Euan Ashley on Integrating Genomic Analysis & Clinical Risk
New Hot Paper Commentary, November 2011
Article: Clinical assessment incorporating a personal genome
Authors: Ashley, EA, et al.
Euan A. Ashley talks with ScienceWatch.com and answers a few questions about this month's New Hot Paper in the field of Clinical Medicine.
Why do you think your paper is highly cited?
There has been a great deal of interest in the potential of the genome to solve medical problems, and while the rapid decline in the cost of sequencing has brought this within reach of a few, a major hurdle remains in how to parse the data. Our paper (1) provides a framework for analyzing a genome within a medical context.
Does it describe a new discovery, methodology, or synthesis of knowledge?
The paper describes a new methodology and the synthesis of a large body of knowledge on genetic variants and their effects on disease and drug response.
Would you summarize the significance of your paper in layman's terms?
In this paper, we asked ourselves the question, "If every patient's genome could be easily available in their medical record, what then?" In practical terms, that meant finding, quality checking, and organizing every gene variant that had been shown to have an effect on any disease or drug response into a pipeline that could be applied to an individual's medical care. The paper describes our application of this effort to the fifth personal genome sequenced, that of my colleague Stephen Quake.
How did you become involved in this research, and how would you describe the particular challenges, setbacks, and successes that you've encountered along the way?
Stephen Quake (left) talks with cardiologist Euan Ashley about his possible disease risks, based on the sequencing of his genome. Photo: Norbert von der Groeben.
We had been thinking for a while that with the declining cost of genome sequencing, at some point a patient would turn up with a genome and ask us for advice. I happened to be meeting with my colleague Steve Quake. Steve had recently sequenced his own genome using technology he invented and we were chatting in his office when he casually brought up his genome on the screen and pointed to a few variants, including one in a gene I recognized—myosin binding protein C.
Since this is one of the two genes most often involved in a condition called hypertrophic cardiomyopathy, a common cause of sudden death in young people, I starting asking him about whether he had any family history of cardiovascular disease. It turned out his family history was significant enough for me to recommend he be checked out in my clinic.
At that point, it dawned on me that I might be the first physician ever to have access to their patient's full genome sequence during a medical consultation. But access is one thing, understanding is quite another. So, I recruited some of my colleagues. As luck would have it, two in particular, Russ Altman and Atul Butte, had been building databases for pharmacogenomics and common variants for many years. Bringing their groups together with my team, who focus mostly on Mendelian disease, gave us the key elements.
Over the course of the following year, this became an obsession for all of us as we tried to see if it was really possible to interpret a whole human genome in the context of the person to whom it belongs.
Where do you see your research leading in the future?
In the immediate future, we are focused on extending the pipeline to families (2) and improving automation. The current cost of a genome sequence is around $3,500 and falling. We will shortly be in a world where millions are in a position to have their genome sequenced if they want to.
And yet, many challenges remain: challenges in achieving high-quality sequence on which to base medical decisions; challenges in identifying variants; challenges in finding a global standard for sharing variant and phenotype data. The challenges are many but we believe the prize is worth the chase.
Do you foresee any social or political implications for your research?
We published alongside this paper a commentary (3) discussing the ethical implications of the ready availability of whole genome sequences. I think in a world where the information is available at minimal cost, we have to remind ourselves as physicians to "first, do no harm," and remember to ask our patients how much they might want to know.
Euan A. Ashley MRCP, DPhil, FACC, FESC
Assistant Professor of Medicine
Director, Center for Inherited Cardiovascular Disease
Stanford University School of Medicine
Stanford, California, USA
- Ashley EA, et al., "Clinical assessment incorporating a personal genome," Lancet, 375(9725): 1525-35, 2010.
- Dewey FE, et al., "Phased Whole-Genome Genetic Risk in a Family Quartet Using a Major Allele Reference Sequence," PLoS Genet 7(9): e1002280, 2011.
- Ormond KE, et al., "Challenges in the clinical application of whole-genome sequencing," Lancet, 375(9727): 1749-51, 2010.
KEYWORDS: CLINICAL ASSESSMENT, PERSONAL GENOME, RIGHT-VENTRICULAR DYSPLASIA/CARDIOMYOPATHY, HYPERTROPHIC CARDIOMYOPATHY, PRAVASTATIN PHARMACOKINETICS, HEREDITARY HEMOCHROMATOSIS, WIDE ASSOCIATION, GENE, MUTATIONS, POLYMORPHISMS, DISEASE, THERAPY.