdles that need to be overcome before researchers start handing back data to their unprepared research subjects:

Data format. A DVD containing gigabytes of text files of As, Ts, Cs and Gs is unlikely to satisfy most WGS research participants. However, providing fully annotated sequences (with lay descriptions of the meaning of every potential disease allele) would be far beyond the means of most research groups, as well as triggering potential regulatory restrictions and litigation risk.

This is a tricky dilemma, and the advice of the NRG authors is irritatingly vague: they simply suggest that any research project involving WGS "should be conducted under a formal research protocol, and ought to include the development of a data return and counselling policy".

That's pretty unhelpful to anyone actually trying to come up with such a policy. My suggestion: if researchers can't afford to provide the annotation themselves, they should at least return the data in a standardised format that makes it easy for participants to get that annotation from other sources. Over the next year or so we will see a profusion of private companies seeking to decipher our genomes for us, for a price; at the same time, I fully expect that online communities and publicly funded research institutes will set about designing browsers that will let us do the same thing gratis. If the research participant has their data in a standard format recognised by all these systems they can decide for themselves who they trust to peer inside their genes.

Clinical follow-up. Anyone who has their genome sequenced will almost certainly learn that they carry several recessive disease variants - variants which cause no harm to them, since they are each complemented by a normal healthy copy of the gene, but may result in severe deformity and disease in their children if they are unlucky enough to mate with someone who carries nasty versions of the same genes. In addition, each of us will carry any number of common variants which are associated with an increased risk of complex diseases such as coronary artery disease or diabetes. Finally, a few of us will find that we carry variants of the worst sort: things like a Huntington disease mutation, which will result in an incurable slide into dementia and death within a few decades. Either way, it's likely that all of us will need someone to explain what these things mean, and point us towards specialist care if this is needed.

The review notes that the medical community is massively unprepared for this: there is a serious shortage of clinicians with the required training to effectively communicate genetic risks. They recommend, quite reasonably, that governments invest in further training of primary care physicians to this end. Surprisingly, although the authors mention "an expanded role for geneticists and genetic counsellors", there is no discussion of increasing the number of university places for non-physician genetic counsellors - despite the fact that these individuals are likely to take on a substantial part of the burden.

Integration of data into medical records. Obviously genetic information that impacts on a study subject's health is just as important as other sources of information - cholesterol, blood pressure and the like. But equally obviously, if a variant has not been well-validated as a genetic risk factor, it shouldn't be described as such to a research participant, and it shouldn't be included in that person's medical records.

The NRG authors make some good recommendations:

1. only validated data of known clinical relevance should be included in the health record;
2. practice guidelines should be outlined for determining what constitutes validated and clinically relevant data; and
   
3. there should be a process by which health records are updated with new knowledge about the clinical relevance of specific genes.

The first two points are fairly self-evident, although it would have been great to see some realistic suggestions regarding those practice guidelines. The third recommendation, updateable records, will become more realistic if and when we start seriously moving into an era of centralised, electronic medical records.

That's more than enough for today. Later I'll discuss the other major ethical challenges discussed in the NRG review: obligations to close relatives of study participants, and future uses of samples and data.


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