The work of geneticists, a category that includes the majority of Genomes Unzipped contributors, typically consists of analyzing DNA sequences from large collection of individuals and this constant flow of data gives us an overview of the diversity of human genotypes. And while in most cases these mutations do not have any functional impact, some rare cases are well documented and have important adverse effects.
A famous example is the BRCA2 gene for which rare mutations have been linked to an increase prevalence of breast and ovarian cancer. Another example: multiple rare variants have been linked to various forms of familial hypercholesterolemia, a condition that significantly increases heart disease risk. I picked these examples because for both cases the identification of carriers of these rare mutations in the general population could improve health: aggressive detection of breast cancer, and use of relevant treatments (such as statins) if you are a familial hypercholesterolemia patient, can make a real difference.
The fact that, in some cases at least, something can be done can put geneticists in a difficult situation. Indeed, we often come across known disease related mutations in the DNA from patients who were not recruited for anything linked to that disease. And it is not clear how this information should be handled. On one hand, we cannot assume that the patient has any desire of knowing anything about his/her disease risk. On the other hand, while analysts always work on anonymous genetic data, the medical staff that collected the sample could potentially get back in touch with the patient who donated his/her DNA. Letting DNA donors know may actually make a difference in their lives (again, this situation is rare but it happens).
What is the legal situation?
Rather systematically research consent forms for DNA donations are overly cautious and do not provide any opportunity to get back to the donor. The current view is that tissue donation, including DNA samples, are considered as gift from the the donor to the researcher (see for example this document from the MRC). And often it is even not practically possible to get back to the patients because the samples have been anonymized (see the Wellcome Trust Case Control Consortium FAQ for example).
There are plenty of be good reasons to not feedback these data, the most important being the practical means by which the patient can be contacted and what he/she should be told whatever information is relevant. In many cases, while we have strong suspicions on the role of some mutations, we are not absolutely sure either. Overall, I find this inability to share useful information with patients potentially eager to obtain this information a frustrating part of my work.
How could we provide this information in a useful way?
This uncertainty is a major hurdle: no one wants to cause panic by suggesting a high cancer risk to a patient who has no reason to worry. Researchers work with doubt and questioning all the time, but most individuals just want a clear assessment of risk and are not at all interested in a lengthy research discussion. And researchers are not at all trained to communicate with patients.
Daniel MacArthur and others have previously suggested (see this and this) an alternative approach that seems rather appealing: this expertise in communicating genetic results to non-scientists is the main strength of direct to consumer (DTC) genetic companies like 23andMe or deCODEme. Their webpages are clear, simple to follow, and they do provide reasonably accurate information. They also know how to deal with legal and technical issues associated with communicating genetic data.
So here is a potential scenario that would address these issues: researchers collecting DNA provide each donor with a barcode associated with their samples. Once generated, data and the barcode are then sent to a DTC private genetic company that will not process the data until the donor decides to claim his/her barcode. Once this happens, the company processes the data and shares with the donor whatever the DTC company thinks is worth knowing. This process would build a partnership between the research institution and the DTC company. It would probably take the data generation step off the hands of the DTC company, but would take advantage of its expertise in communicating the results of the study to interested donors. It would be beneficial to the individuals involved in the study, who would then have a choice to know or ignore the results. It would probably also motivate more individuals to contribute to genetic studies, something of interest to researchers because we need donors of course.
A last addition to this setup would be the opportunity for individuals to make their DNA data available on demand for future studies. For example, because I am in general very willing to be involved in genetic research studies I gave blood and consented to be genotyped several times already, including once I paid for when I used 23andMe services. Of course this redundancy is largely a waste of money. Therefore, a UK research council (taxpayer’s money!) will pay a few hundreds of dollars for a work which has, for the most part, already been paid for by myself willingly. If I could have just shared these data with the researchers taking my blood, it would have been much more efficient.
This approach leads to the idea of a patient being actively involved in multiple research studies at low cost, and something very much within the scope of what 23andMe wants to achieve. Indeed, a recent recent 23andMe publication illustrates the power of this approach. Luke Jostins, another Genomes Unzipped blogger, has commented on this idea already (and so has Daniel McArthur in this post).
