David Hunter, Muin Khoury and Jeffrey Drazen’s Perspective “Letting the Genome out of the Bottle- will we get our wish?” (NEJM 2008. 358;2 105-107) goes further than we have done (below) in its skepticism of consumer genomics services like deCODEme and Navigenics. While Nature Genetics as a research journal can welcome the opportunities for public research participation and ever larger experiments and longitudinal studies, the doctors worry that they will soon be deluged with patients asking them what all this risk information means for them. The authors have some good points, but largely ignore the unpredictable motivational potential inherent in handing people their genomes and asking them to participate in finding out more about their variation and phenotypes. Sometimes, the best doctor will say “we don’t know yet, let’s find out together”. However, we do applaud efforts to build genetics into every stage of medical education and appreciate the authors making their editorial an opportunity to hammer that point.
I take some quotes from the article as the starting point for a few of my own thoughts:
“..premature attempts at popularizing genetic testing…”
Not so much premature as truly disruptive. Personal genomic testing confers a personal stake in the ongoing research effort and a huge incentive to find out more. A personal stake in finding something that was not previously know is the key to getting students into research and may well be a powerful tool to interest individuals in the details of their own health and functioning.
“transparent quality control monitoring”
It is true that the use of multiplex genotyping platforms for genetic epidemiology gains some buffering from large numbers of subjects and replication. At the individual level, it is hard to check for a single miscalled SNP, so it might be desirable to build some redundancy into the genotyping using haplotype information. For the genetics enthusiast, it would be reassuring to see the SNP calls in cluster plot format together with those of other anonymized participants.
“clinical validity…predictive value…the area in which the data are in the greatest flux.”
This is true for conventional exposures and markers too. Physicians no longer prescribe smoking for its “health benefits”, at least not to their patients. Blood pressure and BMI limits now elicit more vigorous treatment from physicians as better information has been gained. It is to be expected that an individual’s risk profile will change with each new study since new variants will be discovered that moderate or exacerbate their individual risk.
“full accounting of disease susceptibility awaits the identification of these multiple variants and their interaction in well-designed studies.”
I don’t think more retrospective studies will entirely solve this problem. In the meantime, individual genomics might be a great recruiting tool for a longitudinal study. Deliver a detailed genotype to the participants right at the beginning.
“assumption that interventions that have proven successful in the general population will behave the same way in a genetically at-risk population.”
Optimizing generally applicable interventions with the enthusiastic participation of the research subjects themselves may be the best way forward.
“interventions – such as smoking cessation, weight loss, increased physical activity and control of blood pressure – are likely to be broadly beneficial in relation to many diseases, regardless of a person’s genetic susceptibility to a specific disease.”
And we pay a physician for this information……why?
It may take years of personal experimentation with different drugs, doses and dose regimens to achieve a balance of blood pressure control and side effects. Would it not be better to have a few clues as to who is likely to achieve blood pressure control via breathing exercises or salt reduction, who by exercise and weight reduction, and who actually needs the beta blockers? OK, gene tests don’t help at the moment with ACE inhibitors or diuretic dosing, but they could when your atherosclerosis gets to the thrombosis stage and are deciding how much rat poison you want to eat.
“patients who test negative may be falsely reassured”
I don’t think I am “falsely reassured” by normal cholesterol, kidney function and blood pressure readings. Individuals have a remarkable ability to use information in their own self interest, indeed to integrate family history and the evidence of their own eyes with the gene test information. For a stunningly candid example of a family affected by Alzheimer disease without the major genetic risk factor, read the Tangled Neuron.
“but a detailed consumer report may be beyond most physicians’ skill sets.”
It should not be beyond most physicians’ ability to explain the quantitative risks conferred by – and the research underlying – the predictors they currently use: BMI, cholesterol, blood pressure, age and sex. A physician should also be able to relate quantitative risks conferred by a family history containing one or more affected relative. A physician should also be able to advise the patient whether or not to participate in research tests such as that for eg. C-reactive protein, with reasons not including “the insurer doesn’t cover that” or “taking additional tests will remain on your insurance record”.
“More information is needed…potential value that genomic profiles can add to that of simpler tools, such as family health history.”
Genomic profiles of families will be much more informative to individuals than their comparison with epidemiological studies. For many, the personal genomic profile is the stimulus to explore family history. Discussion of personal genetic risk factors may act to release family medical history kept private because it had no perceived use.
“encourage them to enroll in formal scientific studies.”
Maybe participation in personal genomics would have this desirable effect. With no personal stake and no current health problems, it may not occur to many individuals that their participation would be welcomed by scientists and the public alike. It would be interesting to compare the general health and health awareness of eg. Framingham Heart Study participants with nonparticipants, I just haven’t had the time to read any such sociology.
“genomic services will galvanize…translational research for the rational integration of genomic information into medical training and practice.”
Here the authors get to the heart of their worries: this is a disruptive technology that has caught doctors in the middle of their effort to bring genetics to its proper place in medical education and they might get deluged with questions they aren’t yet ready to answer. For more on the change of emphasis in medical education toward genetics and the individual, see David Valle’s article referenced below.
“better off spending their money on gym membership or a personal trainer….follow a diet and exercise regimen that we know will decrease his risk of heart disease and diabetes.”
Why not both? Different people have different motivation. Socially body conscious individuals may prefer the gym, the introverted but vain may prefer the attention of the trainer. Intellectually motivated people may choose their sport, or only exercise out of curiosity to see whether they can fulfil the promise of their “elite athlete” SNPs.
Now, some of my favorite quotes from “A Science of the Individual: Implications for a Medical School Curriculum” Childs, Wiener and Valle. Ann Rev. Genomics Hum Genet 2005. 6;313-330.
“Although hypertension is an elevation in systemic blood pressure, each patient reaches that phenotype by different paths, each determined by a unique combination of genetic makeup and experiences of the environment…..Individuality is also apparent in the treatment of hypertension.”
“contradiction between the singularity of the patient and the generality of treatments and prevention.”
“a tradition of typological thinking about biology and disease that does not accommodate variation.”
Finally, highlights from the “Risky Business” Editorial by my colleague, Alan Packer (Nat Genet. 2007. 39;12 1415).
“The need for both physicians and their patients to be better educated about complex genetics has taken on added urgency of late.”
“With the possible exception of age-related macular degeneration, how much can we say with confidence about the spectrum of risk?”
Variants with low relative risk make poor classifiers. This point was made by Alan, and by the NEJM authors. So, individual genomics may not induce anyone to take a clinical test until the list of risk variants adds up the point where it can identify some particularly unlucky individuals. In the meantime, it will have informed thousands by providing a personal stake in one of the most exciting areas of medical research and it may recruit enthusiastic participants in a massive longitudinal study that they will have funded partially from their own pockets.
That being said, they are participants, not patients, and the experiment will be conducted on their own terms!