Personalized Health Care Initiative Workshop: "Understanding the Needs of Consumers in the Use of Genome-based Health Information Services". Medical Decision-making Empowered by Genomic Information

07/07/2008

And it’s been really eight years, so that was June 26 of year 2000, before we finally have seen what has been termed by science the breakthrough of the year. In fact, that’s not only the breakthrough the year for 2007 as it was announced in December, it will be the breakthrough of the year for the next few years because so much is happening so quickly in this space. The two major reasons for this, as I think most people here know, is that ultra high throughput genotyping became possible. In 1997, just over ten years ago, we could only measure one base-pair substitution at a time, assay it, and defined Moore’s Law, in fact, where there would be about 256 by 2007. We’re at a million or more SNPs per individual that can be assessed.

And the other major thing that happened in this space was that the genome, which has relatively unmanageable information, 6.4 billion base pairs in the diploid genome, was now managed by projects such as Perlegen Science and International HapMap breaking the genome into bins and being able to tag those bins, and having only about 250,000 to 500,000 being able to represent a window into the genome. And these two things -- the convergence of the technology, along with the breaking down of the genome into information bins allowed a remarkable state in advancement of human genomic knowledge.

Unlike any other field in science and biomedical research where there’s a hypothesis, this is one in which the genome talks because there is no a priori hypothesis. And the result of that has been a genomics gold rush, which we labeled as such last summer, and it hasn’t stopped at all since a year ago. In fact, I want to just briefly give you a table which shows on a weekly basis since April 2007 -- just about a weekly basis -- over 40 diseases have been approached via these genome-wide association studies relying on the high throughput SNP- typing and the haplotype map information. And you can see this transcends all different disciplines in medicines: cancer, metabolic diseases included obesity and diabetes, immune diseases such as Chrohn’s and lupus and rheumatoid arthritis; cardiovascular diseases such as heart attack, atrial fibrillation. And this goes on -- even Restless Leg Syndrome, which we didn’t accept as a medical condition until we knew the gene markers for this showed up, and you can see that this goes to gallstone disease, macular degeneration, and so on. And in fact, it’s virtually -- all the major cancers have been approached.

And just to take us up to date as of today, yesterday Nature Genetics had another third major gene for obesity, PCSK1. So this type of avalanche of new knowledge has set a template which has never been replicated in the last several decades, all in just a year-and-a-half time because of these breakthroughs. Let me use a few examples to hopefully demonstrate that there is actionable information today for consumers. So, for example, macular degeneration affecting 9 million Americans; blindness, the leading cause of blindness in our society -- we had no idea what was the pathogenesis of this disease. We knew there was this -- on the macula -- there was an inflammation, an accumulation of this inflammatory material known as drusen, and it led to eventual (inaudible) blindness. We also knew that there was a series of environmental factors, like smoking, high-fat diet, sedentary lifestyle, obesity, hypertension that were correlated with macular degeneration. But now we know the principle genes. The principle genes of compliment factors, which are the underpinnings of this disease, and this is what occurs in the inflammation pathway to be the root cause of macular degeneration. Well, why is this important? Now we can take a baby and say that that individual has 0 percent change of ever developing macular degeneration, or we can take an individual and find that they have a 400-fold.

And by the way, if that individual with the very high risk smokes, that risk could go up to 10,000-fold. And indeed, the environmental gene interactions have been assessed in this condition. This was the first genome-wide association study back in 2005, where we have the most knowledge about those sorts of important interactions. So already today we can give people who have compliment factor risk variance a choice. If they smoke, for example, they may have a much higher risk of going on to blindness, whereas a cessation of smoking is an important actionable item.

The chromosome 9p21 marker is a particularly important one in the cardiovascular arena because it not only catches the risk for heart attack, but also abdominal aortic aneurysm and intracranial aneurysm. These are all events that are very hard to predict with all the things that we have today. When do arteries crack or rupture?

Such as occurred in the case of Tim Russert just weeks ago. So this is a remarkable marker, 9p21, which shows a risk with one copy of 70 percent -- 35, 40 percent increase with two copies over 70 to a doubling of risk. And it is of many different conditions, which I mentioned are very difficult to diagnose.