Technical arguments against this idea
An important concern is the ability of this suggested pipeline to feedback genetic data. Existing diagnostic labs go through formal rounds of accreditation to guarantee high quality analysis. For example genetic researchers often deal with processing errors and sample swaps (at least I do), and it is likely that in some cases the data will be sent to the wrong individuals. See for example the recent disaster generated by a sample swap in the 23andMe pipeline. Of course these issues affect any lab and I am not sure that 23andMe is in any way more likely to mess it up than the safest accredited government laboratory.
Moreover, if the findings have important consequences for the donor, repeating the analysis is essential to verify what was found. This will not always be possible in a research setting. If mistakes (like sample swaps) are too common, the resulting cost benefit of sharing these data with the donors will be poor. Consequently, it is likely that each research study will be judged based on its ability to ensure proper sample handling as well as the ability to recontact DNA donors if required. We should therefore expect the rules to vary across research studies.
And ethical arguments against this idea
In addition to these technical issues there are deeper ethical concerns. As mentioned above, the current view is that tissue donations, including DNA samples, are considered as gifts from the donor to the researcher. Within this framework there is no reason for the donor to retain ownership of the data generated. Providing potentially expensive information back to the patient would change the balance between donor and researcher. For example, if donors get involved in the study in order to get their DNA sequenced, they may decide that subsequent studies are not worth the effort once they have obtained the genetic data they were looking for. This type of commercial relationship is certainly not what researchers want to build with individuals donating DNA samples.
My conclusions
In my view, providing the DNA data back to donors is a goal we should be aiming at. The “gift” idea is only the best framework researchers have found so far, but moving away from this is plausible and is unlikely to radically affect the donor-researcher relationship. It is however hard to be certain. Moreover, we do not yet know what the impact of general feedback of DNA data to donors will implicate and given the potential for harm we should be careful. A stepwise process, using DTC companies or not, but starting with small subsets of patients, should be conducted as soon as possible to evaluate the consequences of these changes. It would certainly be disappointing if the overly cautious approach of doing nothing prevailed.
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I agree in principle, but there are difficulties about what should be reported back and where the boundaries of duty of care lie. Should everything be fed back or just selected information? Is it the researcher’s responsibility to ensure that the information is correct (despite lack of diagnostic confirmation)? This has always been an issue in the world of imaging, and as a result I think they generally involve a clinician in the study who feeds back just clinically actionable findings. Should we have a list of clinically validated potentially actionable incidental findings for genetics that should specifically be fed back? (With the associated challenge of how you keep this list up to date!) And if there are any such findings, should the individual be directed towards a qualified physician for the relevant clinical advice? Plus there are thorny issues around non-clinical information, such as uncovering misattributed paternity or parental incest, which individuals really may rather not know!
I know the issue of what to do about incidental findings is a question vexing clinicians too as we move towards an era of whole genome sequencing.
I think we have to be more pro-active by actively increasing the genetic literacy in the population and by making the understanding of the genetic contribution to human health a community effort. In essence this is what 23andme wants. I have done the genetic profile of my parents and my family with 23andme. In a undergraduate genetic class that I teach on human genetics at ETH I discuss genome wide association studies and how little we know even about the genetic contribution to height (44 loci contribute less than 5% of the genetic contribution) in part because the sample size is too small. I show the student what is possible today by giving them a tour through my genome (pointing out how little we still know). When I ask them whether they would contribute their genome/phenotype to scientific research, more than half raise their hands. We have to make students and people aware that they make a contribution to science and human health by providing their genomic and phenotypic information. Donors would become active participants (like in Wikipedia). Services like 23andme should be combined with professional genetic counseling services in the different countries (as 23andme is doing in the US).
Understanding genetic information is more intuitive than understanding the impact of nuclear power or global warming since it is much closer to home. An so far, that knowledge that the predisposition of for a certain condition or disease “runs in the family” is often still a more accurate predictor than a number of SNPs.
In the past, most studies did not even consider the possibility of returning information to subjects and the subjects signed away their rights to know or learn anything. Therefore, these things are only being considered now.
However, as we are getting more into fine mapping and the possibility of detecting serious problems, real or potential, rather than just predispositions, sentiment is changing but we are at the ethics level and we don’t know much about dollar figures. Clearly, costs will be high. Specifically, costs will be needed to:
1. Identify all known or pertinent alleles of risk
2. Locate and communicate those results to the subject
3. Provide a genetic counselor to the subject, perhaps on multiple occasions
Based on some ongoing studies in Spain where the participation and planning have been in place from the
beginning, it will not be difficult to provide such information to the subjects. The major cost will be in terms of providing medical advice regarding any serious
problems that are detected.