What about diabetes? With over 20 million Americans having diagnosed diabetes, no less; many more in which this diagnosis is likely in the future or not yet diagnosed. We now have over 20 genomic markers of bins in the genome which correlate, each individually, somewhere between 20 to 30 to 40 percent increased risk for one copy, and this of course in many cases is additive. And some work has been done to integrate the risk of these different markers to show risk that ranges from 2-fold all the way up to 20-fold on the basis of an additive phenomena of different genomic markers.

What about breast cancer? It’s the guidelines that all women over age 40 are supposed to have a mammogram every year. Is that really necessary when most women carry no risk variance for breast cancer? And so now we have over 20 different variants that have been delineated, we can assess and partition the risk in women whether they’ll have breast cancer in their lifetime. And indeed, a New England Journal paper just two weeks ago modeled on this and talked about how what percent of the population was really at risk when we use the rudimentary genomic markers, no less the ones of the future.

The same is for prostate cancer -- just five different SNP markers in prostate cancer has in an additive way in this particular study published earlier this year. One can find a population of men who have a 10-fold risk of prostate cancer, and this of course overrides the knowledge of the PSA level in the blood or other known clinical risk factors.

Now even beyond that study that was published in January, we have 20 different markers in the genome for prostate cancer, so our knowledge base has been greatly expanded. So basically what is so remarkable about this time in medicine is that our understanding has been enhanced like no other and we have defined new genes and new pathways that are truly the underpinnings of disease.

And so the human disease (inaudible) which is represented here, and in fact that we now know certain pathways are responsible for multiple diseases which we would never have forecasted. In fact, none of these pathways were the ones that had been theorized before genome-wide association studies were performed. So this is quite remarkable in itself. And basically, as Andy Pollack reviewed in a recent Science Times, the textbooks of medicine are being rewritten. The only problem is that they can't be written fast enough because our whole appreciation of diseases and health is being turned over because of this vast avalanche of new information. I don’t want to submit to you that we know so much; in fact, there are lots of inconvenient truths. We still don’t have complete cover of the genome, we haven’t really focused on insertions, deletions, copy numbers to a great extent; there are many repletory elements and smaller (inaudible) that we have little knowledge as is the case for epigenomics and diplomics as well. But nonetheless, we are now into the consumer era, the consumer empowerment if you will. And this was forecasted in a very interesting Forbes piece a year ago when this fellow wrote that you can post on Craigslist, “Single, white male, HNPCC free seeks single, white female, no BRCA1/BARD1.”

And what he also wrote was kind of, you’re going to end up searching for genes on Google. Now this is of course an area I’m particularly interested in and I thought the guy was a little ahead of his time. Well, it wasn’t very long when I started thinking about this whole Google searching your SNP variance, and then I found out that of course like Wikipedia, there’s SNPedia, and any consumer can go to SNPedia and find every information that’s ever been published or resented about any particular SNP, which is quite remarkable.

And so many different articles have focused on this, such as the feature article in Wired, and of course those in the New York Times that were associated with a Pulitzer Prize in the past year about this whole interesting phenomenon. And in fact, three companies: deCODEme, deCODE genetics, 23andME, and avigenics are offering the genome-wide scans with either saliva or a cheek swab up to a million SNPs, continual updating through their internet browser setup at a cost, for some consumers, is affordable.

And also DNA Direct is involved in this, not only by offering special tests like the TCF7L2 in diabetes or the 9p21 marker for heart attack, but also in helping individuals interpret their genome-wide scan.

Now, there has been a reaction in the medical community that we’re not ready for this, and there have been several articles such as “Risky Business” in Nature Genetics, “Ready or not” in Nature, and “Letting the Genome out of the Bottle” in the New England Journal.

These are just representative of the naysayers, if you will. But actually, I tend to disagree with some of these editorialists. In fact, I’ve had my genome scanned through two different of these entities and I learned a lot. So I present to you, for example, I had no risk factors in my family of heart attack. It’s an area that I’ve worked on for the past 25 years. I knew had a risk of cancer. When I got my genome-wide scan, I found that I had two copies of 9p21, that was a big and important step of knowledge just for me, no less to know at least I was protected from some other diseases like obesity and some immune (inaudible) diseases. And the ability to interpret these data by these companies is actually quite remarkable. What they offer for the consumer is a terrific foundation for those who are not savvy, to understand what this means, that it’s probabilistic not deterministic and many other things are still wanting in terms of our knowledge base.

This is an example of the deCODEme to help me interpret what is having two copies of 9p21 variant, a risk factor for heart attack, what does it really mean? Very graphic and very simple in all of the companies in this space are remarkably consumer oriented.

So when I put this (inaudible) together at the end of last year about what you can learn from a gene scan, I thought (inaudible) this is a great movement. And the reason it’s great movement is it will help the physician community that are so reluctant to any change.

And in fact, the concern here is that patients now are coming to their doctor’s office to get help and interpreting their genomic data. And the doctor says, “What’s a SNP?” And this is a significant problem. And what’s going to change the medical community if not the consumer movement? And in fact, that’s paradoxical because we look at this survey -- it’ll be interesting to see Steve’s remarks -- this survey says, “Who do you trust with your genomic data?” Thousands of individuals responded; they don’t trust their employer, they don’t trust their health insurer, as you might expect; they trust the most, their doctor, interestingly who has very little if not any knowledge of this field. They trust their doctor more than their spouse and even researchers studying genetics, which is quite remarkable. And of course, in California, which is where I’m from and the recent cease and desist order by the state was quite surprising because this is, I think, represents a great advance in medicine, and oriented and advocating the rights of consumers. And this sense from the Department of Public Health in California that we are no longer tolerating direct-to-consumer genetic testing in California is so amazing to me, in fact.

So as I close, I just want to leave you with some examples of actionable information, why this is so important today for those who are interested. One, for example, the risk of diabetes or a heart attack, to know that risk, to know that awareness -- those symptoms that could be representing, for example, heart attack or heart disease is quite important, no less the change in lifestyle; the avoidance of 250,000 false positive prostate biopsies a year, for example; the use of ultrasound or MRI in those women who have significant increased risk of genomic markers for breast cancer. And the diagnosis of many elusive things, like abdominal aortic aneurysm, Chron’s disease, and atrial fibrillation as the cause of stroke of unknown ideology. All these things come out of a genome-wide scan. The benefit to consumers, I believe, is quite extraordinary. First of all, this is research-grade data. These are the same platforms, the same ways that data were obtained for all the genome-wide association studies that were published in the leading peer review journals like Nature, Science, and Nature Genetics. Secondly, it’s optional. It’s a right to know, and it’s a potential benefit of course in those individuals who use the information in a guided way. And the sad part is that physicians are uninformed, totally for the most part resistant to change, but hopefully can be prodded like the direct-to-consumer advertising model with respect to learning more, and motivated to learn about genomic medicine.

So I leave you with this representation of where I think the field has been and where it’s going. Would you consider this hockey-stick plot, and this was alluded to by Rick in his opening remarks. There was of course this draft human sequence in 2000, and many people including the public, have been disenchanted, no less the medical community, that it has taken eight years to get to the point where there’s relevant information coming out of studies to effect the practice of medicine, prevention, preemption for the first time. And so in fact we are now in 2008 well into this with consumer genomics, gene specific clinical trials, which we’re coordinating and other centers as well. Over the next few years, the ability to sequence the human genome -- whole genome sequencing, finding those wherever (inaudible) and those other inconvenient truths in 15 minutes is going to be possible. Soon enough, over the next eight-year span, we’ll have a million people fully sequenced, and some aspects of medicine, perhaps not all, will be routine, individualized practice. So in that -- with that framework, we set up a new medical school, Scripps School of Medicine, where every student who enters not only faces a five-year rather than a four-year curriculum, but has deep exposure to sequencing, genotyping, and all the ohmics including mass spec for metabolimics, and hopefully will be a group of physician leaders in the future to advance this field that needs leadership in the years ahead. So I just want to thank my colleagues at our program who have worked together to try to have a unique program that’s using the information of genomics today to advance the field of medicine, and hopefully this conference will achieve that laudable goal as well. Thanks very much for your attention. [Applause]

DR. COWAN: We did not rehearse Eric’s and Rick’s comments, though they said many similar things. We will pile metaphors up -- you get a hockey stick and converging rivers, but I think those all help give us visual images of -- a clarifying picture of a complexifying field that’s very early in its development.

Our next keynoter is Steve Bodhaine. Steve is the Group President for Research and Product Development at Yankelovich. This is an organization that’s been around since 1958 and specializes in collecting and understanding consumer attitudes, beliefs, and aspirations. They do interviews, they do surveys; and he is going to share with us some insights on consumers’ interests in health and consumers’ interest in genomic information. So, Steve.

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